Conditions: Leprosy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144000
Healthy volunteers: yes

Brief summary:
This is a cluster randomized trial on effectiveness of different modalities of Single Double Dose of Rifampicin Post-Exposure Prophylaxis (SDDR-PEP) for leprosy in the Comoros (Anjouan and Mohéli) and Madagascar.

The study aims to identify which approach to the selection of contacts for post exposure prophylaxis is most effective to reduce incident leprosy, and to Interrupt ongoing transmission from asymptomatic persons in the process of developing multibacillary leprosy.

Detailed description:
For the purpose of the study, villages on the Comoros and Madagascar that will be randomly assigned to one of the study arms, will be screened on a yearly basis for 4 consecutive years. Depending on which of the 4 arms a village is assigned to, people in the surroundings of a leprosy patient will or will not be offered Post-Exposure Prophylaxis (PEP) using rifampicin at 20mg/kg single dose:

1. No Post-Exposure Prophylaxis (PEP) is given to anyone
2. PEP is given to all household contacts of incident leprosy cases
3. PEP is given to all people who live in a 100m radius of incident leprosy cases
4. PEP is given to all household contacts of incident leprosy cases as well as to all others who live within a 100m radius of an incident leprosy case and test positive in the UCP-LFA detecting anti-M. leprae PGL-I IgM antibodies (Ab) in fingerstick blood (anti-PGL-1)

Arms:
arm 1: No PEP will be distributed arm 2: PEP will be given to all household contacts of an incident leprosy patient arm 3: PEP will be given to all household contacts of leprosy patients and to all other people living within a 100m radius of an incident leprosy patient. arm 4: PEP will be given to all household contacts of leprosy patients and to all other people living within a 100m radius of an incident leprosy patient who test positive in the UCP-LFA detecting anti-M. leprae PGL-I IgM Ab in fingerstick blood (anti-PGL-I)

Interventions: intervention 1: Rifampicin
Intervention descriptions: intervention 1: Rifampicin will be given in the same way to arms 2, 3 and 4 (weight dependent). Only the strategy of whom to offer PEP differs between the arms.

Protocol document:
Prot_000.pdf: 
 
 
PEOPLE, version 1.7, dated 18-Mar-2022 
 
1 of 34 
 
 
 
Clinicaltrials.Gov. NCT03662022 
 
Post ExpOsure Prophylaxis for LEprosy in the Comoros 
and Madagascar 
 
PEOPLE 
 
Initial Protocol 
Version 1.7, 18-Mar-2022 
 
 
 
 
 
 
 
Sponsor: 
Institute of Tropical Medicine 
Nationalestraat 155 
2000 Antwerpen 
Belgium 
 
 
Coordinating Investigator: 
Dr. Epco Hasker 
 
 
 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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ClinicalTrials.Gov.: 
NCT03662022 
Study Title: 
Post ExpOsure Prophylaxis for LEprosy in the Comoros and 
Madagascar 
Study Acronym 
PEOPLE 
Version and date: 
Version 1.7, 18-Mar-2022 
Partnering 
institutions/sites: 
- 
Institute of Tropical Medicine (ITM), Antwerp, Belgium 
- 
Damien Foundation (DF), Comoros and Belgium  
- 
Centre d9Infectiologie Charles Mérieux (CICM), Madagascar 
- 
Fondation Raoul Follereau (FRF), Madagascar 
- 
Leidsch Universitair Medisch Centrum (LUMC), the Netherlands 
- 
Assistance publique-Hopitaux de Paris (APHP), France 
- 
Genoscreen, Lille, France 
- 
Fiocruz, Rio de Janeiro, Brazil 
Study drug: 
Rifampicin 
Funder: 
European & Developing Countries Clinical Trials Partnership (EDCTP) 
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 
 
- 
Damien Foundation 
Younoussa Assoumani 
Coordinate project activities on Comoros 
yaoussoumani@gmail.com 
 
- 
Fondation Raoul Follereau 
Bertrand Cauchoix 
Coordinate project activities on 
Madagascar 
cauchoixbertrand4@gmail.com 
 
 
- 
Centre d’Infectiologie Charles Mérieux 
Rakoto Andrianarivelo 
Mala 
Process samples on Madagascar 
mala.rakoto@hotmail.fr 
 
 
- 
Leidsch Universitair Medisch Centrum 
Annemieke Geluk 
Process anti-PGL1 RDT strips 
A.Geluk@lumc.nl 
 
- 
Assistance publique-Hopitaux de Paris 
Emmanuelle Cambau 
Molecular testing Madagascar samples 
emmanuelle.cambau@aphp.fr 
 
 
- 
Genoscreen 
Philip Supply 
Genotyping of samples from Comoros 
and Madagascar 
philip.supply@genoscreen.fr 
 
 
- 
Fiocruz 
Philip Suffys 
Genotyping of samples from Comoros 
and Madagascar 
psuffys@gmail.com 
 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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STATEMENT OF COMPLIANCE 
 
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 ESF/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. 
 
 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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DIRECTOR OF THE INSTITUTE OF TROPICAL MEDICINE: 
 
 
Title, Name: Dr. Marc-Alain Widdowson 
Date: 
 
 
Signed: 
 
 
 
 
 
 
 
 
PEOPLE CONSORTIUM COORDINATOR: 
 
 
Title, Name: Prof. Bouke de Jong 
Date: 
 
 
Signed: 
 
 
 
 
 
 
 
 
COORDINATING INVESTIGATOR: 
 
 
Title, Name: Dr. Epco Hasker 
Date: 
 
 
Signed: 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR ON THE COMOROS: 
 
 
Title, Name: Dr. Younoussa Assoumani 
Date: 
 
 
Signed: 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR ON MADAGASCAR: 
 
 
Title, Name: Dr. Bertrand Cauchoix 
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. 
 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .......................................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................................................ 5 
SYNOPSIS ......................................................................................................................................................... 6 
1.1 BACKGROUND .................................................................................................................................................. 8 
1.2 RATIONALE ...................................................................................................................................................... 9 
2. STUDY OBJECTIVES AND OUTCOMES .......................................................................................................... 10 
2.1 PRIMARY ....................................................................................................................................................... 10 
2.2 SECONDARY ................................................................................................................................................... 10 
3. STUDY DESIGN ............................................................................................................................................ 10 
3.1 GENERAL STUDY DESIGN ................................................................................................................................... 10 
4. PARTICIPANTS, POPULATION & SELECTION ................................................................................................ 14 
4.1 STUDY SETTINGS ............................................................................................................................................. 14 
4.2 STUDY POPULATION AND SELECTION CRITERIA ...................................................................................................... 14 
4.3 SAMPLE SIZE ................................................................................................................................................... 15 
4.4 RANDOMIZATION ............................................................................................................................................ 15 
5. STUDY PROCEDURES .................................................................................................................................. 16 
5.1 GENERAL STUDY PROCEDURES .......................................................................................................................... 16 
5.2 LABORATORY PROCEDURES ............................................................................................................................... 16 
6. STUDY INVESTIGATIONAL PRODUCT .......................................................................................................... 18 
6.1 PURCHASING .................................................................................................................................................. 18 
6.2 PARTICIPANT COMPLIANCE MONITORING ............................................................................................................ 18 
6.3 PRIOR AND CONCOMITANT THERAPY .................................................................................................................. 18 
6.4 PACKAGING.................................................................................................................................................... 19 
6.5 RECEPTION, STORAGE, DISPENSING AND RETURN .................................................................................................. 19 
7. SAFETY ASSESSMENT .................................................................................................................................. 19 
8. STUDY MANAGEMENT ............................................................................................................................... 21 
9. DATA ANALYSIS .......................................................................................................................................... 21 
10. MONITORING AND QUALITY ASSURANCE ................................................................................................ 22 
11. DATA MANAGEMENT ............................................................................................................................... 22 
11.1 SURVEY DATA COLLECTION (PER ISLAND) ........................................................................................................... 22 
11.2 FOLLOW-UP SURVEY PREPARATION AND DATA COLLECTION .................................................................................. 24 
11.3 REGISTRATION OF LEPROSY PATIENTS AND FOLLOW-UP ........................................................................................ 26 
11.4 FILING AND ARCHIVING .................................................................................................................................. 26 
12. ETHICAL ISSUES ........................................................................................................................................ 27 
12.1 ETHICAL AND REGULATORY REVIEW .................................................................................................................. 27 
12.2 PROTOCOL AMENDMENTS .............................................................................................................................. 27 
12.3 INFORMED CONSENT ...................................................................................................................................... 28 
12.4 CONFIDENTIALITY .......................................................................................................................................... 29 
12.5 POTENTIAL RISKS .......................................................................................................................................... 29 
12.6 BENEFITS ..................................................................................................................................................... 30 
12.7 COMPENSATION FOR PARTICIPATION ................................................................................................................ 30 
12.8 INSURANCE .................................................................................................................................................. 30 
13. DISSEMINATION OF RESULTS, INTELLECTUAL PROPERTY .......................................................................... 31 
14. ARCHIVING ............................................................................................................................................... 31 
15. REFERENCES ............................................................................................................................................. 32 
16. LIST OF ABBREVIATIONS ........................................................................................................................... 34 


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SYNOPSIS 
 
This study will evaluate different modalities of post exposure prophylaxis (PEP) for leprosy on 
Madagascar and the Comoros. The islands of Anjouan and Mohéli on the Comoros are hyperendemic 
for leprosy with annual incidence rates of close to 10 per 10,000.[1] On Madagascar the disease is less 
endemic but still on an annual basis around 1,500 new cases are detected, while there are reasons to 
believe that the actual incidence may be substantially higher. One of the interventions currently 
advocated to curb transmission of leprosy is post exposure prophylaxis (PEP). However, in its 2016-
2020 global leprosy strategy, WHO calls for more research into optimal implementation modalities.[2]  
Building on the results of the COLEP study that was conducted in Bangladesh, we will identify optimal 
target populations for PEP.[3]  The COLEP study was a large cluster randomized trial in which the 
intervention arm was a single dose of Rifampicin (SDR) that was provided to close contacts of leprosy 
patients. In intervention clusters, there was a 57% reduction in leprosy incidence over a two-year 
period when compared to a placebo group. The highest protective efficacy was found in non-blood 
related contacts. Another trial on PEP for leprosy, the LPEP trial, is currently ongoing in India, Indonesia, 
Myanmar, Nepal, Sri Lanka, Tanzania, Brazil and Cambodia and is designed to evaluate effectiveness, 
impact and feasibility of contact tracing and SDR-PEP for leprosy under routine program conditions.[4, 
5] The LPEP trial addresses aspects of feasibility of PEP under program conditions but does not address 
the issue of which contacts to target. An earlier study in Indonesia has shown that in hyperendemic 
contexts SDR-PEP given to household contacts alone may not be sufficiently effective.[6]  
Therefore, the planned PEOPLE trial will be a cluster randomized trial aiming to: 
1. Identify which approach to the selection of contacts for post exposure prophylaxis is most 
effective to reduce incident leprosy 
2. Interrupt ongoing transmission from asymptomatic persons in the process of developing 
multibacillary leprosy. 
 
Studies by Boeree et al. in tuberculosis treatment have shown that the early bactericidal effect of 
rifampicin is proportional to the dose used, and that safety is excellent and not dose related.[7] Even 
weight banding does not appear to be necessary. A recent study performed by our own group 
(ClinicalTrials.gov Identifier: NCT02153528) has provided extensive safety data for daily use of high 
rifampicin doses in adults for weeks, up to 6 months. This study too showed no increase in the risk of 
adverse events. We therefore opted for doubling the dose of Rifampicin in SDR-PEP from 10 mg per kg 
to 20 mg per kg and will refer to this regimen as 8single double dose rifampicin post exposure 
prophylaxis9 or SDDR-PEP.   
 
There will be four study arms to which villages on three islands (Anjouan, Mohéli and Madagascar) will 
be randomly allocated. These villages have been preselected based on leprosy incidence over the 
period 2013-2017. In all four study arms, annual door-to-door surveys will be conducted covering 
entire villages. All permanent residents will be invited for screening for leprosy.. Leprosy patients 
(further referred to as 8index patients9) detected will be offered free treatment according to the 
international and country guidelines. In arm 1 no PEP will be provided, which is the current routine 
care on Madagascar and the Comoros. In arms 2, 3 and 4 SDDR-PEP will be offered to all eligible 
participants who have not received PEP in the preceding 2-year period. In arm 2 only household 
contacts of an index patient will be provided with SDDR-PEP, which target group is considered the 
standard approach when PEP is provided for leprosy. In arms 3 and 4 SDDR-PEP will also be provided 
to neighborhood contacts living within a radius of 100 meter of an index patient. In arm 3 all such 
contacts (including household contacts) will be provided SDDR-PEP, in arm 4 SDDR-PEP will be provided 
to all household contacts and to all those within the 100-meter perimeter testing positive to a 
serological screening test. Detailed costing will be performed of all study procedures.  
 


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In a second part of the study all incident leprosy patients identified during the trial period will be 
recruited and samples will be collected, in particular skin biopsies, slit skin smears, tongue swabs (only 
in Comoros) and nasal swabs. These samples will be used for DNA extraction and genotyping of the 
bacilli, which will allow us to assess at which level leprosy is clustered in the study villages/ islands.  
 
The primary outcome measure will be the incidence rate of leprosy by study arm measured between 
the first and the fourth survey round. Incidence rate ratios will be calculated using the rate observed 
in arm 1 (no PEP) as reference category. As secondary outcomes we will calculate risk ratios for leprosy 
based on physical distance from the nearest index household, proportions of phylogenetically 
clustered patients, proportions of patients belonging to the social network of another patient, and cost 
per person treated with SDDR-PEP for each study arm. 
 


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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. Delayed treatment can lead to visible 
deformities, causing stigma. In 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.[8] Leprosy prevalence has since then been greatly reduced, 
from almost 5 million in the 1980s to approximately 172,000 by early 2017. 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 decline between 2000 and 
2005, reported worldwide leprosy incidence has now plateaued above 200,000 annually, showing 
continued transmission of the M. Leprae.[9]  
 
The islands of Anjouan and Mohéli of the Comoros have been highly endemic for leprosy since decades, 
despite good adherence to WHO leprosy control guidelines. Yearly 300-400 new leprosy cases are 
detected on a population of approximately 450,000. Patients are generally detected at an early stage 
though, reflected in the fact that less than 3% of newly diagnosed patients present with visible 
deformities.[10] Madagascar has a much larger population (approximately 26 million) and has been 
reporting approximately 1,500 new leprosy patients per year over the last decade, without any 
apparent trend towards decline. In comparison to the Comoros, a much higher proportion (19% in 
2016) present with visible deformities at time of diagnosis. In both countries, a substantial proportion 
of patients are children below 15 years of age (8% on Madagascar, 27% on the Comoros), indicative of 
ongoing active transmission.[10] 
 
The WHO Global Leprosy Strategy 2016-2020 mentions post exposure prophylaxis (PEP) as one of the 
strategies requiring further research to overcome the current stalemate.[2] Studies in Indonesia and 
Bangladesh have shown that substantial reductions in leprosy incidence can be achieved when 
Rifampicin is provided to contacts of leprosy patients. In Bangladesh 57% reduction in incidence was 
achieved when comparing intervention clusters to placebo clusters, over a two-year period. [3] A single 
dose of Rifampicin had been provided to household contacts as well as close social contacts of leprosy 
patients. In Indonesia a three-fold reduction in incidence was achieved when treating an entire island 
population with two doses of Rifampicin given in an interval of one month.[6] On the contrary, in this 
hyperendemic setting, treating only household and social contacts showed no effect. Though a trial on 
a more potent regimen (PEP++ trial, including three doses of Rifampicin plus Moxifloxacin) is in the 
planning stages, the current standard of care when it comes to PEP is Rifampicin in a single dose (SDR-
PEP). The aim of the trial described in this protocol (PEOPLE) is to document effectiveness of three 
alternative ways of implementing SDR-PEP at village level, by comparing to villages in which no PEP is 
provided.   
 
We will also enroll all leprosy patients diagnosed during the trial and collect samples (skin biopsy, slit 
skin smear, tongue swabs (only in Comoros)  and nasal swab) with the aim of genotyping the causative 
bacilli to establish chains of transmission. With this study, we are in the search for less invasive samples 
to confirm microbiologically a leprosy diagnosis. A recent study on tuberculosis confirmed that 
Mycobacterium tuberculosis (transmitted via the upper respiratory tracts) is present on the papillae of 
the tongue of TB patients, and can be collected and confirmed with qPCR. The main transmission route 
for Mycobacterium leprae is also via the upper respiratory tract and thus we hope that M. leprae is 
also present on the tongue of clinically diagnosed leprosy patients, so that in the future we could 
replace invasive sampling by minimally invasive sampling like a tongue swab. 


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1.2 Rationale 
Though SDR-PEP has been shown to be effective in reducing leprosy incidence, uncertainty exists about 
the optimal implementation modalities, particularly in environments of high incidence. In the PEOPLE 
trial we will compare different modalities of SDR-PEP and we will also perform DNA finger printing of 
strains of all incident cases in the study areas.  
 
We will compare a study arm without PEP, which is the current standard of care in leprosy, to three 
intervention arms in which SDR-PEP is provided in different modalities. The first arm is the comparator 
arm in which door to door screening will be conducted but no PEP will be provided. In the second arm 
only household contacts of an incident case will be provided SDR-PEP, in the third arm SDR-PEP will be 
provided to all those residing within 100 meter of an incident case. In the fourth arm we will first 
conduct a rapid screening test for antibodies against M. leprae (anti-phenolic glycolipid-I or anti-PGL1) 
and treat all household contacts plus those residing within 100 meters that test positive to anti-PGL1. 
If in the third or fourth arm more than 50% (arm 3) or 75% (arm 4) of the village population need to 
be covered (with anti-PGL1 testing and/or provision of SDR-PEP), we will cover the entire village. The 
effect will be measured by comparing incidence in each of the intervention arms (arms two, three and 
four) to incidence in the comparator arm (arm one).  
 
Including the study arm with the serological test (arm 4) will serve two purposes. The assumption is 
that transmission of leprosy is maintained by clinically apparent multi-bacillary patients. It has however 
been hypothesized that clinical multi-bacillary patients may just be the tip of the iceberg and that 
asymptomatic persons at the multibacillary side of the spectrum may be  more important as sources 
of transmission because of their higher numbers. Such persons are expected to test positive to anti-
PGL1 and can therefore be identified by a screening test. If this can be demonstrated, this would not 
only be important because of its effect on transmission but it would also seriously reduce the number 
needed to treat with PEP.    
 
The results of DNA finger printing of incident leprosy patients will allow us to identify chains of 
transmission and levels of clustering (i.e. households, neighborhoods or entire villages), which will 
allow us to further rationalize the decisions on which groups of contacts to target with PEP.  
 
In the COLEP study in Bangladesh there was a clear and statistically significant reduction of leprosy 
incidence in the two years following SDR-PEP implementation using Rifampicin in a dose of 10 mg/kg 
however the effect was only 50-60%.[3] The PEP++ trial, which is currently still in the planning stage, 
will use a reinforced PEP regimen consisting of three doses of Rifampicin plus Moxifloxacin for adults 
or Rifampicin plus Clarithromycin for children. The three doses will be administered with intervals of 
one month in between. This combination is expected to have higher efficacy (90% instead of 50-60%) 
but this still needs to be verified. Moreover administering three doses over a two-months period is 
logistically much more complex than administering a single dose. For reasons explained below we opt 
for a single dose of Rifampicin, but at a higher dosage than usual.  
 
Rifampicin is also one of the cornerstones of tuberculosis treatment. When the drug was introduced 
in the 1970s, a dose of 10 mg/kg was chosen based on cost considerations and fears for toxicity.[7] 
This dose is probably at the lower limit of optimal efficacy.[11]  Diacon et al. (2007) studied early 
bactericidal activity of Rifampicin in tuberculosis, comparing the regular dose (10 mg/kg) to a double 
dose (20 mg/kg). They observed a doubling of early bactericidal activity when the dose is doubled. 
More recently Boeree et al. tested even higher doses of Rifampicin, up to 35 mg/kg.[7] . They 
concluded that two weeks Rifampicin up to 35 mg/kg was safe and well tolerated, and that there was 
a non-linear increase in exposure to Rifampicin due to saturation of first-pass excretory capacity of the 
liver. In our very recent study 8Optimization of the TB Treatment Regimen Cascade (OneRIF, 
ClinicalTrials.gov Identifier: NCT02153528) no increase in toxicity was observed among 475 adult 


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patients who received  Rifampicin in a dosage of 20mg/kg daily for six months as part of their treatment 
for tuberculosis, compared to 468 control patients receiving the regular dosage of 10 mg/kg. In leprosy 
too, higher doses of Rifampicin have been used both as post exposure prophylaxis and as treatment. 
Cartel et al. used a dosage of 25 mg/kg in a trial in French Polynesia.[12-14] Pattyn et al. treated leprosy 
patients with a single dose Rifampicin of 40 mg/kg, a regimen that proved effective in PB patients with 
a negative bacillary index. [15] Importantly the regimen was well tolerated and no side effects were 
observed among 240 patients evaluated. We therefore opted for a Single Double Dose Rifampicin Post 
Exposure Prophylaxis, or SDDR-PEP, of 20 mg/kg in the PEOPLE trial. 
 
Since we will be conducting door-to-door surveys and pulmonary tuberculosis (PTB) is a major public 
health problem on the Comoros as well as on Madagascar, we will seize the opportunity to also enquire 
about chronic cough (of longer than two weeks9 duration) and collect sputum samples from the 
individuals concerned. In both countries the leprosy and TB control programs are fully integrated at 
district level, allowing for easy referral of PTB suspects and/or patients identified.   
 
 
2. STUDY OBJECTIVES AND OUTCOMES 
 
2.1 Primary 
To  compare effectiveness in curbing transmission of leprosy of three different approaches of post 
exposure prophylaxis 
Outcome: Three incidence rate ratios between the comparator arm and each of the 
intervention arms. These ratios will be based on incidence rates measured between the first 
and fourth household survey in each of the intervention arms, divided by that of the 
comparator arm. 
 
2.2 Secondary 
1. To assess cost and feasibility of SDDR-PEP under program conditions 
Outcome: Costs will be calculated per person screened, per person treated with SDDR-
PEP and per leprosy case averted. 
 
2. To identify patterns of clustering in transmission of leprosy, allowing better targeting of control 
measures 
Outcome: We will quantify the degree of clustering as the average proportion of 
leprosy cases belonging to a same phylogenetic cluster by village. Geographic 
clustering will also be assessed by calculating risk ratios for being diagnosed with 
leprosy as a function of geographic distance from incident cases diagnosed earlier in 
each of the four arms 
 
3. To monitor rifampicin resistance among leprosy patients 
Outcome: We will quantify prevalence of Rifampicin resistant strains of M. leprae on 
each of the study islands making use of molecular markers.  
 
3. STUDY DESIGN 
 
3.1 General study design 
The PEOPLE study is a phase 3-4 cluster randomized trial on effectiveness of different modalities of 
SDDR-PEP, i.e. PEP in the form of a single dose of 20 mg per kg bodyweight of Rifampicin. There are 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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four study arms to which villages on three islands (Anjouan, Mohéli and Madagascar) will be randomly 
allocated. 
 
In all four study arms, four annual door-to-door surveys will be conducted covering entire villages. All 
permanent residents will be invited for screening, All leprosy patients detected will be offered free 
treatment according to the international and country guidelines. 
 
In arm 1 no SDDR-PEP will be provided, which is the current routine care on Madagascar and the 
Comoros. In arms 2, 3 and 4 SDDR-PEP will be offered to all eligible participants who have not received 
PEP in the preceding two-year period. In arm 2 only household contacts of an incident case will be 
provided with SDDR-PEP, which is the most common choice for PEP for leprosy. In arms 3 and 4 SDDR-
PEP will also be provided to neighborhood contacts living within a radius of 100 meter of an index 
patient. In arm 3 all such contacts (including household contacts) will be provided SDDR-PEP, while in 
arm 4 all household contacts will be provided with SDDR-PEP, as well as other neighborhood contacts 
testing positive to a serological screening test. The test that will be used for this purpose is the anti-
phenolic glycolipid-I (anti-PGL-I) test.(7) The test is in the format of a lateral flow test that can be read 
in the field, afterwards the test strips are sent to LUMC for quality assurance. The anti-PGL-I test 
identifies multi bacillary (MB) leprosy patients but also those who are still asymptomatic but 
progressing towards MB leprosy. Though passive case finding will continue throughout the year, anti-
PGL-I testing and provision of PEP will only be done on a yearly basis, at the time of the screening 
rounds. However when deciding on risk zones and PEP provision, all leprosy patients identified will be 
taken into account, also those found in between surveys. In case in villages allocated to arm 3 more 
than 50% of the population would be included for SDDR-PEP, the entire village will be enrolled. In case 
in villages allocated to arm 4 more than 75% of the population would be included for SDDR-PEP and 
PGL1 screening, the entire village will be enrolled.  
 
Before the start and during the first year of this clinical study there will be an anthropological study for 
which a separate protocol will be submitted. The main purpose of this sub-study will be to identify 
possible ways of improving acceptability. The anthropological study will also include a social network 
analysis. In case the anthropological study will reveal ways to improve acceptability, the PEOPLE 
protocol will be amended to include these. 
 
Apart from the general population enrolled during door-to-door surveys, we will also enroll all leprosy 
patients detected during the study period. For this substudy a separate informed consent will be asked. 
This will be part of secondary objective number 2: 8To identify patterns of clustering in transmission of 
leprosy, allowing better targeting of control measures9. For this purpose several samples will be 
collected, i.e. nasal swab, tongue swabs (only in Comoros), slit skin smear and a 4mm punch biopsy of 
the lesion (except if the lesion is in the face). Samples to be collected include nasal swabs and tongue 
swabs (only in Comoros)  for all patients and skin biopsies from non-facial lesions. Slit skin smears will 
be collected from all multi-bacillary patients. These samples will be tested with Ziehl-Neelsen (ZN) 
microscopy, with anti-PGL-I and with qPCR for M. leprae DNA. M.leprae DNA from qPCR positive 
samples will be used for DNA finger printing, which will in turn be used to establish phylogenetic 
clusters. Phylogenetic clustering will allow us to assess to which degree patients are infected by near 
neighborhood contacts or whether more remote contacts also play a role. In arm 4 in which all close 
neighborhood contacts will be tested with anti-PGL-I, in the second survey round we will also collect 
nasal swabs for qPCR from a subset of all contacts enrolled, to assess whether the presence of M. 
leprae DNA, indicating exposure/ <carrier state=, is a risk factor for developing incident leprosy. The 
presence of DNA does not confirm that persons have colonization or disease with live M. leprae.  
 
Figure 1: Flow chart of the PEOPLE trial (not including samples collected for tuberculosis screening) 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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In addition to the immunological and molecular studies, as part of the anthropological sub-study, social 
networks of patients will be mapped. For this study a separate protocol will be submitted for ethics 
approval. This again will help in corroborating whether or not observed reductions in incidence can be 
attributed to PEP having been provided to close neighborhood contacts. 
 
While conducting the door-to-door surveys, staff will also ask whether or not each person screened 
for leprosy has been coughing for more than two weeks. Any person reporting cough of more than two 
weeks9 duration will be asked for a sputum sample which will be tested for pulmonary tuberculosis by 
ZN smear microscopy and/or GeneXpert (according to the national TB program guidelines). Further 
management of tuberculosis patients and or suspects identified will be the responsibility of the 
national tuberculosis control programs. In both countries these programs provide free anti-
tuberculosis treatment and care according to international standards.  
 
The study is expected to start in the fourth quarter of 2018, and will end October 1st, 2022. 
A Gantt chart of the main project activities is presented below. The total study duration is estimated 
to be 42 months with a six months preparatory phase and three months for analysis.  


 
 
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Activity 
2018 
2019 
2020 
2021 
2022 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
1. Obtaining ethics approval main 
study protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Finalizing survey procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Informing communities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. First door-to-door survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Outline risk areas arm 3 and 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. Baseline anti-PGL-1 testing 
(arm 4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. Baseline PEP (arm 2,3,4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. Second door-to-door survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. Redefine risk area 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. Anti-PGL-I testing + PEP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. Third door to door survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12. Redefine risk area 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. Anti-PGL-I testing + PEP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14. Fourth door-to-door survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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4. PARTICIPANTS, POPULATION & SELECTION 
 
4.1 Study settings 
The study takes place in two African countries, Comoros and Madagascar. On the Comoros we will 
include 56 villages distributed across two islands (Anjouan and Mohéli), on Madagascar 16 to 24 
clusters of hamlets (fokontanys) from one district will be sampled. In both countries there are national 
leprosy and tuberculosis control programs (NLTCP) in place that provide free diagnostic and treatment 
services for both diseases, in accordance with international standards. 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 national 
leprosy control programs, to whom they can also refer patients for consultation. In both countries the 
national leprosy control programs provide specific treatment 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, any leprosy patient diagnosed receives full treatment. Such 
outreach campaigns, also called 8mini-campaigns9 have been introduced on the Comoros since 2008 
and were initiated more recently on Madagascar. For the PEOPLE trial, door-to-door screening 
activities will be carried out by mobile units under the direct supervision of the respective NLTCPs and 
under responsibility of the PI of each country. On the Comoros such surveys have already been 
successfully carried out by NLTCP staff in August/ September, 2017, covering four villages with an 
estimated population of 8,400. The mobile units will receive the necessary protocol and GCP training 
prior to the start of the study. 
 
Any leprosy or tuberculosis patients identified will be treated according to the national guidelines of 
the countries, which are in accordance with WHO guidelines.  
 
 
4.2 Study population and selection criteria 
All those eligible for participation in the study will be screened yearly for leprosy and tuberculosis. As 
per study design, participants living in the surroundings of an index case may be given SDDR-PEP. 
Participants may choose to be screened for leprosy, but refuse to take PEP. Eligibility criteria only 
applicable for those receiving SDDR-PEP are marked below with (*).  
 
All leprosy patients diagnosed during the study period will also be enrolled for addressing the second 
secondary objective: 8To identify patterns of clustering in transmission of leprosy, allowing better 
targeting of control measures9.  
 
Inclusion criteria 
1. Living in one of the study villages (32 on Anjouan, 16 on Mohéli and 16-24 on Madagascar) 
2. Aged 2 years and above, as leprosy is very rare among infants and young toddlers 
3. Able and willing to provide informed consent for leprosy and tuberculosis screening, and  
SDDR-PEP administration (as applicable in the different arms) 
4. For leprosy index cases only: able and willing to provide informed consent for participation 
and sampling 
 
Exclusion criteria 
1. Signs of active leprosy (*) 
2. Signs of active pulmonary tuberculosis (cough ≥2 weeks duration) (*) 
3. Having received Rifampicin within the last 24 months (*) 


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4.3 Sample size 
The sample size has been calculated based on the needs for the primary objective, using the 
methodology described by Hayes and Bennet for pair matched randomized controlled trials.(10) We 
will compare the arm with no PEP to each of the three intervention arms. At the start of the trial we 
assume an annual incidence rate of 1.5/1,000 based on data from the Comoros for 48 villages over the 
period of 2013-2017.  
 
Our aim is to show a 50% reduction in incidence in any of the intervention arms in comparison to the 
comparator arm, over a 3-year period. Taking into account the fact that we will make 3 comparisons 
we opted to perform all tests at a significance level of 0.017. Based on the data from the Comoros we 
calculated a coefficient of variation between clusters (κ) of 0.29. To achieve a power of 80% with an 
average cluster size of 2,400, 13 clusters per study arm would be required, i.e. 4 * 31,200 participants. 
To account primarily for inaccuracies in the census data but also for absentees and non-responders, 
we opted for 36,000 participants per study arm, i.e. 15% extra. 
 
4.4 Randomization 
Randomization will be at the level of villages . These villages have been preselected based on leprosy 
incidence over the period 2013-2017. Per island they have been listed in order of decreasing incidence 
and then regrouped into blocks of four, so that an equal number of villages will be allocated to each of 
the four arms. Within these blocks we have used random numbers to allocate each village to one of 
the study arms (the highest random number to arm 1, the second highest to arm 2, etc.).  
 
On Madagascar a slightly different allocation method will be used, taking into account the fact that 
there is a lack of reliable baseline data at village level. We have selected a highly endemic district and 
within this district we selected an area of 35,000 inhabitants that is made up of five sub-districts or 
communities.  Communities are again subdivided in 8fokontanys9, a 8fokontany9 is a cluster of hamlets. 
During the first year of the study, door-to-door screening will take place in all 8fokontanys9, at the end 
of which we will select 16 to 24 with the highest baseline leprosy prevalence, aiming at a total 
population of approximately 20,000. These fokontanys will then be listed in order of decreasing 
prevalence, divided into blocks of four, and within each block there will be a random allocation to the 
four study arms.     
 
In each of the study arms we will measure the incidence rate of leprosy between the first and fourth 
door-to-door survey and calculate rate ratios using the non-intervention village (arm 1) as reference 
group. To ensure equal duration of follow-up between the study arms all villages/fokontanys within 
the same block of four will always be surveyed in parallel. On Madagascar for the incidence rate we 
will not consider the first year since PEP will only be provided after all villages have been surveyed 
once.  
 
The nature of the trial, requiring anti-PGL-I testing on capillary blood samples in one of the study 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 all four study arms. 
 
 
 
 


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5. STUDY PROCEDURES 
 
5.1 General Study Procedures 
Each village will be screened door-to-door for four years in a row. Prior to the start of the study the 
village elders will be informed on procedures and purpose of the study. During the yearly screening 
rounds for leprosy, residents of the selected villages will be checked for eligibility, informed on all 
study procedures, and requested to provide informed consent. The health worker will then perform 
a physical examination to look for signs of leprosy. Note that for this study, the 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 fact bacilli. Results of qPCR and anti-PGLI 
testing will be not be used as diagnostic criteria. The health worker will also collect the necessary 
additional personal information from every individual. 
 
In case the household is eligible for receiving PEP (i.e. an incident leprosy case is found in the 
household or in the surroundings – depending on the arm to which the village is assigned), the correct 
dose of Rifampicin will be distributed according to the schedule below: 
- 
10-20 kg: 300 mg 
- 
>20-30 kg: 600 mg 
- 
>30-45 kg: 900 mg 
- 
>45 kg: 1200 mg 
 
The health worker will witness the intake of the medication by the participant. In case the village is 
part of arm 4, the applicable households will first undergo an anti PGL-I test, and only those testing 
positive will be given PEP. 
 
During the yearly screening for leprosy, the health workers will also collect a sputum sample from all 
participants who have been coughing for more than 2 weeks, to test for tuberculosis (according to the 
national TB program guidelines). Participants who are diagnosed with tuberculosis (based on the 
routine criteria of the national control program) will be referred to the national control program for 
treatment. 
 
If a screened person is diagnosed with leprosy, he/she will be requested to sign an additional consent 
form for the collection of samples. This person will subsequently be treated as per the standards of 
the National Leprosy Control Program. 
 
5.2 Laboratory procedures 
5.2.1 Harmonizing protocols 
APHP, CICM and ITM will exchange and harmonize protocols for DNA extraction from clinical samples 
and for M. leprae DNA detection through the RLEP qPCR and later on also the Deeplex-Myclep. 
 
5.2.2 Sampling schedule 
The local leprosy control teams on each island will be responsible for identifying new leprosy cases and 
collecting the samples. All samples will be identified by a patient-specific barcode only. Nasal swab, 
tongue swabs (only in Comoros) and skin biopsy sample from the lesion(s) (except from lesions in the 
face) are being collected from all newly diagnosed patients. In addition, for those patients who have 
MB leprosy, Skin Slit Smears are taken. During the second survey round nasal swabs will also be 
collected from a subset of close neighborhood contacts in arm 4. Fingerstick blood samples will be 
collected from all newly diagnosed patients and additionally in arm 4 from all close neighbourhood 
contacts. 


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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. 
 
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 disolol for DNA extraction (not for 
histopathology). Local anaesthesia with 2% lidocaine will be administered subcutaneously prior to 
punching the biopsy. 
 
Nasal swabs (NS) will be obtained from all consenting leprosy cases (and in arm 4 from a subset of all 
contacts during the second survey round) by gently rubbing a perinasal swab, in one side of each nostril 
over the lateral conchae. After collection, the swab containing cotton edge will be immersed (and 
broken off at the breakpoint) in a sterile and labelled tube containing disolol.  
 
 
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.  In addition blood 
drops will be spotted on filter paper (Whatmann) and stored at room temperature. 
 
Tongue swabs (TS) will be obtained from all consenting leprosy patients in the Comoros by rubbing the 
tongue with a swab for 15 seconds. After collection, the swab containing cotton edge will be immersed 
(and broken off at the breakpoint) in a sterile and labelled tube containing disolol. 
 
 
5.2.3 Specific tests 
For Madagascar and the Comoros the specific tests on all the samples (except for the fingerstick blood 
samples) will be executed by CICM and ITM respectively. 
Analysis of the Anti-PGL1 LFA (fingerstick blood sample) will be done by the local leprosy controls team 
with a portable reader. 
 
Slit skin smears 
The SSSs will be coloured by the ZN staining in the local laboratories by the designated local leprosy 
control teams after a day of sampling. The subsequent microscopy reading of these slides will be done 
in the local laboratories. 
 
Fingerstick blood 
The fingerstick blood collected in a buffer, will be brought to the local laboratory after a 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). 
 
Nasal swabs, tongue swabs (only in Comoros), skin biopsies & SSS 
a. DNA extraction: 
DNA will be extracted with the slightly modified Maxwell LEV extraction procedure from biopsies, 
swabs and slit skin smears. 
 
b. Diagnostic RLEP qPCR: 
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 36 out of the 37 RLEP repetitive elements 
occurring in the genome of M. leprae.  
After DNA extraction, all the samples will be processed by this RLEP qPCR. The presence of DNA in 
minimally-invasive samples (tongue, nose) may be due to colonization rather than leprosy disease. 


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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 will be done by a novel sequencing technique called the Deeplex® MycLep assay, which 
consists of a single hi-plex amplification of 15 phylogenetic SNPs, 17 VNTR markers, and drug resistance 
conferring gene regions followed by next generation sequencing analysis. This assay is being validated 
in the ongoing COMLEP study. APHP, ITM, and potentially CICM, will perform amplification and 
targeted deep sequencing of the resulting amplicons, with quality control done at Genoscreen. 
 
d. Clustering analyses: 
We will establish transmission chains between newly diagnosed patients and the proportion of 
patients with genetically clustered bacteria. 
All samples will be classified by SNP types and subtypes according to Sharma et al. 2015, with SNP type 
1 expected to be predominant in Comoros and Madagascar based on genotyping results from Reibel 
et al. (2015). To fully explore the epidemiological relationships between isolates, VNTRs patterns will 
be analysed using Bionumerics, by constructing a similarity matrix using UPGMA and the Dice similarity 
coefficient. A Hunter-Gaston discriminatory index (HGDI) for each marker will be calculated, to 
determine how discriminatory these markers are in order to include/exclude them for further analysis.  
Transmission links will be defined as identical genotypes. The definition of clustering will be based on 
comparison of the copy number of the VNTRs using two different stringencies: either considering those 
that presented identical copy number for all 17 alleles, or considering those that had identical copy 
number excluding the most variable loci, according to the HGDI.  
 
5.2 Shipment samples  
The samples of Madagascar will be analysed at CICM. The samples of the Comoros will be shipped to 
the ITM for further analysis.  
 
 
6. STUDY INVESTIGATIONAL PRODUCT 
6.1 Purchasing 
Rifampicin has been selected from the following WHO Prequalified manufacturer: Rifampicine - 
Eremfat® from Fatol Arzneimittel (registered in Germany). The product will be shipped by the supplier 
directly to the applicable national leprosy control programs. 
 
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 countries. 
 
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 data collection tool that the participant has taken the medication. 
 
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. 
 
6.3 Prior and concomitant therapy 
Due to the single dose administration of the drug, no specific precautions are needed regarding 
concomitant drugs. 
 


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The metabolism or activity of rifampicin is not known to be affected by concomitant drugs. 
 
6.4 Packaging 
The commercial formulation of rifampicin procured for the study will be used.  
 
 
6.5 Reception, storage, dispensing and return 
All study drugs will be stored in the central air-conditioned stock of the national leprosy control 
program. The mobile teams will be supplied with sufficient medication during their screening visits to 
the different villages. This medication will be kept in 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. 
 
 
7. SAFETY ASSESSMENT 
The regimen used for prophylaxis, single dose Rifampicin, has been extensively tested in a number of 
leprosy PEP trials and is the current choice when PEP is implemented programmatically. Very recently 
(on 28 June, 2018) WHO have issued a guidelines for the diagnosis, treatment and prevention of 
leprosy which state 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.[16]  
 
Rifampicin has been on the market for over 50 years and is the cornerstone of tuberculosis treatment 
as well as leprosy treatment. In tuberculosis treatment it is administered daily over a 6 months period, 
always in combination with other potentially hepatotoxic drugs. In this trial we will provide only one 
single dose of Rifampicin maximum once per two years, though the dosage will be higher (20 mg/kg) 
than that commonly used in treatment of tuberculosis and leprosy. As was mentioned in the 8trial 
design9 section, Boeree et al. tested even higher doses of Rifampicin, up to 35 mg/kg and found that 
they were safe and well tolerated.[7] In the OneRIF study in Bangladesh (ClinicalTrials.gov Identifier: 
NCT02153528), results of which are yet to be published, a double dose of Rifampicin (20 mg/kg) was 
given daily for 6 months to 475 TB patients, without any apparent increase in toxicity when compared 
to 468 patients treated with the regular dose. Moreover this trial is not the first using a high dose of 
Rifampicin as post exposure prophylaxis, in an earlier trial in French Polynesia a dose of 25 mg per kg 
was used without any issues related to toxicity. [12-14] 
 
Only passive collection of adverse events (AE) will be done in the study. 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 SDDR-PEP will be instructed to inform 
the study staff of any adverse events while the study teams are still in the village, or afterwards using 
the contact details in the information form of which each household will receive a copy. These reported 
adverse events will be recorded, together with their severity and relatedness to the SDDR-PEP. 
 
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 


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prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, or 5) 
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 and SAE) that occur between the administration 
of the drug and three days after administration will be recorded for study purposes. 
 
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. 
 
The risk of inducing Rifampicin resistance in (undiagnosed) tuberculosis or leprosy patients with one 
single dose of the drug is negligible.[17] As was described by Mitcheson for treatment of tuberculosis, 
resistance emerges as a result of selection of resistant mutants under conditions of monotherapy.[18] 
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 every two years, will not result in drug resistance. To exclude any potential risk 
we will screen for signs and symptoms of pulmonary tuberculosis and exclude those participants from 
SDDR PEP. Also we will not provide SDDR PEP to anyone who has already received Rifampicin within 
the preceding 2 years. Lastly, we will also monitor molecular resistance on samples from all leprosy 
patients, as resistance conferring genes are included as targets in the molecular genotyping studies. 
 
Rifampicin is also known to interact with other drugs, anti-retrovirals (ARV) in particular.[19] 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. [20] 
 
Other risks to the participants are minimal, no invasive diagnostic procedures will be undertaken. In 
study arm 4 a capillary blood sample will be taken by finger prick, and a swab of both anterior nasal 
vestibules, which may cause slight discomfort. Leprosy patients identified will also 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 COMLEP study. 
 


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8. STUDY MANAGEMENT 
A Trial Management Group (TMG) will be set-up for the purpose of the day-to-day management of 
the trial. The TMG will meet at regular basis to discuss the progress of the trial. The TMG will consist 
of representatives of the sponsor and the sites. Minutes will be written, distributed amongst the entire 
study team and filed in the Trial Master File. 
 
A Scientific Advisory Committee (SAC) will be established for the purpose of providing independent 
advice on the quality of the data produced and the preliminary results that have been analyzed during 
the interim analyses. A charter detailing the modalities for this SAC will be made prior to the first 
meeting, which should take place as soon as possible after the start of the study. 
 
 
9. DATA ANALYSIS 
The main analysis will be based on incidence rates of leprosy in each of the four study arms, with 
interim analyses planned after the second and third survey round and final analysis after the fourth 
survey round. There will be four door-to-door surveys of which the first one will allow us to calculate 
a baseline leprosy prevalence per island. Based on results of the second, third and fourth surveys, we 
will calculate incidence rates per study arm. We will then fit a random effects Poisson model with 
study arm as explanatory variable, using the non-intervention group (arm 1) as baseline, and with 
8island9, 8block9 (as described in sample size section, eight on Anjouan, four on Mohéli, four to six on 
Madagascar) and 8village9 as nested random effects. 
 
Two interim analyses will be conducted upon completing the second and third door-to-door surveys 
in which incidence rates of leprosy to date in study arms 2, 3 and 4 will be compared to the incidence 
rate in arm 1, just as in the final analysis. These analyses will allow us to assess whether the a priori 
assumptions on annual incidence made have been realistic or whether an extended study duration 
should be considered.   
 
Results of DNA finger printing will be used to assess the degree of clustering at household and at 
village level. We will calculate proportions of patients belonging to a same cluster by household and 
by village. The space-time K-function will be used to assess clustering in time and space, to be 
triangulated with results of DNA finger printing. For this purpose we will use results of all leprosy 
patients identified, including those found at baseline.[21]   
 
To establish the transmission networks in the Comoros islands and in the study area in Madagascar,  
we will overlay the molecular network with the spatial- and social networks. This will determine 
whether the 100m high risk zones around each index patient, applied in this study, capture most 
transmission events, or whether additional risk factors, beyond spatial, need to be taken into account 
in future PEP administration efforts in the study areas and elsewhere. Phylogenetic clustering of the 
M. leprae isolates allows us to identify risk factors for leprosy due to recent transmission. The findings 
of the spatial and social network analysis can be mapped onto a phylogenetic tree and molecular 
clusters based on the VNTRs, which can reveal risk factors for transmission of leprosy. 
 
Prevalence of Rifampicin resistant strains will be calculated per island with in the numerator all leprosy 
patients with Rifampicin resistant isolates identified and in the numerator all patients tested. 
 
For pulmonary tuberculosis we will calculate the baseline prevalence per island as well as annual 
incidence rates for the next three years.  
 


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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 and average cost per case of 
leprosy averted by study arm and by island. Incremental costs will be calculated using the non-
intervention arm as a baseline.  
 
 
 
 
10. MONITORING AND QUALITY ASSURANCE 
Regular study monitoring visits will be conducted by a representative of the sponsor, who is trained in 
GCP. This responsibility will be shared between the Coordinating Investigator (or representative) and 
the Clinical Research Scientist (CRS) of the Clinical Trials Unit (CTU) of ITM. The PI and involved site 
research staff will allocate adequate time and resources for such monitoring activities. 
 
A report detailing the actions taken during the monitoring visit will be written and shared amongst the 
study team. The CRS will join the sponsor representative during at least one visit per year. The study 
monitoring plan will detail on the activities performed by the CRS.  
 
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 
For data collection in the field sites we will make use of the informed consent forms and of two Android 
apps, to be adapted from apps already used in the framework of the COMLEP project on the Comoros. 
One app is used during door-to-door screening and allows recording village and date of survey, 
geographic coordinates of the households, and results of leprosy and tuberculosis screening for each 
individual. The other app is used to record data on leprosy patients diagnosed during the trial. We will 
first describe in detail the data collection procedures during the surveys. See Figure 5 for a complete 
study and survey data flow of the PEOPLE study. 
 
11.1 Survey data collection (per island) 
Upon arrival in the household the study team will explain the study, provide the information sheet and 
obtain informed consent. Consent will be obtained on the level of the individual. 
 
If the head of the household agrees, the study team will write down on the ICF,  name, age and gender 
of all permanent household members, starting with the head of the household, and ask those present 
to sign (or thumb print) for informed consent. Refusal to participate will be documented. The study 
team will return to the household in case of absent members while the study team is still in the village. 
The ICF (Figure 2) will consist of one A4 sheet per household. The study team will then put a check 
mark in column 8PR9 to indicate those present.  
 
Figure 2: ICF form 


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Next the study team will examine each consenting household member present and use the check 
boxes on the ICF to indicate whether or not a person was examined (column 8EX9), whether signs of 
leprosy were present (column 8MH9), whether or not a BCG scar was observed (column BCG), whether 
or not a sputum sample was collected (column 8CR9), and whether or not PEP was provided (column 
8PEP9). This information is entered directly on the ICF to facilitate the data collection during the visit, 
questioning of present members, and physical and clinical interventions.  
 
When the study team has examined all household members present, they will open the Open Data Kit 
(ODK) smartphone household app to record the serial number of the ICF form and the geographic 
coordinates of the household. Secondly, they will record in the app for each individual the following 
information: 
• 
scan of corresponding barcode on the ICF form 
• 
age and gender 
• 
examination results 
• 
whether or not a sputum sample was collected 
• 
whether or not PEP was provided 
• 
some additional questions on previous or current diagnosis/treatment for leprosy and 
presence of cough for last two weeks. 
 
The empty ICF forms contain pre-printed unique barcodes for each individual in the last column. The 
decoded barcode is always shown below to allow a double check when the barcode is scanned into 
the ODK app. A small piece of cardboard with a cut-out rectangle will be used to cover adjacent 
barcodes and thereby minimize the risk of the wrong barcode being scanned. 
 
In case a sputum sample is taken, the barcode corresponding number of the individual concerned will 
be written on the container.  
 
Figure 3: The Android app used for screening 
 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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Upon returning to their base, the study teams will hand over the ICF forms to the data entry clerks 
who will enter form serial number, name, age, gender and barcode of each individual in a secured MS 
Access database. This ICF database will be password protected and access will be restricted to the 
island study coordinator.  
 
The ODK data from the smartphone will be sent to the secure ITM server using the 8Send Finalized 
Form9 button of the app at least twice per week. The ODK data at ITM will only be accessible to the 
ITM CTU Data Manager and the ITM Coordinating Investigator. Once transferred to the ITM server, all 
data will automatically and permanently be deleted from the smartphone to reduce any risk of loss of 
confidentiality.  
 
The ICF Access databases (1 per island) will be forwarded by the island study coordinator to the ITM 
CTU Data Manager by means of the encrypted Belnet Filesender protocol on a regular basis. The ITM 
CTU Data Manager will download the ODK data from the server (stored in the form of csv files) and 
merge with the Access databases through the barcodes. He will send back to the study coordinators 
on each of the islands their part of the complete database, again using encrypted Belnet Filesender.  
 
The transfer of the ICF database, merging with the ODK dataset by the ITM CTU Data Manager and 
transfer back to the island study coordinators is performed to minimize the risk of any wrong 
manipulation or combining being done in any of the 3 sites. As soon as the complete datasets are sent 
back to the study coordinators, the received ICF databases are completely erased. The names in the 
merged ICF+ODK datasets at ITM will be completely deleted once it is confirmed that the study 
coordinators on the three islands have received a complete database for all their study subjects at the 
end of the study. Over the course of the study these responsibilities will gradually be shifted to the 
local study coordinators on the three islands. 
 
11.2 Follow-up survey preparation and data collection 
During the second, third and fourth survey rounds, each island study coordinator will print out from 
their ICF Access databases automatically generated survey forms per household that are identical to 
the ICF form but in which village name, the original form serial number, and name, age and gender of 
registered household members have already been preprinted, as well as the original barcode of each 
individual (Figure 4).  
 
Figure 4: Example of pre-printed ICF for follow-up surveys 
App: 
Per household: 
Island, district, village, form 
serial number, GPS coordinates, 
number of household members 
Per individual: 
Age, gender, present, history of 
leprosy, examined, signs of 
leprosy, cough > 2 weeks, 
sputum sample collected, 
barcode 
 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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They will also receive a village level map showing all household enrolled with their serial numbers. The 
teams will then go to the village, locate each household and examine those present. They will check 
the boxes on the paper survey form and then record all data using the same app as in the first survey 
round, with exception of the geographic coordinates. Each paper survey form will have a few empty  
rows to record any new household members if applicable, in case an entire new household is enrolled 
the procedure will be the same as in the first survey round. Upon returning to their base the study 
teams will again upload the data from the smartphone to the ITM server and hand over the paper 
survey forms to the data entry clerks. Any new household member or any entirely new household 
enrolled will be added to the ICF Access data base which will again be sent to the ITM CTU Data 
Manager for merging with the data collected through the app. Again, all transfers will be done by using 
the encrypted Belnet Filesender system. 
 
After the ICF forms have been entered in the ICF data base, the paper ICFs as well as later survey forms 
will be stored in a secure cabinet in the offices of the respective national control programs on the three 
islands. They will serve as source documents for monitoring, auditing and inspection purposes. 
 
The CTU Data Manager will provide a de-identified and locked extract from the merged database to 
the CTU Study Statistician for analysis. The use of any data received from other partners/vendors that 
is not entered in ODK falls under the responsibility of the ITM Coordinating Investigator. 
 
Figure 5: Data flow for the PEOPLE project 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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11.3 Registration of leprosy patients and follow-up 
A second app is currently used to register leprosy patients enrolled in the COMLEP study and allows to 
record results of a short interview as well as barcodes of samples taken. We will continue to use this 
app for leprosy patients diagnosed during the PEOPLE trial and enrolled in the study, with a few minor 
adaptations. In particular we will remove the names of patients enrolled and instead scan a unique 
barcode from an individual ICF form. An identical barcode is printed on 6 different stickers, one is stuck 
on the ICF form, the others on each of the samples belonging to the patient concerned. As was done 
for the survey data, ICF forms will be collected and used to enter name and barcode of each subject in 
an Access database. As was the case with the survey data, upon uploading to the ITM server, data will 
automatically and permanently be deleted from the Android device. Access databases will be 
forwarded to the ITM CTU Data Manager via Belnet Filesender, who will download the data collected 
by Android devices from the ITM server and use the barcode to link to the Access files.  
 
11.4 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.  
 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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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.  
 
 
12. ETHICAL ISSUES 
 
12.1 Ethical and regulatory review 
The study will be submitted for review and approval to the 8Comité d'Ethique de la Recherche 
Biomédicale9 (CERBM) in Madagascar and  the 8Comité National d9Ethique pour les Sciences de la Vie 
et de la Santé9 (CNESS) in the 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 answered to, 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, all applicable regulations and according to established international scientific standards. 
Choice of treatment for the patient will not depend on the results of the PEOPLE study.  
 
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. 
 
 
 
 
 
 
 
 


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12.3 Informed consent 
Informed consent for participation in the trial (which includes yearly screening for leprosy and 
treatment with PEP, as applicable depending on the assigned study arm) will be sought from all 
residents in the study area.  
 
As it will be practically and culturally not possible to perform the entire informed consent process for 
every individual in the study area, the procedure will take place per household. This will facilitate the 
study enrolment, while keeping any undue influence to a minimum. 
 
Households will be provided with an approved Participant Information Sheet, detailing in lay language 
the purpose, content, risks and benefits, voluntariness, etc. of the trial. A delegated member of the 
study team will sign this Participant Information Sheet on the date that the information was given to 
the household, stating that all information has been given, that all questions have been answered 
satisfactorily and that consent was freely given by all participating household members. 
On a separate approved Informed Consent Form, all participating household members, as well as the 
guardian and witness, as applicable, can separately sign for participation in the study. For practical 
purposes, this form will also include information on whether or not the participant was examined, was 
diagnosed with leprosy, has given a sputum sample, etc. (as detailed in chapter 11). No separate copy 
of this signature page will be given to the household members. The form will be stored by the study 
team in a secure manner. 
 
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. As these numbers are much lower, the standard signature process will be followed 
(i.e. one copy for the participant and one for the study; signed by the participant and the delegated 
site staff, and the guardian and/or witness as applicable). 
 
Participants who provide samples (i.e. index cases and neighborhood contacts in arm 4) will be 
informed that their samples will be stored for 20 years and may be used for other research in the 
future. They will also be informed that these samples can be shipped abroad. 
 
The legal age of consent in in the Comoros is 18 and in Madagascar 21. For participants, between 2 
andand the legal age of consent in the particular countries, 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.  
 
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, English, 
and Malagasy. Comorian is a rather spoken language and therefore the IFC will be orally translated by 
the interviewer on-site. Translations will be performed by a native speaker with thorough knowledge 
of the English or French language and checked for consistency by another native speaker. 
 
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. 
 
Because the first year of leprosy screening in Madagascar will be used to select 16 to 24 villages with 
the highest baseline leprosy prevalence, a separate informed consent has been created. The process 
will be similar to that of the main study (i.e. all consents of one household on a single page, etc.). The 
selected villages will then be re-consented in the second year based upon the arm their village has 
been assigned to. 


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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 Open Data Kit  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 informed consent form, as is 
required for management purposes by the NTLCPs who are 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 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 ICF data will be 
managed and secured by the NTLCP9s.  
 
Any other forms and reports needed for the study will be anonymous and can only be linked to the 
study participant by barcode.  
 
Participant9s 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 coded manner and by means of a controlled data 
access procedure and after the signing of a data sharing agreement. 
 
12.5 Potential Risks  
The most important risk in this study is loss of confidentiality. This risk 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. For household contacts anti PGL-I testing and nasal swabbing in study arm 4 
and distribution of Rifampicin in study arms 2-4 will be done while the team is still in the household. 
Distribution of Rifampicin to neighborhood contacts (arms 3 and 4) and anti PGL-I testing and nasal 
swabbing (during the second survey round) of neighborhood contacts (arm 4) 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% (arm 3) or 75% (arm 4) 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. In four villages on Anjouan screened in 2017, 84% of the population would reside within these 
100-meter perimeters.  
 
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 the study countries. In 
the areas targeted most villages are known to be affected. On Anjouan since 2008 and more recently 
also on Madagascar and 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 
PEOPLE trial even more villages will be included further reduces the risk of entire villages being 
stigmatized.  
 
In this study, participants will (depending on the arm their village is randomized in) receive a single 
dose of 20mg/kg Rifampicin, which is double of the standard dose used so far as PEP and also double 


PEOPLE, version 1.7, dated 18-Mar-2022 
 
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the standard daily dose used in tuberculosis treatment. As mentioned in the introduction and in the 
safety section, studies have shown that with a daily double dose of Rifampicin during 6 months used 
in treatment of tuberculosis, there is no increase in toxicity compared to the standard dose in 
participants ages 15 years and above. Therefore, the potential risks of receiving a double dose of 
Rifampicin are similar to those of the standard dose and include: vomiting and anorexia, headache, 
tingling sensation in the extremities, insomnia, joint pain and rashes. Nevertheless, the current study 
will include children as of 2 years old. Single dose of Rifampicin has shown to be safe in children under 
15 years of age and clear guidelines are available on the product leaflet. However, no studies have 
shown safety of double dose of Rifampicin in children under the age of 15.  
 
Capillary blood sampling by finger-prick, tongue swabs (only in Comoros) and nasal swab collection 
will be performed on a subset of participants. 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. Moreover, concomitant sputum collection will allow the study staff to 
refer participants with TB to treatment early on. So even for people living in the villages assigned to 
arm 1, there is a benefit of being part of the trial. 
 
For people living in villages assigned to arms 2, 3 or 4 and 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. 
To increase efficacy, a double dose of Rifampicin (20mg/kg) will be used. As mentioned above, no 
increased safety concerns are to be expected from this higher dose.  
 
There will be no compensation to the participants for their participation in the study. As study teams 
will perform door-to-door screening, also no travel reimbursement is foreseen. On the other hand, 
participants will not have to pay for any of the study procedures, nor for the PEP medication provided 
as part of 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 is offered free of charge by the national leprosy control programs, but are not 
part of this study. Participants will not receive any money, nor other form of compensation, for their 
participation. 
 
 
 
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 and which is caused directly or indirectly by their 
participation in the study. Participants will be informed of such insurance in the Participant 
Information Sheet. 
 
 
 


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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. 
 
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. 
 
 
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 (20) 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. 
 


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15. REFERENCES 
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WHO. Global Leprosy Strategy 2016-2020 2016. Available from: 
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Moet FJ, Pahan D, Oskam L, Richardus JH. Effectiveness of single dose rifampicin in 
preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster 
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Barth-Jaeggi T, Steinmann P, Mieras L, van BW, Richardus JH, Tiwari A, et al. 
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Bakker MI, Hatta M, Kwenang A, Van Benthem BH, Van Beers SM, Klatser PR, et al. 
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Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, et al. A dose-
ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir 
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WHO. World Health Assembly 44. Resolutions and decisions. Leprosy: World Health 
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Smith WC, van Brakel W, Gillis T, Saunderson P, Richardus JH. The missing 
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Diacon AH, Patientia RF, Venter A, van Helden PD, Smith PJ, McIlleron H, et al. 
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Nguyen LN, Cartel JL, Grosset JH. Chemoprophylaxis of leprosy in the southern 
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trial in paucibacillary leprosy comparing a single dose of rifampicin with a single dose of 
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16. LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALLEA 
All European Academies 
Anti-PGL1 
Anti-phenolic glycolipid-I 
APHP 
Assistance publique-Hopitaux de Paris 
AR 
Adverse Reaction 
BCG 
Bacille de Calmette Guérin 
BS 
Blood Samples 
CICM 
Centre d9Infectiologie Charles Mérieux 
CRF 
Case Report Form 
CRS 
Clinical Research Scientist 
CTU 
Clinical Trial Unit 
DF 
Damien Foundation 
EC 
Ethics Committee 
EDCTP 
European and Developing Countries Clinical Trial Partnership 
ESF 
European Science Foundation 
FRF 
Fondation Raoul Follereau 
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 
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 
 

SAP_001.pdf: 
 
 
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People - Statistical Analysis Plan 
 
24-September-2020 
 
Statistical Analysis Plan 
 
Post Exposure Prophylaxis for Leprosy in the 
Comoros and Madagascar 
 
PEOPLE 
 
Date:  24 September 2020 
 
Author:  
J. Buyze 
 
 
Biostatistician, Institute of Tropical Medicine, Antwerp, Belgium 
 
Approved by:  
Coordinating Investigator 
 
 
 
E. Hasker 
 
 
 
 
 
 
 
 
 
 
 
 
Date: __24__ / _09__ / _2020_ 
 
 
 
 
 
 
______________________________ 
 
 
 
 
 
 
Table of Contents 
 
1. 
Introduction ............................................................................................................ 2 
2. 
Study design and objectives ................................................................................... 2 
2.1. 
Study design .................................................................................................... 2 
2.2. 
Study objectives .............................................................................................. 3 
3. 
Deviations from protocol ....................................................................................... 3 
4. 
Description of study population ............................................................................. 4 
4.1. 
Patient accounting ........................................................................................... 4 
4.2. 
Description of study population ...................................................................... 4 
5. 
Description of efficacy patient populations and outcomes .................................... 4 
5.1. 
Patient populations .......................................................................................... 4 
5.1.1. 
Intention to treat (ITT) analysis ............................................................... 4 
5.1.2. 
Per protocol (PP) analysis ........................................................................ 5 
5.2. 
Efficacy study endpoints ................................................................................. 5 
6. 
Interim analysis ...................................................................................................... 6 
7. 
Analysis of main efficacy outcomes: incidence rate of leprosy ............................ 6 
7.1. 
Subgroup analyses ........................................................................................... 6 
7.2. 
Other aspects ................................................................................................... 6 
a. 
Multiplicity .............................................................................................. 6 


 
 
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b. 
Missing data ............................................................................................. 7 
8. 
Analysis of secondary efficacy objectives ............................................................. 7 
8.1. 
To assess cost and feasibility of SDDR-PEP under program conditions ........ 7 
8.2. 
To identify patterns of clustering in transmission of leprosy, allowing better 
targeting of control measures ..................................................................................... 7 
8.3. 
To monitor rifampicin resistance among leprosy patients .............................. 8 
9. 
Safety analyses ....................................................................................................... 8 
9.1. 
Safety analysis population ............................................................................... 8 
9.2. 
Safety outcomes and analyses ......................................................................... 8 
9.2.1. 
Adverse events ......................................................................................... 8 
 
 
 
1. Introduction 
 
This Statistical Analysis Plan (SAP) provides a detailed and comprehensive 
description of the main, pre-planned analyses for the study “Post Exposure 
Prophylaxis for Leprosy in the Comoros and Madagascar", including interim 
analyses. The purpose of this study is to document effectiveness of three alternative 
ways of implementing post exposure prophylaxis (PEP) at village level, by comparing 
to villages in which no PEP is provided. The study conduct is described in the 
Protocol (Clinicaltrials.Gov. NCT03662022). 
 
These planned analyses will be performed by the statistician(s) at the Clinical Trials 
Unit of the Institute of Tropical Medicine (Antwerp) and the research consortium. The 
analysis results will be described in a statistical analysis report, to be used as the basis 
of the primary research publications. This document describes statistical methods for 
the primary and secondary objectives of the study as defined by protocol. Additional 
analyses may be performed but are not covered by the current analysis plan.  
 
Two interim analyses will be conducted upon completing the second and third door-to-
door surveys in which incidence rates of leprosy to date in study arms 2, 3 and 4 will 
be compared to the incidence rate in arm 1, just as in the final analysis. These interim 
analyses will allow us to assess whether the a priori assumptions on annual incidence 
made have been realistic or whether an extended study duration should be considered.   
 
This analysis plan should be finalized and approved before the first interim analysis 
that will be performed by the study statistician. 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 
 
The PEOPLE study is a cluster randomized trial. There will be four door-to-door 
surveys of which the first one will allow us to calculate a baseline leprosy prevalence 


 
 
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per island. On the Comoros villages have been randomized after having been grouped 
by island into 8Blocks9 of four in decreasing order of incidence over the period 2013-
2017. Within each block villages were randomly and mutually exclusively allocated to 
the four study arms. For the study district in Madagascar reliable incidence estimates 
were not available. For that reason randomization for Madagascar is foreseen only for 
the end of the first study year, once the first screening round has been completed. 
 
There will be four study arms to which villages on Madagascar and the Comoros islands 
Anjouan and Mohéli will be randomly allocated. These villages have been preselected 
based on reported leprosy incidence over the period 2013-2017. In all four study arms, 
annual door-to-door surveys will be conducted covering entire villages. All permanent 
residents will be invited for screening for leprosy. Leprosy patients (further referred to 
as 8index patients9) detected will be offered free treatment according to the international 
and country guidelines. Depending on the study arm, contacts of leprosy patients will 
be offered PEP. In arm 1 no PEP will be provided, which is the current routine care on 
Madagascar and the Comoros. In arms 2, 3 and 4 a single dose of 20 mg per kg 
bodyweight of Rifampicin (hereafter called 8SDDR-PEP9) will be offered to all eligible 
participants who have not received Rifampicin in the preceding 2-year period. In arm 
2 only household contacts of an index patient will be provided with SDDR-PEP, which 
target group is considered the standard approach when PEP is provided for leprosy. In 
arms 3 and 4 SDDR-PEP will also be provided to neighbourhood contacts living within 
a radius of 100 meter of an index patient. In arm 3 all such contacts (including 
household contacts) will be provided SDDR-PEP, in arm 4 SDDR-PEP will be 
provided to all household contacts and to all those within the 100-meter perimeter 
testing positive to a serological screening test. If in arms 3 or 4 more than 50% (arm 3) 
or 75% (arm 4) of the population live within 100 meters of an index case, the entire 
village will in principle be eligible for PEP. 
 
 
 
2.2. Study objectives 
 
Primary objective:  
To compare effectiveness in curbing transmission of leprosy of three different 
approaches of post exposure prophylaxis 
 
Secondary objectives:  
1. To assess cost and feasibility of SDDR-PEP under program conditions 
2. To identify patterns of clustering in transmission of leprosy, allowing better 
targeting of control measures 
3. To monitor rifampicin resistance among leprosy patients 
4. To estimate incidence and prevalence of smear positive pulmonary tuberculosis 
in the study villages 
 
3. Deviations from protocol 
 
In the protocol one of the secondary objectives was to estimate incidence and 
prevalence of smear positive pulmonary tuberculosis (see section above).  The criterion 
to collect sputum was reported cough of 2 weeks duration or more. On a total population 
screened of just over 102,000 during the first year, only 115 (0.11%) reported such 


 
 
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cough. Either the question is not properly understood or cough is not a good screening 
criterion in the context of this study population. It was therefore decided to drop this 
secondary objective.  
 
4. Description of study population 
 
The study population will be described overall, and in each island (Anjouan, Mohéli, 
Madagascar) separately. 
 
4.1. Patient accounting 
 
Details of subjects screened, those who meet the study inclusion criteria, those who are 
eligible and enrolled, those who are eligible but not enrolled, those who withdraw from 
the study after randomization and those who are lost to follow-up will be summarized 
in a CONSORT flow diagram. The number of participants attending each annual survey 
will be reported. Since people were informed about their assigned study arm before 
providing consent and enrollment, the proportion of eligible subjects who are not 
enrolled will also be summarized by study arm. 
 
4.2. Description of study population 
 
Participants in each study arm, overall and by island, will be described with respect to 
baseline characteristics (i.e. at time of randomization). The description will be in terms 
of medians and quartiles for continuous characteristics and using counts and 
percentages for categorical characteristics. The clinical importance of any imbalance 
will be noted but statistical tests of significance of baseline imbalance will not be 
undertaken.  
 
5. Description of efficacy patient populations and outcomes 
 
5.1. Patient populations 
 
Note that in Madagascar enrolment/randomization will only take place at the second 
survey. Hence for Madagascar only data from the second survey onwards will be used 
for the primary objective. For secondary objectives 2 and 3 data from the first survey 
will also be used. 
 
We will analyse the efficacy data using Intention-to-Treat and Per-Protocol approaches, 
with Intention-to-Treat as primary approach.  
 
5.1.1. Intention to treat (ITT) analysis 
 
In the Intention-to-Treat analysis, all participants will be analysed according to their 
randomized allocation, even in case they do not receive SDDR-PEP as allocated, show 
protocol violations prior to or during the study.  
 


 
 
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5.1.2. Per protocol (PP) analysis 
 
In the per-protocol analysis only participants who receive SDDR-PEP as planned, have 
complete follow-up, and follow the protocol as planned are included.  
In Table 1 the protocol violations are classified as minor and major where minor 
violations can be included in the PP analysis population and major violations are 
excluded. 
 
Table 1: The protocol violations classified as minor or major violation 
  
Protocol Violation 
Major/Minor 
Violation 
Comments 
Inclusion criteria 
 
 
1. Living in one of the study villages 
Major 
 
2. Ages 2 years and above (only 
applicable for those receiving SDDR-
PEP) 
Major 
 
3. Able and willing to provide informed 
consent for leprosy and tuberculosis 
screening, and SDDR-PEP 
administration 
Major 
 
4. For leprosy index cases only: able 
and willing to provide informed 
consent for participation and 
sampling 
Major 
 
Exclusion criteria (only applicable for those 
receiving SDDR-PEP) 
 
 
1. Signs of active leprosy 
Major 
 
2. Signs of active pulmonary 
tuberculosis 
Major 
 
3. Having received Rifampicin within 
the last 24 months 
Major 
 
Treatment violations 
 
 
1. Missing SDDR-PEP 
Major 
 
2. Not following the randomized 
intervention 
Major 
 
Follow-up violations 
 
 
1. Incomplete follow-up 
Minor 
 
 
 
5.2. Efficacy study endpoints 
 
Primary endpoint  
The primary efficacy objective is to compare leprosy incidence rate. The health worker 
will perform a physical examination to look for signs of leprosy. Note that for this study, 
the 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 


 
 
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acid fact bacilli. Results of qPCR and anti-PGLI testing will be not be used as diagnostic 
criteria. 
 
Secondary endpoints  
Genotyping will be done by a novel sequencing technique called the Deeplex® MycLep 
assay. 
 
Rifampicin resistance will be tested with molecular markers. 
 
6. Interim analysis 
 
Two interim analyses will be conducted upon completing the second and third door-to-
door surveys in which leprosy incidence rates to date in study arms 2, 3 and 4 will be 
compared to the leprosy incidence rate in arm 1, just as in the final analysis. These 
interim analyses will allow us to assess whether the a priori assumptions on annual 
incidence made have been realistic or whether an extended study duration should be 
considered.   
The analysis performed will be similar to the analysis of the main efficacy outcome 
(Section 7) but restricted to data up to the second resp. third survey. Hence the interim 
analysis after completing the second survey will only include data from the Comoros. 
 
7. Analysis of main efficacy outcomes: incidence rate of leprosy 
 
Each diagnosis of leprosy made after the survey in which the participant was enrolled 
will be counted as an incident case. Note that not only diagnoses made at the annual 
surveys but also diagnoses made in between the surveys will be counted. For each 
individual we will calculate the exact time at risk. For individuals residing in 
intervention villages (arms 2, 3 and 4) we will use the number of days from the median 
date of the first SDDR-PEP administration in the village  until end of follow-up or until 
diagnosis of leprosy. 
 
We will fit a random effects Poisson model with incident case (0/1) as dependent 
variable, study arm as explanatory variable, using the non-intervention group (arm 1) 
as baseline level, log(time at risk) as offset, and with 8island9, 8block9 (as described 
above, eight on Anjouan, four on Mohéli, four to six on Madagascar) and 8village9 as 
nested random effects. As study outcome we will report incidence rate ratios between 
arm 1 and each of the other arms with 95% confidence interval, considering a p-value 
of < 0.017 as statistically significant to account for the fact that we make three 
comparisons. 
 
7.1. Subgroup analyses 
 
No subgroup analyses are planned. 
 
7.2. Other aspects 
 
a. Multiplicity 
 


 
 
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A p-value of < 0.017 will be considered as statistically significant to account for the 
fact that we make three comparisons. Interim analyses will be performed, but these 
analyses will not influence the continuation of the study. 
 
b. Missing data 
 
Data will be used until time point at which participant is last seen. If there are 
intermediate missing results, these will be considered to be negative for leprosy. 
 
 
8. Analysis of secondary efficacy objectives 
 
8.1. To assess cost and feasibility of SDDR-PEP under program conditions 
 
Costs will be calculated per person screened, per person treated with SDDR-PEP and 
per leprosy case averted. 
 
8.2.  To identify patterns of clustering in transmission of leprosy, allowing better 
targeting of control measures 
 
Results of DNA finger printing will be used to assess the degree of clustering at 
household and at village level. We will calculate proportions of patients belonging to 
a same cluster by household and by village. The space-time K-function will be used to 
assess clustering in time and space, to be triangulated with results of DNA finger 
printing. For this purpose, we will use results of all leprosy patients identified, 
including those found at baseline. 
  
To establish the transmission networks in the Comoros islands and in the study area in 
Madagascar, we will overlay the molecular network with the spatial- and social 
networks. This will determine whether the 100m high risk zones around each index 
patient, applied in this study, capture most transmission events, or whether additional 
risk factors, beyond spatial, need to be taken into account in future PEP administration 
efforts in the study areas and elsewhere. Phylogenetic clustering of the M. leprae 
isolates allows us to identify risk factors for leprosy due to recent transmission. The 
findings of the spatial and social network analysis can be mapped onto a phylogenetic 
tree and molecular clusters based on the VNTRs, which can reveal risk factors for 
transmission of leprosy. 
 
Mixed effects Poisson model (same model as for the main analysis) with study arm 
(only when comparing 2019 to 2020 data) and distance to nearest index case as fixed 
covariates will be used to test for an association between distance to index case and 
leprosy incidence rate. We will compare six distance categories: same household, 
neighbors at < 25 meters and neighborhood contacts at 25-<50 meters, at 50 - < 75 
meters, at 75 - < 100 meters and at 100 meters or beyond. Two models will be fitted. 
The first model will use leprosy diagnosis at the time of the survey in 2019 (either a 
new diagnosis or a patient still on treatment) as outcome and distance to nearest index 
case from 2019 as independent variable, the second model will use incident leprosy 
cases in 2020 as outcome and distance to nearest index case from 2019 as independent 
variable.  In addition we will use Kulldorff9s spatial scan statistic to fit a purely spatial 
Poisson model to identify clusters of high leprosy prevalence. 


 
 
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8.3. To monitor rifampicin resistance among leprosy patients 
 
All leprosy patients with a positive/negative test result for Rifampicin resistance will 
be included in a random effects logistic regression model with rifampicin resistance 
(0/1) as dependent variable, island as explanatory variable, and with 8block9 (as 
described above, eight on Anjouan, four on Mohéli, four to six on Madagascar) and 
8village9 as nested random effects. Based on this model, prevalence of Rifampicin 
resistance per island will be estimated with 95% confidence interval.  
 
 
9. Safety analyses 
 
9.1. Safety analysis population 
For the analysis of safety outcomes, all participants who effectively received a SDDR-
PEP dose are included in the safety analysis (all-patients-treated approach).  
 
 
9.2. Safety outcomes and analyses 
 
9.2.1. Adverse events 
 
General 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 participants with 
a specific category and not on counts of individual adverse events. The relationship 
between AEs and treatment is determined by the local investigator and categorized as 
"drug-related" if possibly, probably or definitely related to treatment. Only adverse 
events that occur between the administration of the drug and three days after 
administration will be recorded for study purposes. 
 
The following summaries will be presented: 
 
a. description of all deaths of participants up to three days after SDDR-PEP 
administration; 
 
b. the total number and percentage of participants with any AE by preferred term 
and body system up to three days after SDDR-PEP administration; 
 
c. the total number of participants and percentage with any drug-related AE by 
preferred term and body system up to three days after SDDR-PEP 
administration; 
 
d. the total number of participants and percentage with any SAE by preferred term 
and body system up to three days after SDDR-PEP administration; 
 
e. the total number of participants and percentage with any drug-related SAE by 
preferred term and body system up to three days after SDDR-PEP 
administration; 


 
 
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95% confidence intervals will be calculated for the following statistics: 
 
a. percentage of participants with any AE, any serious AE, any drug-related AE, 
any drug-related serious AE; 
 
b. percentage of participants with the most common AEs, drug-related AEs, SAEs, 
drug-related SAEs (most common: with an incidence of 10% or more). 
 
 
These confidence intervals will be calculated based on a random effects logistic 
regression model with 8island9, 8block9 (as described above, eight on Anjouan, four on 
Mohéli, four to six on Madagascar) and 8village9 as nested random effects.