Clinical trial NCT05406479
Conditions: Leprosy
Sponsor: Institute of Tropical Medicine, Belgium
Start date: 2022-07-14; Completion date: 2023-01-26
Enrollment: 313 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Eligible participants will receive one dose of Bedaquiline plus Rifampicin arm 2: Eligible participants will receive one dose of Rifampicin (WHO recommendation)
Interventions: intervention 1: BE-PEP (Bedaquiline) intervention 2: SDR-PEP intervention 3: BE-PEP (Rifampicine)
Intervention descriptions: intervention 1: Single dose of Bedaquiline intervention 2: Single dose of Rifampicin intervention 3: Single dose of Rifampicin

Protocol documents:
Prot_000.pdf: 
BE-PEOPLE, version 5.1, dated 01- March-2023 
 
1 of 58 
 
 
Clinicaltrials.Gov. NCT05406479 (Phase 2)/ NCT05597280 (Phase 3) 
 
Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy (BE-PEOPLE) 
 
 
Initial Protocol 
Version 5.1, 01-March-2023 
 
 
 
 
 
 
 
Sponsor: 
Institute of Tropical Medicine 
Nationalestraat 155 
2000 Antwerpen 
Belgium 
 
 
Coordinating Investigator: 
Dr. Epco Hasker 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 2 of 58 
ClinicalTrials.Gov.: 
NCT05406479 (Phase 2) / NCT05597280 (Phase 3) 
Study Title: 
Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy (BE-
PEOPLE) 
 
Study Acronym 
BE-PEOPLE 
Version and date: 
Version 5.1 01 March-2023 
Partnering 
institutions/sites: 
- 
Institute of Tropical Medicine (ITM), Antwerp, Belgium 
- 
Damien Foundation (DF), Comoros and Belgium  
 
Study drugs: 
Bedaquiline and Rifampicin 
Funder: 
Janssen Pharmaceutica 
Sponsor: 
Institute of Tropical Medicine, Antwerp, Belgium 
Coordinating 
Investigator: 
Dr Epco Hasker 
Institute of Tropical Medicine - Department of Public Health 
 
Task division by collaborating partners: 
- 
Institute of Tropical Medicine  
Bouke de Jong 
Trial coordination 
Molecular testing samples Comoros 
bdejong@itg.be, +32(0)32476590 
Epco Hasker 
Trial coordination 
ehasker@itg.be, +32(0)32470726 
 
- 
National Tuberculosis and Leprosy Control Program of the Comoros 
Aboubacar 
Mzembaba 
Supervise project activities in Comoros 
a.mzembaba@gmail.com 
 
 
- 
Damien Foundation 
Younoussa Assoumani 
Coordinate project activities in Comoros 
yaoussoumani@gmail.com 
 
 
- 
Leidsch Universitair Medisch Centrum 
Annemieke Geluk 
Process anti-PGL1 RDT strips 
A.Geluk@lumc.nl 
 
 
- 
Amsterdam Universitair Medische Centra 
Christian van der 
Werf 
Support ECG monitoring in phase 
2 study 
c.vanderwerf@amsterdamumc.nl 


BE-PEOPLE, version 5.1, dated 01 March 2023 3 of 58 
STATEMENT OF COMPLIANCE TEST 
 
By signing this protocol, the Investigator(s) acknowledge(s) and agree(s): 
 
This protocol contains the necessary information for conducting this clinical study. The Principal 
Investigator will conduct this study as detailed herein and will make every reasonable effort to complete 
the study within the time designated. The Principal Investigator commits to carry out the study in 
compliance with the protocol, amendments, applicable procedures and other study-related documents 
provided by the Sponsor, and in compliance with the Declaration of Helsinki, Good Clinical [Laboratory] 
Practice (GC[L]P), the ALLEA Code of Conduct for Research Integrity, and applicable regulatory 
requirements.  
The protocol and all relevant study information, which is provided by the Sponsor, will be made available 
to the physicians, nurses and other personnel who participate in conducting this study. The Investigator 
will use this material for their training so that they are fully informed regarding the drugs and the conduct 
of the study. 
The Sponsor of this study – the Institute of Tropical Medicine in Antwerp, Belgium (ITM) – will at any 
time have access to the source documents from which Case Report Form information may have been 
generated and will be permitted to perform trial-related monitoring and audits. All study material will be 
maintained according to regulatory requirements and until the Sponsor advises that retention is no longer 
necessary.  
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 4 of 58 
 
DIRECTOR OF THE INSTITUTE OF TROPICAL MEDICINE: 
 
 
Title, Name: Dr. Marc-Alain Widdowson 
Date: 
 
 
Signed: 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Title, Name: Dr. Epco Hasker 
Date: 
 
 
Signed: 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR ON THE COMOROS: 
 
 
Title, Name: Dr. Younoussa Assoumani 
Date: 
 
 
Signed: 
 
 
 
 
 
 
 
 
Signing this document, I commit to carry out the trial in accordance with the protocol, Good Clinical 
Practice and applicable ethical and regulatory requirements. I also acknowledge the paragraph 
relevant to study confidentiality and authorize the Institute of Tropical Medicine, Antwerp, Belgium to 
record my data on a computerized system containing all the data pertinent to the study. 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 5 of 58 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE TEST .................................................................................................................. 3 
TABLE OF CONTENTS ........................................................................................................................................ 5 
SYNOPSIS ......................................................................................................................................................... 7 
1.1 BACKGROUND ................................................................................................................................................... 9 
1.2 RATIONALE ..................................................................................................................................................... 11 
2. STUDY OBJECTIVES AND OUTCOMES .......................................................................................................... 12 
2.1 PHASE 2 STUDY ............................................................................................................................................... 13 
2.1.1 Primary: .............................................................................................................................................. 13 
2.1.2 Secondary ........................................................................................................................................... 13 
2.2 PHASE 3 STUDY ............................................................................................................................................... 13 
2.2.1 Primary ............................................................................................................................................... 13 
2.2.2 Secondary ........................................................................................................................................... 13 
3.1 GENERAL STUDY DESIGN .................................................................................................................................... 14 
4. PARTICIPANTS, POPULATION & SELECTION ................................................................................................ 19 
4.1 STUDY SETTINGS .............................................................................................................................................. 19 
4.2 STUDY POPULATION AND SELECTION CRITERIA ....................................................................................................... 19 
4.3 SAMPLE SIZE ................................................................................................................................................... 22 
4.4 RANDOMIZATION ............................................................................................................................................ 23 
4.5 WITHDRAWAL AND TERMINATION OF THE STUDY ................................................................................................... 24 
4.5.1 Reasons for Withdrawal from the study ............................................................................................. 24 
4.5.2 Reasons for Withdrawal from the study intervention ........................................................................ 24 
4.5.3 Handling of Withdrawals .................................................................................................................... 24 
4.5.4 Lost to follow-up ................................................................................................................................. 24 
4.5.5 Termination of Study .......................................................................................................................... 24 
5.1 GENERAL STUDY PROCEDURES ........................................................................................................................... 25 
5.2 LABORATORY- AND SAFETY MONITORING PROCEDURES ........................................................................................... 29 
5.2.1 Phase 2 pharmacovigilance: monitoring for hepatitis ........................................................................ 29 
5.2.2 Sampling schedule for clinically confirmed leprosy patients .............................................................. 29 
5.2.3 Sampling of presumptive TB patients ................................................................................................. 30 
5.2.4 Specific tests ....................................................................................................................................... 30 
5.2.5 Shipment and storage of samples ...................................................................................................... 32 
6. STUDY INVESTIGATIONAL PRODUCT .......................................................................................................... 32 
6.1 PURCHASING .................................................................................................................................................. 32 
6.2 PARTICIPANT COMPLIANCE MONITORING .............................................................................................................. 32 
6.3 IMP PREPARATION AND ADMINISTRATION ............................................................................................................ 32 
6.4 PRIOR AND CONCOMITANT THERAPY .................................................................................................................... 32 
6.5 PACKAGING .................................................................................................................................................... 33 
6.6 RECEPTION, STORAGE, DISPENSING AND RETURN.................................................................................................... 33 
7. SAFETY ASSESSMENT .................................................................................................................................. 34 
7.1 RATIONALE FOR SAFETY AND EFFICACY OF STUDY DRUGS .......................................................................................... 34 
7.1.1 Safety of Rifampicin 600mg ................................................................................................................ 34 
7.1.2 Expected efficacy of bedaquiline 800mg against M. leprae ............................................................... 34 
7.1.3 Safety of Bedaquiline 800mg .............................................................................................................. 35 


BE-PEOPLE, version 5.1, dated 01 March 2023 6 of 58 
7.1.4 Rationale for combining bedaquiline 800mg and rifampicin 600mg ................................................. 36 
7.2 SAFETY MONITORING ........................................................................................................................................ 36 
7.2.1 Safety monitoring for QT prolongation in Phase 2 ............................................................................. 36 
7.2.2 Safety monitoring for hepatitis in Phase 2 ......................................................................................... 37 
7.2.3 (S)AE monitoring ................................................................................................................................. 37 
7.2.4 Special Reporting Situation ................................................................................................................. 41 
7.2.5 Product Quality Complaints (PQC) ...................................................................................................... 41 
7.3 SURVEILLANCE FOR SELECTION FOR MYCOBACTERIAL DRUG RESISTANCE ...................................................................... 42 
7.4 OTHER RISKS ................................................................................................................................................... 42 
8. STUDY MANAGEMENT ............................................................................................................................... 43 
9. STATISTICAL ANALYSIS ............................................................................................................................... 44 
9.1 BASELINE CHARACTERISTICS: .............................................................................................................................. 44 
9.2. PHASE 2 STUDY: ............................................................................................................................................. 44 
9.2.1. Primary analysis ................................................................................................................................. 44 
9.2.2. Secondary analysis ............................................................................................................................. 44 
9.3. PHASE3 STUDY ............................................................................................................................................... 44 
9.3.1. Primary analysis ................................................................................................................................. 44 
9.3.2 Secondary analyses ............................................................................................................................. 45 
9.3.3 Interim analyses .................................................................................................................................. 45 
10. MONITORING AND QUALITY ASSURANCE ................................................................................................ 46 
11. DATA MANAGEMENT ............................................................................................................................... 46 
11.1 DATA COLLECTION, HANDLING AND RETENTION ................................................................................................... 46 
11.2 DATA SECURITY AND CONFIDENTIALITY ............................................................................................................... 47 
11.3 DATA PROTECTION AND SECURITY ..................................................................................................................... 48 
11.3 FILING AND ARCHIVING ................................................................................................................................... 48 
12. ETHICAL ISSUES ........................................................................................................................................ 49 
12.1 ETHICS AND REGULATORY REVIEW ..................................................................................................................... 49 
12.2 PROTOCOL AMENDMENTS ............................................................................................................................... 49 
12.3 INFORMED CONSENT ...................................................................................................................................... 49 
12.4 CONFIDENTIALITY .......................................................................................................................................... 50 
12.5 POTENTIAL RISKS ........................................................................................................................................... 51 
12.6 BENEFITS ..................................................................................................................................................... 52 
12.7 COMPENSATION FOR PARTICIPATION ................................................................................................................. 52 
12.8 INSURANCE................................................................................................................................................... 52 
13. DISSEMINATION OF RESULTS, INTELLECTUAL PROPERTY .......................................................................... 52 
14. ARCHIVING ............................................................................................................................................... 53 
15. REFERENCES ............................................................................................................................................. 54 
16. LIST OF ABBREVIATIONS ........................................................................................................................... 57 
17. ANNEX 1: FAGG OPINION TO THE PROTOCOL ........................................................................................... 58 


BE-PEOPLE, version 5.1, dated 01 March 2023 7 of 58 
SYNOPSIS 
 
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. We call this new trial the 8Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy9 or 
8BE-PEOPLE9 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. Leprosy patients diagnosed over the course of the study 
will be enrolled in a sub-study, which will include genotypic testing for dug resistance.  
 
Single dose rifampicin post exposure prophylaxis (SDR-PEP) for leprosy has been recommended by 
WHO since 2018 to reduce the risk of leprosy for close contacts of leprosy patients. [1] In the PEOPLE 
trial there are four study arms to which villages on two islands of Comoros (Anjouan and Mohéli) and 
in one district of Madagascar have been randomly allocated. These villages had been preselected 
based on leprosy incidence over the period 2013-2017. In all four study arms, annual door-to-door 
surveys are being conducted covering entire villages. All permanent residents are invited for screening 
for leprosy. Leprosy patients detected are offered free treatment according to the international and 
country guidelines. All cases detected since the start of screening or under treatment during the first 
screening round are considered 8index case9. In arm 1 no PEP is provided, which is the current standard 
of care in Madagascar and Comoros. In arms 2, 3 and 4 SDR-PEP is offered to different categories of 
participants aged 2 years and above who have not received rifampicin in the preceding 2-year period. 
In arm 2 only household contacts of index leprosy cases are eligible, in arm 3 anyone living within 100 
meters of an index case is eligible (or the entire village if >50% are eligible), in arm 4 household contacts 
as well as neighborhood contacts within 100 meter and testing positive to a serological test (anti-PGL 
I) are eligible.  Based on studies in both tuberculosis and leprosy that showed high doses of rifampicin 
to be safe and more effective than the standard dose of 10 mg/kg, in the PEOPLE trial we opted for a 
dose of 20 mg/kg and refer to this regimen as 8single double dose rifampicin post exposure prophylaxis9 
or SDDR-PEP. [2-5] The BE-PEOPLE trial will continue only in Comoros, where the highest leprosy 
incidence was found so far during the PEOPLE trial.  
 
The total enrolment to date in the PEOPLE trial in Comoros has been approximately 86,000. Out of 
15,569 persons eligible for PEP in 2019, 12,101 (83.1%) actually took PEP. A preliminary analysis based 
on data for the second year (2020) shows an incidence of approximately 1.1 per 1,000 (96 new cases). 
In a Poisson model controlled for differences in baseline prevalence and with village nested in island 
as random effects to control for contextual confounding, we found incidence rate ratios of 1.23, 0.78 
and 0.89 when comparing respectively arms 2, 3 and 4 to arm 1, the comparator arm. None of these 
associations was statistically significant (p ≥0.70). At individual level the effect of PEP controlled for 
distance to nearest index case was a borderline statistically significant reduction in risk of leprosy, with 
an incidence rate ratio of 0.48 (95% confidence interval 0.21-1.13).  
 
Based on the individual effect of SDDR-PEP and taking into account the fact that less than two out of 
three years of follow-up have passed, the associations at study arm level might still become more 
pronounced but we do already want to test a stronger PEP regimen making use of the established set 
up. The regimen we intend to test is a combination of rifampicin and bedaquiline, hereafter referred 
to as 8Bedaquiline enhanced post exposure prophylaxis9 or BE-PEP. Rifampicin will be provided at a 
dose of 10 mg/kg, the WHO standard, i.e. 600 mg for an adult. Bedaquiline will be provided at a dose 
of 800 mg for an adult, double the daily dose used in treatment of rifampicin resistant tuberculosis.[6] 
Based on pharmacological considerations and pre-clinical studies we expect this regimen to have a 
synergistic action against M. leprae. BE-PEP will be administered as a single dose, repeated after four 


BE-PEOPLE, version 5.1, dated 01 March 2023 8 of 58 
weeks only for household contacts, as preliminary data from the PEOPLE trial show that their residual 
risk is still up to three times higher when compared to the rest of the population. 
 
In our analysis of baseline data of the PEOPLE trial we found strong degrees of clustering of leprosy 
not just within households but also in neighborhoods, with statistically significant associations up to 
100 meters from an index case.[7] For this reason for the BE-PEOPLE trial we opted for a blanket 
approach, comparable to arm 3 of the PEOPLE trial. PEP will be provided to anyone living within a 100 
meter radius of an index case (or to the entire village if more than 50% of the population would be 
eligible). An additional argument for the blanket approach is the fact that, as mentioned above, even 
though at individual level SDDR-PEP appears to protect reasonably well, the overall incidence during 
the first year of follow-up in the study arm targeting only household contacts (arm 2) was slightly 
higher than the incidence in the comparator arm. As stated earlier, this difference was by no means 
statistically significant but it appears to confirm the findings of Bakker et al. in a high incidence setting 
in Indonesia where PEP was only effective when blanket coverage was provided.[8]  Blanket coverage 
within a 100 meter radius has now also been recommended in a recent WHO guideline. [9] 
 
During the PEOPLE trial we have created teams of dedicated field workers and supervisors and gained 
precious experience with electronic data capturing and georeferencing of our study population. For 
these reasons it is crucial not to let the capacity that has been built dissipate, and to start a follow-up 
trial without delay. The PEOPLE trial will end in 2022, after a fourth round of door-to-door screening 
in all four study arms.  Out of 48 villages in Comoros that are part of the PEOPLE trial we will retain 30, 
based on incidence to date and population size. Based on prevalence during the 2022 survey, these 
will be randomized within island and PEOPLE study arm to the two arms of the BE-PEOPLE trial, along 
with ten additional villages where a baseline screening will also take place in 2022 (and early 2023). In 
the PEOPLE study, in 2022 nobody will have received rifampicin so all will eligible again for rifampicin 
in 2023. 
 
Given the fact that we 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, we 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. We 
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 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 we will perform the same 
stringent monitoring with ECG and liver function tests also applied in those receiving BE-PEP. 
 
Assuming the phase 2 study will not reveal any drug related adverse events and following the advice 
of the DSMB and the involved ethics committees, we will proceed with a phase 3 study for which 
randomization will take place in early2023. There will be two study arms. Arm 1 will be the intervention 
arm in which we will provide BE-PEP to all persons residing within 100 meters of an index case, to be 
repeated after four weeks for household contacts. Arm 2 will be the comparator arm in which the 
WHO recommended standard PEP will be provided, i.e. 10 mg/kg of rifampicin in a single dose. PEP 
distribution and eligibility will be evaluated at village level once the annual screening round in the 


BE-PEOPLE, version 5.1, dated 01 March 2023 9 of 58 
respective village has been completed. For the first PEP distribution round in 2023, any leprosy case 
recorded during the first village screening that year or in the preceding five-year period, i.e. since 
January 1st, 2018, will be considered an index case. As of the 2nd annual screening round, any leprosy 
case detected after the screening of the previous year and up to and including the village9s screening 
round of the current year will be considered an 8index case9. First eligibility at household level will be 
determined based on the distance of the household to the closest index case (Eligibility based on PEP 
zone). In both arms we will target anyone living within 100 meters of an index case or the entire village 
if more than 50% of the population are eligible. Afterwards the eligible households will be visited and 
individual inclusion and exclusion criteria for the annual PEP distribution will be checked before 
offering PEP to a study participant. Provision of PEP will start in 2023 and follow-up will continue for 4 
years. Our main study outcome will be the comparison of leprosy risk in individuals that received 
standard WHO SDR-PEP versus individuals that received BE-PEP. In addition, we will compare the 
overall leprosy incidence over the follow-up period between the two study arms.  
 
As stated above, our primary outcome measure will be the incidence rate ratio of leprosy between 
those who received BE-PEP and those who received the standard SDR-PEP. From this analysis we will 
exclude those not eligible for BE-PEP, i.e. children below 5 years of age and/or with a weight below 20 
kg. We will fit a Poisson model with village nested in island as random effect and controlled for distance 
to the nearest index case at baseline. In addition, we will compute compare the incidence rate ratios 
between the entire BE-PEP and SDR-PEP arms over a period of 4 years starting at the first screening 
round up to the last follow up after 4 years, also based on a Poisson model with village nested in island 
as random effect. From this analysis we will not exclude anyone not eligible for BE-PEP.  
 
Throughout the BE-PEOPLE trial we will continue sampling all leprosy patients identified (Slit skin 
smears, blood sample, nasal and tongue swabs, tongue scraping, face mask sampling, a skin biopsy 
from the edge of non-facial lesions) on Anjouan and Moheli, with the aim of using molecular assays for 
M. leprae as quality assurance mechanism. If sufficient DNA is available Deeplex-MycLep will be used 
for typing the strains, which will allow us to perform highly sensitive surveillance for (traces of) 
resistance to rifampicin and bedaquiline. As part of BE-PEOPLE, we will moreover enroll all 
microbiologically confirmed tuberculosis patients on all islands of Comoros (Moheli, Anjouan, and 
Grande Comore, where bedaquiline will not be introduced, maximum 100 patients/ year) and assess 
whether they ever received (BE-)PEP or leprosy treatment. We will genotype their samples with 
Deeplex-MycTB XL, which includes all M. tuberculosis genes (potentially) involved in resistance to 
rifampicin and bedaquiline, to be able to detect the earliest traces of acquired resistance to these 
drugs, which is unexpected after single dose administration. 
 
The overall goal of BE-PEOPLE is to validate a robust and safe leprosy PEP regimen, and its optimal 
administration, that prevents leprosy in the individual and interrupts transmission at the village level. 
If BE-PEP turns out to be safe and successful, we aim to adjust national guidelines in Comoros towards 
island wide implementation on Anjouan and Moheli, allowing to sustainably eliminate leprosy.  
 
 
 
1.  INTRODUCTION 
1.1 Background 
Leprosy is an ancient infectious disease transmitted from man to man, probably via the airborne route. 
After contact with the causative microorganism (M. leprae) and before the onset of skin and nerve 
lesions, an infected person may be asymptomatic for years. [10-12] Post exposure prophylaxis (PEP) 
provided during this incubation period might prevent progression from infection to disease.[13] In 


BE-PEOPLE, version 5.1, dated 01 March 2023 10 of 58 
1991, the World Health Assembly decided on a leprosy elimination strategy aiming at reducing the 
prevalence to below 1 per 10,000 worldwide, assuming that at such levels transmission will eventually 
cease.[14] Leprosy prevalence has since then been greatly reduced, from more than 5 million in the 
1980s to 129,192 by the end of 2020. However much of the reduction in prevalence has been due to 
changes in case definition and in treatment duration, the latter having been reduced from lifelong to 
maximum two years and then again to maximum one year. The decline in leprosy incidence has been 
less impressive. After a steep decrease between 2000 and 2005, reported worldwide leprosy incidence 
has now plateaued above 200,000 annually, showing continued transmission of M. leprae.[15] One of 
the measures endorsed by WHO in 2018 to overcome the current stalemate is post exposure 
prophylaxis based on a single dose of rifampicin (SDR-PEP) provided to close contacts of leprosy 
patients.[16] PEP based on a single dose of rifampicin has been shown to reduce the risk of leprosy by 
50-60% in a pivotal trial in Bangladesh.[17]  
 
The current study protocol is a sequel to the PEOPLE trial on post exposure prophylaxis for leprosy in 
Comoros (48 villages) and Madagascar (16 villages), funded by EDTCP, which in turn built on the 
ComLep cohort of leprosy patients on Anjouan (Comoros), 2017-2019, funded by R2Stop.[18]  PEOPLE 
consists of a cluster randomized trial, which will end towards the end of 2022, in which three different 
approaches to post exposure prophylaxis for leprosy (PEP) are compared to an intervention arm in 
which no prophylaxis is provided. We opted for single dose rifampicin post exposure prophylaxis, as 
recommended by WHO. [1] But based on studies in both tuberculosis and leprosy that showed high 
doses of rifampicin to be safe and more effective than the standard dose of 10 mg/kg, in the PEOPLE 
trial we opted for a dose of 20 mg/kg and refer to this regimen as 8single double dose rifampicin post 
exposure prophylaxis9 or SDDR-PEP. [19] Arm 1 is the comparator arm in which no PEP is provided, in 
arm 2 SDDR-PEP is provided to household contacts of index cases. In arm 3 SDDR-PEP is provided not 
only to household contacts but to anyone living within a 100 meter perimeter of an index case, if this 
entails more than 50% of the village population the entire village is eligible. In arm 4 SDDR-PEP is given 
to household contacts but also to those living within a 100 meter perimeter of an index case and testing 
positive to anti-PGL-I, an antibody detection test for M. leprae. If more than 75% of the village 
population lives within 100 meters of an index case, eligibility for anti-PGL-I positive non-household 
contacts is extended to the entire village. Door-to-door screening is performed on an annual basis in 
all villages The main outcome measure will be the incidence rate ratios of leprosy between the 
comparator arm and each of the intervention arms.  
 
During the first year of follow up 8 new cases were detected in Madagascar on a population screened 
of 19,039, an incidence of 4.2 per 10,000, versus 80 on 62,266 screened in Comoros, equivalent to an 
incidence of 13.2 per 10,000. On the total population under follow-up in Comoros of 86,160, 96 cases 
were detected, equivalent to an incidence of 11.1 per 10,000. In Comoros post exposure prophylaxis 
had been provided from the start, in Madagascar only from the second year onwards. It is because of 
the higher incidence that we have decided to focus on Comoros for the new trial described in this 
protocol.  We have seen some impact of SDDR-PEP in Comoros but we would like to seize the 
opportunity to also test another potentially more efficacious PEP regimen. So far, based on just one 
year of follow up, a Poisson model controlled for differences in baseline prevalence and with village 
nested in island as random effects to control for contextual confounding, shows incidence rate ratios 
of 1.23, 0.78 and 0.89 when comparing respectively arms 2, 3 and 4 to arm 1, the comparator arm. 
None of these associations was statistically significant (p ≥0.70) and based on data available to date 
for the third project year we already have a clear indication that the differences between the 
intervention arms and the comparator arm are not increasing. At individual level the effect of PEP over 
the first year of follow-up, controlled for distance to nearest index case at baseline, was a borderline 
statistically significant reduction in risk of leprosy, with an incidence rate ratio of 0.48 (95% confidence 
interval 0.21-1.13). The individual effect is in line with the results of the pivotal COLEP trial that showed 
57% reduction in incidence, albeit COLEP used 600mg of rifampicin and enrolled close contacts 


BE-PEOPLE, version 5.1, dated 01 March 2023 11 of 58 
only.[17] Though the 2018 WHO guideline is based on the individual effect of SDR-PEP, in a more recent 
guideline WHO has also included a blanket approach, typically covering an area of 100 meters around 
an index case. [9] 
 
The available set-up and experience gained so far during the PEOPLE trial present an ideal platform for 
a follow-up study. In this follow-up trial which we have called 8Bedaquiline Enhanced Post ExpOsure 
Prophylaxis for Leprosy9 or 8BE-PEOPLE9, we will test a reinforced regimen made up of rifampicin and 
bedaquiline which we will hereafter refer to as BE-PEP. In the PEOPLE study, in 2022 nobody will have 
received rifampicin so all will eligible again for rifampicin in 2023. The main objective of the study is to 
assess effectiveness of BE-PEP in comparison to the standard WHO recommended SDR-PEP regimen. 
We will assess not only the individual protective effect but also the effect on incidence at village level.  
 
1.2 Rationale 
As was explained above, based on preliminary data for the first year of follow-up of the PEOPLE trial 
and taken into account differences in baseline prevalence, in Comoros we find incidence rate ratios of 
1.23, 0.78 and 0.89 when comparing respectively arms 2, 3 and 4 to arm 1, the comparator arm. None 
of these associations was anywhere near statistically significant (p ≥0.70) and already we observe that 
during the second year of follow-up differences between intervention arms and comparator arm are 
not increasing. Though we do start seeing an effect at individual level, a marginally significant reduction 
in risk of 52%, we hypothesize that a more effective PEP regimen is required to not just prevent 
individual progression from asymptomatic infection to disease but to have an impact on transmission 
as well.  
 
The setup of the ongoing PEOPLE trial provides an ideal context to test an alternative PEP regimen. A 
strong data collection system has been developed and extensively field tested, survey teams have been 
trained and quality assurance mechanisms established. Important lessons have been learnt to which 
our system has been adapted. Whereas in Madagascar we found a relatively low incidence to date, 
approximately 4.2 per 10,000 in the first year of follow-up, in Comoros the overall incidence over the 
first year of follow-up was still 11.1 per 10,000 per year, despite SDDR-PEP being provided in three of 
the four study arms. Moreover, there are some larger villages in Comoros that were not included in 
the PEOPLE trial out of concerns for an imbalance between study arms upon randomization, in these 
villages we continue to see high leprosy incidence, in the order of 20-30 per 10,000 per year over the 
past five years.  
 
The PEP regimen we will test is a combination of bedaquiline and rifampicin. It will be provided as a 
single dose, to be repeated once after four weeks for household contacts because the PEOPLE study 
has unequivocally shown that they are most at risk, even after risk reduction with SDDR-PEP.[7] 
Rifampicin has been endorsed for post exposure prophylaxis of leprosy since 2018.[1] Bedaquiline, the 
first new drug to be developed against M. tuberculosis in 40 years, received conditional FDA approval 
in 2012 for treatment of multi-drug resistant tuberculosis. Bedaquiline targets the subunit c of the ATP 
synthase in the respiratory chain, and has become a 8game changer9 in the treatment of tuberculosis 
(TB) patients with advanced resistance. Bedaquiline is typically given once daily for 2 weeks, followed 
by 3x weekly dosing for 6 months or longer. It has a very long half-life once steady state is established. 
In the clinical studies preceding bedaquiline approval, safety was established for a single 
supratherapeutic dose of 800 mg (see 7.1.4 below). In bedaquiline dose ranging studies in TB patients, 
the highest dose used consisted of a loading dose of 700mg bedaquiline followed by a dose of 500mg 
on day 2, which showed the strongest early bactericidal activity.[20] In vitro M. tuberculosis studies 
show that bedaquiline as well as rifampicin are active against both replicating and non-replicating 
bacteria, whereas moxifloxacin and isoniazid only kill replicating bacteria.[21] The combination of 
rifabutin, with the same mode of action as rifampicin, plus bedaquiline produced sustained 
intracellular mycobactericidal activity that was greater than the sum of their individual effects.[22] 


BE-PEOPLE, version 5.1, dated 01 March 2023 12 of 58 
While bedaquiline is a substrate the cytochrome P450 isoenzyme CYP3A4, of which rifampicin is a 
strong  inducer, a single dose as used for PEP is not expected to lead to drug-drug interactions [23]. 
 
To assess transmission of leprosy, the value of door-to-door surveys is limited because of the long 
incubation period, moreover from a cost perspective they are not sustainable. A possible alternative 
could be serological surveys among children, as is done for lymphatic filariasis.[24] For leprosy a 
serological test, anti-PGL-I, has been available for years but to date longitudinal data required for 
validation as a surveillance tool are lacking.[25] The available data from the PEOPLE trial, including age 
specific sero prevalence rates as well as leprosy prevalence rates in villages that belong to arm 4, 
provide a unique opportunity. At the end of the BE-PEOPLE trial after the last screening round  will 
therefore conduct another anti-PGL-I sero survey in the original arm 4 villages of PEOPLE. We expect 
that as a result of nine years of active case finding combined with different forms of PEP, transmission 
of M. leprae in these villages will have been substantially reduced. We want to use the PGL-I survey as 
a proof of principle to assess whether such surveys can be used as instruments to measure 
transmission. We expect that, especially in young children, anti-PGL-I positivity will have strongly and 
significantly declined. 
 
While the concern that a single dose of rifampicin selects for resistance to rifampicin in leprosy and/or 
tuberculosis has been refuted on theoretical grounds, this has not been formally tested. Unpublished 
findings from the PEOPLE trial (manuscript in preparation) reveal the complete absence of (even 
subpopulations of) resistant M. leprae bacilli in Comoros, also in two patients who developed leprosy 
after having received rifampicin based PEP. To ensure continued monitoring for drug resistance in the 
BE-PEOPLE trial, we will continue to enroll in a sub-study all cases of leprosy diagnosed from all villages 
of Anjouan and Mohéli. From these patients we will collect skin biopsies from non-facial lesions, nasal- 
and tongue swabs and scrapings, and masks, to be tested with qPCR and Deeplex-MycLep if sufficient 
DNA is available and for additional molecular tests for M. leprae. Apart from testing just for rifampicin 
and fluoroquinolone resistance as we are currently doing, in BE-PEOPLE we will extend the genotyping 
of M. leprae with bedaquiline resistance conferring genes.  
 
To date, Xpert MTB/RIF, implemented on Anjouan since 2018, has never detected a patient with 
rifampicin resistant tuberculosis. To further monitor resistance in tuberculosis in the wake of 
introduction of BE-PEP we will also enroll tuberculosis patients to test whether any rifampicin or 
bedaquiline resistant M. tuberculosis bacilli are detectable. This will be done on all three islands of 
Comoros, including Grande Comore where no BE-PEP will be provided.  
 
To summarize, preliminary results of the PEOPLE trial indicate that to interrupt transmission of leprosy 
in all probability requires a stronger prophylactic regimen than the current SDDR-PEP, in particular in 
high endemicity environments such as Comoros. A combination of bedaquiline and rifampicin is 
expected to have a synergistic effect and could still be provided as a single dose, even if repeated once 
after four weeks for household contacts.[22] To achieve maximal impact of a single administration, 
safety and pre-clinical data support bedaquiline at 800mg. The available set up in Comoros, established 
for the PEOPLE trial, presents an ideal backdrop for a follow-up trial. In addition we will assess the 
potential of PGL-I sero surveys as a tool to measure transmission of M. leprae and we will closely 
monitor for any potential emergence of resistance against bedaquiline or rifampicin both in leprosy 
and in TB patients.    
 
2. STUDY OBJECTIVES AND OUTCOMES 
The study is made up of two parts, a phase 2 study to reconfirm the safety of the trial regimen, i.e. the 
combination of bedaquiline and rifampicin administered as a single dose, and a phase 3 study in which 
we will evaluate effectiveness of this regimen in preventing leprosy, compared to the standard WHO 
regimen consisting of a single dose of rifampicin only. Implementation of the phase 3 study will be 


BE-PEOPLE, version 5.1, dated 01 March 2023 13 of 58 
conditional upon the safety results of the phase 2 study. In addition will enroll leprosy patients 
diagnosed, as well as tuberculosis patients, to monitor resistance against the study drugs. We will also 
conduct a PGL-I sero survey in part of the study population for whom earlier PGL-I data are available 
to assess the potential of such surveys as a tool to monitor transmission of M. leprae. These sub-studies 
are an integral part of BE-PEOPLE because we need to be able to monitor whether resistance against 
the drugs used, bedaquiline and rifampicin, is emerging, from the earliest possible stages. Also we 
need to be able to assess whether post exposure prophylaxis has an impact not only on progression 
from infection to disease but on transmission as well; this requires a tool that needs to be validated.  
2.1 Phase 2 study 
2.1.1 Primary: 
To confirm safety of the study regimens, single dose bedaquiline plus rifampicin and single dose 
rifampicin, in a field setting in Comoros 
 
Outcome: Advice by DSMB on whether or not phase 3 trial can be implemented as foreseen 
in this protocol, taken into account QTc data, observed (S)AEs and predetermined stopping criteria.    
 
2.1.2 Secondary 
1. To determine the baseline frequency of ALT and AST elevations and QTc prolongations in the 
population. 
2. To document for each of the two regimens post administration QTc levels, as well as any 
potentially frequent adverse events such as gastro-intestinal (nausea, vomiting), nervous 
system-related (headache, dizziness) and cutaneous reactions. 
2.2 Phase 3 study 
2.2.1 Primary 
To evaluate effectiveness of PEP based on a combination of rifampicin and bedaquiline (BE-PEP), in 
preventing leprosy among contacts of incident cases. 
Outcome: The incidence rate ratio of leprosy between contacts who received the trial 
regimen (BE-PEP: rifampicin 600 mg plus bedaquiline 800mg, repeated once after 
four weeks for household contacts) and those who received the WHO standard 
prophylactic regimen (SDR-PEP: rifampicin 600 mg, single dose). 
 
2.2.2 Secondary 
1. To assess effectiveness of the BE-PEP regimen at village level. 
Outcome: The incidence rate ratio between villages that received BE-PEP and villages 
that received SDR-PEP.  
 
2. To quantify frequency of potential adverse events such as gastro-intestinal (nausea, vomiting), 
nervous system-related (headache, dizziness) and cutaneous reactions. 
Outcome: The proportion of participants treated with BE-PEP that report adverse 
events, with a breakdown by type of event.  
 
3. To assess anti-PGL-I sero surveys as a tool to monitor leprosy transmission 
  
Outcome: Age specific anti-PGL-I sero prevalence rates in villages belonging to arm 4 
     
of the original PEOPLE trial at the time of the first survey round in 2019 and the final  
  
round of BE-PEOPLE in 2026 
 
4. To monitor rifampicin and bedaquiline resistance among leprosy and tuberculosis patients 


BE-PEOPLE, version 5.1, dated 01 March 2023 14 of 58 
Outcome: We will quantify the prevalence of rifampicin and/or bedaquiline resistant 
strains of M. leprae and M. tuberculosis on each of the study islands making use of 
molecular markers.  
 
5. To assess cost-effectiveness of the BE-PEP regimen compared to SDR-PEP. 
               Outcome: Cost per case averted between BE-PEP arm and SDR-PEP.  
 
 
3. STUDY DESIGN 
3.1 General study design 
We will conduct a phase 3 intervention trial comparing the effectiveness of two different regimens of 
post exposure prophylaxis for leprosy. Because we will be using a new drug (bedaquiline) that has not 
been used before for this indication, we have planned a phase 2 safety study to start in July, 2022. For 
this study we will select a small village (Gégé, Anjouan) that is part of the comparator arm of the 
PEOPLE trial and in which to date eight leprosy cases were diagnosed but that will not be included in 
the BE-PEOPLE trial because of its small population size (n=908). In this village, in May 2022, we will 
conduct the final round of door-to-door screening for leprosy in the framework of the PEOPLE trial. All 
cases identified will be treated in accordance with the national standards. Upon completion of 
screening, a random sample of 150 participants not meeting the exclusion criteria will be offered BE-
PEP with strict monitoring for adverse events, in particular ECG and liver function will be monitored 
pre- and post-drug administration. The remainder will receive single dose rifampicin (SDR-PEP), as per 
WHO recommendation. Of those a random sample of 150 will also be subjected to the same 
procedures for monitoring adverse events as those receiving BE-PEP. Results will be presented to an 
independent data safety management board and the regulatory authority in the Comoros who will 
then decide whether or not the main phase 3 trial can go ahead. The full BE-PEOPLE study is expected 
to run from January, 2022 until 4 year follow-up is finished in all phase 3 participating villages (expected 
by the start 2027) A Gantt chart of the main project activities is presented in figure 2 below. 
 
The BE-PEOPLE study is a follow-up to the ongoing PEOPLE study, in Comoros only. Baseline screening 
will take place in 2022 and the beginning of 2023, partially overlapping with the final screening round 
of PEOPLE. We will then re-randomize 34 out of 48 villages that were already part of PEOPLE as well 
as 10 new clusters to two new study arms: arm 1 in which BE-PEP i.e. bedaquiline (400 or 800 mg 
depending on weight band) combined with rifampicin (10 mg/kg) will be provided as post-exposure 
prophylaxis, and arm 2 in which only SDR-PEP (rifampicin 10 mg/kg) will be provided. Anyone living 
within 100 meters of an index case (PEP zone) will be eligible for PEP. In case 50% of the village 
population or more lives within 100 meters of an index case the PEP zone will be extended to the entire 
village. For the first PEP distribution at village level any leprosy case included in the study population 
detected during the annual village screening or in the preceding five-year period, i.e. since January 1st, 
2018 will be considered an index case. The following years, any leprosy case detected after the last 
year9s screening up to and including the village9s screening round of the current year will be considered 
an index case.  
 
Annual village screening rounds will take place for 4 years starting in 2023. When annual screening is 
completed in a village, a list of eligible households (based on the PEP zone) will be elaborated followed 
up with PEP intervention to those individually eligible based on annually evaluated inclusion and 
exclusion criteria listed in the protocol. If a participant whose village is randomized to the BE-PEP arm, 
is individually ineligible for BE-PEP, but individually eligible for SDR-PEP, the participant may receive 


BE-PEOPLE, version 5.1, dated 01 March 2023 15 of 58 
SDR-PEP. Because there has been no distribution of PEP during the final PEOPLE survey round in 2022, 
all participants will in principle be eligible again for PEP when the BE-PEOPLE intervention starts in 
2023.  
 
The final screening round will take place 4 years after the first screening round in 2023 and will in a 
subset of villages (those that belonged to arm 4 of PEOPLE) be followed by a serological survey (PGL-I) 
aimed at measuring prevalence of infection with M. leprae.  
 
As we did in the PEOPLE trial, we will continue to enroll all leprosy patients who are detected island- 
wide on Anjouan and Mohéli in a sub-study for which a separate informed consent will be asked. This 
also includes patients from outside BE-PEOPLE villages. For each consenting leprosy patient identified 
different samples can be taken such as a slit skin smears, blood sample, nasal and tongue swabs, 
tongue scraping, face mask sampling, and a skin biopsy  from the edge of a lesion, except if there are 
only facial lesions. These samples are subjected to qPCR and, if positive with a sufficiently high bacterial 
load, DNA is tested for mutations associated with resistance against bedaquiline, rifampicin, dapsone 
and fluoroquinolones. [26] This sub-study is an integral part of BE-PEOPLE because without it we will 
not be able to monitor resistance to the study drugs. So far out of 1030 patients sampled in the PEOPLE 
trial, 755 (73.3%) were confirmed qPCR positive whereas none of the negative control samples that 
are concurrently collected in the field tested positive, indicative of the high quality of diagnostic 
procedures in the field. Out of 260 biopsy extracts that had sufficient DNA for processing with Deeplex 
Myc-Lep, none showed any indications of drug resistance, not even minority populations (S. Braet, 
manuscript in preparation). This component will continue as part of the quality assurance of the BE-
PEOPLE trial as well as for monitoring emergence of drug resistance.  
 
We will also enroll all tuberculosis patients from all villages on all three islands of Comoros, for 
surveillance of bedaquiline and/or rifampicin resistance on sputum samples and possibly tongue- and 
nasal swabs. This sub-study too is an integral part of BE-PEOPLE because when distributing rifampicin 
and bedaquiline on large scale it is imperative to monitor for even the earliest signs of possible drug 
resistance emerging. The reason for including the third island, Grande Comore, where no bedaquiline 
will be administered, is to identify any baseline (minority) bacterial populations with mutations in gene 
Rv0678, implicated in low level bedaquiline resistance, as control group. Table 1 below provides and 
overview of the main activities over the project period. 
 
Year  
Activity 
2022, 2023 
Phase 2 
study 
Baseline screening + 
randomization 
Sampling 
leprosy patients 
 
 
Year 1 
Start in 2023 
Phase 3 
study 
Screening Arm 1 & 2 
+ PEP intervention 
Sampling 
leprosy patients 
Sampling 
TB patients 
 
Year 2 
Phase 3 
study 
Screening Arm 1 & 2 
+ PEP intervention 
Sampling 
leprosy patients 
Sampling 
TB patients 
 
Year 3 
Phase 3 
study 
Screening Arm 1 & 2 
+ PEP intervention 
Sampling 
leprosy patients 
Sampling 
TB patients 
 
Year 4 
Phase 3 
study 
Final screening  
Arm 1 & 2 
Sampling 
leprosy patients 
 
PGL-I survey 
Table 1: Time table BE-PEOPLE 
 
Participants in the new villages will be asked for informed consent for baseline screening in 2022. 
Informed consent for the phase 3 intervention trial will be asked during the first intervention round in 
2023, when we know to which study-arm villages have been randomized. Informed consent for the 
leprosy patient cohort will remain separate, the same applies to the TB patients being enrolled. For 
the PGL-I survey in 2026, separate informed consent will be asked ahead of the survey. 


BE-PEOPLE, version 5.1, dated 01 March 2023 16 of 58 
 
Figure 1 below shows how villages belonging to the various arms of PEOPLE will merge into BE-PEOPLE. 
We have dropped some villages that had a low incidence so far during the PEOPLE trial or a small 
population size. To arrive at the required sample size we will also include nine new villages, eight on 
Anjouan and one on Mohéli, the latter to be split into two clusters. Villages will be arranged by PEOPLE 
study arm and by island in order of decreasing prevalence during the 2022 baseline survey and 
regrouped into pairs.  Within each pair they will be randomized to arm 1 or arm 2 of BE-PEOPLE. 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 17 of 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
* One village on Mohéli (the capital Fomboni) will be split into two clusters 
         1 Arm 1: PEP regimen bedaquiline (400 or 800 mg) plus rifampicin (10 mg/kg) 
         2 Arm 2: PEP regimen rifampicin (10 mg/kg) 
 
Figure 1: Inclusion and randomization BE-PEOPLE (Phase 3) trial 
 
The main outcome measure of BE-PEOPLE will be the incidence rate ratio of leprosy between 
individuals in arm 1 who received BE-PEP and individuals in arm 2 who received SDR-PEP, controlled 
for potential confounding by distance to nearest index case at baseline, as well as for contextual 
confounding through the use of a random effects model (village nested within island). To avoid a 
potential selection bias, those who received SDR-PEP but would not have been eligible for BE-PEP, i.e. 
children below the age of 5 or with a weight below 20 kg, will be excluded from this analysis. Details 
are described in chapter 9, 8Data analysis9.  
 
We will make optimal use of the setup created in the PEOPLE project with five survey teams on the 
island of Anjouan and two on the island of Mohéli that have recorded and georeferenced all study 
participants to date in the PEOPLE trial (> 85,000). In addition, on both islands there are central teams 
that supervise activities in the field, confirm leprosy suspects identified, sample leprosy patients for 
molecular confirmation, and supervise their treatment.  
 
Immediately following the final round of door-to-door screening of BE-PEOPLE a PGL-I survey will be 
conducted covering eight villages that originally were part of arm 4 of the PEOPLE trial (n = 17,000), 
with the aim of comparing age specific seroprevalence rates to those at baseline of PEOPLE, in 2019. 
The purpose of this comparison is to assess whether anti-PGL-I surveys have potential as a tool to 
monitor leprosy burden and -transmission. Earlier studies in Indonesia and Brazil have shown mixed 
results. [27, 28]  
 
Detailed records on costs will be maintained allowing an assessment of cost effectiveness of BE-PEP 
compared to SDR-PEP.  
Figure 2 below shows a Gantt chart  of all activities planned throughout the project.
New villages 
Anjouan (8) 
Mohéli (1*) 
Arm 1 PEOPLE 
Anjouan (6) 
Mohéli (2)  
Arm 2 PEOPLE 
Anjouan (6) 
Mohéli (2) 
Arm 3 PEOPLE 
Anjouan (8) 
Mohéli (0) 
Arm 4 PEOPLE 
Anjouan (6) 
Mohéli (2) 
Arm 1 BE-PEOPLE1 
Anjouan (4+3 +3+4+3) 
Mohéli (1+1+1+1+1)  
Arm 2 BE-PEOPLE2 
Anjouan (4+3 +3+4 +3) 
Mohéli (1+1+1+1+1)  
    Baseline 
    Intervention 
Randomization


BE-PEOPLE, version 5.1, dated 01- March-2023 
 
18 of 58 
 
Figure 2: Gannt chart of the BE-PEOPLE trial 
 
 
 
2022 
2023 
2024 
2025 
2026 
2027 
Activity 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
1. Obtaining ethics and administrative approval for study 
protocol 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Finalizing study procedures 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Conduct Phase 2 study 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. Go no-go decision for phase 3 based on advice of DSMB 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Obtain green light from authorities in Comoros for phase 3 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. Baseline survey BE-PEOPLE 
(overlaps with final survey of PEOPLE in 32 villages) 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. Randomization BE-PEOPLE arm 1 and 2 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. First Leprosy screening round BE-PEOPLE, Provide SDR-PEP 
and BE-PEP 
 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. Second Leprosy screening round BE-PEOPLE, Provide SDR-
PEP and BE-PEP 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
10. Third Leprosy screening round BE-PEOPLE, Provide SDR-PEP 
and BE-PEP 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
11. Final Leprosy screening  round BE-PEOPLE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
12. Continue sampling of incident leprosy patients 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
13. Sampling incident tuberculosis patients 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
14. Collect costing data 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
15. Analyze costing data 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
16. Anti-PGL-I testing of former arm 4 villages 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
 
17. Interim analyses 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
18. Cost effectiveness analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
19. Final analysis on effectiveness of BE-PEP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 


BE-PEOPLE, version 5.1, dated 01- March-2023 
 
19 of 58 
 
4. PARTICIPANTS, POPULATION & SELECTION 
4.1 Study settings 
The study takes place in Comoros, an island nation in the Indian ocean, just north of Madagascar. We 
will build on the existing setup of the PEOPLE trial on the islands of Anjouan and Mohéli. In Comoros 
the national leprosy and tuberculosis control program (NLTCP) provides free diagnostic and treatment 
services for both diseases, in accordance with international standards. The NLTCP is supported by 
Damien Foundation, an international NGO with headquarters in Brussels, Belgium. In Comoros the 
leprosy burden is concentrated on two of the three islands, Anjouan and Mohéli. On the main island, 
Grande Comore, only sporadic leprosy cases are reported, with higher notifications of tuberculosis. 
Rifampicin resistant tuberculosis is exceedingly rare, and has not yet been observed since introduction 
of universal Xpert MTB/RIF testing in 2017. Patients with skin conditions can present at public health 
centers where they are examined by general health services staff who have been trained in diagnosing 
and treating leprosy. They are supervised by staff from the NLTCP, to whom they can also refer 
patients for consultation. Specific treatment for leprosy is provided free of charge, either directly or 
through the primary healthcare system. In addition outreach campaigns at village level are organized 
in which persons with skin conditions are invited to present themselves for screening. Free treatment 
is provided for minor skin conditions and any leprosy patient diagnosed receives full treatment. Such 
outreach campaigns, also called 8mini-campaigns9 have been introduced in Comoros since 2008. For 
the BE-PEOPLE trial, door-to-door screening activities will be carried out by teams that were 
established in the framework of the PEOPLE study which will be complemented by several new teams, 
under the direct supervision of the NLTCP and under responsibility of the country PI. The teams will 
receive the necessary protocol and (refresher) GCP training prior to the start of the BE-PEOPLE study. 
They will also receive training on aspects of concomitant medication. Any leprosy patients identified 
will be treated according to the national guidelines of Comoros, which are in accordance with WHO 
guidelines. 
 
4.2 Study population and selection criteria 
For the phase 2 study we have selected the village of Gégé, a leprosy endemic village on the island of 
Anjouan at one hours9 driving distance of the main hospital in the capital. The village has an estimated 
population of approximately 900 and is currently part of arm 1 op PEOPLE, the comparator arm. 
Therefore no PEP has been provided yet although 8 leprosy cases were diagnosed during the PEOPLE 
trial so far. The village will be screened once more in the framework of the PEOPLE trial, in May, 2022. 
After this final screening, BE-PEP and SDR-PEP will be provided for the phase 2 study of BE-PEOPLE. 
The village will not be part of the phase 3 study of BE-PEOPLE. A random sample of 150 eligible 
participants will receive BE-PEP, the remainder will receive SDR-PEP. Those receiving BE-PEP as well 
as a random sample of 150 among those receiving only SDR-PEP will be strictly monitored for adverse 
events. As an additional safety measure BE-PEP administration will start with adults 18 years and 
older, followed by children aged 13-17, and finally children aged 5-12. Provision of BE-PEP to children 
aged 13-17 will start once post BE-PEP QTc measurements for adults are available and have shown no 
indication for concern, similarly distribution to children aged 5-12 will start once post BE-PEP QTc 
measurements for children aged 13-17 are available and show no reasons for concern.  
 
Inclusion and exclusion criteria for the phase 2 study will be the following: 
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.  
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 20 of 58 
 
 
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. 
 
 
Children between 2 and 5 years of age or weighing between 10 and 20 kg will be offered SDR-PEP but 
not BE-PEP.  
 
For the phase 3 study we will include 34 villages already part of the PEOPLE trial plus 9 additional 
villages/towns, they will be regrouped into 44 clusters be randomized to arms 1 or 2. New 
villages/clusters selected include the town of Fomboni on Mohéli and the villages of Adda Daoueni, 
Domoni, Koni Djodjo, Koni Ngani, Dzindri, Ouani, Mirontsi and Tsembéhou on Anjouan. Fomboni will 
be split into two clusters, of the other villages we will retain either the entire village or the part with 
the highest leprosy prevalence. As will be explained in more detail in the section on sample size, we 
aim to include a total study population of approximately 124,000 for the new trial, approximately 30% 
of the total population on Anjouan and Moheli. The phase 3 study population will consist of everyone 
who gave their informed consent to participate in the study and was screened at least once 
throughout the 4 years. 
 
Every year the individual inclusion and exclusion criteria for PEP listed below will be checked for  all 
participants who are part of a household living in the annually calculated PEP zone before PEP 
distribution: 
 
Inclusion criteria PEP (SDR-PEP & BE-PEP): 
1. Living in one of the study clusters (34 on Anjouan, 10 on Mohéli), in good state of health 
2. Age & weight 
a. SDR-PEP: Aged 2 years and above and weighing 10kg or more, as leprosy is very 
rare among infants and young toddlers.  
b. BE-PEP: Aged 5 years and above and weighing 20kg or more 
If PEP eligible they will receive only rifampicin.  
3. Able and willing to provide informed consent  
4. Examined for leprosy & TB  
 
 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 21 of 58 
Exclusion criteria PEP (SDR-PEP & BE-PEP): 
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. Having received rifampicin or bedaquiline (if applicable) in the last 2-year period 
5. Self-reported (suspected) pregnancy or breastfeeding 
6. Self-reported history of liver or kidney problems 
 
Exclusion criteria only valid for BE-PEP: 
1. Concurrent (within the last three week period before PEP administration) use of 
medication not present on the 8safe9 list  
 
 
Remarks regarding PEP distribution: 
• 
Children between 2 and 5 years of age or weighing between 10 and 20 kg or people taking 
medication from the unsafe list will be excluded from BE-PEP and offered SDR-PEP if eligible.  
• 
Study participants living in the PEP zone but ineligible for PEP due to the PEP inclusion or 
exclusion criteria or being absent during the village PEP distribution round will not be 
automatically included in the PEP distribution the following year. It is possible that a study 
participant is not eligible one year due to the PEP inclusion or exclusion criteria but will be 
eligible for PEP the next year when the household is again part of the newly calculated PEP 
zone and the individual inclusion or exclusion criteria are respected.  
• 
Household contacts of an index case in the BE-PEP arm absent during the 1st annual PEP 
distribution but present during the 2nd annual PEP distribution will only be offered PEP once 
that year and will not be revisited after 30 days.   
• 
Participants who are not BE-PEP eligible due to concomitant medication not present on the 
8safe list9 can be provided SDR-PEP, provided they do not meet any other exclusion criteria. 
• 
Children who are not BE-PEP eligible solely for not meeting age and weight criteria, can be 
provided SDR-PEP if aged 2 years or above and weighing 10 kg or above. 
 
All leprosy patients diagnosed during the study period, even those from non-study villages, will also be 
enrolled in a sub-study in which potentially a nasal/tongue swab, a tongue scraping sample, face mask 
sample and skin biopsies  will be collected from non-facial lesions. qPCR on these samples will allow to 
verify the accuracy of the clinical diagnosis and further processing with Deeplex Myc-Lep V3 of qPCR 
positive samples (or WGS if needed), will allow to monitor drug resistance and assess the impact of 
the intervention on transmission of M. leprae. As drug resistance may also affect treatment for 
tuberculosis, we will also sample all GeneXpert positive tuberculosis patients identified on Anjouan, 
Mohéli, and Grande Comore during the study period for drug resistance testing with Deeplex Myc-TB 
XL, and verify whether they received rifampicin and/or bedaquiline in the past.   
 
 
 
 
 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 22 of 58 
4.3 Sample size 
The sample size for the phase 2 trial is based on non-inferiority of the BE-PEP regimen compared to 
the SDR-PEP regimen in terms of adverse events, in particular QTc prolongation. We assume that in 
the SDR group the mean QTc will be equal to that of a reference population, i.e. 384 ms (SD 20 ms) 
based on the Fridericia correction method. [29]   
 
The sample size calculations were performed by simulation, in a scenario where there is truly no 
difference between the standard and experimental treatment. A sample size of 64 patients are 
required per arm to achieve 80% power in the comparison that the upper limit of a one-sided 95% 
confidence interval will be below the non-inferiority limit of +10 ms.  
 
For this part of the trial we have selected a village with a total recorded population of 908, 51% of 
whom are aged 18 years or above. As explained in chapter 4.2 above, as a matter of precaution we will 
first enroll adults and preliminarily assess their outcomes before we will start enrolling minors. The 
numbers of adults to be enrolled will be proportional to the observed age distribution at the time of 
the 2022 survey. To arrive at an accurate estimate of mean QTc for adults as well as for minors, we will 
recruit 150 participants per study arm, approximately 75 adults and 75 minors.  
 
Overall, all ages combined, our intended sample size of 150 in each arm, which will provide 99% power 
to show that the upper limit of a one-sided 95% confidence interval will be below the non-inferiority 
limit of +10ms, assuming that in the larger population QTc does not differ between those receiving 
SDR-PEP and those receiving BE-PEP.  Sample size calculations were done in R version 4.0.2.[30]  
 
To calculate the sample size required for the phase 3 trial, with the main objective of assessing the 
impact of BE-PEP versus SDR-PEP on leprosy risk at individual level, we used the methodology 
described by Hayes and Bennet for cluster randomized trials.(10) Our aim is to show a 50% reduction 
in risk of leprosy over a 3-year period for those that received BE-PEP (arm 1) compared to those that 
received SDR-PEP (arm 2). We assume that in the latter arm the risk over a 3-year period will be 0.0033, 
i.e. 1.1 per 1,000 per year. The mean population size of the villages targeted is 2,819, however children 
below 5 years of age or weighing below 20 kg are not eligible for BE-PEP and make up 27% of the 
population. Even though part of them will be eligible for SDR-PEP, we will exclude them from this 
analysis because the risk of leprosy varies with age. We will therefore only compare individuals aged 5 
years or above and weighing 20 kg or above. We also took into account the participation rate, i.e. the 
proportion of eligible participants that agreed to take PEP, which in the PEOPLE trial was 83%. Thus on 
a population of 2,850, only 1,708 will effectively be available for analysis. For the PEOPLE trial we 
calculated a coefficient of variation between clusters (κm) of 0.34, in the BE-PEOPLE trial we assume a 
slightly higher Km, 0.4. To achieve a power (1-β) of 90% with an average cluster size of 1,708 and α = 
0.05, 22 clusters per study arm would be required, i.e. 75,152 subjects for the two arms combined. To 
enroll 75,152 eligible subjects we need to target a population of approximately 124,000 in total. We 
therefore selected 43 villages with a total population of 124,035, of which one will be divided into two 
clusters.  
 
Of the 43 villages selected, 34 are already enrolled in the PEOPLE trial with a total population of 
approximately 73,000. In addition we have selected 9 new villages with an estimated available 
population of 51,000. For the new villages we have assumed a coverage of 50% only as they are large 
villages and we will exclude the neighborhoods from which leprosy patients are seldom reported.  
 
For the secondary objective of assessing the effect of BE-PEP at village level, the entire population 
examined will be considered in the analysis. If incidence at village level is 1.1 per 1,000 per year, as 
observed in the PEOPLE trial, and a 50% reduction is achieved with BE-PEP, the available sample size 
would provide a power of approximately 90% over a three-year follow-up period.   


BE-PEOPLE, version 5.1, dated 01 March 2023 23 of 58 
 
For the surveillance for resistance in tuberculosis patients, with the Deeplex Myc-TB XL, we will include 
all microbiologically confirmed TB patients on the three islands of Comoros, and request samples that 
may include tongue and nasal swabs, in addition to sputum. Annually 50-60 such patients are being 
reported in recent years. Elsewhere, minority bacterial populations with mutations in M. tuberculosis 
gene Rv0678, an efflux pump regulator, which can give low level bedaquiline resistance, have 
sporadically been found in patients and populations never exposed to bedaquiline or clofazimine. We 
therefore will do this surveillance throughout BE-PEOPLE phase 3, also include as controls TB patients 
identified in Grande Comore, where bedaquiline is not used. 
4.4 Randomization 
For the phase 2 safety study we will first complete the final survey round of the PEOPLE study and then 
enumerate all those aged 5 years or above, weighing 20 kg or above and not currently suffering from 
leprosy.  They will be divided into three age categories, 5-12 years, 13-17 years, and 18 years and 
above. We will then determine the overall proportions of the three age groups, the proportion 
multiplied by 150 will be the number of participants to be recruited per study arm for each age group. 
Next we will prepare sealed envelopes containing a note indicating either BE-PEP or SDR-PEP as PEP 
regimen, 300 in total. They will be divided into three groups with equal numbers per PEP regimen, one 
group of envelopes for each of the three age categories.  
 
The next step will be to enroll the required numbers of adults (age 18 years and above) by visiting the 
households one by one and inviting eligible subjects to be enrolled. Each time a person agrees, an 
envelope will be drawn and either SDR-PEP or BE-PEP will be provided as indicated on the note inside 
the envelope. This process will continue until all envelopes for adults have been allocated. Provided 
no concerning adverse events are observed, the procedure will be repeated for the 13-17 years old. 
Again if no concerning adverse events are observed, the 5-12 years old will be enrolled following the 
same procedure. The remainder of the village population aged 2 years and above and not meeting 
other exclusion criteria will then be offered SDR-PEP.  
 
Randomization for study arms 1 and 2 of the phase 3 study, will take place upon completion of the 
baseline survey. We will then arrange all villages by island and by group (former arm 1, 2, 3 or 4 or new 
villages), in order of decreasing prevalence. As was explained earlier, Fomboni, the capital of Mohéli, 
will be split into two clusters. Thus we will arrive at 22 pairs of clusters. Blocked randomization will be 
used to allocate clusters into the two study arms. The randomization schedules will be prepared by an 
independent sponsor biostatistician. The randomization list will be prepared using SAS 9.4 (SAS 
Institute, Cary NC). 
 
 
 
 
 
 
 
 
 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 24 of 58 
4.5 Withdrawal and termination of the study 
4.5.1 Reasons for Withdrawal from the study 
Participants may be withdrawn from the study if they withdraw consent.   
4.5.2 Reasons for Withdrawal from the study intervention 
Participants may be withdrawn from the study intervention if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the subject. Examples of this are  
• 
When a patient is found to be pregnant 
• 
Treatment limiting adverse events (e.g. kidney or liver failure, or severe vomiting) 
• 
Need for medication that interferes with study medication 
• 
Changes that make patients no longer eligible for the study intervention according to inclusion 
criteria 
Patients that are withdrawn from the study intervention will still be followed up as planned, since they 
will be analyzed in the ITT population. 
4.5.3 Handling of Withdrawals 
For participants that withdraw consent, no further evaluations will be performed, and no efforts to 
collect information will be carried out. These participants will be referred to routine care for further 
treatment if required.  
For participants withdrawn from the study intervention, thorough efforts will be made to document 
study outcomes and safety data (three attempts to contact the participant in his/her home unless it is 
clear that the participant will not return or refuses further contacts). Participants will be scheduled for 
their regular follow-up visits, will undergo all study procedures and will be analyzed in the ITT analysis 
until the end of the study. Data collected up to the time of withdrawal will remain in the study data 
base and be used for analysis whether or not the participant continues with the follow-up visits.  
Participants withdrawn from the study intervention for medical reasons will be referred to adequate 
health facilities for further care if necessary. The reason for withdrawal will be documented on the 
CRF.   
4.5.4 Lost to follow-up 
Patients will be considered lost to follow-up if not present during the fourth and  final survey round., 
after one additional attempt has been made to contact them. In this case follow-up time will be 
calculated based on the last available follow-up.  
4.5.5 Termination of Study  
The end of the study is defined as the date of the last visit (or last contact) of the last patient in the 
study. 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the 
reason(s) for the termination or suspension. The ECs will also be informed promptly and provided the 
reason(s) for the termination or suspension by the Sponsor or by the investigator/institution, as 
specified by the applicable regulatory requirement(s). 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 25 of 58 
5. STUDY PROCEDURES 
5.1 General Study Procedures 
The study has been planned in two phases. The main, phase 3 study will be preceded by a phase 2 
study in the village of Gégé on Anjouan. In this village we will conduct door-to-door screening for 
leprosy in May, 2022, coinciding with the final screening round of the PEOPLE study. We will then ask 
for informed consent for inclusion in the phase 2 study of BE-PEOPLE. To those who consent we will 
provide post exposure prophylaxis with BE-PEP or SDR-PEP with intensified safety monitoring, as was 
described in chapter 4.4 above. Safety monitoring will include an ECG taken less than 1 week before 
treatment  and approximately 24 hours after treatment, as well as liver function tests less than 1 week 
before and 14 days after treatment. In case of an ALT/AST elevation adverse event on visit D14 or 
absolute AST/ALT value increase of >=35 between the prerecruitment visit and visit D14, liver function 
tests will also be included on visit D30. The team, including a medical doctor will be present during 
the PEP administration round (=D0), as well as the day after (=D1) to collect safety data (including 
QTc). The team, again including a medical doctor, will investigate the participant at the study center 
14 days after (=D14) to collect additional safety data (ALT + AST) and to follow up on any ongoing 
(S)AE9s. In case any SAE9s are ongoing during the visit on D14 additional visits will be organized to 
follow up. A final visit to collect adverse events will be organized on D30 at the participant9s house. In 
case liver function tests are necessary on visit D30, the participant will be invited to the study house 
for visit D30. 
 
In case of any serious adverse events, transport to the hospital in the island capital Mutsamudu will 
be ensured, where cardiological care is provided including monitoring, electrolyte correction, and 
cardiac resuscitation. A project vehicle will be on standby in the village for this purpose. The results of 
this phase 2 safety study will be presented to the data safety monitoring board (DSMB), involved 
ethical committees, and local regulatory authority who will provide an opinion on whether or not the 
green light can be given for the main phase 3 study.  
 
Ahead of the main phase 3 study and partially overlapping with the phase 2 study we will conduct the 
baseline screening which will cover 34 villages already part of the PEOPLE study (part of PEOPLE study), 
plus nine additional villages (specific for BE-PEOPLE study). Conditional on a positive advice by the 
DSMB and approval by the applicable (local) ethical and regulatory authorities, randomization will 
take place after screening activities in all villages are finished for the phase 3 study to start.  
 
During the phase 3 study, each village will be screened door-to-door annually for four in a row years 
starting in 2023. Every year the PEP zone will be determined  in each village and PEP will be provided 
to those eligible. Prior to the start of the study the village elders will be informed on procedures and 
purpose of the study, followed by community sensibilization. During the first screening for leprosy, 
residents of the selected villages will be checked for eligibility informed on all study procedures, and 
requested to provide informed consent. Those previously enrolled in the PEOPLE trial will be asked 
informed consent for enrolment in the new trial in 2023, once we know to which study arm they have 
been randomized. Participants in the new villages will be asked informed consent twice, first for the 
baseline screening and again in 2023, when we know to which study arm they have been randomized.  
 
After informed consent has been obtained, the health worker will perform a physical examination to 
look for signs of leprosy and TB. Diagnosis of leprosy will be made based on the so-called cardinal 
signs, i.e. a patch with loss of sensation, enlarged peripheral nerves and/or a slit skin smear positive 
for acid fast bacilli. Results of qPCR testing will not be used as diagnostic criteria, as the test is at best 
85% sensitive, less so in paucibacillary patients. For patients with doubtful clinical signs, the diagnostic 
team does not classify them as having leprosy, yet revisits them in subsequent months for repeat 


BE-PEOPLE, version 5.1, dated 01 March 2023 26 of 58 
diagnostic investigation, per routine care. The health worker will also collect the necessary additional 
personal information from every individual enrolled. 
 
Afterwards the PEP zone will be determined and a list of households living in the PEP zone will be 
provided to the teams who will revisit the participants. In case the participant is eligible for PEP (i.e. 
belonging to a household in the PEP zone and individual PEP inclusion/exclusion criteria are 
respected), the correct dose of bedaquiline and/or rifampicin will be distributed according to the 
schedule below: 
- 
<10 kg or age <2 years  
: No PEP 
- 
≥10-<20 kg and age 2-4 years : rifampicin:150 mg 
- 
≥20-<30 kg and age ≥5 years 
: bedaquiline*: 400 mg, rifampicin: 300 mg 
- 
≥30-<45 kg 
 
 
: bedaquiline*: 800 mg, rifampicin: 450 mg 
- 
=>45 kg 
 
 
: bedaquiline*: 800 mg, rifampicin: 600 mg 
*Arm 1 only to participants eligible for BE-PEP 
 
The health worker will offer a snack and a drink to assist with the ingestion of the pills  and will witness 
the intake of the medication by the participant and enter relevant information in a designated app. 
All participants enrolled on PEP, will be re-visited by a health worker the next day (safety FU visit, 
window defined in table 3) to ask whether the PEP has not been vomited up and whether there have 
been any (serious) adverse events ([S]AE). In case of ongoing SAE9s at the safety FU visit, the team will 
conduct follow-up. In case PEP has been vomited, this will be recorded but the dose will not be 
repeated.  
 
The nature of the trial, requiring intake of different PEP regimens in different arms, makes blinding 
impossible. We will however use additional approaches to validate study results and detect possible 
observer bias, such as quantitative PCR (qPCR) testing of skin biopsy samples from leprosy patients 
diagnosed in both study arms. 
 
If a screened person is diagnosed with leprosy or TB, he/she will be requested to sign an additional 
consent form for the collection of samples. Irrespective of further participation in the study, this person 
will be treated as per the standards of the National Leprosy Control Program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 27 of 58 
 
 
 
 
Tables 2 and 3 below provide an overview of assessments during phase 2 and 3 respectively. 
 
TABLE 2: SCHEDULE OF ASSESSMENTS PHASE 2 
1 
Medical history deemed medically relevant for the study will be collected before signing informed consent to 
participate in the phase 2 trial. 
2 
All PEP treatment will be delivered by the health worker and intake will be directly observed. 
3 
Concomitant medication should be recorded from 3 weeks before D0 (day of IP administration) until 3 weeks after 
IP administration. After that concomitant medication should only be reported if given for an SAE.  
4 
In case of an ALT/AST elevation adverse events on visit day 14 or absolute AST/ALT value increase of >=35 between 
the prerecruitment visit and visit day 14, liver function tests will also be included on visit day 30. In this case the 
participant will be invited to the study house to conduct visit D30. 
 
 
Screening 
Enrollment 
Day 1 (V1) 
Day 14 (V2) 
Day 30 (V3) 
Timing (window) 
 
 
D0 
D1 (+0 d.) 
D14 (+-2 d.) 
D30 (+3 d.) 
Medical history1 
 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
Informed Consent 
 
X 
 
 
 
 
Clinical 
examination 
 
X 
X 
 
 
 
Blood sample for 
ALT/AST 
 
X 
 
 
X 
(X)4 
ECG 
 
X 
 
X 
 
 
IP Administration3 
 
 
X 
 
 
 
Concomitant 
medication4 
 
X 
X 
X 
X 
 
Adverse Event 
collection 
 
 
X 
X 
X 
X 


BE-PEOPLE, version 5.1, dated 01- March-2023 
 
28 of 58 
 
 
TABLE 3: SCHEDULE OF ASSESSMENTS PHASE 3  
 
Screening 
Y1 – Y4 
PEP zone 
Y1 – Y3 
PEP 1St dose 
Y1 – Y3 
Safety FU  
Day 1 
Y1 – Y3 
PEP 2nd dose 
BE-PEP6 
Y1 – Y3 
Safety FU  
2nd dose  
Day 1 
Y1 – Y3 
Timing (window) 
- V1 
- V2: V1+365 (+-90) 
- V3: V2+365 (+-90) 
- V4: V3+365 (+-90) 
- V1+25 (+-25)9 
- V2+25 (+-25) 9 
- V3+25 (+-25)9 
 
- D0:V1+30 (+-30)10 
- D1:V2+30 (+-30) 10 
- D2:V3+30 (+-30) 10 
 
- D0 +1 (+3) 
- D1 +1 (+3) 
- D2 +1 (+3) 
 
- D0*: D0 + 30 (+-7)  
- D1*: D1 + 30 (+-7) 
- D2*: D1 + 30 (+-7) 
 
- D0* +1 (+3) 
- D1* +1 (+3) 
- D2* +1 (+3) 
 
Enrolment participant1 
X 
 
X7 
 
 
 
Informed Consent 
X2 
 
X7 
 
 
 
Leprosy & TB physical 
examination 
X 
 
X7 
 
 
 
Eligibility based on PEP zone3 
 
X 
 
 
 
 
PEP Eligibility based on PEP 
Inclusion/exclusion criteria 
 
 
X 
 
X 
 
IP Administration 4,5 
 
 
X 
 
X 
 
Adverse Event collection  
 
 
X 
X 
X 
X 
Leprosy and/or TB sampling8 
(X) 
 
(X) 
 
 
 
1 
Every year new household members/household can be added to the study population  
2 
For new BE-PEOPLE villages (not included in the PEOPLE study) a baseline screening ICF is collected during the first screening visit. For villages enrolled in the PEOPLE study, informed 
consent was collected in this study to collect data and to share data with future research such as the BE-PEOPLE study. 
3 
PEP zone: Anyone living within a 100 meter radius of an index case or to the entire village if more than 50% of the population lives within a 100 meter radius of an index case 
4 
Conditional on Leprosy & TB physical examination, PEP inclusion and exclusion criteria and exposure to index cases 
5 
All PEP treatment will be delivered by the health worker and intake will be directly observed. 
6 
In arm 1, household contacts of an index case will receive an extra dose of BE-PEP after 4 weeks  
7 
Household members living in a household eligible based on the PEP zone but absent during screening can be enrolled and screened during the 1st dose PEP administration visit and 
receive PEP if eligible 
8 
If leprosy or TB clinical signs present, after collecting a specific ICF for leprosy index case or TB suspicion, samples to be collected. 
9 
+-25 after the last person screening (=V1) in a village during the annual screening round 
10 +-30 days after the last person screening (=V1) in a village during the annual screening round 
 
 
For all visits, especially important for safety FU visits: if a participant is not home (and is not permanently absent), the site staff should visit the household at least one more time to conduct the 
visit.  Participants will be informed they may always report adverse events by phone


BE-PEOPLE, version 5.1, dated 01- March-2023 
 
29 of 58 
 
5.2 Laboratory- and safety monitoring procedures  
5.2.1 Phase 2 pharmacovigilance: monitoring for hepatitis 
In the Phase 2 study, participants will have venous blood drawn within 1 week prior to PEP 
administration for baseline ALT/AST (GPT/GOT) determination on serum in a dedicated and calibrated 
biochemistry analyzer at the central laboratory in the hospital Hombo or Bambao. Those who at 
baseline have an ALT or AST value > 3 times the upper limit of normal (ULN) will not be offered PEP. 
The venous blood draw for ALT/AST determination will be repeated 14 days after PEP administration. 
In case of an ALT/AST elevation adverse events on visit D14 or absolute AST/ALT value increase of >=35 
between the prerecruitment visit and visit D14, liver function tests will also be included on visit D30. 
Any surplus remaining serum may be used for exploratory analyses of leprosy related biomarkers at 
the LUMC. 
 
5.2.2 Sampling schedule for clinically confirmed leprosy patients 
The local leprosy control teams on Anjouan and Moheli will be responsible for identifying new leprosy 
cases and collecting the samples. All samples will be identified by a patient-specific barcode only. A 
nasal/tongue swab , a tongue scraping sample, face mask sample and a skin biopsy sample from the 
lesion(s) (except from lesions in the face) may be collected from all newly diagnosed patients. In 
addition, for those patients who have MB leprosy, skin slit smears (SSS) are taken. Fingerstick blood 
samples will be collected from all newly diagnosed patients. 
 
Slit skin smears (SSS) will be collected from all consenting MB participants. The SSS will be taken from 
the two earlobes and one additional site presenting an active lesion. For this, skin will be pressurized 
and a small incision will be made in the skin and scraped, followed by spreading the smear over the 
surface of the glass slide. After drying the slides, they will be fixated by heating on site. The SSSs will 
be colored by the ZN staining in the local laboratories by the designated local leprosy control teams at 
the end of each day of sampling. The subsequent microscopy reading of these slides will be done in 
the local laboratories. Quality control of microscopy reagents is conducted at the central laboratory in 
Grande Comore. Rereading of slides is performed as quality assurance. 
 
Skin biopsy (SB) samples will be obtained from all consenting leprosy cases by using a 4 mm punch and 
the removed tissue placed in a sterile 1.5 mL tube and stored in a buffer for nucleid acids extraction 
(not for histopathology). Local anesthesia with 2% lidocaine will be administered subcutaneously prior 
to punching the biopsy. 
 
Nasal swabs (NS) will be obtained from all consenting leprosy cases by gently rubbing a perinasal swab, 
in one side of each nostril over the lateral conchae. After collection, the swab will be immersed (and 
broken off at the breakpoint) in a sterile and labelled tube containing a buffer.  
 
Tongue swabs (TS)  will be obtained from all consenting leprosy cases by gently rubbing 2/3rd of the 
tongue for 15 seconds. After collection, the swab will be immersed (and broken off at the breakpoint) 
in a sterile and labelled tube containing a buffer.  
 
Tongue scraping (TSC) may be obtained from all consenting leprosy cases by gently scraping with a 
tongue scraping device for 15 seconds. The sample on the scraper will be collected with a swab and 
immediately immersed (and broken off at the breakpoint)  in a sterile and labelled tube containing a 
buffer. 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 30 of 58 
Face mask sampling (FMS) may be obtained from all consenting leprosy cases. The patient will wear a 
duck bill surgical mask, containing a polyvinyl alcohol (PVA) strip, for 30 minutes. Thereafter the mask 
will be put in a plastic bag for further processing. 
 
 
Blood samples (BS) blood drops are obtained from all consenting leprosy cases by finger prick. The 
blood is captured in a capillary and subsequently put in a tube containing buffer. 
 
5.2.3 Sampling of presumptive TB patients 
 
Nasal swabs (NS) may be obtained from all consenting presumptive cases by gently rubbing a perinasal 
swab, in one side of each nostril over the lateral conchae. After collection, the swab will be immersed 
(and broken off at the breakpoint) in a sterile and labelled tube containing a buffer.  
 
Tongue swabs (TS)  will be obtained from all consenting presumptive cases by gently rubbing 2/3rd of 
the tongue for 15 seconds. After collection, the swabs will be put (and broken off at the breakpoint) in 
a sterile and labelled tube. 
 
Tongue scraping (TSC) may obtained from all consenting presumptive cases by gently scraping with a 
tongue scraping device for 15 seconds. The sample on the scraper will be collected with a swab and 
immediately immersed (and broken off at the breakpoint)  in a sterile and labelled tube containing a 
buffer. 
 
Face mask sampling (FMS) may be obtained from all consenting presumptive cases. The presumptive 
case will were a duckbill surgical mask, containing a polyvinyl alcohol (PVA) strip, for 30 minutes. 
Thereafter the mask will be put in a plastic bag for further processing. 
 
 
Two Sputa will be collected from the presumptive TB patients to confirm TB, which is part of routine 
diagnosis. 
 
5.2.4 Specific tests 
The molecular tests (RLEP qPCR, IS6110 qPCR, Deeplex Myc-Lep, Deeplex Myc-Lep-TB, WGS,... ) on all 
the samples (except for the fingerstick blood samples) will be executed by  ITM. In 2022, ITM tried to  
validate the RLEP LAMP assay against RLEP qPCR results so that the confirmation of leprosy patients in 
the trial could be performed in Comoros. However, the validation showed lower sensitivity for the 
RLEP LAMP assay, and therefore was not implemented. We search for other appropriate tools for 
molecular confirmation of leprosy in Anjouan and Moheli. Molecular tests are very important to assess 
the impact of the intervention on transmission of M. leprae and to closely survey the possible 
emergence of drug resistance. GeneXpert for identification of M. tuberculosis and some drug resistant 
targets will be done in the Comoros. 
 
During the final survey round in former arm 4 villages in 2026, analysis of the Anti-PGL I LFA (fingerstick 
blood sample) will be done by the local leprosy control team with a portable reader, with quality 
assurance performed by the University of Leiden. 
 
Slit skin smears 
The SSSs will be colored by the ZN staining in the local laboratories by the designated local leprosy 
control teams at the end of each day of sampling. The subsequent microscopy reading of these slides 
will be done in the local laboratories. 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 31 of 58 
Fingerstick blood 
The fingerstick blood collected in a buffer, will be brought to the local laboratory at the end of each 
day of sampling and run on the LFA strips (provided by the University of Leiden). The strips must dry 
up and are read by the portable reader (provided by the University of Leiden). 
 
Face mask samples 
Strips will be transferred into a 15 mL falcon tube containing 5 mL molecular-grade water. 
Subsequently, tubes will be loaded onto a shaker to dissolve the strips.  Then, the dissolution will be 
processed for molecular analysis, such as with GeneXpert. A surgical mask is a loose-fitting, disposable 
device that creates a physical barrier between the mouth and nose of the wearer and potential 
contaminants in the immediate environment. 
 
Skin biopsies , swabs , scrapings and SSSs 
a. Nucleic acids extraction: 
Nucleic acids will be extracted with the Maxwell LEV extraction procedure from biopsies, swabs, 
scrapings and slit skin smears.  
 
b. Diagnostic RLEP qPCR/LAMP: 
The RLEP qPCR is a highly sensitive and specific diagnostic qPCR, which targets the RLEP repetitive 
element, which is specific for M. leprae. This test targets 35 out of the 37 RLEP repetitive elements 
occurring in the genome of M. leprae. After nucleid acids extraction, all the samples will be processed 
by this RLEP qPCR. If the RLEP LAMP assay is validated against RLEP qPCR, it can be used for 
confirmation. For the swabs/scrapings collected from TB presumptive patients the IS6110 qPCR will be 
performed. 
 
c. Genotyping: 
Genotyping will be performed on DNA extracts that are M. leprae positive as defined by a positive RLEP 
diagnostic test. We expect that samples from all MB patients and a subset of PB patients will have 
sufficient DNA for further genotyping. Genotyping strains circulating in the country is essential for 
measuring the impact of the intervention of transmission and to survey the possible emergence of 
drug resistance. Whole genome sequencing may be done to obtain higher resolution on identification 
of transmission chains and to assess for mutations (outside the targeted regions of Deeplex Myc-Lep) 
that could possibly be linked with drug resistance. 
 
Genotyping will be done by a novel sequencing technique called the Deeplex® MycLep assay, which 
consists of a single hi-plex amplification of 18 phylogenetic SNPs, 11 VNTR markers, and drug resistance 
conferring gene regions followed by next generation sequencing analysis. This assay is being validated 
in the PEOPLE study. We will ask Genoscreen to expand the multiplex PCR with the M. leprae atpE 
target to be able to perform surveillance for bedaquiline resistance, resulting in a next version of the 
Deeplex® MycLep assay . M. leprae does not possess the efflux pump involved in M. tuberculosis cross 
resistance to bedaquiline and CFZ. ITM will perform amplification and targeted deep sequencing of the 
resulting amplicons, with quality control done at Genoscreen. 
 
Presumptive tuberculosis patients will be managed according to the national guidelines, not part of 
this study protocol. Sputum samples and possibly tongue swabs will be collected from patients with 
presumptive TB, and will be stored in ethanol after smear microscopy (sputum) and Xpert MTB/RIF 
(sputum and possibly tongue swabs). DNA will be extracted for Deeplex MycTB XL at ITM from those 
with sufficient bacillary burden.  WGS may be done to assess additional drug resistance targets of TB 
strains 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 32 of 58 
5.2.5 Shipment and storage of samples  
The samples from Comoros will be shipped to the ITM for further analysis. Fingerstick blood samples 
collected during the PGL-I survey will be shipped to LUMC. MTAs will be written accordingly and signed 
by all parties concerned. 
 
Samples will be stored for 20 years, as indicated in section 12.3 below this will be mentioned in the 
informed consent form. 
 
6. STUDY INVESTIGATIONAL PRODUCT 
6.1 Purchasing 
Bedaquiline in the form of SIRTURO® 100mg tablets will be donated by Janssen Pharmaceutica NV and 
shipped to Comoros by Damien Foundation. During the phase 3 trial 20 mg dispersible tablets will also 
be made available.  
 
Rifampicin in the form of 150 and 300 mg capsules has been selected from McLeods, a WHO 
Prequalified manufacturer. The product will be shipped by the supplier directly to the national leprosy 
control program of the Comoros. 
 
No medication for treatment of skin diseases will be purchased for study purposes. All treatment is 
part of the routine leprosy control programs in the Comoros. 
 
6.2 Participant compliance monitoring 
All PEP treatment will be delivered by the health worker and intake will be directly observed. The 
health worker will indicate in the specific form of the electronic study database in REDCap that the 
participant has taken the medication, including the dose. 
 
The site staff will keep a study-specific inventory of all medication that is received for the study and all 
medication that has been distributed. IP Accountability at participant level will be documented by 
entering the IP dose in redcap. 
 
6.3 IMP preparation and administration 
The preparation and administration of tablets of bedaquiline and rifampicin capsules will be 
described in an IMP preparation and administration SOP. 
 
6.4 Prior and concomitant therapy 
Rifampicin is known to interact with other drugs, anti-retrovirals (ARV) in particular.[31] It is an inducer 
of various genes controlling drug metabolism and transport, such as cytochrome P450 isoenzymes and 
the drug efflux pump p-glycoprotein. As a result plasma concentrations of concomitantly administered 
drugs may be reduced. In this study only one single dose of Rifampicin will be provided. As Rifampicin 
has a serum half-life of less than 5 hours, the effect of such interactions would be expected to be 
negligible, regardless of the dosing. [32] 
 
Even though due to the single dose administration of the drugs, no drug-drug interactions or QT 
prolongation are expected, the concurrent use of additional QT prolonging drugs with single dose 
bedaquiline is not recommended.[33] For phase 2 study participants will be asked whether they take 
any other medications. These will be checked against a list of permitted medications to be used 
together with rifampicine and bedaquiline. If drugs are not on the permitted list, and not on the list of 


BE-PEOPLE, version 5.1, dated 01 March 2023 33 of 58 
prohibited drugs, the ITM team will review the specific drug for interactions with bedaquiline and add 
to the permitted or prohibited list. The participant whose medication was permissible may 
subsequently still receive BE-PEP. For phase 3 participants will be excluded when taking medication 
not mentioned on the safe list up to  3 weeks prior to PEP distribution visit. 
 
6.5 Packaging 
The commercial formulation of rifampicin (capsules of 150 mg and 300 mg) procured for the study will 
be used. For phase 2 bedaquiline tablets of 100mg are provided in blister packs protected against 
humidity and light.  For phase 3 20 mg and 100 mg tablets are provided in bottles. 
 
6.6 Reception, storage, dispensing and return 
All study drugs will be stored in the central air-conditioned and temperature-controlled stock of the 
national leprosy control program, this for all islands. For Bedaquilline the temperature cannot surpass 
40 °C, for rifampicine the temperature cannot surpass 40 °C. If the temperature surpasses 40 °C for 
rifampicin or bedaquilline, the sponsor should be contacted immediately. The medication cannot be 
used before the sponsor9s approval. If medication is shipped between islands in the Comoros, a 
temperature monitor device should always accompany the shipment. The temperature monitoring log 
should be read out right before medication is inventorized.  
 
The mobile teams will be supplied with sufficient medication during their PEP distribution visits to the 
different villages. This medication will be kept at ambient temperatures. Medication that has been 
provided with a mobile team and that is returned to the central stock, will no longer be used as the 
conditions in which it was stored cannot be guaranteed. An inventory will be kept of all incoming and 
outgoing medication. The inventory should also be documented for all medication that was returned 
after field visits, as this medication should be destroyed. Expired study drugs and study drugs that 
returns from the field will be separated from usable inventory and quarantined to prevent accidental 
assignment and/or dosing to subjects. 
 
The final fate of unused bedaquiline will be agreed at the end of the study. In case of destruction, this 
will be documented on a dedicated destruction log.  
 
Left-over, non-expired, Rifampicin medication will be used in routine care. Unused expired rifampicin 
can be destroyed during the conduction of the study, but only after the monitor was on site to give 
his/her approval. 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 34 of 58 
 
 
7. SAFETY ASSESSMENT 
7.1 Rationale for safety and efficacy of study drugs 
7.1.1 Safety of Rifampicin 600mg 
The regimen used for prophylaxis in arm 2, single dose Rifampicin, has been extensively tested in a 
number of leprosy PEP trials and is the current choice when PEP is implemented programmatically. In 
2018 WHO issued a guideline for the diagnosis, treatment and prevention of leprosy which states that: 
8Single-dose rifampicin (SDR) may be used as leprosy preventive treatment for contacts of leprosy 
patients (adults and children aged 2 years and above), after excluding leprosy and tuberculosis (TB) 
disease, and in the absence of other contraindications9.[34]  
 
Indeed, in the first two years of the PEOPLE trial in which rifampicin was used at a dose of 1200 mg, no 
adverse events were identified related to the study medication. In BE-PEOPLE the WHO recommended 
dose of 600mg will be used as comparator arm, in order to test whether bedaquiline enhanced WHO 
recommended PEP is more effective at preventing leprosy. 
 
7.1.2 Expected efficacy of bedaquiline 800mg against M. leprae 
In M. leprae infected mice, a single 25 mg/kg dose of bedaquiline killed more than 95% of viable M. 
leprae bacilli and maximum effect (Emax) was reached after such a single bedaquiline dose of 25 
mg/kg. The equivalent efficacy of daily and monthly bedaquiline dosing in the mouse footpad model 
indicates that bacterial killing is driven by total area under the time-concentration curve (AUC) and not 
by Cmax. The minimal effective dose for TB is 6.5 mg/kg when given 5 times per week and the lowest 
fully bactericidal dose is 12.5 mg/kg. The minimum effective dose to kill M. leprae (1 mg/kg) is thus 6 
times lower than the minimum effective dose to kill M. tuberculosis in mice. In mice, a 25-mg dose is 
associated with an AUC of 20 μg.h/mL. In order to take into account an expected equal contribution of 
the M2 metabolite, the target AUC of 40 μg.h/mL bedaquiline was selected (i.e., similar exposure as 
obtained in the mouse model at 25 mg/kg once monthly). In a thorough QT/QTc study in healthy 
human volunteers, a dose of 800 mg, administered under well controlled feeding conditions, resulted 
in an AUC24h of 71.7 μg.h/mL (N=44, primarily non-black). However, in a programmatic setting, 
exposure may be lower: in the phase 2 studies in MDR-TB patients (C208 and C209), it was concluded 
that bioavailability in these patients was 50% lower. Additionally, a 34% lower exposure is expected in 
black patients. Based on these data, 800 mg bedaquiline is needed to obtain the target AUC of 40 
μg.h/mL. 
 
Janssen has completed recruitment in a proof-of-concept study of bedaquiline treatment of active 
leprosy in 11 patients, 4 of whom have completed 8 weeks of bedaquiline monotherapy. The 
preliminary safety data indicates that 8 weeks of bedaquiline monotherapy was safe and well tolerated 
in MB leprosy patients at the dose studied (200 mg once daily for 2 weeks followed by 100mg three 
times a week for the following 6 weeks). The outcome results are pending. 
 
In September 2021, Janssen submitted a request for scientific advice to EMA to seek advice on the trial 
design for a phase 3 trial for bedaquiline based as part of a multi-drug therapy for the treatment of 
multibacillary leprosy. The proposed dosing of bedaquiline in a 6 month regimen (including clofazimine 
and rifampin) is 200mg qd for 2 weeks followed by 800mg q4w for the remaining 5 months. 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 35 of 58 
7.1.3 Safety of Bedaquiline 800mg 
In tuberculosis treatment bedaquiline is used typically at 400 mg once daily for two weeks followed by 
200 mg three times a week for 24 weeks. Bedaquiline can cause QT prolongation, leading to cardiac 
arrhythmia and/or death. In data submitted to the FDA, a higher mortality was observed in TB  patients 
who received bedaquiline than among those treated with other drugs (11.4 versus 2.5%). In recent 
larger clinical studies, no safety concerns arose with use of bedaquiline, and RR-TB patients treated 
with bedaquiline experienced a mortality benefit.[35, 36] The availability of safety data in healthy 
volunteers at single dose of 800mg, combined with the efficacy data of an equivalent dose in mice 
against M. leprae described above, supports the choice for this dose of bedaquiline. 
 
Janssen is conducting a paediatric trial of bedaquiline for rifampicin resistant tuberculosis. The 
adolescent- and age 5-12 year arms have completed recruitment but the younger age groups are still 
ongoing. The recommended doses in children 5-<12 yrs of age and weighing >=15 kg are weight 
dependent. Based on a collective analysis of the 2 completed study arms and applying Population 
pharmacokinetics based predictions to the larger population, the recommended dose in children 5-12 
years old and adolescents, weighing >= 30 kg is the same as in MDR-TB adults, reflecting similar 
clearance as in adults, whilst the recommended dose in children 5-12 years old and adolescents, 
weighing >= 20 to < 30 kg is half the adult MDR-TB regimen, reflecting approximately 50% reduction in 
clearance. These recommended dosages lead to similar exposures in the respective pediatric age and 
weight ranges as observed in adults following the adult dosing regimen. Based on the non-
compartmental analysis in the pediatric trial, both in adolescent patients with MDR-TB (after multiple-
dose administration of bedaquiline at a dosage of 400 mg/day for the first 2 weeks followed by a 
dosage of 200 mg 3 times per week) and in children (5 to <12 years) with MDR-TB (after multiple-dose 
administration of bedaquiline at a dosage of 200 mg/day for the first 2 weeks followed by a dosage of 
100 mg 3 times per week) the M2 PK was consistent with the multiple-dose PK of M2 in adults with 
MDR-TB. 
 
The risk of QT prolongation by bedaquiline is mainly driven by the M2 Cmax.[37] Based on exposure-
QT M&S, the maximal effect of M2 (Emax,M2) on QT prolongation is 28.6 ms, and the EC50 (effective 
concentration to reach Emax,M2) is 855 ng/mL. Assuming 50% M2 accumulation after two doses of 
800 mg, 4 weeks apart, and bioavailability similar to that observed bioavailability in healthy volunteer 
phase 1 studies, the predicted (worst-case) M2 Cmax after 2 doses of 800 mg, 4 weeks apart, is lower 
than 130 ng/mL, i.e., lower than the QT EC50 concentration of 855 ng/mL and lower than the M2 Cmax 
at steady state (Cmax,ss) of bedaquiline in the recommended MDR-TB regimen,  (ie, 361 ng/mL). To 
follow up on the possible risk of QT prolongation in the Phase 2 study, ECG monitoring is foreseen. 
 
Bedaquiline and M2 are not substrates of P-gp and breast cancer resistance protein (BCRP) in vitro, 
bedaquiline is a weak substrate of organic anion transporting polypeptide (OATP) 1B1, and OATP1B3. 
M2 is not a substrate of OATP1B1 and OATP1B3. Bedaquiline and M2 did not inhibit hepatic uptake 
transporters OATP1B1 and OATP1B3 or efflux transporters P-gp, BCRP. 
  
The effect of repeated dosing of rifampicin QD on the PK of bedaquiline was studied in healthy 
volunteers. Acknowledging this design is not sensitive to evaluate the OATP1B inhibitory effect by 
rifampicin  specifically, the net effect after repeated rifampicin administration (3A4 induction and 
inhibitory effects), showing a similar effect on Cmax and AUC suggests no substantial effect on 
OATP1B-mediated transport of bedaquiline. Cmax is a sensitive PK parameter to detect effect by 
potential inhibitors on liver uptake. 
 In addition, there is indirect in vivo evidence confirming that bedaquiline PK is not sensitive to OATP1B 
transporter inhibitors: as per the FDA, Ritonavir, lopinavir and clarithromycin are OATP1B 


BE-PEOPLE, version 5.1, dated 01 March 2023 36 of 58 
inhibitors.[38]  In vivo drug-drug interaction studies with these perpetrators were conducted and 
showed no substantial effect on bedaquiline Cmax. 
7.1.4 Rationale for combining bedaquiline 800mg and rifampicin 600mg 
Synergy between bedaquiline (which targets the mycobacterial respiratory chain) and rifampicin 
(which inhibits RNA polymerase) was observed in murine studies for M. tuberculosis, supporting the 
use of this combination for leprosy post-exposure prophylaxis. 
 
Bedaquiline has no known drug-drug interaction (DDI) liability as perpetrator. As 3A4 substrate, 
however, inhibition or induction of CYP3A4 may alter the PK of bedaquiline. Rifampicin is a known 
CYP3A4 inducer, with maximal inductive effect reached between 1 to 2 weeks. However, a single dose 
of rifampicin does not induce CYP3A4. The effect of repeated dosing of strong CYP3A4 inhibitors 
(ketoconazole, lopinavir/ritonavir) on single dose of bedaquiline was evaluated. No clinically relevant 
effect on Cmax was observed. An increase of the AUC with 22% was observed. In conclusion, there are 
no significant DDI liabilities anticipated that may require excluding certain concurrent medications 
when administering BDQ and Rifampin as single dose or two single doses, 4 weeks apart. There is one 
exception; if strong CYP3A4 inducers would have been administered repeatedly before the single dose 
of BDQ, that may reduce exposure to BDQ. 
 
The bioavailability of bedaquiline increases with food (2-fold increase in AUC, see label). The exposure 
of rifampicin, when administered with food, decreases slightly but this is not considered clinically 
relevant. 
Therefore, 
the 
drugs 
will 
be 
administered 
under 
fed 
conditions. 
 
7.2 Safety monitoring 
7.2.1 Safety monitoring for QT prolongation in Phase 2 
In March 2022, a training on QT measurement and interpretation on 12-lead ECG and the Kardia 6L 
will be given to the study team by a referent cardiologist with extensive experience in the use of 
bedaquiline for tuberculosis treatment, the cardiologist at a specialist cardiology service, and the study 
investigator. Both dedicated 12 lead ECG instruments with electronic and paper data capture will be 
used as well as the Kardia app (Alivecor), which was FDA approved for the diagnosis of atrial fibrillation, 
and has been validated against 12-lead ECG based QTc measurements with a good correlation. [39] 
The measured QT will be corrected by the Fridericia formula through a dedicated calculator. 
In the phase 2 study planned for July 2022, participants will have their QTc interval screened at baseline 
(within 1 week before PEP administration) by the Kardia app and a 12-lead ECG (reference standard) 
to validate the accuracy of the Kardia app in this specific setting. If QTc ≥ 450ms is confirmed by 
qualified readers, the participant will be excluded from the Phase 2 safety study. If the QTc by 12 lead 
ECG is found to be <450ms, the participant is not excluded. All ECGs will be time stamped and stored 
as pdf in the RedCap database for blinded review by a referent qualified reader based at the 
department of Cardiology of the Amsterdam University Medical Center location AMC.  
Those participants with QTc <450ms, and whose baseline ALT is <3x ULN, will receive study treatment 
if eligible. QTc will be measured 24 hours later, and ALT 14 days after administration. 
If after single dose administration of bedaquiline and/or rifampicin, and in the unexpected event that 
QTc prolongation >60ms since baseline or a value of >500ms is seen, the participant will be urgently 
brought to the cardiology service at a specialist cardiology service for further examination, continuous 
rhythm monitoring, repeated QTc measurements, and measurement of potassium for correction of 
hypokalemia. The ECG will be reviewed for additional warning signs of impending malignant 


BE-PEOPLE, version 5.1, dated 01 March 2023 37 of 58 
dysrhythmias and IV magnesium and isoprenaline may be administered, per the cardiologist9s 
management. These procedures will be described in a separate cardiology monitoring SOP. 
 
7.2.2 Safety monitoring for hepatitis in Phase 2 
For laboratory measurements see section 5.2.1. In case of ALT or AST values of >3x ULN at baseline, 
participants will not be eligible for study medication. In case of ALT/AST elevations >3x ULN after study 
medication, participants will undergo further ALT/AST monitoring with frequency and need for referral 
depending on the level of elevation. 
 
7.2.3 (S)AE monitoring 
The occurrence of any adverse events (AE) will be assessed the day after administration. An AE is any 
untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this product. It can be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to this product. Participants who receive PEP will be 
instructed to inform the study staff of any adverse events occurring between the administration of the 
drug and 30 days after . All relevant study staff will be trained on (S)AE detection, (S)AE monitoring 
mechanisms and (S)AE reporting on site. During the training, examples of (S)AE reporting cases will be 
given. SAE checklists and forms will be explained as well. 
 
In the Phase 2 study, a physician from the study team will be available in the village and a cardiologist 
will be on call at a nearby specialist cardiology service. In the Phase 3 study, the participants are 
encouraged to contact the study staff while the study teams are still in the village, or afterwards a 
community health officer or by using the contact details in the information form of which each 
household will receive a copy. For all  participants provided study medication, study teams will- on 
arrival in the village the next day- start by visiting their houses to verify for any (S)AEs. In case the 
participant is not at home, another attempt will be made within the next 3 days.  
 
For phase 2 the medical staff will specifically enquire about gastro-intestinal (nausea, vomiting, 
diarrhea), nervous system-related (headache, dizziness), cardiac symptoms (syncope) and cutaneous 
reactions. These reported adverse events will be recorded, together with their severity and relatedness 
to the study medication. 
 
During phase 3, active adverse event monitoring will take place the during the safety follow-up visit 
after PEP intake. All participants that took PEP will be revisited and will be asked if they experienced 
any adverse events. The participants absent during the 1st safety follow-up visit will be revisited one 
additional time. Further participants that took PEP and the community health officer (agent de santé 
Communautaire) present during PEP intake will be sensitized on reporting/being vigilant of adverse 
event appearing after the safety follow-up visit or pregnancies within 30 days of the PEP intake. They 
will be informed that in this case they will need to reach out to the study team that will be responsible 
for follow-up and reporting of the respective event. These will be considered spontaneously reported 
adverse events. 
 
Medical staff in health facilities in the districts concerned will also be informed about the trial in 
advance (and at the beginning of every yearly screening round) and will be asked to report any possible 
adverse reactions (AR) or serious adverse event (SAE) to the study team. An AR is an AE for which there 
is at least a reasonable possibility that it might be linked to the medicinal product under study. A SAE 
is an AE that 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or 
prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, or 5) 


BE-PEOPLE, version 5.1, dated 01 March 2023 38 of 58 
is a congenital anomaly/birth defect. ARs will be reported in the same manner as AEs. In case of a SAE 
however, the SAE report template will be completed by the study team and sent to the sponsor 
(pharmacovigilance@itg.be) within 24 hours following the notification of the SAE to the study team as 
per the SAE reporting instructions.  
 
Only events (AE, AR,SAE and pregnancies) that occur between the administration of the drug and 30 
days after will be recorded for study purposes. Any additional safety information obtained until 30 
days after each dose of the Janssen Product(s) Under Study will be reported to Janssen Pharmaceutica 
NV. All subsequent AEs, ARs and SAEs spontaneously reported beyond 30 days after each dose of the 
Janssen Product(s) under study shall be collected/reported if the investigator considers the event to 
be causally related to the use of the Janssen Product(s) under study.  
 
All SAE9s whether or not deemed drug related or expected must be reported immediately or within 24 
hours (one working day) using the SAE Notification Form by email to: 
 
 
Clinical Trials Unit 
 
Institute of Tropical Medicine 
 
Nationalestraat 155 
 
B-2000 Antwerp – Belgium 
 
Email: pharmacovigilance@itg.be 
 
Line listings of all reported SAE9s will be sent to the IRB of the ITM and the independent EC, on a yearly basis. 
A study safety checklist SOP will be prepared describing all responsibilities and actions that are required 
in case of an SAE.  
 
 
For phase 2, concomitant medication will be recorded in the REDCap study database and as explained 
in section 4.2 above, a safe list will be provided that contains all essential medications registered in 
Comoros that are not considered a risk when administering BE-PEP. For any medication encountered 
that is not on this safe list and that is also not on the list of forbidden medications, the field teams will 
consult the local PI and an expert on the matter (Dr. Younoussa Assoumani and Dr Alberto Piubello) to 
decide whether it will be added either to the safe list or to the list of forbidden medication. 
 
As part of the baseline survey in the new villages of BE-PEOPLE that were not part of the PEOPLE trial, 
we will collect information on medications used to allow us to update the safe list ahead of the start 
of the phase 3 intervention in 2023. During phase 3, this list will be used to determine PEP eligibility 
on an individual level (see inclusion/exclusion criteria). Participants will be excluded from Bedaquiline 
when they take a medication not included on the safe list. This medication will be reported. 
Concomitant medication included on the safelist will not be reported. Throughout the phase 3 trial, 
the safe list may be periodically updated based on the exclusion data captured in REDCap.  
 
For BE-PEOPLE, an independent Data Safety Monitoring Board (DSMB) will review the (S)AEs and 
outcome of the Phase 2 study, with pre-specified criteria on stopping (see section 8) versus continuing 
in the Phase 3 study. During the phase 3 study the DSMB will also review active (S)AE follow-up. 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 39 of 58 
 
 
NOTE (1): In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or out-patient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious 
criteria, the event is an SAE. When in doubt as to whether <hospitalization= occurred or was necessary, 
the event should be considered an SAE. Hospitalization for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an SAE, nor hospitalization for non-medical reasons 
(e.g., the participant stays at the hospital overnight because (s)he lives too far and/or there is not 
transport). 
NOTE (2): The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. 
sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
NOTE (3): The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
 
All SAEs must be: 
• 
recorded on the appropriate SAE report form 
• 
followed through resolution by a study clinician 
• 
reviewed and evaluated by a study clinician. 
• 
Follow-up until resolution (by sending updates on the SAE form) 
 
 
Severity, relationship of event to study drug and outcome 
All (S)AE9s (phase 2 and phase 3) will be assessed by the clinician (obligatory for SAE9s) or study nurse 
using a predefined grading system:  
1. Mild: events require minimal or no treatment and do not interfere with the participant9s daily 
activities. 
2. Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures.  Moderate events may cause some interference with functioning. 
3. Severe: events interrupt a participant9s usual daily activity and may require systemic drug 
therapy or other treatment.  Severe events are usually incapacitating. 
4. Life-threatening: Participant at risk for death at the time of the event 
 
Changes in the severity of an (S)AE will be documented to allow an assessment of the duration of the 
event at each level of intensity to be performed.  Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Assessment of causality   
The investigator or study nurse is obliged to assess the relationship between investigational product 
and the occurrence of each (S)AE. The investigator (for AE9s and SAE9s) or study nurse (for AE9s) will 
use clinical judgement to determine the relationship. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the 
event to the IMP will be considered and investigated. The investigator will also consult the drug 
information and the DSMB as needed in the determination of his/her assessment. 
 
For phase 2, the relationship of an adverse event to study drug is to be assessed according to the 
following definitions and can only be done by the study physician:  


BE-PEOPLE, version 5.1, dated 01 March 2023 40 of 58 
1. Definitely unrelated: Reserved for those events which cannot be even remotely related to 
study participation (e.g. injury caused by a third party). 
2. Unlikely: There is no reasonable temporal association between the study drug and the AE 
and the event could have been produced by the participant's clinical state or other modes of 
therapy administered to the participant.  
3. Possible: The suspected AE may or may not follow a reasonable temporal sequence from 
study drug administration but seems to be the type of reaction that cannot be dismissed as 
unlikely. The event could have been produced or mimicked by the participant's clinical state 
or by other modes of therapy concomitantly administered to the participant. 
4. Likely: The suspected adverse event follows a reasonable temporal sequence from study 
drug administration, abates upon discontinuation of the drug, and cannot be reasonably 
explained by the known characteristics of the participant's clinical state.  
5. Definitely related: Reserved for those events which have no uncertainty in their relationship 
to test drug administration: this means that a re-challenge was positive. 
 
 
For phase 3, the relationship of an adverse event to study drug is to be assessed according to the 
following definitions: 
1. Possibly related: Any AE with a potential link to PEP. Any AE presenting within 24 hours of PEP 
administration will be considered related to PEP if it is listed below: 
-  
Nausea 
Syncope 
Headache 
Palpitation 
Diarrhea 
Dizziness 
Vomiting 
Skin reactions 
 
Other AEs occurring within 24 hours after PEP administration or AEs presenting after 24 hours 
will need to be evaluated on a case-by-case basis. 
 
2. Not related: Any AE that is unrelated to the use of PEP OR the AE is related to the participant's 
medical condition or other treatment unrelated to the study. 
For each SAE the outcome must also be assessed according to the following classification: 
Recovered: The participant recovered from the event with no residual problems.  
Not yet recovered: This outcome can only be used for Serious Adverse Events.  The event no longer 
meets a 8Serious9 criterion, but medical event is not yet completely cured. The remaining event 
should be listed as a separate adverse event in the adverse event table, and with its own outcome.  
Permanent damage: The event has resulted in permanent impairment.  
Ongoing: the participant is continued to be followed for the event. 
Death: The participant died. This term should only be used for the event which resulted in death. 
Any other events which were present at the time of death, but were not the cause of death, should 
be listed as 8Ongoing9. 
Unknown: The participant cannot be traced and no final outcome for the event could be 
determined. 
There may be situations when an SAE has occurred, and the investigator has minimal information to 
include in the initial report to the Sponsor. However, it is very important that the investigator always 
makes an assessment of causality for every event prior to transmission of the report to the Sponsor. 
The investigator may change his/her opinion of causality in light of follow-up information, amending 
the SAE-report form accordingly. 


BE-PEOPLE, version 5.1, dated 01 March 2023 41 of 58 
7.2.4 Special Reporting Situation 
All special reporting situations must be reported within 3 business days using the SAE or pregnancy 
form by email to: 
 
 
Clinical Trials Unit 
 
Institute of Tropical Medicine 
 
Nationalestraat 155 
 
B-2000 Antwerp – Belgium 
 
Email: pharmacovigilance@itg.be 
 
A study safety checklist SOP will be prepared describing all responsibilities and actions that are 
required in case of a special reporting situation. 
 
An overview of all special reporting situations: 
•              Drug exposure during pregnancy (paternal, maternal) 
•              Suspected transmission of any infectious agent via administration of a drug under study. 
•              Overdose of a drug(s) under study* 
•              Exposure to a drug(s) under study from breastfeeding* 
•              Suspected abuse/misuse of a study product(s) under study* 
•              Inadvertent or accidental exposure to a study Product(s) under study* 
•              Any failure of expected pharmacological action (i.e., lack of effect) of a study Product(s) 
under study * 
•              Medication error (includes potential, intercepted or actual) involving a study product (with 
or without patient exposure to the Janssen Product(s) under study, e.g., name confusion)* 
•              Unexpected therapeutic or clinical benefit from use of a study Product(s) under study* 
 
* These special reporting situations only need to be reported to Janssen within 3 business days if the 
event is associated with an SAE. If the event is not associated with an SAE, the SS should be recorded 
in the CRF and sent annually to Janssen. 
 
7.2.5 Product Quality Complaints (PQC) 
All PQC9s must be reported within 3 business days using the PQC Notification Form by email to: 
 
 
Clinical Trials Unit 
 
Institute of Tropical Medicine 
 
Nationalestraat 155 
 
B-2000 Antwerp – Belgium 
 
Email: pharmacovigilance@itg.be 
 
Any complaint that indicates a potential quality issue during manufacturing, packaging, release testing, 
stability monitoring, dose preparation, storage or distribution of the product or delivery system is 
considered a PQC. Not all PQCs involve a patient.  
A study safety checklist SOP will be prepared describing all responsibilities and actions that are 
required in case of an PQC. 
Examples of PQC include but are not limited to: 
• 
Mislabelling or misbranding   


BE-PEOPLE, version 5.1, dated 01 March 2023 42 of 58 
• 
Information concerning microbial contamination, including a suspected transmission of 
any infectious agent by a product 
• 
Any significant chemical, physical, or other changes that indicate deterioration in the 
distributed product 
• 
Any foreign matter reported to be in the product 
• 
Mixed product, e.g., two drugs are mixed-up in the packaging process 
• 
Incorrect tablet sequence (e.g., oral contraceptive tablets) 
• 
Insecure closure with serious medical consequences, e.g., cytotoxics, child-resistant 
containers, potent drugs 
• 
Suspected counterfeit or tampered product 
• 
Adverse Device Effects including any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, implantation, installation, 
operation, or any malfunction of a medical device or combination product. This also 
includes any event that is a result of a use error or intentional misuse and dosing device 
malfunctions (e.g., auto-injector button not working, needle detaching from syringe, 
etc.) 
• 
Physical defect (e.g., abnormal product odour, broken or crushed tablets, etc.) 
 
7.3 Surveillance for selection for mycobacterial drug resistance 
The risk of inducing rifampicin resistance in (undiagnosed) tuberculosis or leprosy patients with one 
single dose of the drug is negligible.[40] As was described by Mitcheson for treatment of tuberculosis, 
resistance emerges as a result of selection of resistant mutants under conditions of monotherapy.[41] 
This requires high numbers of bacilli as observed in cavitary pulmonary tuberculosis, combined with 
prolonged exposure, as mycobacteria are slow to replicate. Repeated cycles of starting a treatment 
regimen, interrupting treatment, and restarting after some days can mimic monotherapy because of 
differential activity of drugs during the first days of treatment. However a single dose of rifampicin, 
possibly repeated once after four weeks, will not result in drug resistance. The BE-PEP regimen consists 
of two drugs, rifampicin and bedaquiline, further reducing the risk of selection of resistant mutants, 
although the half-life of bedaquiline and its metabolites far exceeds that of rifampicin.  
 
To further decrease any potential risk of acquired drug resistance we will screen for signs and 
symptoms of pulmonary tuberculosis and exclude those participants from PEP.  
 
We will also monitor molecular resistance for rifampicin and bedaquiline on samples from all leprosy 
patients, using an expanded Deeplex MycLep assay in which the atpE gene of M. leprae is included and 
using whole genome sequencing. Lastly, we will also recruit presumptive tuberculosis patients in 
Comoros for analysis of sputum and/or tongue swabs and genotype extracted M. tuberculosis DNA 
with the Deeplex MycTB XL, which includes additional targets potentially associated with bedaquiline 
resistance. Whole genome sequencing may be used to track the spread of drug resistant TB. 
 
7.4 Other risks 
Other risks to the participants are minimal. Leprosy patients identified will have a slit skin smear and a 
4mm punch biopsy from the edge of the lesion taken (except if the lesion is in the face). The biopsy 
will be collected under local anesthesia. These procedures may cause slight pain, and carry a small risk 
of bleeding, which will be controlled by the person collecting these samples. The staff on the Comoros 
are already executing these procedures as part of the ongoing PEOPLE study. 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 43 of 58 
8. STUDY MANAGEMENT 
In the framework of the PEOPLE study, a bi-weekly meeting has been set-up for the purpose of the 
day-to-day management of the study and to discuss the progress of the trial. The meeting is attended 
by representatives of the sponsor and when required by representatives of the sites. These meetings 
will be continued within the BE-PEOPLE study (frequency will depend on study status). They will be 
organized by the clinical trials unit of ITM.  
 
Also in the PEOPLE trial a Scientific Advisory Committee (SAC) has been established for the purpose of 
providing independent advice on the preliminary results that have been analyzed during the interim 
analyses. A charter detailing the modalities for this SAC has been drawn up. Members of the current 
SAC of the PEOPLE study will be asked to stay on as members of the SAC for BE-PEOPLE, if necessary 
additional members will be solicited. A new charter will be set-up and signed for BE-PEOPLE purposes.  
 
For BE-PEOPLE, once Phase 2 study is finalized and after statical analysis is done, an independent Data 
Safety Monitoring Board (DSMB) will review the (S)AEs and outcomes of the Phase 2 study and advice 
on stopping versus proceeding to phase 3. The sample size chosen will allow for a precise estimate of 
the mean QTc and its variance. It will be left to the judgement of the DSMB whether any observed 
prolongation of QTc is clinically relevant and has implications for proceeding to Phase 3. Besides this, 
the Phase 2 study enrollment will be paused at any moment, if any of the below criteria is met.  
1. Death of a participant considered related to study drug 
2. One or more participants experience an SAE or Gr 4 AE or a persistent (upon repeat testing) 
Gr 4 laboratory abnormality that is determined to be related to study drug 
3. Three or more participants experience a Gr 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) Gr 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 after intake of the study medication 
6. One or more participants has AST or ALT > 8x ULN, in absence of causative explanation, after 
intake of the study medication 
 
In this case a DSMB consultation will be held asap to discuss the further conduct of the trial. 
Enrollment and randomization should be paused until a DSMB decision is made, other follow-up 
visits can continue.  
 
During the phase 3 study the DSMB will also review active (S)AE follow-up on the day after study 
medication administration.  
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 44 of 58 
 
9. STATISTICAL ANALYSIS 
The statistical analysis will be described in the statistical analysis plan (SAP), written by the 
biostatistician, which is binding and will be finalized before database lock or before any other analysis 
takes place. 
9.1 Baseline characteristics: 
Both an intention to treat (ITT) and a per-protocol (PP) approach will be used to define the analysis 
populations in both phase 2 and phase 3 studies. In the Intention-to-Treat analysis, all participants will 
be analyzed according to their randomized allocation, even in case they do not receive the randomized 
treatment, show protocol violations prior to or during the study.  
In the per-protocol analysis only participants who received PEP as planned, have completed follow-up, 
and follow the protocol as planned are included.  
In the phase 2 study, the PP population will be the primary analysis population as indicated for non-
inferiority studies by the ICH-E9 guidelines. For the phase 3 study, the intention to treat will be the 
primary approach. 
The number of participants screened and enrolled or excluded will be summarized according to reason 
for exclusion. Of the enrollees, the number of patients discontinued or lost to follow-up will be 
recorded by reason and time of discontinuation. These figures will be summarized in a CONSORT flow 
diagram. 
 
Subjects in each treatment group will be described according to baseline characteristics. The 
description will be in terms of medians and interquartile ranges for continuous variables and using 
counts and percentages for categorical variables. Standard statistical tests of significance of imbalance 
in baseline characteristics will be performed.  
9.2. Phase 2 study:  
9.2.1. Primary analysis 
The main objective about the difference in QTc between the two arms 24 hours after treatment 
administration will be assessed using a two-sample t-test.  
9.2.2. Secondary analysis 
Baseline frequency of ALT/AST elevations and QTc prolongations in the population, before and after 
study drug administration will be estimated using 95% confidence intervals for each time point and 
by study arm. No formal comparison will be done between time points or between arms.  
Potentially frequent adverse events such as gastro-intestinal (nausea, vomiting), nervous system-
related (headache, dizziness) and cutaneous reactions will be tabulated and presented using standard 
descriptive statistics. A comparison between the two arms will be done using Fisher9s exact test.  
 
9.3. Phase3 study 
9.3.1. Primary analysis 
The main analysis will be to assess the effect of BE-PEP at individual level. Because in the first study 
year anyone living within 100 meter of an index case over the period 2018-2023 will be eligible for PEP 
and if this is more than 50% of the village population the entire village population above 2 years of age 
will be eligible where for the first year any leprosy case included in the study population detected 


BE-PEOPLE, version 5.1, dated 01 March 2023 45 of 58 
during the annual village screening or in the preceding five-year period, i.e. since January 1st, 2018 will 
be considered an index case. The following years, any leprosy case detected after the last year9s 
screening up to and including the village9s screening round of the current year will be considered an 
index case. Therefore , we assume that in the first year there will be blanket coverage with either SDR-
PEP or BE-PEP. We will fit a Poisson model adjusted for follow-up time as an offset term with village 
nested in island as random effect and type of PEP (BE-PEP or SDR-PEP), as explanatory variable. Those 
who did not receive PEP and those below the age or weight limits for BE-PEP will be excluded from this 
analysis, SDR-PEP will be our reference category. Outcome variable will be incident leprosy. We will 
consider all cases diagnosed after the first intervention round in 2023, until the final survey in 2026.  
 
9.3.2 Secondary analyses 
In a second analysis we will calculate the incidence rate ratio of leprosy at village level between 
arms 1 and 2. Here all participants enrolled will be taken into account, even those that did not 
receive PEP. A similar model as in the primary analysis will be used, including all persons in the 
villages randomized, even those who were not eligible to receive the study treatment due to age or 
weight restrictions.   
 
Prespecified adverse events such as gastro-intestinal (nausea, vomiting), nervous system-related 
(headache, dizziness) and cutaneous reactions will be tabulated and presented using counts and 
percentages. Comparisons between study arms will be done using Fisher9s exact test.  
 
In the villages that were originally allocated to arm 4 of the PEOPLE trial, the fourth and final screening 
round will be accompanied by one final anti-PGL1 sero-survey. Based on the comparison of age 
specific anti-PGL-I sero-prevalence rates at the time of the 2019 survey and in the final survey in 2026, 
we will assess the potential of anti-PGL-I surveys as a tool to monitor leprosy transmission. We will 
compare seroprevalence rates in different age groups of 2019 to 2026, both overall and by village and 
island to assess whether a trend can be identified and whether this trend is consistent across 
villages/islands. This analysis will be primarily descriptive.  
 
Cost data will be gathered throughout the study and used to calculate the average cost per person 
screened for leprosy by island, average cost per case detected by island. If BE-PEP is shown to be more 
effective than SDR-PEP, a cost-effectiveness analysis will be done estimating the average cost per case 
of leprosy averted by study arm and by island. Incremental costs will be calculated using the SDR-PEP 
arm (arm 2) as baseline.  
 
Prevalence of bedaquiline and/or rifampicin resistant strains will be calculated per island with in the 
numerator all leprosy patients with rifampicin or bedaquiline resistant isolates identified and in the 
denominator all patients tested. Along with the proportions 95% confidence intervals using the 
Wilson9s method will be calculated.  
 
Results of genotyping of M.leprae will be analyzed separately in the framework of the project titled: 
8Improving leprosy prevention strategies by integrating social network analysis with spatial and 
molecular epidemiology data of Mycobacterium leprae in the Comoros9. 
9.3.3 Interim analyses 
An interim analysis will be conducted upon completing the second door-to-door survey after 
randomization, in early 2025. This analysis will include both the individual effect of PEP and the effect 
of PEP at village level, as described above. 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 46 of 58 
 
10. MONITORING AND QUALITY ASSURANCE 
The clinical research scientist of CTU will perform on-site monitoring visits, with the purpose of source 
document verification and follow-up of local study implementation in line with ICH-GCP guidelines 
(including e.g. investigator file completeness). The monitoring activities and frequency will be 
described in a monitoring plan.  A report detailing the actions taken during the monitoring visit will be 
written and shared amongst the study team. 
The coordinating investigator will also visit the study team at regular intervals for project coordination 
and follow-up. 
A pharmacist in Comoros has been trained on GCP and will serve as local quality responsible IP 
management such as completing inventory- and temperature log monitoring). The PI and involved site 
research staff will allocate adequate time and resources for such monitoring activities.  
 
The sponsor will inform the Investigators concerned immediately upon notification of a pending study 
centers inspection by any regulatory authority or funder. Likewise, the investigator will inform the 
sponsor of any pending inspection. 
 
11. DATA MANAGEMENT 
In the BE-PEOPLE study for the baseline survey we will continue to use formats developed in the 
PEOPLE study consisting of a paper survey form, three forms in in Android app and an Access database 
with barcode, name, age and gender of each participant enrolled. After the baseline survey in 2022, 
which partly overlaps with the final survey of PEOPLE, we will shift from ODK Collect used in the PEOPLE 
trial to REDCap, which is GCP compliant. REDCap will also be used in the phase 2 study in 2022.  
 
Data Management will be performed by the CTU data managers in collaboration with the Principal 
Investigator and with the study staff involved in collecting and handling the study data. The continued 
follow-up of the cohort of leprosy patients established during the PEOPLE trial and the preceding 
ComLep trial, of which drug resistance surveillance is a part, we also shift to REDCap. Drug resistance 
surveillance will be extended to tuberculosis patients, data collection for this part will also be 
integrated in the REDCap database.  
 
A separate Data Management Plan will be prepared, with following essential aspects: 
11.1 Data collection, handling and retention 
The phase 2 study organized in 2022 will consider the collecting and managing of participant-level data 
comprising medical data and in particular safety data referring to adverse events, medical history, 
concomitant medication, ECG and liver function tests.  
The phase 3 study starting in 2023 will finish after the fourth and final annual screening round. The 
phase 3 study will consider the collecting and managing of household-level data (Household ID, 
geographic coordinates) and participant-level data (participant ID, demographic, health and medical 
data with reference to examinations,  leprosy and TB diagnosis and treatments, registration of PEP 
eligibility and intake, averse event monitoring).  
Both studies will have their own database and be based on a system of data collection and 
management via electronic questionnaires on mobile devices (smartphones, tablets and/or laptops), 
by using REDCap.  


BE-PEOPLE, version 5.1, dated 01 March 2023 47 of 58 
REDCap (Research Electronic Data Capture) is a software widely used in the academic research 
community for building and managing surveys, databases and research studies. It is a secure web 
application as well as mobile application that can be used to collect, clean and manage subjects9 
information in accordance with various standards and applicable regulations (GCP, CFR 21 part 11, 
HIPAA). Furthermore, the software features amongst others a query management system and 
capabilities for importing and exporting data in various forms. REDCap allows for offline data collection 
in remote places. When connecting to the internet or cellular networks, data from the mobile device 
can be synchronized with the study server where the study data will be securely retained. 
Paper survey forms will be used if deemed necessary (e.g. as a backup when having issues with the 
electronic device) or to identify households. Only data defined by the study protocol will be collected.  
Questionnaires will be tested and validated before the household visits start. All study personnel will 
be trained on informed consent and study procedures, data collection and entry before the study start. 
Edit checks and branching logic, programmed onto the electronic forms will validate at the point of 
data entry and support quality data. In addition, the data will be reviewed and monitored during the 
course of the study by various study collaborators. Data cleaning and querying of inconsistent, 
inaccurate and missing data will be done following a Data Validation Plan to achieve a timely database 
lock. 
The following data will be entered in the eCRF via direct data entry: 
- 
AE9s* 
- 
Special reporting Situations (except if reported via SAE/pregnancy report) 
- 
PEP inclusion/exclusion criteria/eligibility 
- 
Clinical examination  
- 
Concomitant medication (for phase 2) 
- 
Medical history (for phase 2) 
- 
Visit confirmation 
- 
Study medication administration 
- 
TB and leprosy diagnosis, sampling, treatment and lab results 
- 
Study withdrawal before the fourth screening round (for phase 3)Household information 
such as village and GPS coordinates (for phase 3) 
 
*For phase 3 an exception is possible for spontaneous reported AE9s, which might be documented on 
paper first. 
11.2 Data security and confidentiality 
The data management/IT system that will be used includes a robust security architecture including 
encryption, firewalls, antivirus software and controlled user access (smartphone/tablet 
authentication, username, personal password and authorized user role). A list with all users who have 
access to the system will be kept updated during the study. A daily backup of data will be provided at 
the ITM server. 
Both the sponsor and the study sites will see to it that the necessary measures are taken to ensure 
that all confidential documentation and critical devices (study Data Management Plan, procedures, 
completed questionnaires) and IT devices and equipment (mobile devices, computers, server) are kept 
secure (closed cupboards, closed and/or badge controlled offices and/or rooms). 
Private data of the study participants will be handled confidentially. Household addresses, geographic 
coordinates of households, participant name and other contact data for each household or participant 
will be kept separate and limited to authorized staff at the study site(s) only. For analysis purposes 


BE-PEOPLE, version 5.1, dated 01 March 2023 48 of 58 
household addresses or geographic coordinates, participant names and contact data will be replaced 
by a specific study household and subject identification code (=pseudonym).  
 
The funder will be provided (i) de-identified study data for the Phase 2 interim analysis, including, but 
not limited to, interim analysis data outputs as provided to the study’s Data Safety Monitoring Board 
(DSMB) as well as the interim study report and (ii) de-identified data from the Phase 3 trial, including 
but not limited to annual reports, final study report, open-access publications, and other de-identified 
open-access safety and efficacy data suitable for third-party sharing, but will otherwise not have 
access to the study data. 
11.3 Data protection and security  
This study will be performed in compliance with the European General Data Protection Regulation. The 
sponsor will also be the data controller and the lawful ground for the personal data processing of 
participants will be the public interest, because the study has got a potentially big impact for the public 
health policies regarding leprosy and TB treatment and strategies. The controller also has got a public 
mandate, responsibility and expertise to perform scientific research in this area and the personal data 
will only be shared with involved non-commercial stakeholders such as the MoH, NTLCP and – taking 
privacy restrictions into account - will be made openly accessible as much as possible. 
 
Considering that the study will collect special categories of personal data such as medical data on a 
large scale, including data from minors and vulnerable subjects or populations, a Data Protection 
Impact Assessment will be performed prior to the start of the data processing. 
 
The data uploaded to the server will be barcoded, without personal identifiers. The database 
containing names and barcodes of participants will remain on the Comoros. 
 
Appropriate organizational and technical measures will be implemented for all parties involved and all 
applications and software systems used for the study. This will be further elaborated in the Data 
Management Plan and DPIA. The ITM Data Protection Officer will be involved to perform such proper 
assessments.  
 
11.3 Filing and archiving 
All essential documents for the trial will be kept in paper format in the Investigator Files at the study 
sites. Each Principal Investigator is responsible for completeness and ensuring a secure and 
appropriate location for storage of the Investigator Files and any other study related documentation 
present at sites, as well as for ensuring that only site staff that is competent and delegated to work for 
the study have got access to the files.  
 
After study completion, all the relevant study documentation should be retained for a period of 20 
years or in accordance with the local legislation. ITM should be informed prior to destruction of study 
files. 
 
The Investigator Files should at all times remain available for internal audits and/or inspections of 
regulatory authorities, also after completion of the project. 
 
The Trial Master File and any other sponsor related documentation will be archived at ITM at a secure 
and appropriate location and will only be accessible for competent and delegated sponsor staff. After 
completion of the study, the Trial Master File will remain available for internal audits and/or 
inspections of regulatory authorities for a period of 20 years or according to regulatory requirements.  


BE-PEOPLE, version 5.1, dated 01 March 2023 49 of 58 
 
12. ETHICAL ISSUES 
12.1 Ethics and regulatory review 
The study will be submitted for review and approval to the 8Comité National d9Ethique pour les 
Sciences de la Vie et de la Santé9 (CNESS) as well as to the 8Agence NAtionale des Medicaments et des 
EVacuations sanitaires9 (ANAMEV) in Comoros. As ITM is the sponsor of this project, approval by the 
Institutional Review Board (IRB) of the ITM will also be requested. In addition, the study will be 
submitted for approval to the Ethics Committee (EC) of the University of Antwerp Hospital in Antwerp. 
Potential comments from all these review boards will be addressed, the same applies to comments 
from the selected collaborating partners. No participants will be enrolled or participant related 
activities performed before written approval from all these bodies in Belgium and in the study country 
concerned is obtained. Any substantial amendment to the study (documents) will also require 
approval from the above mentioned bodies. A yearly update on the status of the study will be 
provided as required. The study will be carried out according to the principles stated in the Declaration 
of Helsinki, GCP, GDPR and all applicable regulations and according to established international 
scientific standards.  
 
Prior to the start, this study will also be included in the Clinicaltrials.gov public registry. 
 
12.2 Protocol amendments 
Once the final clinical study protocol has been issued and signed by the authorized signatories, it 
cannot be informally altered. Protocol amendments have the same legal status and must pass through 
the appropriate steps before being implemented. Any substantial change must be approved by all the 
bodies and EC9s that have approved the initial protocol, prior to being implemented, unless it is due 
to participant9s safety concerns (in which case the immediate implementation can be necessary for 
the sake of participant9s protection. In case modifications to the protocol or amendment are 
requested by any local EC/CA during the review process, these must be discussed and agreed upon 
with the Sponsor prior to any resubmission incorporating those changes. 
 
12.3 Informed consent 
In the villages that are already part of the PEOPLE trial, we will ask verbal informed consent if 
participants agree to be recontacted for other future research as well as if their data collected during 
the PEOPLE trial can be used in future research. This information will be entered in the electronic data 
collection form used in the final screening round of PEOPLE. For baseline screening in the new villages, 
not included in the PEOPLE trial, we will ask written informed consent. This consent will be collected 
on a survey form of which there will be one per household.  
 
At the start of the phase 3 study in 2023 for all study participants a written individual  consent on 
separate ICF forms will be collected. This consent will include a question if past data collected during 
the PEOPLE study can be used for further research (covering PEOPLE participants absent during 2022 
screening).In Redcap the date of signing consent will be documented via direct data entry. 
 
All participating household members, as well as the legal guardian and witness, as applicable, will then 
be asked to sign for participation in the study on individual informed consent forms. For the baseline 
survey we will continue to use a form per household with a separate line for each household member 
as currently practiced in the PEOPLE trial. The forms will be stored by the study team in a secure 
manner. 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 50 of 58 
Written informed consent will be obtained before any study specific procedure is performed. For the 
sample collection for incident leprosy cases identified during the yearly screening, a separate consent 
will be obtained. Also for (presumptive) TB patients informed consent will be obtained to test sputum 
samples for resistance to rifampicin and bedaquiline, for this purpose there will be a separate ICF.  
 
Participants who provide samples (i.e. leprosy cases, (presumptive) tuberculosis patients and 
inhabitants of villages randomized to arm 4 of the original PEOPLE trial, phase 2 participants) will be 
informed that their samples will be stored for 20 years and may be used for other research related to 
leprosy and/or tuberculosis in the future. They will also be informed that these samples can be shipped 
abroad. Leprosy index cases will also be asked if they can be recontacted for future studies on leprosy 
susceptibility, investigating genetic risk factors.  
 
The legal age of consent in in the Comoros is 18. For participants, between 2 and 18, informed consent 
of the parents or guardian will be sought. However, as of the age of 12, additional signed assent from 
the minor is needed before he/she can participate in the study. However, for female or male 
participants under 18 years old who are married (or already divorced), the participant has the right to 
give consent him/herself without informed consent of a parent or guardian, if the local EC in the 
Comoros approves. If a participant becomes of legal age throughout the phase 3 trial, oral consent to 
continue participation in the study will be sought and will be documented in the eCRF by the site staff. 
 
The informed consent interviews will be conducted in the preferred language of the patients by a 
qualified person formally delegated by the PI. Informed consents will be available in French. Comorian 
is a rather spoken language and therefore the ICF will be orally translated by the interviewer on-site. 
Translations will be performed by a native speaker with thorough knowledge of the French language 
and checked for consistency by another native speaker. A recorded translation will be provided to 
ensure consistency and completeness of delivered information across different interviewers. 
 
In case participants are illiterate, an independent witness will be sought to ensure that the participants 
receive complete information. In such case, the participant will thumbprint the consent form and the 
witness will add his/her signature. 
 
The population will be informed about the general purpose of the study before the start of phase 3 
and individual participants/ households will receive detailed information before participating. 
12.4 Confidentiality 
Incident leprosy cases will not be made publicly known outside the household to avoid stigmatization. 
Data for the study will be collected by the study team via an Android application, in which participants 
will be identified by their geographical location and a barcode. The data will be uploaded regularly to 
a secure ITM server. Upon uploading to the ITM server, data will automatically be deleted from the 
Android device. Names will be recorded on the survey form, as is required for management purposes 
by the NTLCP which is responsible for follow-up and treatment of all leprosy and TB suspects or cases 
identified. The names will be linked to the data collected in the Android app through a barcode. For 
the final analysis a dataset without names will be used.  
 
The Informed Consent Forms and survey forms with the participant names will be stored in a secured 
location in a lockable cabinet with access limited to country PI9s only. The Access database with survey 
form data will be managed and secured by the NTLCP9s.  
 
Any other forms and reports needed for the study will be pseudonymised and can only be linked to 
the study participant by barcode.  
 


BE-PEOPLE, version 5.1, dated 01 March 2023 51 of 58 
Participant study information will not be released to anybody outside the medical team, except as 
necessary (and under confidentiality agreement) for the purpose of monitoring, auditing and 
inspection by competent authorities. 
 
During or after final publication of results, individual level participant data might be shared for 
secondary research purposes in an anonymized or pseudonymised manner and by means of a 
controlled data access procedure and after the signing of a data sharing agreement. 
 
12.5 Potential Risks  
In this study, participants will (depending on the arm their village is randomized in) receive a single 
dose of 10mg/kg of rifampicin or a single dose of 10mg/kg rifampicin plus 400 or 800mg of bedaquiline 
depending on age and weight. Because bedaquiline has not been registered for treatment or 
prophylaxis of leprosy and because we will be using it in combination with rifampicin, stringent safety 
procedures have been put in place. we have asked the advice from the Belgian regulatory authority 
for pharmaceuticals (FAGG) who have given an advise with different, detailed recommendations. The 
study has been split into two phases, a phase 2 study to reconfirm safety of the proposed BE-PEP 
regimen and a phase 3 study that is conditional upon a positive advice from an independent DSMB, 
taking into account the results of the phase 2 study.   
 
For rifampicin the dosing and indication are fully adherent to WHO recommendations. Safety of 
bedaquiline has been established for a single dose of 800 mg as well as in EBA studies in which 700mg 
on the first day was followed by 500mg on the second day. QT prolongation is not expected after 
single dose administration. 
 
The Covid-19 pandemic has so far had limited impact in Comoros although a sudden upsurge in early 
2021, in particular on the island of Mohéli, caused the cumulative death toll to increase from 10 at 
the beginning of the year to 144 by early March. Since then there have been few additional cases and 
only 5 additional deaths to date. So far approximately 30% of the population have been fully 
vaccinated, health workers have been prioritized. Door-to-door surveys for the PEOPLE study have 
been interrupted on Mohéli and resumed on April 1st. While in the villages, PEOPLE study teams wear 
surgical masks and gloves. All survey staff, both from the central team and those recruited at village 
level, have been fully vaccinated. As long as required during the BE-PEOPLE study wearing of masks 
and gloves will be continued. An early warning system established as part of the PEOPLE study in 
which health workers were tested for antibodies on a regular basis has now been abandoned because 
almost all health workers are vaccinated, moreover sufficient testing capacity is now in place on all 
three islands.    
 
The risk of loss of confidentiality is minimized by targeting for screening entire villages/hamlets, thus 
presence of the team cannot be interpreted as presence of leprosy patients in a household. Screening 
will be for skin conditions in general and for signs of pulmonary tuberculosis. Distribution of PEP to 
neighborhood contacts will be done upon completion of the door-to-door survey in the village. 
However since we are using a 100 meter common perimeter around all leprosy cases identified, the 
numbers of households included will always be large. If more than 50% of households are to be 
included, we will include the entire village. Unlike in an approach where PEP would be provided to 
neighbors, or neighbors of neighbors, in the approach used in this trial it will be almost impossible to 
deduce where the source case was located. Other potential breaches in confidentiality are minimized 
by GDPR compliant data management. A Data Protection Impact Assessment will be conducted to 
assess potential data protection risks and to define actions on how to mitigate those risks. 
 
At a higher level there could be a risk of villages or neighborhoods being stigmatized because of being 
involved in the study. This risk is not very high because leprosy is widespread in Comoros. In the areas 


BE-PEOPLE, version 5.1, dated 01 March 2023 52 of 58 
targeted most villages are known to be affected. On Anjouan since 2008 and more recently also on 
Mohéli, villages are regularly visited by leprosy control program teams for active case finding activities. 
In these villages such problems have never occurred. The fact that in the BE-PEOPLE trial even more 
villages will be included further reduces the risk of entire villages being stigmatized.  
 
Capillary blood sampling by finger-prick will be performed on a subset of participants at the time of 
the final survey round in 2028. No side effects apart from minor discomfort are to be expected from 
these tests. 
 
Skin biopsy and slit skin smear require making a small incision in the skin and taking a superficial skin 
sample. Local anesthesia will be applied to reduce the discomfort for the participants to a minimum. 
 
12.6 Benefits 
The yearly door-to-door screening as part of the study yields the greatest advantage of the study for 
the people living in the study target area, as this will guarantee early detection of leprosy and 
consequently early treatment. For people living in close proximity of a leprosy case, the study is 
expected to reduce transmission of leprosy due to PEP being offered through the study.  
12.7 Compensation for participation 
All tests and procedures that are part of this study are free of charge for the participants. Also 
treatment for leprosy and for minor skin conditions is offered free of charge by the national leprosy 
control programs, but are not part of this study. For phase 2, on the day of pre-recruitment, day 1 and 
day 14 (visits at the study house), a compensation will be provided to the participants. In case of a 
blood draw at the study house during visit D30, an additional compensation will be provided to the 
participant. This compensation will consist of a food package per visit (5kg rice, 5 milk sachets, 6 boxes 
of sardines with a total value of 10 euros on average). In case of participant referrals due to potential 
adverse events, transport costs will be reimbursed by the study. 
 
12.8 Insurance 
Prior to the start of the trial, ITM as sponsor of the trial will obtain a no-fault study insurance to cover 
any injury, damage or loss to study participants which is caused directly or indirectly by their 
participation in the study. Participants will be informed of such insurance in the Participant 
Information Sheet. 
 
13. DISSEMINATION OF RESULTS, INTELLECTUAL PROPERTY 
All study documents are provided by the Sponsor to the Investigators and his/her appointed staff in 
confidence. None of this material may be disclosed to any party not directly involved with the study, 
without written permission from the Sponsor and other partners as described in the MTA and study 
agreement. 
 
The results of this study will be presented in a scientific articles submitted to peer- reviewed journals. 
They will also be presented in other fora such as the Leprosy Research Initiative (LRI) meeting. 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 53 of 58 
 
14. ARCHIVING 
The sponsor and Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be verified. The relevant (essential) documents 
are those documents which individually and collectively permit to assess the conduct of the trial, the 
quality of the data produced and the compliance with GCP standards and applicable regulatory 
requirements.  
 
All the relevant study documentation present at all partners involved should be retained for a 
minimum of twenty years, unless differently requested by national authorities. The Sponsor should 
be informed prior to destruction of the files. After completion of the study, the IF will remain available 
for internal audits and/or inspections of regulatory authorities for a period of twenty years, unless 
differently requested by national authorities. 
 
 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 54 of 58 
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BE-PEOPLE, version 5.1, dated 01 March 2023 57 of 58 
16. LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALLEA 
All European Academies 
Anti-PGL-I 
Anti-phenolic glycolipid-I 
AR 
Adverse Reaction 
BCG 
Bacille de Calmette Guérin 
bedaquiline 
Bedaquiline 
BS 
Blood Samples 
CFZ 
Clofazimine 
CRF 
Case Report Form 
CRS 
Clinical Research Scientist 
CTU 
Clinical Trial Unit 
DF 
Damien Foundation 
DSMB 
Data and safety monitoring board 
EC 
Ethics Committee 
EDCTP 
European and Developing Countries Clinical Trial Partnership 
ESF 
European Science Foundation 
FSN 
Form serial number 
GC(L)P 
Good Clinical (Laboratory) Practice 
HGDI 
Hunter-Gaston Discriminatory Index 
HH 
Household 
IRB 
Institutional Review Board 
ITM 
Institute of Tropical Medicine 
LRI 
Leprosy Research Initiative 
LUMC 
Leidsch Universitair Medisch Centrum 
MB 
Multi bacillary 
NS 
Nasal swabs 
NTLCP 
National Tuberculosis and Leprosy Control Program 
ODK 
Open Data Kit 
PEOPLE 
Post ExpOsure Prophylaxis for LEprosy in the Comoros and Madagascar 
PEP 
Post Exposure Prophylaxis 
PI 
Principal Investigator 
PTB 
Pulmonary Tuberculosis 
qPCR 
Quantitative Polymerase Chain Reaction 
RIF 
Rifampicin 
SAC 
Scientific Advisory Committee 
SAE 
Serious Adverse Event 
SB 
Skin Biopsy 
SDDR-PEP 
Single Double Dose Rifampicin Post-Exposure Prophylaxis 
SDR 
Single Dose Rifampicin 
SSS 
Slit skin smears 
TMG 
Trial Management Group 
ZN 
Ziehl-Neelsen 
 
 


BE-PEOPLE, version 5.1, dated 01 March 2023 58 of 58 
17. ANNEX 1: FAGG opinion to the protocol 
 


CONFIDENTIAL 
 
famhp - National Scientific-Technical Advice                                                                                                                               1 of 14 
 
 
 
 
 
 
 
 
 
 
 
 
 BEDAQUILINE, CLOFAZIMINE, RIFAMPICIN 
Post exposure prophylaxis for leprosy  
Institute for Tropical Medicine 
 
National Scientific-Technical Advice (Type II) 
FAMHP/H/M/II/NR/05-07-21/454 
 
 
 
 
 
 
 
 
 
 
FINAL ADVICE REPORT 
OCTOBER 6TH, 2021 
 
 


CONFIDENTIAL 
 
famhp - National Scientific-Technical Advice                                                                                                                               2 of 14 
 
 
 
 
 
 
 
 
 
 
Applicant Representatives:  
 
Institute for Tropical Medicine (ITM) 
• 
Epco Hasker, MD PhD, Professor in Epidemiology, Principal Investigator 
• 
Bouke de Jong, MD PhD, Professor in Mycobacteriology, Co-investigator 
• 
Yven Van Herrewege, PhD, head of the ITM Clinical Trial Unit (CTU) 
• 
Natascha Herssens, project manager in the ITM CTU  
 
Janssen Pharmaceutica (observatory role) 
• 
Bart Remmerie, Clinical Pharmacology Lead  
• 
Karin Rombouts, Regulatory Lead 
• 
Alexander Pym, Head of R&D for Mycobacterial diseases 
 
 
FAMHP Representatives(*): 
 
Involved assessors :  
• 
Diederica Claeys, clinical assessor, FAMHP 
• 
Coraline Claeys, clinical assessor, PK, FAMHP 
• 
Karen Van Malderen, non-clinical assessor, FAMHP, PDCO member (EMA) 
• 
Amandine Bellenguez, clinical trial assessor, FAMHP (not present at the meeting) 
 
 
File manager: 
 
• 
Christophe Lahorte, Head of the National Innovation Office and Scientific-Technical 
Advice Unit, FAMHP 
• 
Iris Zwaenepoel, scientific filemanager National Innovation Office and Scientific-Technical 
Advice Unit, FAMHP 
 
(*) Remark: No potential conflicts of interest were declared by the FAMHP at the start of the 
scientific advice meeting. 
 
 
Disclaimer: 
The scientific and/or regulatory opinions issued in this document by the involved NCA are to 
be considered as not legally binding for any future application of the concerned 
product(s)/topics. The issued opinions are not legally binding neither towards the involved 
NCA, nor to the applicant/applicant9s legal representative and they are based on the 
submitted questions and information provided in the briefing document by the Applicant and 
cannot account for any future changes and developments in scientific knowledge or 
regulatory requirements.  
 


CONFIDENTIAL 
 
famhp - National Scientific-Technical Advice                                                                                                                               3 of 14 
 
 
I. 
BACKGROUND INFORMATION AS SUBMITTED BY THE 
APPLICANT1 
 
I.1 
Background information on the disease to be treated 
 
The Institute of Tropical Medicine has over the past five years become involved in leprosy control 
efforts on the Comoros. The Comoros are an island nation in the Indian Ocean, highly endemic for 
leprosy. Together with the Belgian NGO Damien Foundation and the national leprosy control program 
of the Comoros, ITM is currently implementing a trial on post exposure prophylaxis for contacts of 
leprosy patients, a strategy that was endorsed by the World Health Organization in 2018. The drug 
used for post exposure prophylaxis is rifampicin of which one single dose is provided. Though a 
protective effect at individual level is seen, so far, no clear effect on transmission of leprosy was 
observed. Incidence of the disease remains high and many children are still affected. 
 
To overcome the current stalemate and push leprosy to extinction, the applicant would like to test a 
stronger post exposure prophylaxis regimen, based on a combination of bedaquiline, rifampicin and 
clofazimine. Whereas the latter two drugs have been used for decades as standard treatment for 
leprosy, bedaquiline to date has only been used in the treatment of multi drug resistant tuberculosis. 
The applicant states he realizes very well that for treatment of multi drug resistant tuberculosis 
different safety considerations apply than for prophylaxis for leprosy. On the other hand there is now 
over a decade of experience with bedaquiline, provided daily for many months, and no major safety 
issues have emerged. In post exposure prophylaxis for leprosy only one single dose is provided, to be 
repeated once after four weeks for household contacts. 
 
I.2 
Background information on the medicinal product 
 
SmPC9s for Bedaquiline, Clofazimine, Rifampicine and Rifapentine are included in the briefing package. 
 
 
I.3 
Regulatory status of the product 
 
All products have marketing authorizations, SmPC9s are included in the briefing package. 
 
 
I.4 
Rationale for seeking advice 
 
The Institute of Tropical Medicine has over the past five years become involved in leprosy control 
efforts on the Comoros. The Comoros are an island nation in the Indian Ocean, highly endemic for 
leprosy. Together with the Belgian NGO Damien Foundation and the national leprosy control program 
of the Comoros, the Institute of Tropical Medicine is currently implementing a trial on post exposure 
prophylaxis for contacts of leprosy patients, a strategy that was endorsed by the World Health 
Organization in 2018. The drug used for post exposure prophylaxis is rifampicin of which one single 
dose is provided. Though a protective effect at individual level is seen, so far no clear effect on 
transmission of leprosy has been observed. The incidence of the disease remains high and many 
children are still affected. 
 
To overcome the current stalemate and push leprosy to extinction, the applicant would like to test a 
stronger post exposure prophylaxis regimen, based on a combination of bedaquiline, rifampicin and 
clofazimine. Whereas the latter two drugs have been used for decades as standard treatment for 
leprosy, bedaquiline to date has only been used in the treatment of multi drug resistant tuberculosis. 
The applicant states they realize very well that for treatment of multi drug resistant tuberculosis 
different safety considerations apply than for prophylaxis for leprosy. On the other hand there is now 
over a decade of experience with bedaquiline, provided daily for many months, and no major safety 
issues have emerged. In post exposure prophylaxis for leprosy only one single dose is provided, to be 
repeated once after four weeks for household contacts. 
 
 
1 All annexes mentioned under the Applicant’s position refer to the documentation submitted with the request. 


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famhp - National Scientific-Technical Advice                                                                                                                               4 of 14 
 
 
As stated in the Q&A document, the applicant believes that the benefit of potential elimination of 
leprosy transmission on the Comoros outweighs the minimal risk of serious adverse events. 
Unfortunately the Comoros do not have regulatory bodies such as FAGG. The local Ministry of Health is 
a partner in this ongoing project but the applicant would like to have an independent expert opinion 
before proceeding.  
 
 
 


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famhp - National Scientific-Technical Advice                                                                                                                               5 of 14 
 
 
II. 
CLINICAL QUESTIONS FROM THE APPLICANT 
 
II.1 
Question 1 : We expect that the proposed regimen is safe and that if no safety 
concerns emerge from the trial in the small village, the full phase 3 trial can safely 
be initiated. The specific questions on which we seek FAMHP consultation are as 
follows:  
II.1.a. We assume that based on the established safety profiles of clofazimine and 
 
rifampicin in leprosy patients and the known and favorable safety profile of 
 
bedaquiline in the treatment of MDR-TB, a priori there are no major safety concerns 
 
about the proposed regimen. If no serious adverse events emerge during the small 
 
safety study (n=100-150) under strict conditions of pharmacovigilance, a full scale 
 
phase 3 trial as proposed can go ahead. Does the FAMHP agree for us to investigate 
 
in a two-stage trial the effectiveness of the proposed leprosy post exposure 
 
prophylaxis regimen consisting of bedaquiline, rifampicin and clofazimine? 
II.1.b. Rifamycins have been in use for decades and have a very favorable safety profile, 
 
this also applies to rifapentine.  We assume that replacing rifampicin by rifapentine 
 
in the proposed regimen will not lead to additional safety concerns. Does the FAMHP  
 
agree that to exchange rifampicin with rifapentine at the same dosing scheme (1200 
 
mg for adults) poses no additional safety concerns?  
II.1.c. Both bedaquiline and clofazimine are known to be associated with QT prolongation. 
 
We assume that with a single dose, even if repeated after four weeks, the risk posed 
 
is negligible and is outweighed by the benefit of potentially preventing leprosy. In 
 
case the FAMHP is of the opinion that for the combination of bedaquiline and 
 
clofazimine this risk of QT prolongation outweighs the potential benefit of preventing 
 
leprosy, would the FAMHP agree to a regimen of only bedaquiline and  rifampicin as 
 
post exposure prophylaxis for leprosy?  
 
 
Applicant’s position 
 
Rifampicin monotherapy at a dose of 10 mg/kg has been recommended by WHO as post exposure 
prophylaxis for contacts of leprosy patients since 2018.[1]  We intend to initiate a trial on a new 
regimen for post exposure prophylaxis for leprosy in the Comoros, an island nation in the Indian ocean 
that is hyperendemic for leprosy. Despite a well-organized leprosy control program and over 40 years 
of support from the Belgian NGO Damien Foundation, leprosy remains hyperendemic on the islands of 
Anjouan and Mohéli, Comoros.[2]  
Our group started a trial on post exposure prophylaxis provided to contacts of leprosy patients on 
Anjouan and Mohéli as well as in one district of Madagascar in 2019 (the 8PEOPLE9 trial, 
ClinicalTrials.gov Identifier: NCT03662022). The regimen used is single dose rifampicin, the dosage is 
20 mg/kg, double the standard dose recommended by WHO. Depending on the study arm, post 
exposure prophylaxis is provided to household contacts of index leprosy patients, to neighborhood 
contacts in a radius of 100 meter, or to household contacts plus neighborhood contacts within 100 
meter testing positive to a serological screening test for infection with the leprosy bacillus (M. 
leprae).[3] In the comparator arm no prophylaxis is provided. This trial is now in its third year and 
preliminary results of an interim analysis after the first year show an impact of single dose rifampicin 
post exposure prophylaxis at individual level of around 70% decreased incidence of leprosy, similar to 
the study on which the WHO guidelines were based, but no clear impact yet at community level. We 
also see a clear gradient in risk of leprosy with household members incurring 7-8 times more risk when 
compared to those living at 100 meter or beyond of an incident leprosy patient.[4]  
We therefore wish to test a reinforced regimen with bedaquiline as backbone, in combination 
with rifampicin and clofazimine. This regimen will again be provided as single dose but will be 
repeated once, after four weeks, for household members. We expect that clofazimine and 


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famhp - National Scientific-Technical Advice                                                                                                                               6 of 14 
 
 
rifampicin can be safely used in a single dose regimen, even if repeated once after four weeks. These 
drugs have been the standard treatment for multibacillary leprosy since the 1980s and have an 
excellent safety profile.[1]  
 
Rationale for Bedaquiline in Leprosy: 
Bedaquiline as part of combination therapy has been approved for treatment of multi-drug resistant 
tuberculosis, by the FDA in 2012, and EMA in 2014.[5, 6] WHO treatment guidelines recommend 
bedaquiline as <Group A drug= (to be included in all regimens) for the treatment of rifampicin resistant 
tuberculosis.[7] Bedaquiline is a mycobacterial-specific ATP synthase inhibitor, a key component of the 
bacterial respiratory chain that is required for production of energy. There exists close amino acid 
sequence homology in ATP synthase across M. tuberculosis and M. leprae, but M. leprae  lacks the 
efflux pump through which bedaquiline resistance is mediated in M. tuberculosis.[8-10] 
 
Data from animal models supports efficacy of bedaquiline in leprosy and moreover suggests that 
bedaquiline may have a more potent effect on M. leprae than on M. tuberculosis. Once monthly 
treatment of leprosy in mice with 25 mg/kg bedaquiline resulted in no acid fast bacilli (AFB) being seen 
under light microscopy examination of the mice footpad.[8] This is a more potent effect than seen in 
M. tuberculosis, in which a dose of 50 mg/kg once every two weeks resulted in a reduction, but not 
complete eradication, in colony forming unit (CFU) counts. [11] A dose of 1 mg/kg was found to be 
bactericidal for M. leprae, whereas doses of 1.5 mg/kg and 3.2 mg/kg were inactive against M. 
tuberculosis.[8, 12] In the mouse model of M. leprae, 1 mg/kg given 5x/week and 25 mg/kg once 
monthly were equally efficacious in that both regimens killed all bacilli, suggesting that low and 
intermittent dosing is promising for the treatment of leprosy [13]. Additionally, in a mouse footpad 
system, bactericidal activity of bedaquiline against M. leprae was equal to that of rifapentine, 
rifampicin, or moxifloxacin and significantly greater than that of minocycline and linezolid.[10] Based 
on this encouraging preclinical data, Janssen is planning to conduct a phase III trial with bedaquiline 
as part of a multi-drug regimen for the treatment of leprosy.  
 
 
Dosing: 
In our study the dosing schedule proposed is the following:  
 
 
Clearly in treatment of multi-drug resistant tuberculosis risk/benefit considerations are different than 
those that apply to post-exposure prophylaxis for leprosy, but we do not expect any toxicity issues 
with the proposed post exposure prophylaxis regimen. For both bedaquiline and rifampicin we intend 
to use higher than the standard dosages at which these drugs are normally used on a daily basis.  
For rifampicin in the PEOPLE trial we are already using a double dose (20 mg/kg), based on studies 
that show increased bioavailability and early bactericidal effect of increased doses rifampicin.[13] 
Moreover rifampicin has already been used as post exposure prophylaxis for leprosy at an even higher 
dose of 25 mg per kg. [14] Clofazimine will be provided in the same dosage already in use for 
treatment of multibacillary leprosy, i.e. 300 mg; in leprosy treatment this is given once a month in 
addition to daily doses of 50 mg.  


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famhp - National Scientific-Technical Advice                                                                                                                               7 of 14 
 
 
As an alternative for rifampicin we consider rifapentine, a longer acting rifamycin, based on increased 
efficacy against M. leprae in mice. [15] As also clofazimine and bedaquiline have longer half-lives, this 
three drug combination is not only likely superior to the rifampicin based one; the drugs may also 
protect each other better against the selection of resistant mutants. We assume that replacing 
rifampicin by rifapentine will not cause additional safety concerns, with rifapentine 1200mg used safely 
on a daily basis for four months for TB patients.[16, 17] We also do not anticipate any drug-drug 
interaction with monthly dosing of rifampicin, nor rifapentine, in context of the Cytochrome P450 3A4 
(Cyp3A4) metabolism of bedaquiline. 
 
For leprosy post exposure prophylaxis we will provide one single dose of bedaquiline (800 mg), 
maximum two doses four weeks apart in combination with clofazimine and rifampicin, whereas adult 
MDR-TB patients receive bedaquiline 400 mg q.d. for 2 weeks and 200 mg three times a week for 22 
weeks (six months in total) in combination with other drugs, often including clofazimine and 
fluoroquinolones.  
 
A bedaquiline dose of 800 mg, for adults, has been administered to healthy individuals and 
demonstrated safe exposure.  A double-blind, single-dose study in 88 subjects was conducted to 
evaluate the effect of a single 800 mg dose on the QT/QTc interval. A total of 44 subjects received 
bedaquiline. Holter ECG monitoring was performed continuously for 72 hours for each subject on Day -
1 (Baseline), Day 1, and Day 2. No QTc values >500 ms or changes in QTc from baseline >60 ms were 
observed and no ECG-related AEs were reported.[18] The largest upper limit of the 90% CIs of the 
difference between bedaquiline and placebo in time-matched changes from baseline in QTcF was below 
the threshold of 10 ms, indicating that this thorough QT study was negative per ICH E14 guideline. 
Adverse reactions were consistent with those observed in clinical studies at the recommended dose. PK 
data from this study suggests that there is no significant accumulation of bedaquiline or its metabolite 
M2, which is the main driver of cardiovascular toxicity, with the 800 mg dosing. The observed M2 
Cmax in the TBC1003 study was found to be lower than the Cmax at steady state of M2 when 
compared to TB dosing of bedaquiline.[18] 
 
The safety of bedaquiline for the treatment of MDR-TB has been established. Although in the pivotal 
phase 2b trial, more deaths occurred in the bedaquiline treatment group than in the placebo group, 
the imbalance in death is unexplained and no evidence of a causal relationship with bedaquiline 
treatment was found. [7] This is reflected in the section 4.4 8Special warnings and precautions for use9 
in the EU Prescribing Information.[6, 19] Since then, a decade of safety data on bedaquiline has been 
obtained and additional clinical trial data and post-marketing experience in multiple different regimens 
has not identified a relationship between bedaquiline and mortality. [20-23] In fact, programmatic 
data on the use of bedaquiline showed a reduced mortality of TB patients in South Africa who received 
a bedaquiline containing regimen.[23] Additional results of a phase 3 trial of bedaquiline for the 
treatment of MDR-TB are expected to be released in 2023. We therefore assume that the risk of a 
single 800 mg dose of bedaquiline is minimal, even if repeated once after four weeks. We assume that 
the benefits associated with being able to eliminate transmission of leprosy outweigh the risk of 
adverse events caused by the proposed post exposure prophylactic regimen. To confirm safety, we 
propose to first apply the regimen under strict conditions of pharmacovigilance, including ECGs and 
liver function tests, in a small village (estimated population N=150) from which many leprosy patients 
have been reported in recent years. If no safety concerns emerge we intend to proceed with the full 
scale phase 3 trial with an intended sample size of approximately 120,000 participants, of whom 
60,000 would be eligible to receive the proposed post exposure prophylaxis regimen; the other 60,000 
would be in the comparator arm in which no post exposure prophylaxis is provided 
 
 
Important Remark: 
 
Just before the scientific advice meeting with the FAMHP took place, the proposed drug 
regimen was changed by the Applicant to rifampicin 600 mg and bedaquiline 800 mg single 
dose PEP for leprosy. This is the PEP dose for rifampicin currently recommended by the WHO, i.e. 
half the dose that was originally proposed by the applicant, with addition of an 800 mg bedaquiline 
dose and no addition of clofazimine.  
The reasons for changing the proposed drug regimen after consultation with global leprosy experts and 
ethicists were as follows: 
• 
There is solid evidence that bedaquiline strengthened leprosy prevention is superior and has the 
most likely impact on strengthened leprosy control. 
Aim for inclusion on WHOs essential medicines list 


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famhp - National Scientific-Technical Advice                                                                                                                               8 of 14 
 
 
• 
Clofazimine also prolongs QT 
The applicant considers this unlikely after a single dose, even if combined with bedaquiline, yet 
the safety concerns are higher 
• 
Rifapentine has a stronger effect than rifampicin in mouse models, but it lacks the indication for 
leprosy treatment 
• 
=> Clofazimine is dropped and rifampicin is used instead of rifapentine 
Addition of only one additional drug will also allow a clearer comparison with rifampicin that is 
currently used. 
Following this change, the original questions as mentioned in the initial briefing package of 
the advice request were reformulated by the Applicant before the formal scientific meeting 
with the FAMHP to one single question: 
Question 1 : We expect that the proposed regimen is safe and that if no safety concerns 
emerge from the trial in the small village, the full phase 3 trial can safely be 
initiated. The specific question on which we seek FAMHP consultation is as follows:  
 
1: We assume that based on the established safety profiles of rifampicin in leprosy 
patients and the known and favorable safety profile of bedaquiline in the treatment 
of MDR-TB, a priori there are no major safety concerns about the proposed regimen 
of rifampicin 600 mg and bedaquiline 800 mg single dose PEP for leprosy.  If no 
serious adverse events emerge during the small safety study (n=100-150) under 
strict conditions of pharmacovigilance, a full scale phase 3 trial as proposed can go 
ahead. 
Does the FAMHP agree for us to investigate in a two-stage trial the effectiveness of the 
proposed leprosy post exposure prophylaxis regimen consisting of bedaquiline and 
rifampicin? 
 
 
Subsequently, the discussion during the scientific advice meeting focused mainly on this single 
remaining question. 
The FAMHP requested that in future requests for scientific advice submitted to the FAMHP any change 
to submitted questions and/or the briefing documentation (i.e. after formal validation of the advice 
request by the FAMHP) should be avoided as it made it very challenging to give appropriate advice, 
although in this case it did not have a material impact on the scientific advice given.   
 
It was also clarified during the meeting that – in general - the role of the FAMHP in providing national 
scientific advice is not to give any kind of preapproval for eg. a future clinical study nor to perform a 
pre-assessment of the CTA but rather to issue advice on whether the type and extent of supportive 
data for a proposed study could potentially meet the current requirements, including safety, should the 
trial take place in Belgium. 
 
Before the discussion, Epco Hasker presented the proposed trial and some background information. 
 
 
FAMHP answer to question 1 
 
• 
At the moment the FAMHP cannot state that the two-stage trial design could be approved or 
not. 
• 
It is very likely that the currently proposed drug regimen could be approved, though the 
following comments should be taken into account: 
• 
The need for a more effective regimen than single dose rifampicin PEP should be better 
substantiated 
o Next to the points that have already been raised by the Applicant, additional points 


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famhp - National Scientific-Technical Advice                                                                                                                               9 of 14 
 
 
could be added, e.g. that the current regimen could also not be effective against the 
higher load in contacts with subclinical infection which would support the need for an 
enhanced dosing regimen. 
• 
The drug combination regimen should be better substantiated: 
o Non-clinical models for the drugs that will be used off-label (rifampicin (though WHO 
recommended) and bedaquiline) 
Data for bedaquiline have been provided, though it would be preferred that details of 
this non-clinical study would be discussed in more detail by the applicant. 
o Rationale for combining these drugs based on non-clinical studies or clinical studies, data 
substantiating the expected synergism should be provided 
o Already available clinical data in the treatment and/or prophylaxis of leprosy should be 
provided, especially for the drugs that will be used off-label. 
o Rationale based on mode of action should be provided, and should also discuss the 
impact of early bactericidal activity, bacteriostatic effect, sterilizing effect of the 
different drugs. 
• 
The proposed dosing regimen should be better substantiated.  
o Dose rationale: Now we get the impression that for bedaquiline, the highest single dose 
that has been investigated and has been confirmed to be relatively safe will be used, 
while the lowest effective dose should be used. 
o Extrapolation from the PK data in non-clinical studies (mouse study) could be used for 
dose prediction in humans and should be provided. 
o Are any PK/PD/efficacy data available to further support the proposed dosing regimen? 
• 
Frequency of administration 
o This was touched upon during the presentation and is based on mouse studies. Why it is 
not offered more than twice? 
 
• 
Timing of repeated administration 
o The choice of the 4week time window between administrations should be substantiated. 
• 
Drug-drug interactions (DDIs), timing of administration and food effect should be taken into 
account regarding the dosing administration. 
o Will the drugs be administered with or without food? The Applicant should note that 
different recommendations are given in the respective SmPCs regarding the 
administration with respect to meals. The impact of food on efficacy due to the decrease 
in Cmax is not clear. 
▪ 
Bedaquiline administered with food increased oral bioavailability by about 2-fold 
▪ 
Rifampicin should be taken on an empty stomach to ensure rapid and complete 
absorption. Concomitant intake of food delays absorption and reduces the peak 
concentration, but does not decrease bioavailability 


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famhp - National Scientific-Technical Advice                                                                                                                               10 of 14 
 
 
Post-meeting note: more details have been provided on the effect of food on the 
bioavailability of bedaquiline and on the rifampicin exposure and the conditions of 
administration with regards to food post-meeting. It has been clarified that the 
drugs will be administered under fed conditions. The uncertainties on the clinical 
relevance of a decrease of the Cmax of rifampicin under these conditions of 
administration should be taken into account.  
o DDIs between the drugs under investigation; the effect of other potentially administered 
drugs on bedaquiline and rifampicin; as well as the effect of bedaquiline and rifampicin 
on other potentially co-administered drugs should be discussed in detail. If necessary 
this should be reflected in the exclusion criteria. 
Post-meeting note:  The potential PK drug-drug (DDI) with bedaquiline and rifampicin 
were further discussed during the meeting mainly focusing on bedaquiline as CYP3A4 
substrate and impact of inhibition or induction of CYP3A4 on the PK of bedaquiline. 
Recommendations are provided in the current SmPC of Sirturo with regards to the 
concomitant administration of moderate or strong CYP3A4 inhibitors as well as 
moderate or strong CYP3A4 inducers. 
In addition, it should also be considered that bedaquiline is also a substrate of OATP1B1 
and OATP1B3 in vitro while a single dose of rifampicin inhibits OATP1B transporters. The 
potential of DDI through this mechanism should be further clarified after administration 
of a single dose of rifampicin with a high (single) dose of bedaquiline. Regarding the 
perpetrator potential of bedaquiline and rifampicin, even if the single dose 
administration mitigate the risk, a clinically relevant DDI trough an inhibition mechanism 
cannot be ruled out for BCRP substrates and OATP1B1/1B3 substrates on the day of 
administration of bedaquiline+rifampicin. This should be taken into account when 
assessing the risk of DDI with potential concomitant drugs. In the assessment of the risk 
of clinically relevant DDI, the uncertainties in the linearity of the PK of bedaquiline and 
its metabolite at the dose of 800 mg bedaquiline and the exposures achieved after the 
administration of this high dose should also be considered. It should also be kept in mind 
that uncertainties are still remaining on how the metabolite of bedaquiline M2 is 
eliminated. 
 
• 
Administration in the paediatric population: 
o Individuals weighing 10-20 kg will receive only rifampicin but no bedaquiline. Safety of 
bedaquiline is not established in children under 5 years of age or weighing less than 
15 kg. Bdq will not be administered to paediatric patients with a body weight below 
20 kg. This more or less corresponds with the currently approved age range of 5 years 
and above. 
o Rifampicin will be administered in patients aged 2 years and above. 
o Age-appropriate formulations for both rifampicin and bedaquiline should be used to 
ascertain that the correct and targeted dose will be administered to the paediatric 
patients. No PK data will be obtained to ascertain correct dose administration. 
 
• 
Dose determination in the paediatric population should be substantiated 


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famhp - National Scientific-Technical Advice                                                                                                                               11 of 14 
 
 
o It should be discussed how the doses for the paediatric population and for the lower 
body weights have been determined. Usually PK data are used to provide a similar 
exposure as obtained in the adult population, if the disease process is similar in adults 
and the paediatric population and the outcome is likely to be comparable. 
 
• 
If the potential benefit and proposed dosing regimen is thoroughly substantiated and would be 
approvable, it can be assessed whether the expected relative risk/benefit profile would be 
acceptable. 
Post meeting note: Additional data have been provided during the meeting supporting the 
potential benefit and rationale for the proposed combination regimen and mainly for the 
proposed dose (regimen). These have, however, not been assessed in detail. 
• 
The major safety issues are cardiovascular and hepatic safety: 
o The risk for QT interval prolongation related to bedaquiline administration is considered 
not being higher than during MDR-TB treatment with bedaquiline. The main driver of 
the cardiovascular toxicity is its metabolite M2. The observed M2 Cmax in the thorough 
QT study with a bedaquiline 800 mg single dose was found to be lower than the Cmax at 
steady state of M2 when compared to tuberculosis dosing of bedaquiline. 
The risk for QT interval prolongation cannot be excluded and caution is still warranted, 
see warnings and precautions in the bedaquiline SmPC. 
 
Post-meeting note: In the thorough QT study, the upper bound of the 95% one-sided 
confidence interval for the largest time-matched mean effect of the drug on the QTc 
interval must exclude 10 ms, while the 90% confidence interval is reported in the study 
report. QT interval prolongation is a known risk for bedaquiline. 
Post-meeting note: More detailed modeling and simulation data can be provided to 
predict the expected QT interval prolongation, though details have not been assessed as 
this has been provided post meeting. 
o Risk for overlapping hepatic toxicity with co-administration of rifampicin and bedaquiline 
is considered of more limited importance as it is usually reported after multiple doses of 
bedaquiline. It should however, be discussed by the applicant. 
A nested phase 2 study is recommended with stringent evaluation of safety of the proposed 
rifampicin/bedaquiline combination regimen, including monitoring of ECG and liver enzymes and 
with more stringent exclusion criteria related to these safety issues. 
 
Post-meeting note: The safety assessment and discussion during the meeting focused mainly on 
the major safety issues (related to cardiovascular and hepatic safety), though other acute side 
effects, some reported for both bedaquiline and rifampicin, should be taken into consideration 
as well, e.g  gastro-intestinal (nausea, vomiting), nervous system-related (headache, dizziness) 
and cutaneous reactions, as these can have an impact on the safety, tolerability and 
acceptability of the drug regimen.  
This further supports the need for a nested phase 2 study. In this context it would be advisable 
to assess safety and tolerability of the proposed drug regimen in a minimum number of adult 
patients first, followed by a first cohort of patients between 12 and 18 years of age, before 


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famhp - National Scientific-Technical Advice                                                                                                                               12 of 14 
 
 
enrollment in the cohort 5-12 years of age. 
 
• 
Additionally, the potential risk could be limited by the trial design, e.g. inclusion and exclusion 
criteria, safety monitoring. 
o Additional exclusion criteria should be considered 
▪ 
Additional WHO exclusion criteria for prophylaxis: history of liver or kidney 
disorders, pregnancy, allergy to active drugs [WHO, 2020 p 23 and 24] 
▪ 
Exclusion criteria related to the major safety issues (QT interval prolongation 
and hepatic safety). These will likely be more stringent for the phase 2 part of 
the study than for the phase 3 part. If the treatment regimen is considered safe 
after assessment of the data from the phase 2 part of the study, phase 3 of the 
trial could be started with less stringent inclusion criteria. 
 
o The safety monitoring for phase II should be further described 
See Protocol 5.1 General Study Procedures 
“The phase 2 study in the village of Chitsangachele will take place in April, 2022. Detailed 
standard operating procedures will be developed. The village will be screened door to 
door and based on the incidence observed in the last 5 years, all those eligible will be 
provided with E-PEP. We thus expect to provide E-PEP to approximately 100 participants. 
Those participants will be strictly monitored, including ECG and liver function tests. If 
no SAEs are reported, the intervention in arm 5 will go ahead as planned, starting in 
January, 2023.” 
 
o The Tmax of the different drugs and their metabolites should be taken into account for 
the close safety monitoring as well as the half-life of the drugs. 
In the thorough QT study with a single 800 mg bedaquiline dose, the mean change from 
baseline in the QTcF interval was maximal at 16 hours post dose. Due to the long half-life 
of both bedaquiline and its M2 metabolite, the M2 Cmax after the second dose will be 
higher. 
 
o Other safety related comments on the protocol 
▪ 
Data Safety Monitoring Committee 
Although all products used in this trial have a marketing authorizations, the 
applicant intend to initiate a study with a new regimen/combination that has 
not been tested before for post exposure prophylaxis for leprosy.  Therefore, the 
Applicant is highly recommended to establish a Data Safety Monitoring 
Committee.  A brief description of the composition and the tasks and 
responsibilities of this committee should be provided in the study protocol. 
Further details should be outlined in a DSMC charter for the intended study, 
outlining the role of the committee, organizational flow, committee 
membership, committee meetings and communication. 
The agency refers to the following guidelines:  
- Guidance on data monitoring committees 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-data-


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famhp - National Scientific-Technical Advice                                                                                                                               13 of 14 
 
 
monitoring-committees_en.pdf 
- Questions and answers on Data Monitoring Committees issues 
https://www.ema.europa.eu/en/documents/scientific-guideline/questions-
answers-data-monitoring-committees-issues_en.pdf 
 
• 
Discontinuation criteria for study subjects and study stopping criteria should 
be added. 
Note to the applicant: these should also be included in the phase 3 part of the 
study 
 
• 
The eligibility of pregnant women/breastfed infants and lifestyle measures for 
this population should be clarified. 
 
• 
COVID-19 pandemic 
The Applicant should described in the protocol how they will adjust the 
management of this study and participants during the COVID-19 pandemic.  
The agency refers to the <Guidance On The Management Of Clinical Trials During 
The Covid-19 (Coronavirus) Pandemic= version 4 dated 04/02/2021  
https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf  
 
• 
The safety (and efficacy) data from the phase 2 part of the study should be assessed before the 
start of the phase 3 part of the study. In Belgium these data should normally be submitted to the 
competent authority for assessment in order to obtain approval for the start of the phase 3 part 
of the study. 
 
 
 
 
 
 
 
Abbreviations: 
 
Bdq 
 
Bedaquiline 
MDR-TB 
Multiple drug resistant tuberculosis 
PEP 
 
Post-exposure prophylaxis 
 
 
 
References: 
WHO 2020 Leprosy/Hansen disease: Contact tracing and post-exposure prophylaxis Technical Guidance 
 
 


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famhp - National Scientific-Technical Advice                                                                                                                               14 of 14 
 
 
III. 
OTHER COMMENTS (NOT DIRECTLY RELATED TO THE 
QUESTIONS) 
 
 
Comments from the FAMHP 
 
A couple of additional FAMHP comments were raised during the scientific advice meeting and addressed 
by the Applicant in below: 
• 
The re-use of villages participating in the PEOPLE study in the proposed trial and what is the 
expected impact. Because villages will be randomized to the two arms of the new study within the 
arms of the PEOPLE trial, this will not introduce any bias. Moreover in the villages to be re-
randomized (arm 2 and arm 4 of PEOPLE trial), limited numbers of persons so far received PEP and 
impact on incidence at village level has been minimal. 
• 
The FAMHP asked whether there is stratification for age (<18 yrs and elderly). In the 
assessment of the individual effect of PEP it is possible to do such sub-group analyses but they are 
likely to be underpowered.  
• 
As the trial will not take place in Belgium, the final approval will need to be given by the Comoros 
regulatory authorities after consultation with the ethics committee of the University of Antwerp. 
It should be assessed whether the authorities of the Comoros will require review of data after 
positive outcome nested phase II study and before initiating larger phase 3 community level 
study. 
• 
The nitrosamine level in rifampicin has been tested and confirmed to be below the required 
safety limits. 
Post-meeting note (FAMHP): As the administration is only once or twice, this would not be a 
major issue. 
 
 

SAP_001.pdf: 
 
1 
 
BE-PEOPLE - Statistical Analysis Plan 
 
6-Sep-2022 
 
Statistical Analysis Plan 
 
Bedaquiline Enhanced Post ExpOsure Prophylaxis for 
Leprosy (BE-PEOPLE) – PHASE 2 
 
 
Date:  06-September-2022 
 
Author:  
Achilleas Tsoumanis, Els Genbrugge 
 
 
Biostatistician, Institute of Tropical Medicine, Antwerp, Belgium 
 
Approved by:  
International Coordinating Investigator 
 
 
 
Epco Hasker 
 
 
 
 
 
 
 
 
Date: __09__ / __08_ / _2022_ 
 
 
                         
 
 
 
____________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
2 
 
BE-PEOPLE - Statistical Analysis Plan 
 
6-Sep-2022 
 
Table of Contents 
 
1. 
Introduction ................................................................................................................................................ 3 
2. 
Study design and objectives ....................................................................................................................... 3 
2.1. 
Study design ........................................................................................................................................ 3 
2.2. 
Study objectives .................................................................................................................................. 4 
2.2.1. 
Primary objectives ....................................................................................................................... 4 
2.2.2. 
Secondary objectives ................................................................................................................... 4 
2.3. 
Study hypothesis ................................................................................................................................. 4 
3. 
Study outcomes and variables of interest................................................................................................... 4 
3.1. 
Study outcomes ................................................................................................................................... 4 
3.1.1. 
Primary outcomes ........................................................................................................................ 4 
3.1.2. 
Secondary outcomes .................................................................................................................... 4 
3.2. 
Definitions ........................................................................................................................................... 5 
4. 
Description of study population ................................................................................................................. 5 
4.1. 
Participant accounting ......................................................................................................................... 5 
4.2. 
Description of study population .......................................................................................................... 5 
5. 
Description of analysis populations ........................................................................................................... 6 
5.1. 
Analysis populations ........................................................................................................................... 6 
5.1.1. 
Intention to treat (ITT) analysis ................................................................................................... 6 
5.1.2. 
Per protocol (PP) analysis ............................................................................................................ 6 
6. 
Statistical Methods ..................................................................................................................................... 7 
6.1. 
Primary safety analysis........................................................................................................................ 7 
6.2. 
Secondary safety analysis.................................................................................................................... 7 
6.3. 
General safety aspects ......................................................................................................................... 8 
6.4. 
Interim analysis ................................................................................................................................... 8 
6.5. 
Other aspects ....................................................................................................................................... 8 
6.5.1. 
Subgroup analyses ....................................................................................................................... 8 
6.5.2. 
Multiplicity adjustment ................................................................................................................ 8 
6.5.3. 
Missing data and sensitivity analysis ........................................................................................... 8 
6.5.4. 
Exploratory analysis..................................................................................................................... 8 
 
 
 


 
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1. Introduction 
 
This Statistical Analysis Plan (SAP) provides a detailed and comprehensive description of the main, pre-
planned analyses for the phase 2 study " Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy (BE-
PEOPLE)". The purpose of this phase 2 study is to determine the safety of the combination of the trial regimen 
i.e. bedaquiline and rifampicin (BE-PEP) in healthy volunteers in Comoros. The study conduct is described 
in the study protocol (version 2.1 finalized on 17th March 2022) and in clinicaltrials.gov (registration to be 
completed). 
 
These planned analyses will be performed by the statistician(s) at the Clinical Trials Unit of the Institute of 
Tropical Medicine (Antwerp) in collaboration with the research consortium. The analysis results will be 
described in a statistical analysis report, to be used as the basis of the main research publications according to 
the study publication plan. This document describes statistical methods for the primary and secondary safety 
outcomes of the phase 2 study as defined by the protocol. Additional analyses may be performed but are not 
covered by the current analysis plan. Statistical methods for these additional analyses will be described 
together with their respective results.  
 
At the end of the study, all data points will be locked, analyzed and results may be submitted for publication. 
This analysis plan will be finalized and approved before the database lock for the phase 2 analysis. Major 
changes in statistical methodology used for the main and pre-planned analyses from this SAP, will require 
detailed description and justification in the statistical analysis report. The final analysis datasets, programs, 
and outputs are archived following good clinical practice guidelines (ICH E9). 
 
 
2. Study design and objectives 
 
2.1. Study design 
 
This is a single-site, randomized, non-inferiority, phase 2 clinical trial, comparing the safety between a single 
dose rifampicin (SDR-PEP) and single dose bedaquiline plus rifampicin (BE-PEP) among contacts of recent 
leprosy cases.  Safety will be closely monitored and evaluated by an independent data and safety monitoring 
board (DSMB). The study setting is the village of Gégé, Anjouan, that is part of arm 1 of the PEOPLE trial in 
which 8 new cases have been diagnosed since 2019 but no PEP has been provided.  
 
During the final survey round of the PEOPLE study, all individuals in the village aged 5 years or above, 
weighing 20 kg or above and not currently suffering from leprosy will be enumerated and screened for the 
study inclusion and exclusion criteria (see 5Description of analysis populations Description of analysis 
populations for more details).  
Three hundred of the eligible individuals from the village will be stratified proportionally over three age-
groups (18 years and above, 13-17 years, and 5-12 years) and will be randomized (1:1) into one of the two 
study arms: 
• Arm 1: single dose of bedaquiline plus rifampicin (BE-PEP) (n=150) 
• Arm 2: single dose of rifampicin (SDR-PEP) (n = 150) 
 
Randomization will occur sequentially, first enrolling persons above 18 years of age. Provided no concerning 
adverse events are observed, the randomization and enrollment will continue for the 13-17 years old age 
category. Again if no concerning adverse events are observed, the enrollment will proceed for children aged 
5-12 years old. The remainder of the population of this village aged 2 years and above will be offered single 
dose rifampicin as per WHO recommendations. 


 
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All randomized 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 any 
other adverse events, including but not limited to gastro-intestinal (nausea, vomiting), nervous system-related 
(headache, dizziness) and cutaneous reactions.  
 
2.2. Study objectives 
 
2.2.1. Primary objectives 
 
To confirm overall safety of the study regimens, single dose bedaquiline plus rifampicin and single dose 
rifampicin, in a field setting in Comoros. 
 
2.2.2. Secondary objectives 
 
• To determine baseline liver function (frequency of ALT and AST elevations) and cardiac abnormalities 
(QTc prolongations) in the population. 
• To document for each of the two regimens post administration QTc levels, ALT and AST results.  
• To document for each of the two regimens any potentially frequent adverse events, such as gastro-
intestinal (nausea, vomiting), nervous system-related (headache, dizziness) and cutaneous reactions. 
 
2.3. Study hypothesis 
 
It is hypothesized that BE-PEP is not inferior the SDR-PEP in terms of safety. 
 
 
3. Study outcomes and variables of interest 
 
 
3.1. Study outcomes 
 
3.1.1. Primary outcomes 
 
• Mean difference in QTc interval between the two arms 24 hours after treatment administration.  
 
• 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 SAE or Gr 4 AE or a persistent (upon repeat testing) Gr 4 
laboratory abnormality that is determined to be related to study drug 
3. Three or more participants experience a Gr 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) Gr 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 AST or ALT > 8x ULN, in absence of causative explanation 
 
 


 
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3.1.2. Secondary outcomes 
 
• Baseline ALT and AST results  
• Baseline QTc prolongations 
• Post administration QTc prolongation, ALT and AST results 
• Frequency of potentially common adverse events such as gastro-intestinal (nausea, vomiting), nervous 
system-related (headache, dizziness) and cutaneous reactions 
• Occurrence of any (serious)AEs 
 
 
 
3.2. Definitions 
 
QT interval: The measured QT will be corrected by the Fridericia formula through a dedicated calculator. At 
baseline, QTc prolongations are defined as QTc >450ms. Participants with a QTc value above the cut-off point 
will be excluded from the study. Their QTc measurement will be entered in the database and will be used in 
the analysis to describe the baseline QTc distribution in the population.  
 
Liver function measurements: ALT and AST (U/L) will be measured at baseline (day 0) and on day14. In 
both time points, participants with ALT and/or AST >3x upper limit normal (ULN) will be considered to 
have abnormal (elevated) values. If a participant has an elevated ALT/AST result at recruitment, they will be 
excluded from the study. The ULN values for ALT and AST used for this study are 55 U/L and 48 U/L 
respectively (https://www.mayoclinic.org/tests-procedures/liver-function-tests/about/pac-
20394595#:~:text=Normal%20blood%20test%20results%20for,8%20to%2048%20U%2FL). Potassium and 
magnesium levels will only be recorded in case of QTc prolongation, ≥ 500 ms at baseline or > 60 ms 
increase as compared with baseline. Analysis of this data (potassium and magnesium results) will be purely 
descriptive.  
 
Adverse events’ categories and how they will be summarized are further described in section 6.3.  
 
4. Description of study population 
 
 
4.1. Participant accounting 
 
The number of participants screened, those who meet the study inclusion criteria and enrolled (randomized) 
or excluded will be summarized according to reason for exclusion. Of the enrollees, the number of participants 
discontinued or lost to follow-up will be recorded by reason and time of discontinuation. Additionally, the 
number and proportion of participants who were excluded at baseline because of a QTc > 450 ms, as well as 
the number of exclusions due to elevated AST or ALT will be described by treatment arm and age stratum. 
These figures will be summarized in a CONSORT flow diagram. A table summarizing the enrolment process 
by treatment arm will also be produced.  
 
 
4.2. Description of study population 
 
Participants in each treatment group and overall will be described with respect to selected baseline 
characteristics, both by age strata and by allocation arm. The description will be in terms of medians and 
interquartile ranges for continuous characteristics and using counts and percentages for categorical 


 
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characteristics. Differences between the two arms will be noted, but no formal statistical testing will be 
performed.  
 
 
5. Description of analysis populations 
 
5.1. Analysis populations 
 
For the safety analysis, both an intention-to-treat (ITT) and a per-protocol (PP) approach will be adopted. In 
both ITT and PP populations, participants will be analyzed according to their administered treatment. The PP 
population will be the primary analysis population as indicated for non-inferiority studies by the ICH-E9 
guidelines.  
 
5.1.1. Intention to treat (ITT) analysis 
 
In the Intention-to-Treat analysis, all participants will be analyzed according to their administered allocation, 
even in case they show protocol violations prior to or during the study. 
 
5.1.2. Per protocol (PP) analysis 
 
An analysis based on a <per protocol= approach will be conducted to assess the non-inferiority of treatments, 
as recommended for non-inferiority studies.  Thus, analyses based on the subjects following the study protocol 
will be the main strategy of analysis adopted for the primary and secondary endpoints. In the per-protocol 
analysis only participants who received PEP as planned, have completed follow-up, and follow the protocol 
as planned are included.  
 
 
Table 1: The protocol deviations classified as minor or major deviation 
Protocol Violation 
Major/Minor 
Deviation 
Comments 
Inclusion criteria 
 
 
1. Being a permanent resident of the study village, in good state of health 
Major 
 
2. Able and willing to provide informed consent 
Major 
 
3. Age 5 years or above and weight of 20 kg or above. 
Major 
 
Exclusion criteria 
 
 
1. Signs of active leprosy 
Major 
 
2. Signs of active pulmonary tuberculosis (cough ≥2 weeks duration) 
Major 
 
3. Signs of active extra-pulmonary tuberculosis (bluish-red nodules that 
cover the lymph nodes, bones or joints, or cervical glands with discharge) 
Major 
 
4. History of liver- or kidney disease 
Major 
 
5. Allergy to rifampicin or bedaquiline 
Major 
 
6. Having received rifampicin or bedaquiline (if applicable) in the last 2-
year period 
Major 
 
7. Not able to swallow bedaquiline 100 mg tablets 
Major 
 


 
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8. Self-reported (suspected) pregnancy or breastfeeding 
Major 
 
9. Concurrent (within the last three-week period before D0) use of 
medications not included in the safe list (for bedaquiline only) 
Major 
 
10 .QT-prolongation of ≥450 msec in baseline ECG within the last week. 
Major 
 
11. Jaundice or self-reported liver function abnormalities or hepatitis 
Major 
 
12. Value of baseline ALT or AST >3x ULN within the last week. In case 
only ALT is available, this would suffice for enrollment. 
Major 
 
Treatment deviations 
 
 
1. Vomiting of allocated treatment 
Major 
 
2. Dosage miscalculation 
Minor/Major 
Minor if less dose is 
given, major if larger 
dose is given 
Follow-up deviations 
 
 
1. Missing visit or samples of QTc at 24h or ALT/AST at day 14 
Minor/Major 
Minor if a participant 
gives ALT/AST until 
the day 30 visit 
 
 
6. Statistical Methods 
 
6.1. Primary safety analysis 
 
The main objective about the difference in QTc between the two arms 24 hours after treatment administration 
will be assessed by calculating the 95% confidence interval for the difference.  
 
Non-inferiority is established if the upper limit of a one-sided 95% confidence interval around the difference 
in means QTc 24 hours after treatment administration (BE-PEP - SDR-PEP) is below the non-inferiority limit 
of +10 ms. 
 
Analysis of covariance (ANCOVA) or an equivalent regression model correcting for the baseline values of 
QTc will also be used to assess the primary objective. Alternatively, the individual difference scores will be 
calculated by subtracting the QTc values at baseline from the ones at day 1. The difference scores will be 
compared using a two-sample t-test.  
 
6.2. Secondary safety analysis 
 
Baseline measurements 
Data from all screened patients with QTc, ALT or AST results will be used to determine the baseline 
distribution of the underlying population. Data will be described both visually and by using standard summary 
statistics for the whole population and by demographic characteristics, such as age (same age categories as 
the ones used for stratified randomization) and sex. The proportion of study participants with ALT/AST values 
above the normal range (> 3 ULN) will be calculated together with 95% Wilson confidence intervals. The 
proportion of study participants with QTc values above the normal range (> 450m) will be calculated together 
with 95% Wilson confidence intervals.  
 
 
 
Post PEP measurements 


 
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ALT/AST results after study drug administration (day 14 and 30) will be described both numerically and as 
proportions above the normal range (> 3 ULN)  using 95% Wilson confidence intervals  pooled and by study 
arm. Chi-square or Fisher’s exact test will be used to compare the proportions between the two study arms. 
The difference of the days 14 and 30 ALT/AST result with the results at baseline will be tabulated broken into 
categories (<0, 0-9, 10-19, etc). 
 
 
The individual differences between baseline QTc and ALT/AST results and results from day 1 (QTc) or day 
14 (ALT/AST) will be calculated. The difference will be described in 20ms categories (<0, 0-19, 20-39, 40-
59 etc.) for QTc and in 10 U/L categories (<0, 0-9, 10-19, etc) for ALT and AST. Analysis of covariance 
(ANCOVA) or an equivalent regression model correcting for the baseline values of ALT/AST will be used 
similar to the methodology described for the primary objective. Alternatively, the individual difference scores 
will be calculated by subtracting the ALT/AST values at baseline from the ones at day 14 or 30. The difference 
scores will be compared using a two-sample t-test.  
 
 
6.3. General safety aspects 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MEDDRA) and 
will be reported based on MEDDRA preferred terms and body systems. All AEs will be analyzed based on 
counts of subjects with a specific category and not on counts of individual adverse events. The relationship 
between AEs and treatment is determined by the investigator and categorized as "drug-related" if possibly, 
probably or definitely related to treatment. A general summary of safety events will be presented by treatment 
arm. Potentially frequent adverse events such as gastro-intestinal (nausea, vomiting), nervous system-related 
(headache, dizziness) and cutaneous reactions will be tabulated and presented using standard descriptive 
statistics (counts, percentages and 95% Wilson confidence intervals). AEs related to liver function, such as 
hepatitis, liver function elevation, transaminitis, liver toxicity, etc, will be grouped into one category. Fisher’s 
exact test will be used to compare the association between the observed frequencies between the two treatment 
arms. A second table containing each reported AE by preferred terms and body system will be included in the 
analysis. All safety events will be presented both pooled and by time point (day 0, day 1, day 14 and day 30).  
 
 
6.4. Interim analysis 
An interim analysis will take place after the completion of recruitment of each age stratum. Data will be 
cleaned and locked before each interim analysis. The data will include any results until day 30.  
 
6.5. Other aspects 
 
6.5.1. Subgroup analyses 
 
Since this is a stratified randomized trial, all analyses will be done by age-group.  
 
 
6.5.2. Multiplicity adjustment 
 
No adjustments for multiplicity are foreseen. 
 
6.5.3. Missing data and sensitivity analysis 
 
Missing data will be reported, though all specified analyses are complete case analyses. If a significant 
proportion of missing values is observed, then imputation methodology will be considered in a sensitivity 
analysis, after communication with the research consortium.  


 
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6.5.4. Exploratory analysis 
 
The QTc prolongation pre- and post-PEP among participants who report diarrhea as an AE will be examined 
as an exploratory objective. Any surplus remaining serum may be used for exploratory analyses of leprosy 
related biomarkers at the LUMC.  These analyses are not covered in the current SAP and are not a part of the 
main clinical trial.