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      • abstract_of_study<p>\n <strong>ABSTRACT</strong></p>\n<p>\n Shigella species are one of the leading causes of diarrhoea in our region affecting primarily infants and children and diarrhoeal disease accounts for close to half a million under five deaths per year worldwide. Following an acute infection shigellosis is associated with post infective complications, developmental repercussions, cognitive impairment and a negative impact on growth. We propose to evaluate the safety and reactogenicity of a candidate Shigella vaccine. Shigella4V, is composed of O-antigen polysaccharides (PS) from four different <em>Shigella</em> strains representing the most epidemiologically relevant strains: <em>S. sonnei</em>, <em>S. flexneri</em> 2a, 3a and 6, conjugated to the exoprotein A of P. aeruginosa EPA. This will be a first-in human trial.  However, several biconjugate vaccines, and one component of Shigella4V have already been evaluated and have been found to be safe and immunogenic. We will conduct a double blind, multi-site trial in KEMRI-CGMRC and KEMRI/MRD-K, Kericho in 2 steps. Step 1 will involve a safety cohort at KEMRI-CGMRC-.  We will use a randomised control, age descending, dose-escalating approach to evaluate safety and reactogenicity in 16 adults (18-50 years), 48 young children (aged 2-5 years) and 60 infants aged 8-10 months of age. The second step will aim to enrol 468 infants to further evaluate safety and identify the optimum immunogenic dose. Infants in step 2 will be randomised on enrolment to 1 of 4 vaccine doses of (4 ,12, 24, 48 µg) or control vaccines. Adults will receive a 2 dose schedule, 1 month apart  with a total of 7 visits in clinic, and they will be in the trial for about 8 months; children will receive a 3 dose schedule (2 doses 1 month apart then a booster dose 6 months after the 2nd dose) with a total of  10 visits in clinic and they will be in the trial for about 13 months;  infants will receive a 3 dose schedule (2 doses  three months apart then a booster dose 6 months after the 2^nd dose) and a total of 11 visits in clinic, and they  will be in the trial for approximately 15 months. For each vaccine dose, formulation with and without Aluminium adjuvant will be tested.</p>\n
      • study_title<p>\n Safety and immunogenicity of a Shigella-tetravalent bioconjugate vaccine: A phase 1/2 randomized controlled and age descending study including dose finding in 9-month-old infants</p>\n
      • laymans_summary<div>\n  </div>\n<div>\n <strong>What is the problem/background?</strong></div>\n<div>\n LimmaTech Biologics Ab (LMTB) develops vaccines called “glycoprotein bioconjugates”</div>\n<div>\n through a new process. Bioconjugates are sugar/protein mixtures that are made using bacterial</div>\n<div>\n cells. Although this is a first in human trial of this precise bioconjugate, six previous clinical</div>\n<div>\n studies have been conducted with the same technology and protein component as used for this</div>\n<div>\n vaccine. Vaccination with bioconjugates in more than 1000 healthy adults has been reported</div>\n<div>\n as safe and well tolerated. This trial will evaluate a vaccine against Shigella, a disease that</div>\n<div>\n causes diarrhoeal illness. The vaccine targets a disease of major importance for</div>\n<div>\n children/infants in low and middle-income countries (LMICs). According to the Global</div>\n<div>\n Burden of Disease study 2015, diarrhoea is the fourth leading cause of death for children and</div>\n<div>\n is responsible for 8.6% of all deaths of children aged under 5years. The impact of diarrheal</div>\n<div>\n disease (DD) goes well beyond mortality, causing a significant amount of disease that mostly</div>\n<div>\n affects children under 5 years of age. Shigella is the leading pathogen causing DD in LMICs</div>\n<div>\n in children > 1 year of age and is among the top six causes of diarrhoea in children < 1 year.</div>\n<div>\n <strong>What questions are we trying to answer?</strong></div>\n<div>\n We plan to evaluate if Shigella4V, a candidate shigella vaccine, is safe at different doses in</div>\n<div>\n healthy Kenyan adults (aged 18-50 years), young children (aged 2-5 years) and infants (8-10</div>\n<div>\n months) and investigate the immune response following vaccination. We will also determine</div>\n<div>\n the ideal dose for an adequate immune response and the associated safety profile in infants.</div>\n<div>\n <div>\n <strong>Where is the study taking place, how many people does it involve and how are they</strong></div>\n <div>\n <strong>selected?</strong></div>\n <div>\n The study is taking place in two research sites; CGMR-C (Kilifi site) and in CCR (Kericho</div>\n <div>\n site). We aim to recruit healthy participants, exclusion will include conditions such as HIV,</div>\n <div>\n hepatitis B and C, heart, lung and conditions, pregnancy amongst others. This study will</div>\n <div>\n evaluate the safety and immune responses to the vaccine in 2 steps. The 1st step will recruit 16</div>\n <div>\n adults, 48 young children and 60 infants at one research site. Once safety has been</div>\n <div>\n established in this first step, we will progress to determine the best dose in 468 infants at both</div>\n <div>\n sites until the target number is enrolled. We will screen potential participants until we identify</div>\n <div>\n the required number of healthy participants from the different age groups.</div>\n <div>\n <strong>What does the study involve for those who are in it?</strong></div>\n <div>\n Individuals who provide consent and pass screening examination will be enrolled in the study.</div>\n <div>\n Screening will involve a series of blood tests to check for good health, an examination and a</div>\n <div>\n urine test for pregnancy in women. All participants will have pre-test counselling for</div>\n <div>\n Hepatitis and HIV as per local practices and guidelines. Additionally, participants at the</div>\n <div>\n KEMRI/CGMRC site will be screened for sickle cell disease (SCD) after pre-test counselling.</div>\n <div>\n Such test will not be routinely done at the site in Kericho as not supported by the geographical</div>\n <div>\n incidence of SCD. For individuals who are selected for participation, blood will be drawn at</div>\n <div>\n the different time-points (infant volumes will be described in SSA and will be within the</div>\n <div>\n limits stipulated by the World Health Organisation/National Institute of Health Guidelines).</div>\n <div>\n Adults will have an average 459mls taken over 8-10 months, Children 120mls over 13-16</div>\n <div>\n months and infants 90mls over 15-18 months in Kilifi and 130 mls in Kericho. Adults will</div>\n <div>\n have 75 mls of blood taken at each visit except screening when 9 mls will be taken. Children</div>\n <div>\n will have 12 mls taken at all visits. Infants in Kilifi will have 5mls taken at 6 visits and 12 mls</div>\n <div>\n at 5 visits. Infants in Kericho will have on average 12mls taken at 11 visits. The higher blood</div>\n <div>\n volumes collected in a subpopulation of infants (Kericho site) will allow exploratory analyses</div>\n <div>\n for further evaluation of the immune response to the Shigella vaccine. Repeat blood samples</div>\n <div>\n may be taken to verify abnormal results. Urine samples will be collected for adult females to</div>\n <div>\n test for pregnancy and medical history will also be obtained in addition to undergoing a</div>\n <div>\n clinical assessment. Listening to the heart will serve as an assessment of heart function with further investigations if clinically indicated. Those that pass screening will be enrolled in the</div>\n <div>\n trial and for those that don’t if a clinically significant condition is identified they will be</div>\n <div>\n counselled as appropriate then referred to a government facility. Eligible participants will be</div>\n <div>\n randomised to receive Shigella 4V or a control vaccine. Blood will be taken at screening,</div>\n <div>\n prior to each vaccination (to check baseline immunity to Shigella4V in all participants and for</div>\n <div>\n rabies in a small group of the children receiving rabies as a control vaccine), and at several</div>\n <div>\n time points (2 to 3 time points) post each vaccination (to evaluate response to vaccination).</div>\n <div>\n There will be a total of 7 clinic visits for adults, 10 for children and 11 for infants, plus home</div>\n <div>\n visits whenever needed in the week following each vaccination. Should a participant develop</div>\n <div>\n diarrhoea during the course of the study 4mls of blood will be collected in children and</div>\n <div>\n infants and 9 mls of blood will be collected in adults and a stool sample to determine if</div>\n <div>\n diarrhea was caused by Shigella and treatment will be provided. The study duration for each</div>\n <div>\n participant will be approximately 8 to 10 months for adults, 13 to 16 months for children and</div>\n <div>\n 15 to 18 months for infants.</div>\n <div>\n <strong>What are the benefits and risks/costs of the study for those involved?</strong></div>\n <div>\n Participants may benefit from receipt of the vaccine if the immune response is favourable and</div>\n <div>\n the vaccine is safe. Participants will also have close oversight and treatment support from the</div>\n <div>\n study team although this will primarily be for risk monitoring. Participants will benefit from a</div>\n <div>\n vaccine against meningitis (adults and infants), rabies (children) or an additional dose of</div>\n <div>\n DTaP vaccine that will be administered to the infants of the control group and offered free of</div>\n <div>\n charge at the end of the study, to the infants randomized to Shigella4V. Although the</div>\n <div>\n administration schedule of the rabies vaccine being used has been evaluated in clinical trials it</div>\n <div>\n is currently not standard practice, therefore for all children we will recommend that should</div>\n <div>\n they have exposure to high risk bite they get full post-exposure prophylaxis.</div>\n <div>\n There will also be wider benefit in the field of shigella vaccine development and in building</div>\n <div>\n on data available on safety and immune responses to bioconjugate vaccines. Although 1 of the</div>\n <div>\n 4 components of the vaccine has been evaluated in humans before this will be the first study</div>\n <div>\n of Shigella 4V in humans, however 6 very similar vaccines have been evaluated in >1000</div>\n <div>\n healthy adults and been found to be safe and illicit a good immune response. A careful</div>\n <div>\n approach to vaccinate a small number of adults sequentially then children and infants with increasing doses and with close follow up in the days and months following vaccination have</div>\n <div>\n been planned to safeguard the safety of all participants.</div>\n <div>\n At its first administration, Shigella4V will be co-administered with the measles-rubella</div>\n <div>\n vaccine in infants which is routinely given at 9 months of age. Several trials have shown an</div>\n <div>\n acceptable safety profile and non-inferiority in the immune-response when conjugate vaccines</div>\n <div>\n are co-administrated together with measles and rubella vaccine. Furthermore immune</div>\n <div>\n response to measles and rubella will be analysed. Higher volumes of blood are being collected</div>\n <div>\n from infants at KEMRI/MRD-K, Kericho to allow for detailed analysis of the immune</div>\n <div>\n response to all components of the Shigella 4V vaccine. Recurrent venepuncture can lead to</div>\n <div>\n anaemia and as such we will monitor heamoglobin levels to ensure we only collect the</div>\n <div>\n volumes of blood planned at the KEMRI/MRD-K, Kericho site if the haemoglobin (Hb) is</div>\n <div>\n 10g/dL or above. Hemoglobin monitoring will be done at the clinic using HemoCue method</div>\n <div>\n prior to the visit blood draw. Should the level fall below 10g/dL blood volumes will be taken</div>\n <div>\n as specified at KEMRI-CGMRC.</div>\n <div>\n Participants will not have any costs associated to their participation to this trial.</div>\n <div>\n <strong>How will the study benefit society?</strong></div>\n <div>\n Diarrhoea is a big problem all around the world and there is a need to develop vaccines for</div>\n <div>\n vulnerable populations-such as infants and young children, particularly in endemic areas. This</div>\n <div>\n study will build on safety and immunogenicity data of Shigella4V and will provide safety and</div>\n <div>\n immune responses which will inform the nature and need of clinical development of this</div>\n <div>\n vaccine. There is reason to believe this is a promising candidate vaccine given components of</div>\n <div>\n the vaccine and vaccines made using a similar technology have been shown to be safe and to</div>\n <div>\n raise an immune response.</div>\n <div>\n <strong>When does the study start and finish?</strong></div>\n <div>\n The study will start on receipt of ethical and regulatory approvals and will take approximately</div>\n <div>\n 2.5 years.</div>\n</div>\n<p>\n  </p>\n
      • short_titleA study to determine if a new shigella vaccine (Shigella4V) is safe, induces immunity and the best dose among Kenyan infants.
      • protocol_noECCT/19/04/01
      • version_no3.1
      • date_of_protocol09-07-2019
      • study_drugShigella-tetravalent bioconjugate vaccine
      • disease_conditionShigellosis
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines1
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameMenveo, Verorab, Infanrix
      • comparator_registeredYes
      • comparator_countriesMenveo: Not registered in Kenya\nVerorab: Registered in Kenya\nInfanrix: Registered in Kenya
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressctfuser@kemri-wellcome.org
      • applicant_covering_letter1
      • applicant_protocol1
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      • applicant_investigators_cv1
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      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries0
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      • applicant_complete_form(null)
      • applicant_impd1
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      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
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      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantDr. Mainga Hamaluba, Dr. Josphat Kosgei
      • declaration_date103-04-2019
      • declaration_principal_investigatorDr. Mainga Hamaluba
      • declaration_date203-04-2019
      • placebo_presentYes
      • study_objectives<div>\n Study objectives</div>\n<div>\n - The primary objective of this Phase 1/2 study is to obtain first-in-human data (safety</div>\n<div>\n and immunogenicity) following administration of 9-month-old infants and to identify</div>\n<div>\n the preferred dose of Shigella4V.</div>\n<div>\n Secondary objectives:</div>\n<div>\n - To further evaluate safety of Shigella4V through collection of laboratory values from</div>\n<div>\n safety laboratory tests.</div>\n<div>\n - To evaluate immunogenicity of Shigella4V when administered to adults and in 2-5-</div>\n<div>\n year-old children.</div>\n<div>\n - To evaluate persistence of the vaccine-induced immune response, 6 months after the</div>\n<div>\n primary vaccination schedule.</div>\n<div>\n - To evaluate the immunological response and immune persistence induced by a booster</div>\n<div>\n dose of Shigella4V in children and infants.</div>\n<div>\n <div>\n Exploratory objectives:</div>\n <div>\n In this study, additional investigations may include, but are not limited to, the following</div>\n <div>\n immunological and efficacy objectives:</div>\n <div>\n - IgA immunological response induced by vaccination with Shigella4V (i.e. Serum IgA</div>\n <div>\n responses and fold-increases between post- and pre-vaccination samples, from</div>\n <div>\n participants of step 1 and 2).</div>\n <div>\n - Functionality of the antibodies generated following vaccination with Shigella4V (i.e</div>\n <div>\n measuring serum bactericidal activity (SBA) post and pre-vaccination from</div>\n <div>\n participants of step 1 and 2).</div>\n <div>\n - Development of B-memory response in the vaccinated participants, against serotypes</div>\n <div>\n included in Shigella4V.</div>\n <div>\n - Impact of vaccination toward incidence of diarrhoea episodes caused by Shigella</div>\n <div>\n strains of vaccine serotypes (i.e. Number of participants with Shigella positive</div>\n <div>\n (culture or PCR confirmed) diarrhoea in vaccinated vs. control group).</div>\n <div>\n - Impact of vaccination on the severity of symptoms associated with Shigella-positive</div>\n <div>\n diarrhoea in vaccinated vs. control groups.</div>\n <div>\n - To evaluate concomitant administration of measles-rubella vaccine in 9-month-oldinfants.</div>\n <div>\n The study team will administer the measles-rubella vaccine to allow for its</div>\n <div>\n co-administration with the Shigella vaccine. The team will work with the county</div>\n <div>\n officials to make arrangements for the study participants to receive the measlesrubella</div>\n <div>\n vaccine in the study sites</div>\n</div>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n All participants shall satisfy the following criteria:</p>\n<p>\n <strong>All ages </strong></p>\n<ol>\n <li>\n Healthy by medical history, laboratory findings and physical examination before entering into the study (Participants with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator)</li>\n <li>\n Seronegative for HIV, hepatitis B and C (as per screening laboratory tests)</li>\n <li>\n Resident in the study area village during the whole trial period (Kilifi -Kilifi Health and Demographic Surveillance System (Described in more detail in the SSA); Kericho-a 75km radius from the Kericho Clinical Research Centre).</li>\n <li>\n Previously completed routine primary vaccinations (6,10 and 14 weeks or thereabouts) to the best knowledge of the participant/parent/guardian.</li>\n <li>\n Signed/thumb written informed consent, in accordance with local practice, provided by adult volunteers (participants 18 years of age and older), parents or legal representatives for children and infants participants as applicable, who, in the opinion of the investigator, can and will comply with the requirements of the protocol</li>\n <li>\n Demonstrated comprehension of the protocol procedures by passing score of 90% or better on a written/verbal comprehension test.</li>\n</ol>\n<p>\n <strong>Adults</strong></p>\n<ol>\n <li value=\"7\">\n Female and male participants between, and including 18-50 years at the time of first vaccination</li>\n <li>\n Female participants of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause. Female volunteers of childbearing potential may be enrolled in the study if the participant: has a negative urine pregnancy test at the day of screening and vaccinations, respectively, and</li>\n</ol>\n<ul>\n <li>\n agree to use effective contraception for 30 days prior to vaccination and</li>\n <li>\n agree to continue contraception at least for 2 months after completion of vaccination series.</li>\n</ul>\n<p>\n <em>To demonstrate adequate contraception use we will ask female participants to attend with their family planning records for verification. Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly, in accordance with the product label. Examples of these include: combined oral contraceptives; injectable progestogen; implants of etenogestrel or levonorgestrel; intrauterine device or intrauterine system; male partner sterilisation at least 6 months prior to the female participant’s entry into the study, and the relationship is monogamous; male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository); and male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository)</em></p>\n<p>\n  </p>\n<p>\n <strong>Children and Infants</strong></p>\n<ol>\n <li value=\"7\">\n Female and male aged 9 months (+/- 1 month) old (infants) or between, and including, 2-5 years of age (children) at the time of the first vaccination</li>\n <li>\n Born full-term (i.e. after a gestation period of 37 to less than 42 completed weeks)</li>\n</ol>\n
      • principal_exclusion_criteria<p>\n A participant meeting any of the exclusion criteria listed below must be excluded from participating in the trial.</p>\n<p>\n <strong>All ages</strong></p>\n<ol>\n <li>\n Any clinically significant deviation from the normal range in biochemistry or haematological blood tests. Normal ranges for Hb are site specific, as following:</li>\n</ol>\n<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Hb values (g/dl)</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n Kilifi</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n Kericho</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Infants and Children</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n 8.2-12.7</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n 10-15.6</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Adults_Women</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n 8.0-14.9</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n 9.5-16.1</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Adults_Men</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n 10.6-17.0</p>\n </td>\n <td style=\"width:85px;\">\n <p>\n 13.3-18.1</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<ol>\n <li value=\"2\">\n Suspected or known hypersensitivity (including allergy) to any of the vaccine components or to previous vaccine, or to medicinal products or medical equipment whose use is foreseen in this study</li>\n <li>\n Clinical conditions representing a contraindication to intramuscular vaccination and blood draws         </li>\n <li>\n Any confirmed or suspected immunosuppressive or immune-deficient condition.</li>\n <li>\n Systemic administration of corticosteroids (PO/IV/IM): prednisone ≥20 mg/day, or equivalent for more than 14 consecutive days from birth (for infants) / within 90 days prior to informed consent. Inhaled except for doses > 800 mg/day and topical steroids are allowed.</li>\n <li>\n Administration of antineoplastic or radiotherapy from birth / within 90 days prior to informed consent. Participants may be on chronic or as needed medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to participant safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition</li>\n <li>\n Known exposure to <em>Shigella</em> during lifetime of the subject</li>\n <li>\n Concurrently participating in another clinical study, or participation in the preceding month, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device)</li>\n <li>\n Acute disease and /or fever at the time of enrolment</li>\n</ol>\n<p>\n Note: enrolment may be postponed/delayed until such transient circumstances have terminated</p>\n<ol>\n <li value=\"10\">\n History of any malignancy of lymphoproliferative disorder</li>\n <li>\n Known to be part of study personnel or being a close family member to the personnel conducting this study.</li>\n <li>\n Previous history of significant persistent neutropenia, or drug related Neutropenia</li>\n <li>\n Adults with clinical wasting; children with weight-for-age Z score less than -3SD.</li>\n <li>\n History of any chronic or progressive disease (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease) that according to judgment of the investigator could interfere with the study outcomes or pose a threat to the participant's health</li>\n <li>\n History of surgical splenectomy or Sickle cell disease (SCD test performed  at KEMRI-CGMRC only).</li>\n <li>\n Administration of immunoglobulin and/or any blood products within the three months preceding the first dose of study vaccine</li>\n <li>\n Any medical, social condition, or occupational reason that, in the judgment of the investigator, is a contraindication to protocol participation or impairs the volunteer's/parent’s/guardian’s ability to give informed consent, increases the risk to the potential participant because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data   .</li>\n <li>\n Women who are breastfeeding</li>\n</ol>\n<p>\n <strong>Adults</strong></p>\n<ol>\n <li value=\"19\">\n History of chronic alcohol consumption and/or drug abuse. Chronic alcohol consumption is defined as: a prolonged period of frequent, heavy alcohol use; the inability to control drinking once it has begun; physical dependence manifested by withdrawal symptoms when the individual stops using alcohol; tolerance, or the need to use more and more alcohol to achieve the same effects; a variety of social and/or legal problems arising from alcohol use.</li>\n</ol>\n
      • primary_end_points<p>\n <strong><u>Safety</u></strong></p>\n<p>\n Safety and tolerability of the candidate vaccine Shigella4V as determined by occurrence, severity and relationship, of solicited and unsolicited adverse events (AEs) and serious AEs (SAEs), through:</p>\n<ul>\n <li>\n solicited local and systemic AEs during 7 days following each vaccination </li>\n <li>\n unsolicited AEs during 28 days following each vaccination</li>\n <li>\n SAEs and medically relevant AEs throughout the study duration</li>\n</ul>\n<p>\n <strong><u>Immunology</u></strong><strong>:</strong></p>\n<ul>\n <li>\n Serum IgG responses and fold-increases between post- and pre-vaccination samples from infants of step 2, as determined by ELISA against LPS corresponding to the 4 Shigella serotypes included in the Shigella4V bioconjugate.</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others1
      • scope_others_specifyimmunogenicity and dose finding
      • trial_human_pharmacology0
      • trial_administration_humans1
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Kilifi: </strong></p>\n<p>\n The KEMRI-Wellcome Trust Research Programme has long history of conducting clinical trials in illnesses that cause high disease burden and mortality in the local community. These range from locally led ‘academic’ type clinical research and product development/drug registration trials.</p>\n<p>\n The programme has built up experience from assessing safety and efficacy in phase I trials through to evaluating real-life effectiveness in phase IV trials.</p>\n<p>\n There are ongoing trials in the wards and out-patient departments of Kilifi District Hospital, health centres and dispensaries within Kilifi district.</p>\n<p>\n The Clinical Trials Facility (CTF) of the KEMRI-Wellcome Trust Research Programme was set up in 2006 to provide a global standard trial centre within the collaborative programme. Based in Kilifi, the CTF works to help ensure all trials conducted meet international quality standards from the point of setting the research question to analysis and reporting. The core aim of the CTF is to enhance the way trials are organized while at the same time providing an optimum environment for developing highly skilled African trialists. The Clinical Trial Laboratory (CTL) is Good Clinical Laboratory Practices (GCLP) accredited has been audited by regulatory bodies and certification institutions like GlasxoSmithKline Biological (GSK Biologicals), Contract Lab Services (CLS) and Food and Drug Administration (FDA).</p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n In addition to the principal investigator and co-investigators, we will have the following staff: Medical officer-1, Clinical officer - 3, Nurses -2, Fieldworkers - 12, Assistant Research Officer - 2, Study Coordinator -1, Pharmacisit-1</p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Pharmacy Technician-1, Data Manager-1, Data Clerk-2, and Lab Archivist-1</p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n The inpatient facility is already staffed with 3 clincians, 1 paediatrician and 20 nurses. All staff are trained in basic life support and resuscitation facilitaties are available</p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  </p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Kericho:</p>\n<p>\n The KEMRI/WRP CRC is the primary research site in USAMRD-K. Situated on the grounds of the Kericho County Referral Hospital (KDH)/Ministry of Health (MoH), the 7100 square feet CRC supports both research and HIV care & treatment in the southern Rift Valley Province. The CRC is staffed with 5 doctors, 2 pharmacists, 8 clinical officers, 10 nurses, 38 laboratory and auxiliary staff. The Principal Investigator at the site for this study is Dr Josphat Kosgei and the Study Coordinator is Linet Cherono. The CRC is composed of a clinical area including a central pharmacy that has the capacity to support both vaccine and therapeutic studies as well as provide additional non-study medicines for other non-study related care. The CRC laboratory is College of American Pathologist (CAP) accredited laboratory with a state-of-the-art Information Technology (IT) center that supports both HIV research and treatment programs. Both the CRC pharmacy and laboratory are approved by the National Institute of Allergy and Infectious Diseases/Division of AIDS (NIAID/DAIDS) to participate in DAIDS sponsored vaccine (Site # 1521) and therapeutics (Site #12501) studies. To support research, the Kericho CRC has a freezer farm equipped with liquid nitrogen plant and freezers for sample storage. The site has two fully equipped emergency rooms, with a standby ambulance to offer emergency response.</p>\n
      • other_details_explanation<p>\n Not applicable</p>\n
      • other_details_regulatory_notapproved<p>\n <span style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">We are only submitting to PPB.</span></p>\n
      • other_details_regulatory_approved<p>\n Not applicable</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_duration2.5 years
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorplacebo and control vacci
      • design_controlled_other_medicinalYes
      • design_controlled_placeboYes
      • design_controlled_medicinal_otherYes
      • design_controlled_medicinal_specifyMenveo Verorab Infanrix
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites2
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_site1. Kilifi (n=292)\nStep 1 (Safety cohort)= 124 \nStep 2 (dose-finding) =168\n2. Kericho (n=300)\nStep 2=300
      • total_participants_worldwide592
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenYes
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyWe will recruit young children (aged 2-5 years) and infants (8-10 months) who are not capable of giving consent.
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMainga
      • investigator1_middle_name
      • investigator1_family_nameHamaluba
      • investigator1_qualificationMBChB MRCPCH MD
      • investigator1_professional_addressP.O.Box 230, Kilifi 80108, Kenya
      • investigator1_telephone(+254) 795 3204 22
      • investigator1_emailMHamaluba@kemri-wellcome.org
      • organisations_transferred_Yes
      • number_participantsExpected number of participants=592
      • notification
      • approval_date08-07-2019
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted20-02-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<p>\n This phase 1/2 trial multicentre, randomized controlled, double blind, trial is with two steps:</p>\n<p>\n -  step 1: a safety cohort conducted only at KEMRI-CGMRC site</p>\n<p>\n -  step 2: a dose-finding cohort conducted at both KEMRI-CGMRC and KEMRI/MRD-K sites.</p>\n<p>\n Safety of the Shigella4V vaccine was evaluated first in adults and subsequently in children and infants through an age-descending and dose escalation approach (safety cohort, step 1). Following confirmation of vaccine safety, further cohorts of infants (dose-finding cohort, step 2) were enrolled to evaluate immunogenicity of the vaccine at 4 different doses (4 ,12, 24, 48 μg) with/without adjuvant or control vaccines and expand safety data. A control vaccine was used, and participants were randomized at a ratio of 3:1 in adults, 2:1 in children, 2:1 in infants in step 1 and 8:1 in infants in step 2, to receive the candidate vaccine versus the control vaccine.</p>\n<p>\n Screening and enrollment for eligible participants into the safety cohort (step 1) of the trial was completed on 6^th November 2020 with a total number of 124 participants, including 16 adults (1 withdrawal), 48 children (1 withdrawal) and 60 infants (4 withdrawals) and they all completed the study visits and end of study.</p>\n<p>\n Adults were scheduled to have 7 clinic visits, children to have 10 clinic visits and infants to have 11 clinic visits. At selected visits, participants had blood drawn for the evaluation of safety and/or immunological parameters. All solicited and unsolicited adverse events (AEs), and medications for the first 7 days after each vaccination (day 0 – day 6) were collected and documented. Unsolicited AEs were collected for 28 days following each injection. In addition, from enrolment (1^st injection) through study termination, all serious adverse events (SAEs), all AEs leading to vaccine/study withdrawal, any AE medically relevant and associated concomitant medication, as well as any vaccination received were collected and recorded.</p>\n<p>\n Screening for eligible participants into the dose-finding cohort (step 2) commenced on 14^th December 2020 (Kericho site) and 17^th February 2021 (Kilifi site). Enrolment was completed on 2^nd August 2021 and 3^rd August 2021 at Kericho and Kilifi sites respectively with a combined total of 472 infants (341 infants at Kericho site and 131 infants at Kilifi site), including 74 withdrawals.</p>\n<p>\n All study vaccinations including the booster vaccinations, and all follow up visits were completed at both sites. The last participant last visit was conducted on 11^th November 2022 (Kericho site) and 14^th November 2022 (Kilifi site). The close-out monitoring visit was completed on 3^rd March 2023 (Kilifi) and 28 Feb 2023 (Kericho).</p>\n<p>\n Six protocol amendments were submitted to PPB during the study period and approval letters were received for all the submissions. The last protocol version 5.3 dated 23 Sep 2021 has approval letters from SERU and PPB dated 01 December 2021 and 17 February 2022 respectively.</p>\n<p>\n All protocol deviations and violation that occurred in the study were reported and uploaded onto the PPB portal. Response letters were received from SERU for all reported protocol deviations /violation.</p>\n<p>\n All safety data, including solicited and unsolicited AEs that were reported in the adults, children, and infant cohorts was evaluated by the data safety monitoring board (DSMB) and recommendation to proceed to the next stage and subsequently Step 2 of the study was provided by the DSMB. A total of six meetings to review the safety data were conducted by the DSMB and all six meetings had positive outcomes without concerns toward the safety data collected. All the DSMB safety data reports were submitted to PPB via the PPB clinical trials portal.</p>\n<p>\n A total of eight SAEs have occurred in the study, 5 at Kilifi site and 3 at Kericho site, and all were reported to PPB and SERU. All the SAEs were evaluated as not related to the investigational product and all have resolved. Also, one pregnancy was reported in a participant at Kilifi site that became pregnant (LMP 6^th January 2020) after she had missed her injectable contraceptive (Depo Provera) that was due in January 2020. The participant had completed her 2nd (last) vaccination visit on the 11^th October 2019 and was to have the end-of-study (final) visit on 27th March 2020, but this was disrupted as a result of the covid-19 pandemic. The pregnancy was uneventful, and delivery was at term on 20^th November 2020 with no complications reported. The infant was followed up until 6months of age, no complaints were reported by the mother, and baby remained in good condition. </p>\n<p>\n In conclusion, the studied vaccine candidate Shigella 4V was well tolerated in all formulations tested and did not raise any safety concerns. Shigella 4V elicited a robust humoral immune response against the vaccine antigens, independently if administered alone or in combination with the adjuvant, however combination of Shigella 4V with the adjuvant aluminium hydroxide increased immunogenicity to a larger extent post vaccination across all doses. The first two vaccinations elicited robust immune responses which was further amplified from the administration of a booster vaccination, especially 7 days post vaccination highlighting a potential priming effect provided by the first two vaccinations. The good safety profile combined with the robust immune response here reported for Shigella4V in the target population of young infants, provides the necessary information to advance development of this bioconjugate vaccine toward future phase III pivotal field studies.</p>\n
      • implication_results<p>\n The generation of the four valent vaccine and as well the results of the clinical study (S4V01) carry significant implications for the burden of diarrhoeal diseases found in LMICs, especially amongst children under the age of five. As the incidence of Shigellosis is highest in the 12-24 months age range, the target population used was 9-month-old infants. The safety and strong immunogenicity found following the vaccination will drive advancements in the development of this vaccine. There is no Shigella vaccine licensed to prevent shigellosis. The treatment options include antimicrobials, but the rise of antimicrobial resistance is concerning. The development of a Shigella vaccine is an important goal for public health and will have profound effects on the healthcare outcomes of the children within the LMICs most affected by Shigellosis. We anticipate that vaccination of the target population of 9 months infants will result in a measurable reduction in the burden of Shigellosis, with fewer cases, hospitalizations, and deaths attributable to the targeted illness.</p>\n<p>\n In summary, the implications of our vaccine study's achievements are far-reaching, with anticipated outputs and outcomes spanning licensure, disease prevention, healthcare outcomes, and healthcare policy. By leveraging our collaborative efforts and the support of future funding, we aim to realise these outcomes within the specified timelines, contributing to a healthier, more resilient future for communities in LMIC.</p>\n
      • quantity_importedProduct Name in vials and Quantity Received: S4V01 IMP (800); S4V01 IMP Diluent (1100); S4V01 IMP Adjuvant (500); Menveo (62); Verorab (100); Infanrix (35); Measles/ Rubella (114).
      • quantity_dispensedProduct Name in vials and Quantity dispensed: S4V01 IMP (538); S4V01 IMP Diluent (738); S4V01 IMP Adjuvant (297); Menveo (52); Verorab (95); Infanrix (20); Measles/ Rubella (110).
      • quantity_destroyedProduct Name in vials and Quantity destroyed: S4V01 IMP (262); S4V01 IMP Diluent (362); S4V01 IMP Adjuvant (183); Menveo (10); Verorab (5); Infanrix (15); Measles/ Rubella (0).
      • quantity_exportedProduct Name in vials and Quantity returned: S4V01 IMP (0); S4V01 IMP Diluent (0); S4V01 IMP Adjuvant (20 returned to Sponsor); Menveo (0); Verorab (0); Infanrix (0); Measles/ Rubella (4 returned to Kilifi County Hospital KEPI stores).
      • balance_siteThere is no balance left of any product.
      • final_date0000-00-00
      • modified2025-01-30 10:16:58
      • created2019-03-12 19:48:22
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id482
        • application_id773
        • given_nameMainga
        • middle_name
        • family_nameHamaluba
        • qualificationMBChB MRCPCH MD
        • professional_addressP.O.Box 230, Kilifi 80108, Kenya
        • telephone(+254) 795 3204 22
        • emailMHamaluba@kemri-wellcome.org
        • created2019-03-12 19:55:04
        • modified2020-02-20 05:20:18
      • 1(array)
        • id484
        • application_id773
        • given_nameKosgei
        • middle_name
        • family_nameJosphat
        • qualificationMBChB MSc DLSHTM
        • professional_addressWalter Reed Project Kericho, P.O. Box 1357, 20200
        • telephone+254 729 110 122
        • emailjosphat.kosgei@usamru-k.org
        • created2019-03-12 20:17:54
        • modified2020-02-20 05:20:18
    • SiteDetail(array)
      • 0(array)
        • id628
        • application_id773
        • county_id35
        • site_nameKEMRI-United States Army Medical Research Unit-Kenya, Kericho
        • physical_addressKericho
        • contact_detailsWalter Reed Project Kericho, P.O. Box 1357, 20200
        • contact_personJosphat Kosgei
        • site_capacity(null)
        • misc(null)
        • created2019-03-12 19:55:04
        • modified2020-02-20 05:20:18
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
      • 1(array)
        • id630
        • application_id773
        • county_id3
        • site_nameKEMRI Wellcome Trust Research Program-CGMR-C
        • physical_addressKilifi
        • contact_detailsP.O.Box 230, Kilifi 80108, Kenya
        • contact_personMainga Hamaluba
        • site_capacity(null)
        • misc(null)
        • created2019-03-12 20:50:53
        • modified2020-02-20 05:20:18
        • County(array)
          • id3
          • county_nameKilifi
          • created2012-05-31 16:15:49
          • modified2012-05-31 16:15:49
    • Sponsor(array)
      • 0(array)
        • id376
        • application_id773
        • sponsorLimmaTech Biologics AG
        • sponsor_typeIndustry
        • contact_personCristina Alaimo
        • addressGrabenstrasse 3 8952 Schlieren Switzerland
        • telephone_number+41 (0)44 733 85 77
        • fax_number+41 44 733 85 74
        • cell_number+41 (0)79 386 72 28
        • email_addresscristina.alaimo@lmtbio.com
        • created2019-03-12 19:55:04
        • modified2020-02-20 05:20:18
  • 1(array)
    • Application(array)
      • id816
      • user_id81
      • trial_status_id4
      • abstract_of_study<p>\n Malaria is a disease of major public health importance. The only vaccine available is partially effective and targets the pre-erythrocytic stages of the life cycle. Thus, there is a need to identify other potential vaccine targets as well as to develop models to test vaccine efficacy, especially that of transmission-blocking vaccines. Controlled human malaria infection (CHMI) has been shown to be an important tool for the assessment of the efficacy of novel malaria vaccines and drugs. CHMI also allows for the evaluation of immunity to malaria and monitoring of parasite growth rates <em>in vivo</em>. This is particularly useful in individuals from endemic areas with varying levels of exposure and immunity to malaria. Thus, CHMI in individuals with prior exposure to malaria has potential to accelerate malaria vaccine development. In this study, we aim to use CHMI in semi-immune adults to develop a model to assess transmissibility of malaria infection to mosquitoes, to study immune responses that are directed against sexual stages that might block transmission, and as a platform to test vaccines. To achieve this, the study will be carried out in two phases A (N=45 participants) and B (N=60 participants) over a period of 4-6months. We will vary the parasite dose in individuals enrolled for CHMI and use low-doses of anti-malarial drugs to promote the production of gametocytes <em>in vivo</em> (Phase A) and demonstrate transmissibility in mosquito feeding assays (Phase B). Thus, the main outcomes of the study will be: (1) optimisation of sporozoite dose for infections success in individuals with moderate-high malaria exposure; (2) use of sub-curative anti-malaria treatment for induction of gametocytes; and (3) infection of mosquitoes in mosquito feeding assays by induced gametocytes. To achieve this, we will screen up to 250 semi-immune adults who will be recruited from known areas of malaria endemicity in Kenya with varying exposure to malaria and enrol 105 individuals to conduct CHMI studies with serial quantitative polymerase chain reaction (PCR) to measure asexual parasite growth and induction of transmission stages <em>in vivo</em>. In addition, we will comprehensively characterize immunity and identify targets in relation to function assessed by various laboratory assays.</p>\n
      • study_title<p>\n Safety and feasibility of a malaria transmission model in semi-immune Kenyan adults using <em>Plasmodium falciparum</em> sporozoites</p>\n
      • laymans_summary<address>\n <strong>Formal Title: </strong>Safety and feasibility of a malaria transmission model in semi-immune Kenyan adults using <em>Plasmodium falciparum</em> sporozoites</address>\n<address>\n <strong>Lay Title: </strong>Use of malaria infection by injection to study malaria transmission</address>\n<address>\n <strong>What is the problem/background?</strong></address>\n<p>\n Malaria remains a major public health problem with up to half a billion-people infected with the parasite that causes the disease. In recent and ongoing studies, we have conducted controlled malaria infection in 189 Kenyan adults. By measuring malaria parasites in the blood, we have gained insights into the growth of parasites that will guide vaccine development. One other approach to vaccination is to target the transmitting stages of the malaria parasites such that mosquitoes feeding on the infected person would not become infected, thus breaking the life cycle of the parasite. There is a need to develop experimental methods to test the effect of candidate vaccines designed to interrupt transmission to mosquitoes so that vaccines showing evidence of efficacy can then be prioritized for large trials in the field. Furthermore, studying natural immunity in humans to the stages involved in malaria transmission will help characterize potential targets for new vaccines. </p>\n<address>\n <strong>What questions are we trying to answer?</strong></address>\n<p>\n We wish to develop a method to test the efficacy of vaccines and/or drugs designed to block transmission of malaria to mosquitoes and to identify the targets of transmission-blocking immunity to malaria.</p>\n<address>\n <strong>Where is the study taking place, how many people does it involve and how are they selected?</strong></address>\n<p>\n The study will take place in Kilifi, Kenya. The study will involve the recruitment and screening of up to 250 individuals from Ahero and Kilifi to determine eligibility for participation and past exposure to malaria. This will be done after a programme of sensitisation and information giving about the study. The study will be conducted in two phases where individuals with moderate to high malaria exposure will be enrolled to participate in the following:</p>\n<ol>\n <li>\n Phase A (N = 45): “dose-finding” of the dose of sporozoites given and optimisation of the dose of anti-malarial drug that will be used to promote development of transmission stages without clearing the infection completely (i.e. a “sub-curative dose”);</li>\n <li>\n Phase B (N = 60): assessing infectivity of induced malaria transmission stages to mosquitoes.</li>\n</ol>\n<p>\n For each of these phases, selection will be based on level of past malaria exposure and health status. To determine these, blood samples will be taken at the point of screening for each individual participant.</p>\n<address>\n <strong>What does the study involve for those who are in it?</strong></address>\n<p>\n For screening, a blood sample of 21ml will be collected at the time of recruitment. A urine sample and medical history will also be obtained in addition to undergoing a clinical assessment and a test to check the functioning of the heart. For enrollment, a participant will need to have moderate to high malaria exposure and have no clinical disease. Those that meet this criteria, some will be enrolled into phase A and some into phase B (phase A will happen before phase B) for malaria infection studies and be required to stay at an in-patient facility in Kilifi near KEMRI-Kilifi. The participants will be asked to stay at the facility throughout the study so that they are closely monitored by the study staff. To transmit malaria to mosquitoes the human challenge model must first reliably induce infection and of a sufficient duration before being able to develop transmitting stages. We will:</p>\n<ol>\n <li>\n For Phase A: Assign individuals to one of three groups to be given different doses of malaria by injection. These individuals will be further assigned to receive two different anti-malarial drugs (sub-curative treatment)</li>\n <li>\n For Phase B: Based on results from Phase A, give individuals malaria infection by injection at the most successful dose and provide sub-curative treatment that promotes the most transmission stages. At peak time points of transmission stage induction (based on results from Phase A), mosquito feeding assays will be undertaken to determine infectivity to mosquitoes.</li>\n</ol>\n<p>\n Multiple blood samples will be taken for those enrolled for malaria infections (both Phase A and B). For both phases, blood samples will be drawn as follows: a day before infection (40ml); at five days after infection (8ml); twice daily every day from seven days after infection until the day they will receive a sub-curative treatment (cumulative total of 185ml); and then once daily afterwards to twenty-one days after infection (cumulative total of 70ml); then every other day from day twenty-one until day forty-two (cumulative total of 71ml); once daily during curative treatment (cumulative total of 18ml);  and on day fifty-six after infection (40ml). In addition, for participants enrolled into Phase B, direct skin mosquito feeding and blood samples for mosquito membrane feeding assays will also be taken to assess mosquito infectivity (cumulative total of 28ml). The specific days for assessing mosquito infectivity will be dependent on the results from Phase A of the study. For the entire duration of the study (4-6months), a total of 465ml per participant of blood will be drawn for those enrolled in Phase A and a total of 493mls for those in Phase B. This total volume of blood is less than the volume taken during a blood donation. In addition to blood sampling, clinical assessments will be repeated a day before infection including collection of a urine sample and measurements of weights and heights. Observed sub-curative treatment for malaria will be administered on the day the parasites reach a set threshold and a curative dose on day forty-two after infection.</p>\n<address>\n <strong>What are the benefits and risks/costs of the study for those involved?</strong></address>\n<p>\n Controlled human malaria infection has been conducted in one hundred and eighty-nine (189) healthy adults in Kenya (Hodgson et al Front Microbiol. 2014 (Nairobi, N=28 volunteers, 2013) and KEMRI/SERU/CGMR-C/029/3190 (Kilifi, N=161 volunteers, 2016-2018)) and has been proven safe in these individuals. The risks relate to the possibility of developing an allergic reaction upon administration of the malaria infection. In addition, participants may develop signs and symptoms of malaria after infection which are unpleasant, may result in development of severe malaria due to the higher doses of sporozoites being given and may develop some side effects to the drugs used for treatment (sub-curative and curative doses). There are no direct benefits to individuals participating in this study other than information about their health. However, all participants will have their transport costs reimbursed and compensated for all out of pocket expenses for the entire duration of the study.</p>\n<address>\n <strong>How will the study benefit society?</strong></address>\n<p>\n This work is necessary for enhancing our understanding of how malaria transmission stages develop, the immune targets involved and ability to test interventions such as vaccines in populations that have past exposure to malaria. The successful application of such interventions will benefit society by reducing malaria transmission, a major cause of illness, death and impediment to national development. An adaptation of the controlled human malaria infection provides a way of studying transmission of malaria in a very detailed way that is not possible using natural infections, and we believe that this step is now necessary to inform vaccine design and efficacy.</p>\n<address>\n <strong>When does the study start and finish?</strong></address>\n<p>\n The study will start upon receipt of ethical clearance. Data collection, analysis and write up will take place over three years.</p>\n
      • short_titleUse of malaria infection by injection to study malaria transmission
      • protocol_noECCT/19/08/01
      • version_noVersion 3.0
      • date_of_protocol27-03-2019
      • study_drugPfSPZ Challenge CHMI-Transmod
      • disease_conditionMalaria
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressregulatory@kemri-wellcome.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data0
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantMelissa Kapulu
      • declaration_date105-08-2019
      • declaration_principal_investigatorMelissa Kapulu
      • declaration_date205-08-2019
      • placebo_presentNo
      • study_objectives<address>\n <strong>Primary objective</strong></address>\n<p>\n To adapt the Controlled Human Malaria Infection (CHMI) model using <em>P. falciparum</em> sporozoites to induce gametocytes and assess their infectivity to mosquitoes.</p>\n<p>\n <strong>Secondary objective(s)</strong></p>\n<address>\n 1. To determine the safety of varied increased doses of <em>P. falciparum</em> sporozoites in CHMI delivered by Direct Venous Inoculation (DVI) in semi-immune volunteers and optimise the dose of sporozoites that results in 100% infectivity in moderate to highly exposed adults;</address>\n<address>\n 2. To determine if the prevalence, peak density and peak time point of gametocytes is altered by drug-regimen and determine the area under the curve of density over time;</address>\n<address>\n 3. To determine the infectivity of drug-induced gametocytes in mosquito feeding assays;</address>\n<address>\n 4. To measure immunity to gametocyte antigens and determine associations between immunity and transmission-blocking activity in the CHMI model;</address>\n<address>\n 5. To explore the perceptions, attitudes, and experiences of research participants and other community and professional stakeholders involved in the CHMI study.</address>\n
      • principal_inclusion_criteria<ul>\n <li>\n Healthy adults aged 18 to 45 years.</li>\n <li>\n Able and willing (in the Investigator’s opinion) to comply with all study requirements.</li>\n <li>\n Informed consent.</li>\n <li>\n Use of effective method of contraception for duration of study (women only). We will ask the female volunteers to come with their family planning records to verify. Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly, in accordance with the product label. Examples of these include: combined oral contraceptives; injectable progestogen; implants of etenogestrel or levonorgestrel; intrauterine device or intrauterine system; male partner sterilisation at least 6 months prior to the female subject’s entry into the study, and the relationship is monogamous; male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository); and male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository).</li>\n</ul>\n
      • principal_exclusion_criteria<p>\n Any of the following constitutes exclusion criterion:</p>\n<ul>\n <li>\n Body weight of less than 50kg or body mass index (BMI) less than 18 or greater than 25 kg/m² at screening.</li>\n <li>\n Use of systemic antibiotics with known antimalarial activity within 30 days of administration of PfSPZ Challenge (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin).</li>\n <li>\n Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the study period.</li>\n <li>\n Current participation in another clinical trial or recent participation within 12 weeks of enrolment.</li>\n <li>\n Prior receipt of an investigational malaria vaccine.</li>\n <li>\n Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed). This will also include Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) positivity.</li>\n <li>\n Use of immunoglobulins or blood products within 3 months prior to enrolment.</li>\n <li>\n Any serious medical condition reported or identified during screening that increases the risk of CHMI.</li>\n <li>\n Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination.</li>\n <li>\n Women only; pregnancy, or an intention to become pregnant during the duration of the study.  </li>\n <li>\n Sickle cell trait or disease.</li>\n <li>\n History of drug or alcohol abuse.</li>\n <li>\n Known hypersensitivity to or contraindications for use of artemether-lumefantrine, chloroquine, piperaquine, primaquine, sulfadoxine-pyrimethamine, or history of severe (allergic) reactions to mosquito bites.</li>\n <li>\n Confirmed gametocyte positivity at screening and/or a day before challenge</li>\n <li>\n Confirmed parasite positive by PCR a day before challenge i.e. at C-1.</li>\n</ul>\n<p>\n <strong><em>Exclusion Criterion on Day of Challenge </em></strong></p>\n<ul>\n <li>\n Acute disease, defined as moderate or severe illness with or without fever (temperature >37.5^oC).</li>\n</ul>\n
      • primary_end_points<p>\n Not applicable. There are no primary endpoints.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology1
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyHuman challenge study with deliberate infection of participants to induce transmission stages and understand immunogenicity.
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p>\n Medical officer - 1<br />\n Clinical officer - 2<br />\n Nurses - 2<br />\n Fieldworkers - 5<br />\n Research and Assistant Research Officers - 2<br />\n Study Coordinator - 1<br />\n Pharmacisit - 1<br />\n Data Manager - 1<br />\n Data Clerk - 2<br />\n The inpatient facility is already staffed with 3 clincians, 1 paediatrician and 20 nurses.<br />\n All staff are trained in basic life support and resuscitation facilitaties are available.</p>\n
      • other_details_explanation<p>\n Not applicable.</p>\n
      • other_details_regulatory_notapproved<p>\n Submission is only to PPB.</p>\n
      • other_details_regulatory_approved<p>\n Not applicable.</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted<p>\n Not applicable.</p>\n
      • estimated_duration3 years
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKEMRI-Wellcome Trust Research Programme (KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), Kilifi, Kenya.
      • single_site_physical_addressKEMRI-Wellcome Trust Research Programme, Off Bofa Road, Kilifi County Hospital, Kilifi, Kenya
      • single_site_contact_personMelissa Kapulu
      • single_site_telephone+254717501319
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_site105
      • total_participants_worldwide105
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMelissa
      • investigator1_middle_name
      • investigator1_family_nameKapulu
      • investigator1_qualificationPhD
      • investigator1_professional_addressKEMRI-Wellcome Trust Research Programme, P. O. Box 230, Kilifi, Kenya 80108
      • investigator1_telephone+254709983463
      • investigator1_emailmkapulu@kemri-wellcome.org
      • organisations_transferred_No
      • number_participants105
      • notification
      • approval_date15-11-2019
      • submitted1
      • deleted0
      • deleted_date2019-08-09 08:51:39
      • deactivated0
      • date_submitted27-02-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2024-07-29 09:25:54
      • created2019-07-18 14:56:05
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id506
        • application_id816
        • given_nameMelissa
        • middle_name
        • family_nameKapulu
        • qualificationPhd
        • professional_addressKEMRI-Wellcome Trust Research Programme, P. O. Box 230, Kilifi, Kenya 80108
        • telephone+254709983463
        • emailmkapulu@kemri-wellcome.org
        • created2019-07-18 15:09:17
        • modified2020-02-27 12:45:15
      • 1(array)
        • id507
        • application_id816
        • given_namePhilip
        • middle_name
        • family_nameBejon
        • qualificationBSc MBBS PhD
        • professional_addressKEMRI-Wellcome Trust Research Programme, P. O. Box 230, Kilifi, Kenya 80108
        • telephone+254709983549
        • emailpbejon@kemri-wellcome.org
        • created2019-07-18 15:10:33
        • modified2020-02-27 12:45:15
    • SiteDetail(array)
      • 0(array)
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        • created2019-07-18 15:09:17
        • modified2020-02-27 12:45:15
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id395
        • application_id816
        • sponsorUniversity of Oxford
        • sponsor_typeResearch Institution
        • contact_person
        • addressUniversity Offices, Wellington Square, Oxford, OX1 2JD, UK
        • telephone_number+44 1865 270000
        • fax_number
        • cell_number+44 1865 270000
        • email_addressresearch.services@admin.ox.ac.uk
        • created2019-07-18 15:09:17
        • modified2020-02-27 12:45:15
  • 2(array)
    • Application(array)
      • id1245
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      • abstract_of_study<address>\n Diarrhoea caused by <em>Shigella </em>(shigellosis) is of major public health importance. <em>Shigella</em> causes a high burden of disease in low- and middle-income countries (LMICs), where 70% of all cases occur in children under 5 years of age who form the target population for disease prevention through vaccination. However, there are no licensed <em>Shigella</em> vaccines in routine use, with several candidates still in various stages of clinical development. <em>Shigella</em> human infection studies (HIS) have played a key role in vaccine development. These models also allow for the evaluation of immunity and other non-immunological parameters that are important to understand resistance and/or susceptibility to disease. This is particularly useful in individuals from endemic areas with varying levels of prior exposure and immunity to <em>Shigella</em>. Thus, establishing a <em>Shigella</em> HIS would enable the testing of interventions such as vaccines in a population that would most benefit from a subsequent vaccine and has potential to accelerate vaccine development. Here, the goal is to successfully establish a <em>Shigella sonnei </em>human infection model in Kenyan adults. This will be achieved by conducting dose-finding and dose verification <em>Shigella</em> studies that safely and reproducibly induce ≥60% attack rates. In this study, we aim to use <em>Shigella</em> HIS in healthy adults to develop a model as a platform to test vaccines, to study immune responses identifying potential correlates of infection, and non-immunological factors mediating and influencing susceptibility to disease. To achieve this, the study will be carried out in two phases over a period of 12-14 months. Phase A will enroll (N=up to 40 volunteers) and Phase B will enroll an additional (N=30 volunteers). To be eligible to receive a dose of 53G, volunteers must pass the screening visit. We will vary the dose of bacteria in individuals enrolled for challenge to identify the dose needed to cause ≥60% shigellosis (attack rate) (Phase A) followed by testing and demonstrate the reproducibility of the model (Phase B). Thus, the main outcomes of the study will be: (1) optimisation of bacterial dose for infection success (≥60% attack rate); and (2) safety. To achieve this, we will screen healthy adults (18-45 years of age) who will be recruited from known areas of Kilifi County and screened for their exposure to <em>S. sonnei</em> (by measuring antibodies) to enroll up to 70 individuals to conduct <em>S. sonnei</em> infection studies with clinical monitoring, including monitoring for safety, detection of bacterial shedding in stool, and sampling for measures of immunity and non-immunological parameters. In addition, we will comprehensively characterize immunity and identify potential immunological targets in various laboratory assays. Once established, the model will accelerate <em>Shigella</em> vaccine development by facilitating the early selection of the most promising vaccines for more extensive testing in LMICs.</address>\n<p>\n  </p>\n
      • study_title<p>\n Safety and feasibility of a <em>Shigella sonnei</em> 53G controlled human infection model in Kenyan adults: a dose finding and dose verification study</p>\n
      • laymans_summary<p>\n <strong>What is the problem/background?</strong></p>\n<p>\n Diarrhoea caused by the bacteria <em>Shigella</em> is a major public health problem. <em>Shigella</em> is the leading cause of moderate to severe diarrhoea in infants and children in low- and middle-income countries (LMICs) with approximately seventy-five million episodes of diarrhoea occurring annually mainly over the child’s first three years of life. There are 4 main different types of <em>Shigella</em> and one of these, <em>Shigella sonnei</em>, has been found to be a common cause of diarrhoea in Kenya. There are no vaccines available against the disease; however, a number are currently in development and being tested in clinical trials including in trials being conducted in Kenya. There is an urgent need to accelerate the development of these vaccines especially in the advent of resistance to drugs used to treat the disease. Thus, human infection studies (HISs) are needed to test the usefulness of candidate vaccines so that vaccines showing evidence of efficacy can then be prioritised for testing in Phase 2/3 clinical trials in the target age population. Furthermore, there is need to study how the humans respond against to infection and the association between these immune responses with protection may help better understand resistance and/or susceptibility, including characterizing and identifying potential targets for second- or third-generation vaccines. Human infection studies for <em>Shigella</em> have been an important tool in the advancing of the understanding of the disease, how immunity develops, and efficacy of interventions such as vaccines. These, however, have largely been undertaken in individuals not exposed to infection. Human infection studies have been undertaken using <em>Shigella sonnei</em> 53G strain in the USA and Thailand. The expansion of the <em>Shigella</em> HISs to areas where infection commonly occurs, like Kenya, will help address the need to facilitate greater use of the model as a tool to accelerate <em>Shigella</em> vaccine development. </p>\n<p>\n <strong>What questions are we trying to answer?</strong></p>\n<p>\n We wish to understand:</p>\n<ul>\n <li>\n Human and bacterial factors that determine how vulnerability to and recovery from disease develops.</li>\n <li>\n What dose of bacteria is required to reliably cause disease in ≥60% of the volunteers.</li>\n <li>\n How immunity develops in individuals who have past exposure to <em>Shigella sonnei</em>.</li>\n</ul>\n<p>\n <strong>Where is the study taking place, how many people does it involve, and how are they selected? </strong></p>\n<p>\n The study will take place in Kilifi, Kenya. Kilifi County (Kilifi North, Kilifi Town, Kilifi South, and Mtwapa) will be where volunteers will be recruited and undergo the infection phase of the study. The study will involve the recruitment and screening of adults (18-45 years of age, up to 70 volunteers are required) from Kilifi County to determine eligibility for participation and past exposure to the strain of <em>Shigella</em> used for infection. This will be done after a programme of sensitisation and information giving about the study to local community leaders, as well local regulatory and ethical boards. The study will be conducted in two phases (A and B) where volunteers will be enrolled as follows:</p>\n<p style=\"margin-left:.5in;\">\n 1. Phase A (N = up to 40 volunteers) dose-finding: to determine the dose of <em>Shigella</em> <em>sonnei</em> 53G bacteria that will cause infection and result in diarrhoea in at least 60% of the volunteers. Volunteers in Phase A will be enrolled in successive cohorts each with N = 10 volunteers receiving a varying dose of <em>Shigella</em> <em>sonnei</em> 53G bacteria.</p>\n<p style=\"margin-left:.5in;\">\n 2. Phase B (N = 30 volunteers dose verification: further validation of the disease rate assessing infectivity of the dose in Phase A found to give rise to diarrhoea in ≥60% of the volunteers. Volunteers in Phase B will be enrolled into two successive cohorts with N = 15 volunteers in each cohort receiving the dose of bacteria found to reliably cause diarrhoea in ≥60% of volunteers.</p>\n<p>\n For each of these phases, eligibility for enrolment will be based on the health status and level of past exposure to<em> Shigella sonnei </em>(determined by history or serology). To determine these, a clinical assessment and laboratory tests will be performed with blood, saliva, stool, and urine samples taken at the point of screening for each individual volunteer.</p>\n<p>\n <strong>What does the study involve for those who are in it?</strong></p>\n<p>\n All volunteers will attend a screening visit to determine if they are eligible based on review of medical history, a clinical assessment including to check the functioning of the heart, and laboratory tests. For screening, a blood sample of 76 mL will be collected in addition to urine, saliva, and stool samples. For enrolment, volunteers with no exclusionary clinical disease and medical history will be considered and will be screened for past exposure to <em>Shigella</em>. Those that meet the eligibility criteria after screening (there will be screening events for each cohort of volunteers enrolled) will be asked to be part of the challenge phase of the study. In the infection phase, volunteers will be enrolled into Phase A or into Phase B of the study for <em>Shigella</em> infection and will stay at the in-patient challenge facility located within close proximity to KEMRI CGMRC in Kilifi County where they will remain for about 14 days as in-patients. Phase A will happen before Phase B.</p>\n<p>\n Volunteers will be asked to stay at the facility starting five days before infection (to undertake health checks to be sure they are well). During the first 5 days, a COVID-19 test will be performed. In addition, a blood sample will be taken to test for presence of antibiotics that might have impact on establishment of infection. If a volunteer is found to be infected with COVID-19 and/or have antibiotics in their blood, the volunteer will be discharged from the facility before receiving the <em>Shigella</em> germ. On the sixth day, all volunteers will be given a dose of the <em>Shigella</em> germ. After infection, volunteers will be checked regularly by the study doctors and nurses. Five days after the challenge (study day 6), all volunteers will be given a 3-day course of antibiotics to clear the <em>Shigella</em> from their body. After completion of the antibiotics and having 2 stool cultures showing the <em>Shigella</em> is out of their body, volunteers will be able to return home. If the study doctor thinks it is necessary, antibiotics may be started before day 6. The inpatient period will last approximately 14 days. To set up the human infection model we must first reliably induce an infection which will result in disease in ≥60% of the volunteers. We will:</p>\n<p>\n 1. For Phase A: Healthy volunteers, 18–45 years old, will be enrolled into at least one of three cohorts to be given different doses of <em>Shigella</em> <em>sonnei</em> 53G bacteria in suspension to drink. During this part of the study, we want to find out the dose of 53G needed to cause an infection in about 6 of every 10 people. As mentioned before, the study will occur at the challenge in-patient facility within proximity of KEMRI CGMRC in Kilifi County where volunteers will remain for about 14 days. All volunteers will be treated with an antibiotic if they meet criteria (early treatment) or on day 6 after drinking the bacterial suspension. If the study doctor thinks it is important for the health of the volunteer, antibiotics may be started before day 6. Volunteers will be monitored until they have cleared the infection (i.e., no <em>Shigella</em> bacteria being detected in two consecutive negative stool samples with resolution of symptoms). It is likely that some volunteers might require treatment before day 6 based on their clinical presentation (see section 6.1.6.5).</p>\n<p>\n 2. For Phase B: Based on results from Phase A, volunteers will be given the dose of 53G found to cause infection in about 6 of 10 recipients. The rest of Phase B will be the same as described above for Phase A. All volunteers will be treated with an antibiotic on day 6 after infection and will be monitored until they have cleared the infection (i.e., no <em>Shigella</em> bacteria being detected in stool based on two stools with consecutive negative results and resolved symptoms). It is likely that some volunteers might require treatment before day 6 based on their clinical presentation.</p>\n<p>\n During the first 5 days at the in-patient facility, volunteers will be checked to be sure they are well. During this time, COVID-19 and antibiotic testing will be performed. If a volunteer is found to be infected with COVID-19, i.e., found to have detectable virus, the volunteer will be referred for management according to the guidelines at time of testing and discharged from the in-patient facility before receiving the <em>Shigella</em> germ. Five days before infection, all volunteers eligible for enrolment (both Phases A and B) will be invited to the inpatient facility for COVID-19 testing and enrolled for infection after a confirmed negative test result. Any volunteers who are found to be positive will be referred for management based on the prevailing guidelines and their participation in the study will be discontinued.</p>\n<p>\n Multiple samples (blood, saliva, stool, and urine) will be taken for those enrolled for admission (both Phase A and B). For both phases, blood samples will be drawn as follows: five days before challenge (up to 9 mL); a day before challenge (71 mL); days one, two, and three (9 mL each day); day four (49 mL); day five (5 mL); day six (59 mL); day seven (5 mL); day eight (59 mL); day nine (5 mL); day fifteen (29 mL); day twenty-nine (49 mL); day fifty-seven (44 mL); and then at 6 months (day 181) and 12 months (day 366) (40 mL and 10 mL each time point, respectively). In addition, stool and saliva samples will be collected at various time points during the study. For the entire duration of the study (12-14 months), up to a total of 544 mL of blood per volunteer will be drawn for both Phase A and Phase B. The total volume of blood collected in the study is within the limits of the volume taken about the same as during a single unit of blood donation. In addition to blood sampling, clinical assessments will be repeated a day before infection, including collection of a urine sample. Observed antibiotic treatment for shigellosis will be given on day 6, or earlier if the participant meets early treatment criteria.</p>\n<p>\n During the in-patient period, if a volunteer develops signs and symptoms of COVID-19, samples will be taken for testing and if found to be positive (by PCR testing), they will be isolated and symptomatic management for coronavirus disease administered. At the same time, the volunteer will be treated with antibiotics against shigellosis as outlined in this protocol, after which he/she will exit the inpatient phase of the study (only after two stools with consecutive negative stool results and resolved symptoms) and be referred for management or managed based on the COVID-19 guidelines prevailing at the time of diagnosis. For infection control, volunteers will be released only after clearance of the <em>S.</em> <em>sonnei</em> 53G in their stool as evidenced by two negative stool culture results.</p>\n<p>\n <strong>What are the benefits and risks/costs of the study for those involved?  </strong></p>\n<p>\n Human infection studies with <em>Shigella</em> have been conducted in healthy adults in the United States and Thailand and have been proven safe in these individuals. The risks relate to the development of shigellosis which is the primary objective of the study. Illness caused by <em>Shigella </em>ranges from mild (watery diarrhoea being the main symptom) to severe (fever and abdominal pain with frequent bloody stools containing mucus). Volunteers may complain of nausea, vomiting, headache, muscle and/or joint aches, and other symptoms associated with the disease. Symptoms typically are self-resolving in 5-7 days. However, administration of an effective antibiotic will significantly reduce, or eliminate, symptoms within 24 hours of initiation. There is potential risk of developing redness and swelling in various joints in the body, typically 1 to 3 weeks after the onset of diarrhoea. This risk is higher in persons with a particular genetic marker and therefore for this study, potential volunteers who are positive for this genetic marker will be excluded from participation. There is the possibility of increased risk of developing an intestinal disorder causing pain in the stomach, wind, diarrhoea, and constipation. There is the risk of pain, bruising, or infection at the site of venipuncture. There might be risks relating to the possibility of developing an allergic reaction or other side effects due to administration of the antibiotic treatment. There is also a risk of the study staff acquiring the infection from volunteers who will be administered the <em>S. sonnei</em> 53G strain. Therefore, proper personal protective equipment will be worn by staff, and good personal hygiene such as frequent hand washing will be followed by staff and volunteers.</p>\n<p>\n Volunteers are required to be residents in the inpatient unit for safety monitoring and to reduce the risk of spreading the infection. This is a considerable cost to the volunteers on their time but is a requirement for the study to be successful. There are no direct benefits to individuals participating in this study other than gaining information about their health. There might be a perception of benefit from clinical assessment and laboratory screening. However, a successful outcome of the study could lead to the development of a model that will allow easier and more reproducible evaluation of preventive and therapeutic measures against disease due to <em>S. sonnei</em>. Despite there being no direct benefits to the study volunteers, all volunteers will have their transport costs reimbursed (a range between Ksh200 and Ksh1,000) and will be compensated for all out-of-pocket expenses for each study visit during the entire duration of the study (at a rate of Ksh500 for each clinic visit and at a rate of Ksh2,000 per overnight stay).</p>\n<p>\n <strong>How will the study benefit society?  </strong></p>\n<p>\n This work is necessary for enhancing our understanding of how <em>Shigella</em> infection develops, the type of immunity involved, and the establishment of a model to test interventions such as vaccines in a population that has a high burden of infection with this bacterium and the resulting morbidity and mortality associated with both the acute and more long-term aspects of this disease, which would most benefit from a subsequent vaccine. The successful application of such interventions will benefit society by reducing diarrhoea attributed to <em>S. sonnei</em>, a major cause of illness, death, and impediment to national development. The establishment of this human infection model in Kenya provides a way of studying the disease in a very detailed way that is not possible in natural infections. In addition, the establishment of this model in Kenya will ultimately provide a pathway to support efforts to accelerate the efficacy testing of the most promising <em>Shigella </em>vaccine candidates, particularly providing an option for testing these vaccines against important types that lack the field incidence to be assessed in Phase 3 trials. </p>\n<p>\n <strong>When does the study start and finish?</strong></p>\n<p>\n The study will start upon receipt of ethical and regulatory clearance and activation by the study Sponsor. The duration of volunteer participation is 12-14 months from screening to final follow-up. Data collection, analysis, and write-up will take place over three years.</p>\n<p>\n  </p>\n<p>\n  </p>\n
      • short_titleShigella 53G study in Kenya
      • protocol_noECCT/23/04/02
      • version_no1.5
      • date_of_protocol28-03-2024
      • study_drugShigella sonnei 53G Challenge
      • disease_conditionShigellosis
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressCGMRCCSC@kemri-wellcome.org
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      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantStellamaris Akinyi
      • declaration_date120-08-2024
      • declaration_principal_investigatorMelissa Kapulu Principal Investigator
      • declaration_date220-08-2024
      • placebo_presentNo
      • study_objectives<p>\n <strong>Primary Objectives</strong></p>\n<p>\n (a) To determine the safety of increasing doses of lyophilised <em>S. sonnei</em> 53G in Kenyan adults.</p>\n<p>\n (b) To identify a safe dose of lyophilised <em>S. sonnei</em> 53G that consistently yields a shigellosis attack rate of ≥60% in Kenyan adults</p>\n<p>\n <strong>Secondary Objectives</strong></p>\n<p>\n (a) To determine effects of lyophilized <em>S. sonnei</em> 53G on stool output and clinical symptoms.</p>\n<p>\n (b) To estimate qualitative and quantitative faecal shedding patterns of the <em>S. sonnei</em> 53G challenge strain following experimental infection.</p>\n<p>\n (c) To measure mucosal and systemic immune responses to O antigen (O-Ag) on the lipopolysaccharide (LPS) “O” LPS, and invasion protein antigens IpaB and IpaC (both IgA and IgG) following challenge with 53G.</p>\n<p>\n <strong>Exploratory objectives </strong></p>\n<p>\n (a) To undertake exploratory systems biology, microbiome, and other omics-based analyses (including proteomics using antigen arrays and transcriptomics) and their association with clinical outcomes and/or levels of pre-existing immunity to identify potentially protective antigens and immune response profiles in individuals protected from shigellosis.</p>\n<p>\n (b) To identify inflammatory markers and other markers of innate immunity (i.e., anti-microbial peptides and defensins) associated with pre-existing immune responses and outcomes following challenge.</p>\n<p>\n (c) To evaluate serum bactericidal antibody (SBA) titers against <em>S. sonnei</em> 53G at baseline and following challenge and determine the association between baseline titers and outcomes following challenge.</p>\n<p>\n (d) To determine the proportion of seroconversions (≥4-fold rise over baseline) to key <em>Shigella</em> “O” LPS and Ipa antigens by comparing titers at baseline compared to those at post-infection days 8, 15 or 366.</p>\n<p>\n  </p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n To be eligible to participate, each volunteer must fulfill all of the following criteria:</p>\n<p>\n 1. Healthy adults between 18 and 45 years of age (inclusive) Kilifi County residents.</p>\n<p>\n 2. Able and willing (in the Investigator’s opinion) to comply with all study requirements.</p>\n<p>\n 3. Provide informed consent.</p>\n<p>\n 4. Demonstrate comprehension of the protocol procedures and knowledge of study by passing a test of understanding (pass grade 100%).</p>\n<p>\n 5. Use of effective method of contraception for the entire duration of study (prior to study start and up to study completion) (women only). Female volunteers will be asked to provide evidence of their method of contraception for the study team to verify. Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly, in accordance with the product label. Examples of these include: combined oral contraceptives; injectable progestogen; implants of etenogestrel or levonorgestrel; intrauterine device or intrauterine system; male partner sterilisation at least 6 months prior to the female volunteer’s entry into the study, and the relationship is monogamous; male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository); and male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository).</p>\n<p>\n 6. Willingness to participate for an inpatient stay lasting approximately 14 days or longer and an outpatient follow-up lasting about 12 months from challenge.</p>\n<p>\n 7. Available for all planned follow-up visits.</p>\n<p>\n  </p>\n
      • principal_exclusion_criteria<p>\n Any of the following constitutes exclusion criterion:</p>\n<p>\n 1. Presence of a significant medical condition (e.g., psychiatric conditions, alcohol or illicit drug abuse/dependency, or gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis or gastroesophageal reflux disease, inflammatory bowel disease), or other laboratory abnormalities which in the opinion of the investigator precludes participation in the study.</p>\n<p>\n 2. Known immunosuppressive illness for example those with cancer, on immunosuppressive therapy, HIV etc.</p>\n<p>\n 3. Positive serology results for HIV, HBsAg, or HCV antibodies.</p>\n<p>\n 4. Evidence of inflammatory arthritis on exam and/or HLA-B27 positive.</p>\n<p>\n 5. Family history of inflammatory arthritis.</p>\n<p>\n 6. Clinically significant abnormalities in screening lab haematology or serum chemistry, as determined by PI or PI in consultation with the research monitor and Sponsor.</p>\n<p>\n 7. Known allergies to fluoroquinolones, β-lactams or trimethoprim-sulfamethoxazole (any of the three are exclusionary).</p>\n<p>\n 8. Fewer than 3 stools per week or more than 3 stools per day as the usual frequency.</p>\n<p>\n 9. History of diarrhoea in the 2 weeks prior to planned inpatient phase.</p>\n<p>\n 10. Use of antibiotics during the 7 days before receiving the challenge inoculum dosing.</p>\n<p>\n 11. Use of prescription and/or OTC medications that contain imodium, acetaminophen, aspirin, ibuprofen, and/or other non-steroidal anti-inflammatory drugs, during the 48 hours prior to investigational product administration.</p>\n<p>\n 12. Confirmed PCR positive for SARS-COV-2 before challenge i.e., Day -5 or -3.</p>\n<p>\n 13. Use of any medication known to affect the immune function [e.g., oral steroids, parenteral steroids, or high-dose inhaled steroids (>800μg/day of beclomethasone dipropionate or equivalent and others); nasal and topical steroids are allowed] within 30 days preceding receipt of the challenge inoculum or planned use during the active study period.</p>\n<p>\n 14. Serologic evidence of prior <em>S. sonnei</em> infection as determined by ELISA.</p>\n<p>\n 15. A chronic disease (such as hypertension, diabetes, hyperlipidemia, or anxiety/depression) for which doses of prescription medications are not stable for at least the past 3 months.</p>\n<p>\n 16. Have known immunocompromised household contacts for example those with cancer, on immunosuppressive therapy, HIV etc.</p>\n<p>\n 17. A clinically significant abnormality on physical examination, including a systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, or a resting pulse >100 beats/min or <55 beats/min (<50 beats/min for conditioned athletes).</p>\n<p>\n 18. Pregnant, nursing, or planning to become pregnant within 29 days of receipt of the study product.</p>\n<p>\n 19. In the 4 weeks following challenge, volunteer will be living with or having daily contact with elderly persons aged 70 years or more, diapered individuals, persons with disabilities, children <2 years old, a woman known to be pregnant or nursing, or anyone with diminished immunity. This includes contact at work, home, school, day-care, nursing homes, or similar places.</p>\n<p>\n 20. Work in a health care setting, day care center, or as a food handler in the 4 weeks following the challenge with <em>S. sonnei</em>.</p>\n<p>\n 21. Use of any investigational drug or any investigational vaccine within 60 days preceding challenge, or planned use during the 6 months after receipt of the study agent.</p>\n<p>\n 22. Have received a licensed, live vaccine within 28 days or a licensed inactivated vaccine within 14 days of receiving the challenge inoculum.</p>\n<p>\n 23. Inability to comply with inpatient rules and regulations.</p>\n<p>\n 24. Has any other condition that, in the opinion of the Investigator, would jeopardize the safety or rights of a volunteer (e.g., infection with another detected pathogen) or would render the volunteer unable to comply with the protocol.</p>\n<p>\n 25. Received blood or blood products within the past six months.</p>\n<p>\n In addition to the exclusion criteria above, efforts will be made to prioritize volunteers with low levels of antibodies to the challenge organism. Because the level of antibodies to the challenge strain are currently unknown in this population, ongoing testing prior to volunteer enrollment will be utilized to define an algorithm for volunteer selection. This process will be defined in the SOP prior to volunteer enrolment.</p>\n<p>\n  </p>\n
      • primary_end_points<p>\n 1. The primary endpoint is safety of volunteers at each evaluated dose level.</p>\n<ul>\n <li>\n Occurrence and severity of solicited adverse events (AEs) through 11 days post-challenge.</li>\n <li>\n Occurrence, severity, and relatedness of unsolicited AEs through 11 days post-challenge.</li>\n <li>\n Occurrence, severity, and relatedness of serious adverse events (SAEs) throughout the entire study.</li>\n <li>\n Occurrence of abnormal clinical laboratory values within 11 days post-challenge.</li>\n <li>\n Percent of volunteers with nausea, vomiting, anorexia, abdominal pain/cramps rated as moderate to severe.</li>\n</ul>\n<p>\n The severity of these will be graded based on the definitions outlined in the protocol.</p>\n<p>\n 2. Confirmation of the dose with an acceptable safety profile as determined by the PSRT and DSMB that gives an attack rate of ≥60% of shigellosis in Kenyan adults.</p>\n<p>\n  </p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others1
      • scope_others_specifyDose finding and verification
      • trial_human_pharmacology1
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyHuman challenge study with deliberate infection of healthy volunteers
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p>\n Medical officer - 3<br />\n Clinical officer - 3<br />\n Nurses - 3<br />\n Fieldworkers - 5<br />\n Research and Assistant Research Officers and Lab technicians - 5<br />\n Study Coordinator - 1<br />\n Pharmacisit - 1<br />\n Data Manager - 1<br />\n Data Clerk - 3<br />\n The inpatient facility is already staffed with 4 clincians and locum 20 nurses.<br />\n All staff are trained in basic life support and resuscitation facilitaties are available.</p>\n
      • other_details_explanation<p>\n Not applicable.</p>\n
      • other_details_regulatory_notapproved<p>\n Submission is only to PPB.</p>\n
      • other_details_regulatory_approved<p>\n Not applicable.</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted<p>\n Not applicable.</p>\n
      • estimated_duration3 years
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKEMRI-Wellcome Trust Research Programme (KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), Kilifi, Kenya.
      • single_site_physical_addressKEMRI-Wellcome Trust Research Programme, Off Bofa Road, Kilifi County Hospital, Kilifi, Keny
      • single_site_contact_personMelissa Kapulu
      • single_site_telephone+254 709 983463
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_site70
      • total_participants_worldwide70
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsNo
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMelissa
      • investigator1_middle_name
      • investigator1_family_nameKapulu
      • investigator1_qualificationBSc MSc PhD
      • investigator1_professional_addressKEMRI-Wellcome Trust Research Programme, P. O. Box 230, Kilifi, Kenya 80108
      • investigator1_telephone+254 709 983463
      • investigator1_emailmkapulu@kemri-wellcome.org
      • organisations_transferred_No
      • number_participants70
      • notification
      • approval_date21-08-2024
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted14-04-2023
      • is_child0
      • unsubmitted1
      • initial_date_submitted14-04-2023
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed. The Re-inspection has recommended the site (Kilifi county referral Hospital) for use in the study
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-02-28 13:21:28
      • created2023-03-30 08:56:23
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id917
        • application_id1245
        • given_nameMelissa
        • middle_name
        • family_nameKapulu
        • qualificationBSc MSc PhD
        • professional_addressKEMRI-Wellcome Trust Research Programme, P. O. Box 230, Kilifi, Kenya 80108
        • telephone+254 709 983463
        • emailmkapulu@kemri-wellcome.org
        • created2023-03-30 11:29:40
        • modified2024-08-20 14:34:06
      • 1(array)
        • id918
        • application_id1245
        • given_nameFredrick
        • middle_name
        • family_nameSawe
        • qualificationMBChB M.Med
        • professional_addressP.O. BOX 1357 20200 KERICHO
        • telephone+254 703 247902
        • emailFredrick.Sawe@usamru-k.org
        • created2023-03-30 11:51:29
        • modified2024-08-20 14:34:06
    • SiteDetail(array)
      • 0(array)
        • id1467
        • application_id1245
        • county_id(null)
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        • created2023-03-30 11:29:40
        • modified2024-08-20 14:34:06
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id654
        • application_id1245
        • sponsorUniversity of Oxford
        • sponsor_typeResearch Institution
        • contact_personProf Philip Bejon
        • addressUniversity Offices, Wellington Square, Oxford, OX1 2JD, UK
        • telephone_number+44 1865 270000
        • fax_number
        • cell_number+44 1865 270000
        • email_addresskwtrpsponsor@kemri-wellcome.org
        • created2023-03-30 11:29:40
        • modified2024-08-20 14:34:06
  • 3(array)
    • Application(array)
      • id1111
      • user_id32
      • trial_status_id7
      • abstract_of_study<div>\n Title:<span style=\"white-space:pre\"> </span>Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against Plasmodium falciparum, in an Age De-Escalation, Dose-Escalation Trial and a Randomized, Placebo-Controlled, Double-Blind Trial of Children in Western Kenya</div>\n<div>\n Study Description:<span style=\"white-space:pre\"> </span>A two-part, phase 2 trial evaluating the safety and tolerability of one-time subcutaneous (SC) administration of monoclonal antibody (MAb) L9LS in healthy Kenyan children aged 5 months to 10 years, as well as the protective efficacy of one or two doses of L9LS against naturally occurring Plasmodium falciparum (Pf) infection among Kenyan children aged 5 to 59 months at enrollment, in a setting of perennial high transmission. The primary study hypotheses are that L9LS will be safe and will produce protection against malaria infection. Before study agent administration, all subjects will be given dihydro-artemisinin-piperaquine (DP) to clear any preexisting Pf blood-stage infection.</div>\n<div>\n  </div>\n<div>\n Part 1: Age de-escalation and dose-escalation study</div>\n<div>\n In a stepwise fashion, children aged 5-10 years will receive 5 mg/kg of L9LS or placebo and be followed for 3 months to assess tolerability and safety. If acceptable tolerability and safety profiles are met at 1-week post-injection, we will administer the 5-mg/kg dose of L9LS or placebo to children aged 5-59 months while enrolling another cohort of children aged 5-10 years at a dose of 10 mg/kg of L9LS or placebo. If after 1 week, the 10-mg/kg dose is found to be safe in children aged 5-10 years and the 5-mg/kg dose is found to be safe in children aged 5-59 months, we will then administer a 20 mg/kg dose of L9LS or placebo to children aged 5-10 years and a 10-mg/kg dose of L9LS or placebo to children aged 5-59 months. Finally, if these doses are found safe after 1 week, we will administer a 20-mg/kg dose of L9LS or placebo to children aged 5-59 months. Should tolerability and safety of all doses be acceptable in children aged 5-59 months, we will move to part 2 of the trial. Dosing in part 1 of the study will be weight-based and all doses will be administered SC in a double-blinded fashion. We will enroll 12 participants in each age-dose group in a 3:1 ratio of L9LS to placebo, and all participants will be followed for a total of 3 months.</div>\n<div>\n  </div>\n<div>\n Part 2: Efficacy study</div>\n<div>\n Children 5-59 months of age will be randomized to receive a 10-19 mg/kg dose of L9LS or placebo by SC administration. There will be two L9LS cohorts, one 5-17 months of age and another 18-59 months of age, which will constitute one L9LS arm. A placebo arm will be composed of children 5–59 months of age. They will be followed over 12 months with monthly blood smear microscopy and polymerase chain reaction (PCR) and twice-monthly symptomatology and care-seeking behavior questionnaires. Dosing will be based on three weight bands; all doses will be administered SC with fixed doses of 75 mg L9LS or 150 mg L9LS or a combination of the two (225 mg L9LS), resulting in a range of 10-19 mg/kg in a double-blinded fashion. Blood will be drawn to assess antibody titers at baseline, and at three additional time points over 12 months to establish pharmacokinetics (PK). Participants in the L9LS arm will be randomized 1:1 at baseline to receive either a second L9LS injection or a placebo injection to evaluate the additional efficacy of a second dose administered 6 months after the first dose. (Those in the placebo arm will receive a second injection of placebo.) Participants will be followed for an additional 6 months after the second injection with monthly blood smear microscopy and PCR, and a blood draw at month 11 to assess L9LS PK.</div>\n<div>\n Objectives:</div>\n<div>\n Primary Objectives:</div>\n<div>\n Part 1:</div>\n<div>\n 1.<span style=\"white-space:pre\"> </span>Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children.</div>\n<div>\n Part 2:</div>\n<div>\n 2.<span style=\"white-space:pre\"> </span>Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-19 mg/kg by SC administration to healthy Kenyan children.</div>\n<div>\n 3.<span style=\"white-space:pre\"> </span>Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-19 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo.</div>\n<div>\n  </div>\n<div>\n Secondary Objectives:</div>\n<div>\n 1.<span style=\"white-space:pre\"> </span>To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo.</div>\n<div>\n 2.<span style=\"white-space:pre\"> </span>To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo.</div>\n<div>\n 3.<span style=\"white-space:pre\"> </span>To evaluate the efficacy of L9LS at 10-19 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo.</div>\n<div>\n 4.<span style=\"white-space:pre\"> </span>To assess protection of L9LS at 10-19 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo.</div>\n<div>\n 5.<span style=\"white-space:pre\"> </span>To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age.</div>\n<div>\n 6.<span style=\"white-space:pre\"> </span>To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age.</div>\n<div>\n 7.<span style=\"white-space:pre\"> </span>To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-19 mg/kg (part 2) in healthy Kenyan children, and</div>\n<div>\n a.<span style=\"white-space:pre\"> </span>To correlate L9LS serum concentration with Pf infection risk.</div>\n<div>\n b.<span style=\"white-space:pre\"> </span>To correlate L9LS serum concentration with clinical malaria risk.</div>\n<div>\n Endpoints:<span style=\"white-space:pre\"> </span>Primary Endpoints:</div>\n<div>\n 1.<span style=\"white-space:pre\"> </span>Part 1 and Part 2: Incidence and severity of local and systemic adverse events (AEs) occurring within 7 days after the administration of L9LS, and incidence of serious adverse events (SAEs) throughout the study period.</div>\n<div>\n 2.<span style=\"white-space:pre\"> </span>Part 2: Pf blood-stage infection as detected by microscopic examination of thick blood smear for 52 weeks after administration of L9LS or placebo.</div>\n<div>\n  </div>\n<div>\n Secondary Endpoints:</div>\n<div>\n Data from one or both parts of this study will be used to assess the following endpoints:</div>\n<div>\n 1.<span style=\"white-space:pre\"> </span>Pf blood-stage infection as detected by microscopic examination of thick blood smear for 24 weeks after administration of L9LS or placebo.</div>\n<div>\n 2.<span style=\"white-space:pre\"> </span>Pf blood-stage infection as detected by RT-PCR for 24 and 52 weeks after administration of L9LS or placebo.</div>\n<div>\n 3.<span style=\"white-space:pre\"> </span>Incidence of clinical malaria (definition 1, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.</div>\n<div>\n 4.<span style=\"white-space:pre\"> </span>Incidence of clinical malaria (definition 2, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.</div>\n<div>\n 5.<span style=\"white-space:pre\"> </span>Measurement of L9LS in sera of recipients (parts 1 and 2).</div>\n<div>\n 6.<span style=\"white-space:pre\"> </span>PK analysis of L9LS and the association of L9LS concentration with Pf infection risk.</div>\n<div>\n 7.<span style=\"white-space:pre\"> </span>PK analysis of L9LS and the association of L9LS concentration with clinical malaria risk.</div>\n<div>\n  </div>\n<div>\n Study Population:<span style=\"white-space:pre\"> </span>We will enroll a total of 396 healthy Kenyan children, including 72 ages 5 months to 10 years residing in western Kenya for part 1 and 324 ages 5-59 months for part 2.</div>\n<div>\n  </div>\n
      • study_title<p>\n Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against <em>Plasmodium falciparum</em>, in an Age De-Escalation, Dose-Escalation Trial and a Randomized, Placebo-Controlled, Double-Blind Trial of Children in Western Kenya</p>\n
      • laymans_summary<div>\n Malaria is a disease that affects many people in the world, more so in sub-Saharan Africa. It is caused by parasites carried by mosquitoes. When the mosquitoes bite people, the parasites can pass into their blood and cause illness, which if not treated in a timely manner or sufficiently, can cause severe illness or even death. In effect, despite there being medicines to cure malaria, it is still responsible for a huge number of admissions and deaths, especially in Africa. This informs the need to come up with new ways to reduce the impact of malaria, for example, through preventing people from getting malaria in the first place. </div>\n<div>\n  </div>\n<div>\n This is a research study to test an experimental drug, called L9LS, for malaria. L9LS is a type of drug called a monoclonal antibody. Antibodies are natural products made by the human body to fight infection by blocking germs such as bacteria and parasites. Monoclonal means that all the antibodies in the drug are exactly the same. The study drug stays in the blood for several months and blocks the parasite that causes malaria. We hope that, if enough of the drug is in the blood, it will prevent people from getting malaria.</div>\n<div>\n  </div>\n<div>\n The study aims to find out how safe the drug is and whether it prevents malaria and if so, to what extent. This study will be conducted in two parts. In the first part, involving 72 participants, the study will investigate how safe and well tolerated three different increasing doses of the study drug are by administering each dose to older children first (5-10 years of age) then to younger children (5-59 months of age) 1 week after each different dose, if it is well tolerated and safe in the older age group. The study will proceed to part 2 if the doses are safe and well tolerated in the younger age group, as determined by a data safety and monitoring board. The second part of the study will investigate whether the drug prevents malaria, and if so, to what extent. It will enroll an equal number of children aged between 5-17 months and those aged 18-59 months, totalling to about 324 participants. Each age category will further have 3 groups of children assigned by chance to each group. The first group will receive two doses of the study drug 6 months apart, the 2nd group will receive the study drug then placebo (saltwater/an inactive substance similar to study drug) 6 months after, and the 3rd group will receive two doses of the placebo 6 months part. </div>\n<div>\n Other objectives which will be explored by the study include comparing the study drug level with the possibility of getting a malaria infection or detecting malaria parasites in the blood.</div>\n<div>\n  </div>\n<div>\n The study will take place at Siaya County Referral Hospital and Kogelo Dispensary, both in Siaya County, western Kenya. The study duration will be approximately 24 months, with a participant in Part 1 of the study taking 4-5 months and a participant in Part 2 of the study taking 13-14 months.</div>\n<div>\n  </div>\n<div>\n The study procedures in Part 1 will entail assessing participant eligibility, getting consent and enrollment into the study. On enrollment, participants will receive a standard dose of antimalarial  followed by the study drug or placebo after 2 weeks. They will then have another 10 study visits within a 3 months period to monitor various safety measures. The study procedures in Part 2 will entail assessing participant eligibility, getting consent and enrollment into the study. On enrollment, participants will receive a standard dose of antimalarial followed by the study drug or placebo after 2 weeks. They will then have a study visit every month up to end of month 6 when they will receive the 2nd dose of either the study drug or placebo. Other follow up visits will be conducted monthly until end of 12 months from the date of initial study drug or placebo dose. These follow-up visits will assess both safety and efficacy measures.</div>\n<div>\n  </div>\n<div>\n The study will provide information on the safety and usefulness of L9LS as a therapy used in </div>\n<div>\n the prevention of malaria.</div>\n<div>\n  </div>\n
      • short_titleAnti-malaria MAb in Kenyan chi
      • protocol_noECCT/22/05/03
      • version_no2.0
      • date_of_protocol28-03-2022
      • study_drugL9LS
      • disease_conditionMalaria
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_nameL9LS
      • product_type_medical_device_name
      • comparatorNo
      • comparator_nameInactive Normal Saline
      • comparator_registeredYes
      • comparator_countriesGlobal
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresstonysangke@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantTony Sang
      • declaration_date126-05-2022
      • declaration_principal_investigatorTitus Kwambaai
      • declaration_date226-05-2022
      • placebo_presentYes
      • study_objectives<p>\n <u>Primary Objectives</u>:</p>\n<p>\n Part 1:</p>\n<ol>\n <li>\n Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children.</li>\n</ol>\n<p>\n Part 2:</p>\n<ol>\n <li value=\"2\">\n Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-19 mg/kg by SC administration to healthy Kenyan children.</li>\n <li value=\"3\">\n Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-19 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo.</li>\n</ol>\n<p style=\"margin-left:18.0pt;\">\n 1.      To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo.</p>\n<p style=\"margin-left:18.0pt;\">\n 2.      To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo.</p>\n<p style=\"margin-left:18.0pt;\">\n 3.      To evaluate the efficacy of L9LS at 10-19 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo.</p>\n<p style=\"margin-left:18.0pt;\">\n 4.      To assess protection of L9LS at 10-19 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo.</p>\n<p style=\"margin-left:18.0pt;\">\n 5.      To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age.</p>\n<p style=\"margin-left:18.0pt;\">\n 6.      To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age.</p>\n<p>\n To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-19 mg/kg (part 2) </p>\n<p style=\"margin-left:18.0pt;\">\n       in healthy Kenyan children, and</p>\n<p style=\"margin-left:54.0pt;\">\n a.       To correlate L9LS serum concentration with Pf infection risk.</p>\n<p>\n To correlate L9LS serum concentration with clinical malaria risk.</p>\n
      • principal_inclusion_criteria<p style=\"margin-left:36.0pt;\">\n 1.      Healthy children aged 5 months to 10 years (Part 1) or 5-59 months (Part 2).</p>\n<p style=\"margin-left:36.0pt;\">\n 2.      Weight ≥5 kg and weight ≤30 kg (Part 1) or weight ≥5 kg and ≤22.5 kg (Part 2)</p>\n<p style=\"margin-left:36.0pt;\">\n 3.      Hemoglobin level ≥8 g/dL.</p>\n<p style=\"margin-left:36.0pt;\">\n 4.      Height and weight Z-scores >-2.</p>\n<p style=\"margin-left:36.0pt;\">\n 5.      Living within Alego-Usonga sub-county.</p>\n<p style=\"margin-left:36.0pt;\">\n 6.      Able to participate for the duration of the trial.</p>\n<p>\n Parent and/or guardian of participant able to provide informed consent</p>\n
      • principal_exclusion_criteria<ol>\n <li>\n Known sickle cell disease.</li>\n <li>\n Taking long-term cotrimoxazole.</li>\n <li>\n Enrolled in another clinical trial.</li>\n <li>\n Received any doses of any malaria vaccine.</li>\n <li>\n Participation in part 1 of this study (for individuals being screened for enrollment into part 2)</li>\n <li>\n Age < 12 months at the time the RTS,S/AS01 vaccine is anticipated to become available in the whole of Siaya County</li>\n <li>\n Current significant medical condition (cardiac, hepatic, renal, or hematological) or evidence of any other serious underlying medical condition identified by medical history, physical examination, or laboratory examination.</li>\n <li>\n History of any other illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the subject’s participation in the protocol or compromise the scientific objectives.</li>\n <li>\n Any history of menses.</li>\n <li>\n Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the subject to understand and comply with the study protocol.</li>\n <li>\n Parental/guardian study comprehension examination score of <80% correct or per investigator discretion.</li>\n <li>\n Hemoglobin, white blood cell, absolute neutrophil, or platelet count outside the local laboratory-defined limits of normal. (Subjects may be included at the investigator’s discretion for “not clinically significant” values.)</li>\n <li>\n Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal. (Subjects may be included at the investigator’s discretion for “not clinically significant” values.)</li>\n <li>\n Infected with HIV.</li>\n <li>\n Known or documented sickle cell disease by history. (Note: Known sickle cell trait is NOT exclusionary.)</li>\n <li>\n Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies.</li>\n <li>\n Receipt of any investigational product within the past 30 days.</li>\n <li>\n Participation or planned participation in an interventional trial with an investigational product until the last required protocol visit. (Note: Past, current, or planned participation in observational studies is NOT exclusionary.)</li>\n <li>\n History of a severe allergic reaction or anaphylaxis.</li>\n <li>\n Severe asthma (defined as asthma that is unstable or required emergency care, urgent care, hospitalization, or intubation during the past 2 years, or that has required the use of oral or parenteral corticosteroids at any time during the past 2 years).</li>\n <li>\n Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren’s syndrome, or autoimmune thrombocytopenia.</li>\n <li>\n Known immunodeficiency syndrome.</li>\n <li>\n Known asplenia or functional asplenia.</li>\n <li>\n Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of day 0.</li>\n <li>\n Receipt of a live vaccine within the past 4 weeks or a killed vaccine within the past 2 weeks prior to study agent administration.</li>\n <li>\n Receipt of immunoglobulins and/or blood products within the past 6 months.</li>\n <li>\n Known allergies or contraindication to dihydroartemisinin-piperaquine.</li>\n <li>\n Clinical signs of malnutrition.</li>\n <li>\n Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of a subject participating in the trial, interfere with the evaluation of the study objectives, or render the subject unable to comply with the protocol.</li>\n <li>\n Use or known need at the time of enrolment (DP administration) for concomitant prohibited medication.  Patients taking any of the following drugs:\n <ol style=\"list-style-type:lower-alpha;\">\n <li>\n Antimicrobial agents of the following classes (systemic use only):\n <ol style=\"list-style-type:lower-roman;\">\n <li>\n Macrolides (e.g. erythromycin, clarithromycin, azithromycin, roxithromycin)</li>\n <li>\n Fluoroquinolones (e.g., levofloxacin, moxifloxacin, sparfloxacin)</li>\n <li>\n Pentamidine</li>\n </ol>\n </li>\n <li>\n Antiarrhythmic agents (e.g. amiodarone, sotalol)</li>\n <li>\n Antihistamines (e.g. promethazine)</li>\n <li>\n Antifungals (systemic): ketoconazole, fluconazole, itraconazole</li>\n <li>\n Antiretrovirals: Saquinavir</li>\n <li>\n Diuretics (e.g. hydrochlorothiazide, furosemide)</li>\n <li>\n Antipsychotics (neuroleptics): haloperidol, thioridazine</li>\n <li>\n Antidepressants: imipramin, citalopram, escitalopram</li>\n <li>\n Antiemetics: domperidone, chlorpromazine, ondansetron </li>\n </ol>\n </li>\n <li>\n Increased risk of salivary gland hypofunction (dryness of the mouth, swelling under the tongue and/or below the ear, halitosis)</li>\n</ol>\n<p>\n  </p>\n
      • primary_end_points<ol>\n <li>\n Parts 1 & 2: Incidence and severity of local and systemic AEs occurring within 7 days after the administration of L9LS, and incidence of SAEs throughout the study period.</li>\n <li>\n Part 2: Pf blood-stage infection as detected by microscopic examination of thick blood smear for 52 weeks after administration of L9LS or placebo.</li>\n</ol>\n<p>\n  </p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n <strong>Co-Principal Investigators:</strong></p>\n<p>\n Titus Kwambai, MD, PhD, Epidemiologist Centers for Disease Control and Prevention Kenya Malaria Program Phone: +254 722207281 Email: qbb5<a href=\"mailto:LSteinhardt@cdc.gov\">@cdc.gov</a></p>\n<p>\n Laura Steinhardt, PhD, MPH Malaria Branch, US CDC 1600 Clifton Rd., Atlanta, GA 30329 Phone: +1-404-718-4794 Email: <a href=\"mailto:LSteinhardt@cdc.gov\">LSteinhardt@cdc.gov</a></p>\n<p>\n Peter D. Crompton, MD, MPH, Chief, Malaria Infection Biology and Immunity Section Laboratory of Immunogenetics (LIG), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Phone: 240-383-7640 Email: <a href=\"mailto:pcrompton@niaid.nih.gov\">pcrompton@niaid.nih.gov</a></p>\n<p>\n <strong>Co-Investigators</strong></p>\n<p>\n Kevin K’Orimba, MD, MPH,KEMRI Center for Global Health Research (CGHR) P.O. Box: 1578 - 40100, Kisumu, Kenya , Phone: +254722324496, E-mail: <a href=\"mailto:korimbakevin@gmail.com\">korimbakevin@gmail.com</a>, Role(s): A, B, C, D, E, F, G</p>\n<p>\n Martina Oneko, MD ,KEMRI CGHR,P.O. Box: 1578 - 40100, Kisumu, Kenya,Phone: +254-717-747-279, Email: <a href=\"mailto:tinaoneko@gmail.com\">tinaoneko@gmail.com</a>,Role(s): A, B, C, D, E, F, G</p>\n<p>\n Simon Kariuki, PhD,KEMRI CGHR,Phone: +254 725 389 246, Email: <a href=\"mailto:skariuki1578@gmail.com\">skariuki1578@gmail.com</a>,Role(s): A, B, E, F, G</p>\n<p>\n Tony Sang, BPharm,KEMRI CGHR,P.O. Box: 1578 - 40100, Kisumu, Kenya<br />\n Phone: +254 721 246 875,Email: <a href=\"mailto:tonysangke@gmail.com\">tonysangke@gmail.com</a></p>\n<p>\n Kephas Otieno, MSc,KEMRI CGHR, P.O. Box: 1578 - 40100, Kisumu, Kenya<br />\n Phone: +254 721 405 643,Email: kotieno72@yahoo.com,Role(s):</p>\n<p>\n <strong>Trial Pharmacist</strong></p>\n<p>\n Tony Sang, BPharm,KEMRI CGHR,P.O. Box: 1578 - 40100, Kisumu, Kenya</p>\n<p>\n Phone: +254 721 246 875,Email: <a href=\"mailto:tonysangke@gmail.com\">tonysangke@gmail.com</a></p>\n<p>\n Lilian Otieno, DipPharm, BA,KEMRI Center for Global Health Research (CGHR) P.O. Box: 1578 - 40100, Kisumu, Kenya , Phone: +254723934572, Email: <a href=\"mailto:lotieno@kemricdc.org\">lotieno@kemricdc.org</a>, <a href=\"mailto:otililly@yahoo.com\" style=\"font-size: 9pt; font-family: Arial, sans-serif;\">otililly@yahoo.com</a></p>\n<p>\n <strong>Regulatory Officer</strong></p>\n<p>\n Lilian Otieno, DipPharm, BA,KEMRI Center for Global Health Research (CGHR) P.O. Box: 1578 - 40100, Kisumu, Kenya , Phone: +254723934572, Email: <a href=\"mailto:lotieno@kemricdc.org\">lotieno@kemricdc.org</a>, <a href=\"mailto:otililly@yahoo.com\" style=\"font-family: Arial, sans-serif; font-size: 9pt;\">otililly@yahoo.com</a></p>\n<p>\n <strong>Study Coordinator</strong></p>\n<p>\n Reuben Yego, BSPH,KEMRI Center for Global Health Research (CGHR) P.O. Box: 1578 - 40100, Kisumu, Kenya , Phone: +254723934572, E-mail: <a href=\"mailto:lotieno@kemricdc.org\">lotieno@kemricdc.org</a>, <a href=\"mailto:otililly@yahoo.com\" style=\"font-size: 9pt; font-family: Arial, sans-serif;\">otililly@yahoo.com</a></p>\n<p>\n  </p>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n FDA-Submission done, awaiting Approval</p>\n
      • other_details_regulatory_approved<p align=\"left\" style=\"margin-left:144pt;\">\n Bill and Melinda Gates Foundation-DAC BMGF-DAC</p>\n<p align=\"left\" style=\"margin-left:144pt;\">\n National Institute of Allergy and Infectious Diseases (NIAID)</p>\n<p align=\"left\" style=\"margin-left:144pt;\">\n LSTM-Research Ethics Committee (LSTM-REC)</p>\n
      • other_details_regulatory_rejected<p>\n NONE</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration2 years
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorsterile isotonic (0.9%) n
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites2
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_site72 for part 1 and 324 for part 2.
      • total_participants_worldwide396
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenYes
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyChildren aged 5 months to 10 years
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameTitus
      • investigator1_middle_name
      • investigator1_family_nameKwambai
      • investigator1_qualificationMD, PhD
      • investigator1_professional_addressCenters for Disease Control and Prevention Kenya Malaria Program
      • investigator1_telephone+254 722207281
      • investigator1_emailqbb5@cdc.gov
      • organisations_transferred_Yes
      • number_participants396
      • notification
      • approval_date08-08-2022
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted26-05-2022
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe Reviewer queries have been answered adequately
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2024-08-20 11:32:31
      • created2022-01-26 15:22:56
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id784
        • application_id1111
        • given_nameTitus
        • middle_name
        • family_nameKwambai
        • qualificationMD, PhD
        • professional_addressCenters for Disease Control and Prevention Kenya Malaria Program
        • telephone+254 722207281
        • emailqbb5@cdc.gov
        • created2022-01-26 15:26:17
        • modified2022-05-26 23:33:58
      • 1(array)
        • id785
        • application_id1111
        • given_nameLaura
        • middle_name
        • family_nameSteinhardt
        • qualificationPhD, MPH, Epidemiologist
        • professional_addressMalaria Branch Center for Global Health Centers for Disease Control and Prevention
        • telephone+14047184794
        • emailLSteinhardt@cdc.gov
        • created2022-01-26 15:53:08
        • modified2022-05-26 23:33:58
      • 2(array)
        • id786
        • application_id1111
        • given_nameRobert
        • middle_nameA
        • family_nameSeder
        • qualificationMD
        • professional_addressVaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), NIH
        • telephone301-594-8483
        • emailrseder@mail.nih.gov
        • created2022-01-26 15:54:33
        • modified2022-05-26 23:33:58
    • SiteDetail(array)
      • 0(array)
        • id1228
        • application_id1111
        • county_id41
        • site_nameSiaya County Referral Hospital
        • physical_addressOff Hospital Road, Siaya Township
        • contact_details0722207281
        • contact_personDr. Titus Kwambai
        • site_capacity(null)
        • misc(null)
        • created2022-01-26 15:26:17
        • modified2022-05-26 23:33:58
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 1(array)
        • id1229
        • application_id1111
        • county_id41
        • site_nameKogelo Health Center
        • physical_addressKogelo Nyang\'oma
        • contact_details0722207281
        • contact_personDr. Titus Kwambai
        • site_capacity(null)
        • misc(null)
        • created2022-01-26 16:11:18
        • modified2022-05-26 23:33:58
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
    • Sponsor(array)
      • 0(array)
        • id573
        • application_id1111
        • sponsorOffice of Clinical Research Policy and Regulatory Operations (OCRPRO), Division of Clinical Research (DCR), NIAID
        • sponsor_typeResearch Institution
        • contact_personRobert A. Seder, MD
        • addressVaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), NIH
        • telephone_number+1-301-594-8483
        • fax_number
        • cell_number+1-301-594-8483
        • email_addressrseder@mail.nih.gov
        • created2022-01-26 15:26:17
        • modified2022-05-26 23:33:58
  • 4(array)
    • Application(array)
      • id577
      • user_id613
      • trial_status_id8
      • abstract_of_study<p>\n Tuberculosis (TB) is one of the most important global health problems. According to recent estimates from the World Health Organization (WHO), 8.6 million new cases and 1.3 million deaths from TB occurred in 2012. The vast majority of TB cases and TB deaths are in developing countries. The spread of HIV has fuelled the TB epidemic, and TB is the leading cause of death among patients infected with HIV. The national case notification rate is 217/100 000, whilst in Kericho County, the rate is 246 /100 000. TB treatment takes 6 months in Kenya and this relatively long treatment is associated with relatively poor compliance and high relapse rates than if the regimen were shorter. This contributes to increase in patient morbidity and mortality, Mycobacterium tuberculosis transmission and drug resistant TB. Treatment adherence is critical in TB treatment success and a shorter regimen may improve adherence. This highlights the need to shorten further the duration of TB treatment. This study aims to evaluate the efficacy, safety and tolerability of 2 treatment regimens versus the standard drug susceptible TB treatment regimen currently used in Kenya. Male or female participants who are 12 years or older with smear positive pulmonary TB will be enrolled and randomized into either 8 weeks of Rifampicin, Isoniazid, Pyrazinamide, Ethambutol followed by 18 weeks of Rifampicin and Isoniazid or 8 weeks of Rifapentine, Isoniazid, Pyrazinamide, Ethambutol followed by 9 weeks of Rifapentine and Isoniazid or 8 weeks of Rifapentine, Isoniazid, Pyrazinamide, Moxifloxacin followed by 9 weeks of Rifapentine, Isoniazid and Moxifloxacin. The Kericho site will recruit 80-100 participants and follow them up for 18 months. If shorter TB treatment regimen is efficacious compared to current 6 month TB treatment duration, this will potentially have important public health implications by increasing TB cure rates, potentially reducing TB transmission and preventing emergency of MDR TB.</p>\n
      • study_title<p>\n Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: A randomized, open-label, controlled phase 3 clinical trial.</p>\n
      • laymans_summary<p>\n Tuberculosis (TB) is one of the most important global health problems. According to recent estimates from the World Health Organization (WHO), 8.6 million new cases and 1.3 million deaths from TB occurred in 2012. The vast majority of TB cases and TB deaths are in developing countries. The spread of HIV has fuelled the TB epidemic, and TB is the leading cause of death among patients infected with HIV. The national case notification rate is 217/100 000, whilst in Kericho County, the rate is 246 /100 000. TB treatment takes 6 months in Kenya and this relatively long treatment is associated with relatively poor compliance and high relapse rates than if the regimen were shorter. This contributes to increase in patient morbidity and mortality, Mycobacterium tuberculosis transmission and drug resistant TB. Treatment adherence is critical in TB treatment success and a shorter regimen may improve adherence. This highlights the need to shorten further the duration of TB treatment. This study aims to evaluate the efficacy, safety and tolerability of 2 treatment regimens versus the standard drug susceptible TB treatment regimen currently used in Kenya. Male or female participants who are 12 years or older with smear positive pulmonary TB will be enrolled and randomized into either 8 weeks of Rifampicin, Isoniazid, Pyrazinamide, Ethambutol followed by 18 weeks of Rifampicin and Isoniazid or 8 weeks of Rifapentine, Isoniazid, Pyrazinamide, Ethambutol followed by 9 weeks of Rifapentine and Isoniazid or 8 weeks of Rifapentine, Isoniazid, Pyrazinamide, Moxifloxacin followed by 9 weeks of Rifapentine, Isoniazid and Moxifloxacin. The Kericho site will recruit 80-100 participants and follow them up for 18 months. If shorter TB treatment regimen is efficacious compared to current 6 month TB treatment duration, this will potentially have important public health implications by increasing TB cure rates, potentially reducing TB transmission and preventing emergency of MDR TB.</p>\n
      • short_titleRifapentine-containing treatment shortening regimens for pulmonary tuberculosis:
      • protocol_noECCT/16/12/02
      • version_no2.0
      • date_of_protocol14-05-2015
      • study_drugRifapentine, Moxifloxacin, Isoniazid, Rifampicin, Pyrazinamide, Ethambutol
      • disease_conditionPulmonary Tuberculosis
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameRifapentine, Moxifloxacin, Isoniazid, Rifampicin, Pyrazinamide, Ethambutol
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressisaac.tsikhutsu@usamru-k.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries1
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
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      • declaration_applicantISAAC TSIKHUTSU, P.O. BOX 1357 KERICHO
      • declaration_date114-12-2016
      • declaration_principal_investigatorBEATRICE KORIR , P.O. BOX 1357 KERICHO
      • declaration_date214-12-2016
      • placebo_presentNo
      • study_objectives<h1>\n <strong>1.</strong><strong>OBJECTIVES</strong></h1>\n<h2>\n 1.1PRIMARY OBJECTIVE</h2>\n<p style=\"margin-left:63.35pt;\">\n 9.1.1 To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis.</p>\n<p style=\"margin-left:63.35pt;\">\n 9.1.2 To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis.</p>\n<p style=\"margin-left:63.0pt;\">\n  </p>\n<h2>\n 1.2SECONDARY OBJECTIVES</h2>\n<p style=\"margin-left:63.35pt;\">\n 9.2.1 To evaluate the safety of the investigational regimens.</p>\n<p style=\"margin-left:63.35pt;\">\n 9.2.2 To evaluate the tolerability of the investigational regimens.</p>\n<p style=\"margin-left:63.35pt;\">\n 9.2.3 To collect and assess biospecimens from consenting participants for the purpose of research on discovery and validation of TB biomarkers.</p>\n<p style=\"margin-left:63.35pt;\">\n 9.2.4 To determine the correlation of mycobacterial and clinical markers with time to culture conversion, culture status at completion of eight weeks of treatment, treatment failure, and relapse.</p>\n<p style=\"margin-left:63.35pt;\">\n 9.2.5 To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs.  The main objectives of the PK/PD study are to characterize study drug PK parameters and to determine relationships between treatment outcomes and PK parameters.</p>\n<p style=\"margin-left:63.35pt;\">\n 9.2.6 To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with TB/HIV co-Infection taking efavirenz-based combination antiretroviral therapy and TB treatment with rifapentine.</p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n Suspected pulmonary tuberculosis plus one or both of the following: a) at least one sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing, with semiquantitative result of ‘medium’ or ‘high’ and rifamycin resistance not detected</p>\n
      • principal_exclusion_criteria<p>\n Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any one or more of the following: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones. Screening, baseline, and Week 2 study visit sputum cultures all fail to grow M. tuberculosis. M. tuberculosis cultured or detected through molecular assays (Cepheid Xpert MTB/RIF or Hain MTBDRplus assays) from sputum obtained around the time of study entry is determined subsequently to be resistant to one or more of isoniazid, rifampin, or fluoroquinolones.</p>\n
      • primary_end_points<p>\n Primary Efficacy End Point: TB disease-free survival at twelve months after study treatment assignment. Primary Safety End Point: Proportion of participants with grade 3 or higher adverse events during study treatment.</p>\n
      • scope_diagnosis0
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      • scope_therapy1
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      • scope_efficacy1
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      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic1
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n The Kericho CRC, established in 1998, is located 260 km Northwest of Nairobi in Kericho town on the grounds of the Ministry of Health, Kericho County Referral Hospital. USAMRU-K has been in Kenya for 45 years and has partnered with KEMRI since 1980. KEMRI is a Government of Kenya para-state corporation responsible for health research. The CRC has three integrated main components: HIV care, HIV and microbiology research. Since 2003 the CRS has been conducting diverse studies including randomized, double-blind, placebo controlled and IND/FDA-regulated studies The CRS has 181 local and one U.S. staff with appropriate trainings to support the clinical trials and HIV care and treatment programs. The staff includes; 10 doctors, 3 pharmacists, 12 clinical officers, 25 nurses, 36 laboratory technologists and six 6 accountants among others. The CRS has a Community Advisory Board, strong community engagement programs, efficient participant recruitment, retention and follow-up processes. The CRS protocols are reviewed by the KEMRI and WRAIR IRBs. The CRS’s, secure physical infrastructure includes: 1) 13,400 square feet (sq. ft.) clinical research building for reception, waiting areas, clinical procedures, consultation, sample collection, pharmacy, quality assurance, IT servers, data entry, participants’ chart archives, and sample storage, 2) 26,115 sq. ft. Laboratory space, 3) two liquid nitrogen plants, 4) four back-up generators 5) 13,500 sq. ft. administration and 6) 6,000 sq. ft. store. Both the CRC pharmacy and laboratory are approved by the National Institute of Allergy and Infectious Diseases/Division of AIDS (NIAID/DAIDS) to participate in DAIDS sponsored vaccine (Site # 1502) and therapeutics (Site #12501) and International Maternal, Pediatric, and Adolescent AIDS Clinical Trials (IMPAACT) Group (Site # 5121) studies, the only research site with such approval in Kenya. The lab is also College of American Pathologists (CAP) accredited and consists of three main sections: HIV, Microbiology and Mycobacterium Tuberculosis (TB). The KEMRI/WRP CRC research activities are integrated with a large comprehensive public health HIV care, treatment and prevention program managed by KEMRI/WRP and supported by PEPFAR which covers a population of about 2.7 million people in the SRV which is also the CRS research catchment area. Elements supported by the program includes: antiretroviral therapy (ART), non-ART, TB/HIV co-infections, PMTCT, HIV Testing and Counseling (HTC), primary HIV infection prevention in both low and high-risk populations, Orphans and Vulnerable Children (OVC), and Voluntary Medical Male Circumcision (VMMC). Kenya had an estimated population in 2012 of 43 million people, 22% of whom are urban and with an annual population growth rate of 2.4%. The adult (15-64 years) HIV/AIDS prevalence rate is 5.6% (6.9% in women, and 4.4% in men). HIV prevalence among children aged 18 months to 14 years was 0.9%. In 2013, the country notified a total of 89,760 TB cases (all forms of tuberculosis) of whom 37% were also HIV infected and the South Rift Valley had a total of 4,302 TB cases in 2013.</p>\n
      • other_details_explanation<p>\n The trial will be conducted also in the host country of the sponsor</p>\n
      • other_details_regulatory_notapproved<p>\n WALTER REED ARMY INSTITUTE OF RESERACH(WRAIR IRB)- 26-07-2016</p>\n
      • other_details_regulatory_approved<p>\n CDC IRB- 15-10-2016</p>\n
      • other_details_regulatory_rejected
      • other_details_regulatory_halted
      • estimated_duration2 years
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorComparator is the standar
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKEMRI/WRP, KERICHO
      • single_site_physical_addressP.O. BOX 1357, KERICHO
      • single_site_contact_personISAAC TSIKHUTSU
      • single_site_telephone0729 110 124
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states14
      • number_of_sites
      • multi_country_listKenya, Botswana, Malawi, South Africa, Uganda, USA, Spain, China, Vietnam, Peru, Zimbabwe, India, Thailand, Haiti
      • data_monitoring_committeeYes
      • total_enrolment_per_siteminimum 80, maximum 100
      • total_participants_worldwide2500
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenYes
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyWe will enroll children between 12 to 17 years
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameBEATRICE
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      • investigator1_professional_addressP.O.BOX 1357 KERICHO
      • investigator1_telephone0702119191
      • investigator1_emailBeatrice.Korir@usamru-k.org
      • organisations_transferred_No
      • number_participants100
      • notification<p>\n N/A</p>\n
      • approval_date10-01-2017
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      • date_submitted18-05-2020
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      • modified2024-10-28 15:36:37
      • created2016-12-13 10:02:09
      • total_sites(null)
      • ecitizen_invoice(null)
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        • professional_addressP.O. BOX 1357 KERICHO
        • telephone0729 110 124
        • emailIsaac.Tsikhutsu@usamru-k.org
        • created2016-12-13 10:26:19
        • modified2020-05-18 11:12:00
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        • created2016-12-13 10:26:19
        • modified2020-05-18 11:12:00
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        • sponsorU.S. Centers for Disease Control and Prevention
        • sponsor_typeResearch Institution
        • contact_personKimberley Chapman
        • address1600 Clifton Road, Atlanta, Georgia USA 30329-4027
        • telephone_number(404) 639-7570/800-232-4636
        • fax_number
        • cell_number(404) 639-7570/800-232-4636
        • email_addresstbtcstudy31@cdc.gov
        • created2016-12-13 10:26:19
        • modified2020-05-18 11:12:00
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PHP Environment

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