Leprosy
Conditions
Brief summary
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
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.
Interventions
DRUGBE-PEP (Bedaquiline)
Single dose of Bedaquiline
DRUGSDR-PEP
Single dose of Rifampicin
DRUGBE-PEP (Rifampicine)
Single dose of Rifampicin
Sponsors
Damien Foundation
Institute of Tropical Medicine, Belgium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Being a permanent resident of the study village, in good state of health 2. Able and willing to provide informed consent 3. Age 5 years or above and weight of 20 kg or above
Exclusion criteria
1. Signs of active leprosy 2. Signs of active pulmonary tuberculosis (cough ≥2 weeks duration) 3. Signs of active extra-pulmonary tuberculosis (bluish-red nodules that cover the lymph nodes, bones or joints, or cervical glands with discharge) 4. History of liver- or kidney disease 5. Allergy to rifampicin or bedaquiline 6. Having received rifampicin or bedaquiline (if applicable) in the last 2-year period 7. Not able to swallow bedaquiline 100 mg tablets 8. Self-reported (suspected) pregnancy or breastfeeding 9. Concurrent (within the last three week period before D0) use of medications not included in the safe list (for bedaquiline only) 10. QT-prolongation of ≥450 msec in baseline ECG within the last week. 11. Jaundice or self-reported liver function abnormalities or hepatitis 12. Value of baseline ALT or AST \>3x ULN within the last week. In case only ALT is available, this would suffice for enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Difference in QTc Interval Between the Two Arms 24 Hours After Treatment Administration | 24 hours after treatment administration | Mean difference in QTc interval between the two arms 24 hours after treatment administration. Difference (BE-PEP - SDR-PEP) |
| Occurence of Any Predetermined Study Stopping Criteria, Which Will Trigger an Immediate Pause on Enrollment | Until day 30 after treatment administration | Occurence of any of the following predetermined study stopping criteria, which will trigger an immediate pause on enrollment: 1. Death of a participant considered related to study drug 2. 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 3. 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 4. 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 5. Two or more participants experience QTc \> 500 ms 6. One or more participants has Aspartate transaminase (AST) or Alanine transaminase (ALT) \> 8x Upper limit of normal (ULN), in absence of causative explanation |
Countries
Comoros
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BE-PEP (Bedaquiline Post-Exposure Prophylaxis) Eligible participants will receive one dose of Bedaquiline plus Rifampicin
BE-PEP (Bedaquiline): Single dose of Bedaquiline
BE-PEP (Rifampicine): Single dose of Rifampicin | 157 |
| SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) Eligible participants will receive one dose of Rifampicin (WHO recommendation)
SDR-PEP: Single dose of Rifampicin | 156 |
| Total | 313 |
Baseline characteristics
| Characteristic | SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) | BE-PEP (Bedaquiline Post-Exposure Prophylaxis) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 62 Participants | 64 Participants | 126 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants | 93 Participants | 187 Participants |
| Age, Continuous | 41 years | 40 years | 41 years |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Comoros | 156 Participants | 157 Participants | 313 Participants |
| Sex: Female, Male Female | 83 Participants | 84 Participants | 167 Participants |
| Sex: Female, Male Male | 73 Participants | 73 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 157 | 0 / 156 |
| other Total, other adverse events | 65 / 157 | 50 / 156 |
| serious Total, serious adverse events | 1 / 157 | 1 / 156 |
Outcome results
Primary
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. Difference (BE-PEP - SDR-PEP)
Time frame: 24 hours after treatment administration
Population: participants included per protocol
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| BE-PEP (Bedaquiline Post-Exposure Prophylaxis) | Mean Difference in QTc Interval Between the Two Arms 24 Hours After Treatment Administration | Adolescents (13 - 17) | 404.61 msec |
| BE-PEP (Bedaquiline Post-Exposure Prophylaxis) | Mean Difference in QTc Interval Between the Two Arms 24 Hours After Treatment Administration | Adults (> 18) | 396.81 msec |
| BE-PEP (Bedaquiline Post-Exposure Prophylaxis) | Mean Difference in QTc Interval Between the Two Arms 24 Hours After Treatment Administration | Children (5 - 12) | 391.15 msec |
| SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) | Mean Difference in QTc Interval Between the Two Arms 24 Hours After Treatment Administration | Adults (> 18) | 397 msec |
| SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) | Mean Difference in QTc Interval Between the Two Arms 24 Hours After Treatment Administration | Adolescents (13 - 17) | 394.06 msec |
| SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) | Mean Difference in QTc Interval Between the Two Arms 24 Hours After Treatment Administration | Children (5 - 12) | 389.07 msec |
Comparison: Adults95% CI: [-5.146, 4.76]
Comparison: Adolescents (13-17)95% CI: [0.926, 20.185]
Comparison: Children (5-12)95% CI: [-3.374, 7.525]
Primary
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: 1. Death of a participant considered related to study drug 2. 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 3. 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 4. 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 5. Two or more participants experience QTc \> 500 ms 6. One or more participants has Aspartate transaminase (AST) or Alanine transaminase (ALT) \> 8x Upper limit of normal (ULN), in absence of causative explanation
Time frame: Until day 30 after treatment administration
Population: included in per protocol
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BE-PEP (Bedaquiline Post-Exposure Prophylaxis) | Occurence of Any Predetermined Study Stopping Criteria, Which Will Trigger an Immediate Pause on Enrollment | Adults (> 18) | 0 Participants |
| BE-PEP (Bedaquiline Post-Exposure Prophylaxis) | Occurence of Any Predetermined Study Stopping Criteria, Which Will Trigger an Immediate Pause on Enrollment | Adolescents (13 - 17) | 0 Participants |
| BE-PEP (Bedaquiline Post-Exposure Prophylaxis) | Occurence of Any Predetermined Study Stopping Criteria, Which Will Trigger an Immediate Pause on Enrollment | Children (5 - 12) | 0 Participants |
| SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) | Occurence of Any Predetermined Study Stopping Criteria, Which Will Trigger an Immediate Pause on Enrollment | Adults (> 18) | 0 Participants |
| SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) | Occurence of Any Predetermined Study Stopping Criteria, Which Will Trigger an Immediate Pause on Enrollment | Adolescents (13 - 17) | 0 Participants |
| SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis) | Occurence of Any Predetermined Study Stopping Criteria, Which Will Trigger an Immediate Pause on Enrollment | Children (5 - 12) | 0 Participants |