Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy (Phase 2)

Study Overview
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Brief Summary
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This study will evaluate a combination of bedaquiline and rifampicin as post exposure prophylaxis (PEP) for leprosy in Comoros. It will be a follow-up to the PEOPLE trial on PEP with rifampicin, which is ending in 2022. This new trial will be called the 'Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy' or 'BE-PEOPLE' trial. There will be two main study arms, a comparator arm based on the current WHO recommendation of providing a single dose of rifampicin (10 mg/kg) to close contacts of leprosy patients and an intervention arm in which this regimen will be reinforced with bedaquiline, 400 or 800 mg depending on weight, to be repeated once after four weeks for household contacts. The main study will be preceded by a phase 2 safety study.

Detailed Description
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Given the fact that the investigators are going to provide to healthy people a drug that has not been used before for this indication and which has only been conditionally approved for use in multi-drug resistant tuberculosis, they have first foreseen a phase 2 study in which BE-PEP will be provided to a limited number of contacts and in which safety will be closely monitored and evaluated by an independent data and safety monitoring board (DSMB). This will be done in a small village that is part arm 1 of the PEOPLE trial in which 8 new cases have been diagnosed since 2019 but no PEP has been provided. The investigators will conduct door-to-door screening in this village in June 2022 and offer a single dose of BE-PEP to a random sample of 150 people screened aged 5 years and above not meeting the exclusion criteria (active tuberculosis (TB) or leprosy or previously treated leprosy, known liver function or cardiac abnormalities, not able to swallow 100 mg bedaquiline tablets). Participants will be followed up closely with active monitoring for adverse events, including measurement of the corrected QT interval and liver function before and after administration, as well as gastro-intestinal (nausea, vomiting), nervous system-related (headache, dizziness) and cutaneous reactions. The remainder of the population of this village aged two years and above will be offered single dose rifampicin as per WHO recommendations. In a randomly sampled subset of 150 individuals receiving rifampicin only, the same stringent monitoring with ECG and liver function tests also applied in those receiving BE-PEP will be performed.

Official Title
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Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy: Phase 2 Study

Conditions
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Leprosy

Intervention / Treatment
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* Drug: BE-PEP (Bedaquiline)
* Drug: SDR-PEP
* Drug: BE-PEP (Rifampicine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Being a permanent resident of the study village, in good state of health Able and willing to provide informed consent Age 5 years or above and weight of 20 kg or above Exclusion Criteria: Signs of active leprosy Signs of active pulmonary tuberculosis (cough ≥2 weeks duration) Signs of active extra-pulmonary tuberculosis (bluish-red nodules that cover the lymph nodes, bones or joints, or cervical glands with discharge) History of liver- or kidney disease Allergy to rifampicin or bedaquiline Having received rifampicin or bedaquiline (if applicable) in the last 2-year period Not able to swallow bedaquiline 100 mg tablets Self-reported (suspected) pregnancy or breastfeeding Concurrent (within the last three week period before D0) use of medications not included in the safe list (for bedaquiline only) QT-prolongation of ≥450 msec in baseline ECG within the last week. Jaundice or self-reported liver function abnormalities or hepatitis Value of baseline ALT or AST >3x ULN within the last week. In case only ALT is available, this would suffice for enrollment

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BE-PEP (Bedaquiline Post-Exposure Prophylaxis)<br>Eligible participants will receive one dose of Bedaquiline plus Rifampicin | Drug: BE-PEP (Bedaquiline)<br>* Single dose of Bedaquiline<br>Drug: BE-PEP (Rifampicine)<br>* Single dose of Rifampicin<br>|
| Active Comparator: SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis)<br>Eligible participants will receive one dose of Rifampicin (WHO recommendation) | Drug: SDR-PEP<br>* Single dose of Rifampicin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean difference in QTc interval between the two arms 24 hours after treatment administration | Mean difference in QTc interval between the two arms 24 hours after treatment administration | 24 hours after treatment administration | 
| Occurence of any predetermined study stopping criteria, which will trigger an immediate pause on enrollment | Occurence of any of the following predetermined study stopping criteria, which will trigger an immediate pause on enrollment: Death of a participant considered related to study drug One or more participants experience an Serious Adverse Event (SAE) or Grade 4 Adverse Event (AE) or a persistent (upon repeat testing) Grade 4 laboratory abnormality that is determined to be related to study drug Three or more participants experience a Grade 3 or greater AE of the same type (as per medical judgement) that is determined to be related to study drug Three or more participants experience a persistent (upon repeat testing) Grade 3 laboratory abnormality related to the same laboratory parameter and considered to be related to study drug Two or more participants experience QTc > 500 ms One or more participants has Aspartate transaminase (AST) or Alanine transaminase (ALT) > 8x Upper limit of normal (ULN), in absence of causative explanation | Until day 30 after treatment administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline frequency of ALT in the population | To determine the baseline frequency of ALT in the population. | At baseline | 
| Baseline frequency of AST elevations in the population | To determine baseline frequency of AST elevations in the population | At baseline | 
| Baseline frequency of QTc prolongations in the population | To determine baseline frequency of QTc prolongations in the population | At baseline | 
| Post administration QTc prolongation | Post administration QTc prolongation | 24 hours after treatment administration | 
| Post-administration ALT level | Post administration ALT level | Day 14 after treatment administration | 
| Post-administration AST level | Post-administration AST level | Day 14 after treatment administration | 
| Frequency of potentially common adverse events such as gastro-intestinal (nausea, vomiting), nervous system-related (headache, dizziness) and cutaneous reactions | Frequency of potentially common adverse events such as gastro-intestinal (nausea, vomiting), nervous system-related (headache, dizziness) and cutaneous reactions | Until day 30 after treatment administration | 
| Occurrence of any (serious)AEs | Occurrence of any (serious)AEs | Until day 30 after treatment administration |