| Protocol No: | ECCT/22/08/03 | Date of Protocol: | 20-07-2022 |
| Study Title: | An open-label randomised controlled trial comparing novel combination and currently used antibiotic regimens for the empiric treatment of clinically diagnosed neonatal sepsis with a run-in confirmatory pharmacokinetic phase. |
| Study Objectives: |
Primary objectives
Part 1
To confirm that the recommended doses of fosfomycin and flomoxef, when used in combination with each other or amikacin to be studied in Part 2 will provide adequate drug exposure in neonates with sepsis.
Part 2
To provide a ranking of eight different clinically relevant antibiotic regimens for first-line empiric and second-line (after lack of response/deterioration) treatment of neonatal sepsis, in terms of 28-day mortality as the primary outcome measure.
Secondary objective(s)
Part 1
1. To collect safety data on fosfomycin and flomoxef, when used in combination with each other or amikacin.
Part 2
1. To provide a ranking of clinically relevant antibiotic regimens based on other efficacy and safety secondary outcomes, as well as on health economic measures and the potential selection of resistance at an individual neonate and neonatal unit level.
2. To determine efficacy of antibiotic treatment regimen used based on:
• Clinical status at days 3, 7, 14 and 28 after randomisation
• Clinically appropriate need for additional antibiotics beyond the first randomised treatment
Clinically appropriate need for additional antibiotics beyond the first randomised and second (for failure) treatment
• Cure, defined as clinical improvement and no need for further antibiotic treatment for the original sepsis episode, at test of cure (TOC) visit (day 14 ± 3 days after randomisation).
• Length of stay during the index hospitalisation
• Systemic antibiotic exposure (days on antibiotics) during the index hospitalisation
• 90-day mortality
• Change in C-reactive protein from baseline to day 3 and day 7
3. To collect safety data on different antibiotic treatment regimens
4. To determine antibiotic resistance development in neonates treated with different first- and second-line antibiotic regimens
5. To investigate health economic outcomes in neonates treated with different first- and second-line antibiotic regimens
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| Laymans Summary: |
Lay Title
A study comparing new and currently used antibiotic combinations for treatment of newborn babies hospitalised with infection
What is the problem/background?
Babies admitted to hospital with a severe infection of the blood are treated with medicines called “antibiotics.” In many countries, these antibiotics are those recommended by the World Health Organisation (WHO). Other countries use different antibiotics based on local policies but unfortunately these are not always easily available. The use of different antibiotics also varies from baby to baby and between countries and hospitals.
More infections are now being caused by bacteria which are “resistant” to commonly used antibiotics. This means these antibiotics will not kill the bacteria and therefore will not cure the infection. These bacteria are often called multidrug resistant, as they are not killed by most of the antibiotics. We need to find new ways of treating these infections – using combinations of existing antibiotics is one possibility. Fosfomycin, flomoxef and amikacin are three antibiotics that could be combined into different two drug combinations. Another option is to give stronger antibiotics at the start of treatment. The problem with doing this is that not all babies will need these antibiotics – and the more we use them, the more resistance will develop to these antibiotics. So, using stronger antibiotics in lots of babies now, who don’t need them, may mean that in future we will not be able to use them in any babies who might need them.
What questions are we trying to answer?
The NeoSep1 study will test how well giving fosfomycin and amikacin, OR flomoxef and amikacin OR fosfomycin and flomoxef works to treat babies 28 days old or younger who are in hospital with severe infection of the blood. It will also test how well these new combinations work compared to other antibiotics or combinations of antibiotics that are currently used globally.
Where is the study taking place, how many people does it involve and how are they selected?
The study will be divided in 2 parts: Part 1 and Part 2. The study will take place across sites selected in several countries particularly in low- and middle-income countries (LMICs) including Kenya, and South Africa and other countries in Africa and South East Asia. Babies aged 28 days or below hospitalised with severe infection requiring intravenous (IV) antibiotics will be screened at admission to check if they fulfil criteria required for study participation. During screening, clinicians will obtain medical history, perform physical examination, and obtain blood samples for baseline/routine investigations which include full blood count (FBC), kidney function tests, and blood culture. Written informed consent will be obtained from parents/guardians before enrolment in Part 1 or Part 2. In Part 2, verbal assent will parents/guardians of seriously ill babies and this will be followed up by written informed consent. In addition to routine investigations at admission, blood samples to measure liver function and C-reactive Protein (CRP), a marker of infection in blood, will be done after obtaining consent. Each of these tests will require about 0.5-1 ml (a few drops) of blood.
Part 1
The study will start with Part 1. Part 1 will measure the level of fosfomycin and flomoxef in the baby’s blood. Each baby will get one of the three new combinations of antibiotics: fosfomycin and amikacin, OR flomoxef and amikacin OR fosfomycin and flomoxef Approximately 60 babies (a minimum of 10 and a maximum of 40 per site) will be enrolled across 3 study sites (1 site in Kenya (Kilifi County Hospital) and 2 sites in South Africa) to receive one of the 3 antibiotic combinations in order. We will study 20 babies in each of the 3 antibiotic groups. We will use doses recommended in other studies. The information collected for Part 1 will confirm how much fosfomycin and/or flomoxef we should use in the next part of the study.
Part 2
Part 2 will check how well these three combinations, as well as other antibiotics that are used routinely to treat severe infection in newborn babies, treat bacterial infections and stop babies from dying. This part will start after completion of Part 1. Approximately 3000 babies (a minimum of 50 and a maximum of 400 per site) hospitalised with a severe infection of the blood will be enrolled in several countries in Africa and South East Asia, including Kenya and South Africa. In Kenya, up to 3 sites (Kilifi County Hospital in Kilifi, Coast General Teaching and Referral Hospital in Mombasa and Mbagathi Hospital in Nairobi) will participate in Part 2.
What does the study involve for those who are in it?
All babies will get antibiotics for approximately 7 days in the first instance (their “first line” treatment). If a baby’s condition gets worse during this time, or doesn’t get better as would be expected, doctors will be able to give them a different antibiotic (also known as “second-line” treatment) to see if they do better with a different antibiotic.
Part 1
Following start of IV antibiotics, each baby will have 4 blood samples of 0.5ml each collected to measure the level of antibiotics in the blood:
1. Three blood samples will be taken on Day 1 of treatment at one of each of the following timepoints:
a. early: 5 mins or 15 mins after end of dosing
b. middle: 30 mins or 1 h after end of dosing
c. late: 4h or 6h after end of dosing
2. A fourth blood sample will be collected prior to the first dose on Day 5 for those still hospitalised.
If cerebrospinal fluid (CSF) is taken after starting treatment to investigate possible meningitis, then any leftover sample not required for diagnostic purposes will be retained to measure antibiotic levels in the CSF.
CRP will be repeated on Day 5 and 7. FBC, kidney and liver function tests will be repeated on day 5 for all babies and any abnormal tests will be repeated on Days 7, 14, end of treatment (if not Day 7 or 14), and Day 28 following start of treatment until they become normal. Blood culture will be repeated in case of clinical deterioration and before switching to second-line antibiotics. Additional safety blood tests or investigations will be performed to investigate symptoms or monitor laboratory test abnormalities as clinically indicated following routine clinical practice. We will collect data on any side-effects from Day 1 to Day 28. Babies will be followed up for 28 days, with a visit or telephone call 28 and 90 days after entering the study to see if the baby is still doing well.
Part 2
A computer programme will assign “first-line” antibiotic treatments at random (like the flip of a coin) from a set of combinations. If a baby’s condition gets worse during this time, doctors will be able to give them different antibiotics (also known as “second-line” treatment) to see if they do better with different antibiotics. Which specific second-line antibiotics each baby gets will also be chosen at random from a set of combinations that doctors would use after each first-line treatment.
CRP will be repeated on Days 3 and 7. FBC, kidney and liver function tests will be repeated on Day 3 for all babies and any abnormal tests will be repeated until normal on Day 7, Day 14, end of treatment (if not Day 7 or 14), Day 28, and Day 90 after starting treatment. Blood culture will be repeated in case of clinical deterioration and before switching to second-line antibiotics. Additional safety blood tests or investigations will be performed to investigate symptoms or monitor laboratory test abnormalities as clinically indicated following routine clinical practice. We will collect data on any side-effects from Day 1 to Day 90. Babies will have their bottoms/nappys swabbed or a fresh stool sample collected on Day 1 and Day 14/end of treatment to test presence of bacteria resistant to antibiotics. We will collect information of treatment costs from all parents/guardians (e.g. transport costs, family information such as parental age, education level and data on socio-economic status, and information on clinic and hospital visits) and healthcare providers (e.g. costs of medication and procedures, overhead costs and staff costs). Babies will be followed up for 90 days, with a visit or telephone call 28 and 90 days after entering the study to see if the baby is still doing well.
What are the benefits and risks/costs of the study for those involved?
All babies will receive comprehensive medical care while in the ward (including a daily structured review to check progress) and during follow-up. Additional clinical and nursing staff will be recruited and will undertake study duties and assist in general care in the ward, adding to the staff available. Training will be enhanced for all paediatric ward staff on treatment of sick babies. Following discharge from the ward, parents/guardians will have continued access to the study staff via telephone contact and will be advised to bring their babies to the study clinic for review in case of illness while at home.
Drawing a blood sample carries the risks of damage to the vein and infection. However, the study staff will be trained on careful procedures including cleaning the skin to help prevent these. Blood sample volumes obtained for investigation will be minimal, based the baby’s body weight/percentage total blood volume. In Part 1, day 5 blood samples for repeat FBC, kidney and liver function tests will be collected at the same time as the sample for measuring antibiotic levels to minimise blood sampling. Swabs of baby’s bottom are minimally invasive and can be taken in a standardised manner independent of passing stools using a soft swab. The risks of swabbing a baby’s bottom are minimal and our study sites have experience in obtaining these samples. Side effects that may be associated with the antibiotics include changes in the level of salts/sodium in blood following administration of fosfomycin. Babies will be monitored for side effects and treated appropriately in case they occur. Parents/guardians will receive transport reimbursement and an out-of-pocket allowance (during scheduled visits) for clinic visits. However, costs related to hospitalisation will not be reimbursed.
How will the study benefit society?
The study will enable us to measure the doses of new antibiotics and confirm optimal doses that can be used to treat babies with infection. We will compare different antibiotic combinations, including new ones and those already used in hospitals to see which ones are safe and the best in treating babies with infection. Knowledge of safe and effective antibiotic combinations in sick babies will help decision-making about the first antibiotics to give babies who have infection when they are admitted to hospital to improve their outcomes. This will also help to minimise chances of development and spread of bacteria that are resistant to the antibiotics in use. Knowledge of how bacteria resistant to antibiotics spreads in hospitalised babies will help in finding ways to prevent emergence and spread of resistance and inform development and use of effective antibiotics. Knowledge of individual and provider healthcare costs will guide policymakers on planning and allocation of limited resources to meet the population’s health needs.
When does the study start and finish?
The study aims to start as soon as scientific and ethical approval is granted and is expected to continue for about 5 years until follow-up of participants is completed and the results are available.
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| 1 | Part 1 The study will start with Part 1. Part 1 will measure the level of fosfomycin and flomoxef in the baby’s blood. Each baby will get one of the three new combinations of antibiotics: fosfomycin and amikacin, OR flomoxef and amikacin OR fosfomycin and flomoxef for up to 14 days (if blood culture is positive). Approximately 60 babies (a minimum of 10 and a maximum of 40 per site) will be enrolled across 3 study sites (1 site in Kenya (Kilifi County Hospital) and 2 sites in South Africa) to receive one of the 3 antibiotic combinations in order. We will study 20 babies in each of the 3 antibiotic groups. We will use doses recommended in other studies. The information collected for Part 1 will confirm how much fosfomycin and/or flomoxef we should use in the next part of the study. What does the study involve for those who are in it? All babies will get antibiotics for approximately 7 days in the first instance (their “first line” treatment). If a baby’s condition gets worse during this time, or doesn’t get better as would be expected, doctors will be able to give them a different antibiotic (also known as “second-line” treatment) to see if they do better with a different antibiotic. First-line treatment is expected to continue for 7±2 days based on doctor’s judgement of the baby’s condition for babies with negative blood culture and 10 days (-3 or +4) for babies with positive blood culture. If antibiotics are switched to second-line treatment, the total duration of antibiotic treatment including first- and second-line is 14 ±7 days depending on the baby’s condition. |
| Abstract of Study: | Increasing antimicrobial resistance (AMR) threatens to undermine the effectiveness of World Health Organization (WHO) recommended antibiotic treatments for neonatal sepsis in most low- and middle-income country (LMIC) settings where disease burden is high. The key threat is multidrug-resistant (MDR) Gram-negative bacteria, where there are limited well established neonatal treatment options and a wide use of meropenem, driving carbapenem resistance. Accumulating data show that these MDR Gram-negative bacteria are now the dominant cause of neonatal sepsis in many high-burden settings. Current WHO guidelines, however, continue to recommend empiric first- and second-line regimens for neonatal sepsis that have remained unchanged for nearly 20 years, despite considerably higher observed rates of AMR. There is therefore an urgent need to re-evaluate guidance for empiric treatment and develop updated first-line empiric and second-line regimens with improved efficacy in the context of increasing MDR sepsis in neonates. It is critically important to directly compare suitable novel regimens, including off-patent drugs with a neonatal licence but not currently widely used for the treatment of neonatal sepsis, to currently recommended and used regimens given the lack of evidence supporting use. Although large pragmatic randomised controlled trials are needed, study designs with either two or multiple arms are not feasible for various reasons, and novel trial designs are crucial to allow for multiple parallel group comparisons from sites randomising different sub-populations of neonates across different sets of clinically relevant regimens for their site and specific sub-population. NeoSep1 trial, will test three novel dual combinations of three existing, off-patent drugs, namely fosfomycin + amikacin, flomoxef + amikacin and fosfomycin + flomoxef, and compare these to WHO recommended and other currently used broad spectrum antibiotic combinations. Reflecting that they have been infrequently used in neonatal populations, we will perform a run-in non-randomised pharmacokinetic (PK) study of the fosfomycin and flomoxef when given with amikacin or each other to confirm plasma drug levels at the proposed doses based on other studies and collect safety data (Part 1) before the start of the main randomised trial (Part 2). In Part 1 of the trial, a total of 60 neonates with all 3 PK samples on Day 1 will be enrolled across the 3 study sites, providing 20 neonates in each of the 3 sequential treatment cohorts. In addition, across both fosfomycin cohorts, 10 neonates with a post-natal age under 7 days with complete Day 1 samples and Day 5 samples are required. The final sequential cohort will continue recruiting until both targets are achieved. The Kilifi site will enrol a minimum of 10 and maximum of 40 participants for Part 1. An additional PK sample will be collected prior to the first dose on day 5. Residual cerebrospinal fluid (CSF) will be used for PK analysis if lumbar puncture for diagnostic purposes is deferred after initiation of antibiotics. All neonates in Part 1 will be followed up for 28 days. In Part 2 of the trial, approximately 3,000 neonates (a minimum of 50 and a maximum of 400 per site) hospitalised with clinical signs of neonatal sepsis will be randomised across trial sited located in sub-Saharan Africa and Asia, including Kenya and South Africa, to locally relevant first- and second-line antibiotic regimens and followed up for 90 days for safety and efficacy outcomes. In Kenya, up 3 sites (Kilifi County Hospital in Kilifi, Coast General Teaching and Referral Hospital in Mombasa, and Mbagathi Hospital in Nairobi) will participate in Part 2. First-line treatment is expected to continue for 7±2 days based on clinician’s judgement of the baby’s condition for babies with culture negative sepsis and 10 days (-3 +4) for culture positive sepsis. If antibiotics are switched to second-line treatment, the total duration of antibiotic treatment including first- and second-line is 14 ±7 days depending on the neonate’s condition. Assessment of safety (Part 1 and 2) and efficacy (Part 2 only) will include blood investigations (C-reactive protein, full blood count, kidney and liver function tests) and clinical assessment using a recovery score respectively. Peri-rectal swabs will be taken at baseline, at the end of treatment, and on day 14, to assay carriage of commensal organisms and antimicrobial resistance genes in Part 2. Healthcare-related costs will be measured in Part 2 of the trial. Results obtained from this trial will inform treatment guidelines and improve survival of neonates hospitalised with sepsis. |