Pharmacy and Poisons Board: Applications

List Applications

Protocol No:

ECCT/19/11/06

Date of Protocol:

20-11-2018

Study Title:	An Open Label Phase 2 Pharmarcokinetic Study to Evaluate Double - Dose Levonorgestrel Emergency Contraception in Combination withEfavirenz Based Antiretroviral Therapy or Rifampicin Containing Anti - Tuberculosis Therapy. A5375
Study Objectives:	1.0 HYPOTHESES AND STUDY OBJECTIVES 1.1 Hypotheses 1.1.1 Primary Hypotheses 1.1.1.1 Women receiving double-dose levonorgestrel (LNG) emergency contraception (EC) with efavirenz (EFV)-based antiretroviral therapy (ART) will achieve similar LNG concentrations compared to women receiving standard-dose LNG EC on dolutegravir (DTG)-based ART. 1.1.1.2 Women receiving double-dose LNG EC with rifampicin (RIF)-containing tuberculosis (TB) therapy will achieve similar LNG concentrations compared to women receiving standard-dose LNG EC on DTG-based ART. 1.1.2 Secondary Hypotheses 1.1.2.1 Among women receiving EFV-based ART, double-dose LNG EC will achieve significantly higher LNG concentrations than standard-dose LNG EC. 1.1.2.2 Women receiving standard-dose LNG EC with EFV-based ART will achieve significantly lower LNG concentrations than women receiving standard-dose LNG EC on DTG-based ART. 1.1.2.3 Double-dose and standard-dose LNG EC will have similar safety profiles. 1.2 Primary Objectives 1.2.1 To determine if doubling the dose of the LNG EC effectively overcomes the known drug-drug interaction (DDI) with EFV-based ART. 1.2.2 To determine if doubling the dose of the LNG EC effectively overcomes the expected DDI with RIF-containing TB therapy. 1.3 Secondary Objectives 1.3.1 To estimate the difference in LNG pharmacokinetic (PK) exposure with double-dose LNG EC compared to standard-dose LNG EC in women receiving EFV-based ART. 1.3.2 To estimate the difference in LNG PK exposure with standard-dose LNG EC in women receiving EFV-based ART compared to women receiving DTG-based ART. 1.3.3 To verify the absence of significant DDI between LNG EC and DTG-based ART. 1.3.4 To compare the safety of double-dose LNG EC compared to standard-dose LNG EC. 1.3.5 To evaluate the relationship between baseline measures of body weight (body fat percentage, total weight, and body mass index [BMI]) and LNG PK exposure. 1.4 Exploratory Objectives 1.4.1 To explore whether PK interactions between EFV, DTG, RIF, and LNG are affected by human genetic polymorphisms that have been reported to affect metabolism of these drugs. 1.4.2 To characterize the relationship between short- and long-term adherence to ART or TB therapy and LNG exposure using objective pharmacologic measures. 1.4.3 To assess the acceptability and practicality of EC as a contraceptive option in ACTG trials.
1	To determine if doubling the dose of the LNG EC effectively overcomes the known drug-drug interaction (DDI) with EFV-based ART. To determine if doubling the dose of the LNG EC effectively overcomes the expected DDI with RIF-containing TB therapy.
Laymans Summary:	LAY SUMMARY Title: An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel Emergency Contraception in Combination with Efavirenz-Based Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy Lay Title: A non-blinded Phase II Study that is evaluating the effect of doubling the dose of Levonorgestrel emergency contraception when taken together with antiretroviral medicines containing Efavirenz or with anti-TB medications containing Rifampicin. What is the problem/background? Adolescent girls and young women continue to be disproportionately affected by HIV, especially in sub-Saharan Africa despite the worldwide response. Women constitute more than half of all people living with HIV in the world. In Sub-Saharan Africa, women account for approximately 56% of all new people living with HIV, and the incidence of HIV in women between the ages of 15 and 24 years accounts for 25% of all new infections. Tuberculosis remains one of the greatest threats to public health, surpassing HIV as the leading cause of death from an infectious pathogen. Moreover, the HIV epidemic has fueled the resurgence of TB, leading to a dramatic increase in TB infections in low- and middle-income countries LMIC. HIV infection increases the risk for TB (acquisition, reactivation, and reinfection), alters its clinical presentation, and reduces survival compared to patients with TB who are not living with HIV For patients with latent TB, HIV is a significant risk factor for development of active TB [7, 8], and TB remains the most common cause of illness in patients living with HIV in resource-limited countries. In 2014, women between 15-24 years old had a higher incidence of TB than men in areas of sub-Saharan Africa with high baseline TB prevalence. In such settings of active TB treatment, preventing pregnancy becomes even more important in order for women to attain a level of health that will support future healthy pregnancies. Additionally, treatment options for TB may be limited during pregnancy because of concerns about effect on the unborn children. For instance, exposure of an unborn child to Rifampicin one of the medicines use in treatment for TB although generally considered safe, is associated with bleeding disorders. Treatment of TB before pregnancy prevents TB exposure in the newborn and thus prevents infant deaths. Therefore, providing effective contraception and understanding potentially important interactions between TB medications and contraceptives in populations of women living with either HIV or TB are both of paramount importance. What questions are we trying to answer? This study aims at evaluating if a double dose of levonorgestrel (LNG) emergency contraception (EC) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based anti-HIV medicine (ART) or rifampicin (RIF)-containing tuberculosis (TB) treatment. The study will also compare how safe the double-dose LNG EC is as compared to the standard-dose. Where is the study taking place, how many people does it involve and how are they selected? This is a multicenter study that will be done in many sites. The study will enroll a total of 116 women above 16 years of age. Kericho site will enroll up to 40 participants. The participants at the Kericho site will be recruited from HIV clinics and TB clinics of the Kericho County Referral Hospital and surrounding Hospitals. What does the study involve for those who are in it? Participants will first sign informed consent form before screening evaluations are done. Those found to be eligible for the study based on screening evaluations and inclusion criteria will be enrolled via a centralized subject enrollment system. Participants will be given the study medication to swallow after which blood will be taken severally over a period of 9-10 hours. Participants will come back for a blood draw at 24 hours and 48 hours after taking the study medication. The participants will take a questionnaire over the phone at 1 week, 2 weeks and 4 weeks after study entry. What are the benefits and risks/costs of the study for those involved? Study participants will benefit from more frequent follow-up for HIV infection than at a public hospital, more thorough HIV screening, and 24-hour availability of a dedicated staff for medical attention. Potential risks that participant’s my experience include the side effects of medicine to be given. These include heavier menstrual bleeding, nausea, lower abdominal pains, fatigue, headache, dizziness, breast tenderness and delay of menses. Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the body, and in rare cases, fainting or infection. How will the study benefit society? Results from this study may benefit the society by providing information about interaction of levonorgestrel an emergency contraception pill with rifampicin used to treat TB and Efavirenz a drug used in treatment of HIV. The right dose of levonorgestrel required when used in combination with rifampicin and Efavirenz will be established. This will increase the range of available family planning choices in TB and HIV patients. Family planning is of critical importance to avoid unintended pregnancies and delay pregnancies in TB and HIV patients until their health improves. When does the study start and finish? The study will start on receipt of ethical and regulatory approvals and will end after data analysis is completed. A5375 is a phase II, non blinded four parallel groups; partially randomized, pharmacokinetic (PK)
1	7 LAY SUMMARY Title: An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel Emergency Contraception in Combination with Efavirenz-Based Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy Lay Title: A non blinded Phase II Study that is evaluating the effect of doubling the dose of Levonorgestrel emergency contraception when taken together with antiretroviral medicines containing Efavirenz or with anti-TB medications containing Rifampicin. What is the problem/background? Adolescent girls and young women continue to be disproportionately affected by HIV, especially in sub-Saharan Africa despite the worldwide response. Women constitute more than half of all people living with HIV in the world. In Sub-Saharan Africa, women account for approximately 56% of all new people living with HIV, and the incidence of HIV in women between the ages of 15 and 24 years accounts for 25% of all new infections. Tuberculosis remains one of the greatest threats to public health, surpassing HIV as the leading cause of death from an infectious pathogen. Moreover, the HIV epidemic has fueled the resurgence of TB, leading to a dramatic increase in TB infections in low- and middle-income countries LMIC. HIV infection increases the risk for TB (acquisition, reactivation, and reinfection), alters its clinical presentation, and reduces survival compared to patients with TB who are not living with HIV For patients with latent TB, HIV is a significant risk factor for development of active TB [7, 8], and TB remains the most common cause of illness in patients living with HIV in resource-limited countries. In 2014, women between 15-24 years old had a higher incidence of TB than men in areas of sub-Saharan Africa with high baseline TB prevalence. In such settings of active TB treatment, preventing pregnancy becomes even more important in order for women to attain a level of health that will support future healthy pregnancies. Additionally, treatment options for TB may be limited during pregnancy because of concerns about effect on the unborn children. For instance, exposure of an unborn child to Rifampicin one of the medicines use in treatment for TB although generally considered safe, is associated with bleeding disorders. Treatment of TB before pregnancy prevents TB exposure in the newborn and thus prevents infant deaths. Therefore, providing effective contraception and understanding potentially important interactions between TB medications and contraceptives in populations of women living with either HIV or TB are both of paramount importance. What questions are we trying to answer? This study aims at evaluating if a double dose of levonorgestrel (LNG) emergency contraception (EC) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based anti-HIV medicine (ART) or rifampicin (RIF)-containing tuberculosis (TB) treatment. The study will also compare how safe the double-dose LNG EC is as compared to the standard-dose. Where is the study taking place, how many people does it involve and how are they selected ? This is a multicenter study that will be done in many sites. The study will enroll a total of 116 women above 16 years of age. Kericho site will enroll up to 40 participants. The participants at the Kericho site will be recruited from HIV clinics and TB clinics of the Kericho County Referral Hospital and surrounding Hospitals. What does the study involve for those who are in it? Participants will first sign informed consent form before screening evaluations are done .Those found to be eligible for the study based on screening evaluations and inclusion criteria will be enrolled via a centralized subject enrollment system. Participants will be given the study medication to swallow after which blood will be taken severally over a period of 9-10 hours. Participants will come back for a blood draw at 24 hours and 48 hours after taking the study medication. The participants will take a questionnaire over the phone at 1 week, 2 weeks and 4 weeks after study entry. What are the benefits and risks/costs of the study for those involved? Study participants will benefit from more frequent follow-up for HIV infection than at a public hospital, more thorough HIV screening, and 24-hour availability of a dedicated staff for medical attention. Potential risks that participant’s my experience include the side effects of medicine to be given. These include heavier menstrual bleeding, nausea, lower abdominal pains, fatigue, headache, dizziness, breast tenderness and delay of menses. Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the body, and in rare cases, fainting or infection. How will the study benefit society? Results from this study may benefit the society by providing information about interaction of levonogestrel an emergency contraception pill with rifampicin used to treat TB and Efavirenz a drug used in treatment of HIV. The right dose of levonogestrel required when used in combination with rifampicin and Efavirenz will be established. This will increase the range of available family planning choices in TB and HIV patients. Family planning is of critical importance to avoid unintended pregnancies and delay pregnancies in TB and HIV patients until their health improves. When does the study start and finish? The study will start on receipt of ethical and regulatory approvals and will end after data analysis is completed. A5375 is a phase II, non blinded four parallel groups; partially randomized, pharmacokinetic (PK)
Abstract of Study:	Tuberculosis (TB) and human Immunodeficiency Virus (HIV) are important health problems world wide with TB remaining to be one of the greatest threats to public health and a leading cause of death from an infectious pathogen. In 2014 women aged 15-24 years had a higher incidence of TB than men in subsaharan Africa. In settings of active TB treatment, preventing pregnancy becomes even more important in order for women to attain a level of health that will support future healthy pregnancies. Therefore providing effective contraception and understanding potentially important drug drug interaction between antimicrobials and contraceptives in populations of women living with either HIV or TB are both of paramount importance. This study aims to evaluate the effect of Rifampicin and Efavirenz on Levonorgesterel (LNG). Data on appropriate dose of LNG to be used by these women will increase the range of contraceptive choices. Kericho site will enroll up to 40 participants Rifampicin or Efavirenz. participants will be given study provided LNG and samples drawn for pharmakokinetics.