Clinical trial NCT05597280: Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy
Official title: Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy: Phase 3 Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Leprosy
Lead sponsor: Institute of Tropical Medicine, Belgium
Sponsor class: OTHER
First posted: 2022-10-28
Enrollment: 124000
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: There will be two study arms. Arm 1 will be the intervention arm in which there will be provided BE-PEP to all persons residing within 100 meters of an index case, to be repeated after four weeks for household contacts. Arm 2 will be the comparator arm in which the WHO recommended standard PEP will be provided, i.e. 10 mg/kg of rifampicin in a single dose. In both arms the investigators will target anyone living within 100 meters of an index case or the entire village if more than 50% are eligible. Provision of BE-PEP will start in 2023 and follow-up will continue until 2026. The main study outcome will be the comparison of leprosy risk in individuals that received BE-PEOPLE standard WHO SDR-PEP versus individuals that received BE-PEP. In addition the investigators will compare the overall leprosy incidence over the follow-up period between the two study arms.

Detailed description: Assuming the phase 2 study will not reveal any drug related adverse events and following the advice of the DSMB and the involved ethics committees, the investigators will proceed with a phase 3 study for which randomization will take place in December, 2022. There will be two study arms. Arm 1 will be the intervention arm in which there will be provided BE-PEP to all persons residing within 100 meters of an index case, to be repeated after four weeks for household contacts. Arm 2 will be the comparator arm in which the WHO recommended standard PEP will be provided, i.e. 10 mg/kg of rifampicin in a single dose. In both arms anyone living within 100 meters of an index case will be targeted or the entire village if more than 50% are eligible. Provision of BE-PEP will start in 2023 and follow-up will continue until 2026. The main study outcome will be the comparison of leprosy risk in individuals that received standard WHO SDR-PEP versus individuals that received BE-PEP. In addition the overall leprosy incidence over the follow-up period will be compared between the two study arms. As stated above, the primary outcome measure will be the incidence rate ratio of leprosy between those who received BE-PEP and those who received the standard SDR-PEP. From this analysis the investigators will exclude those not eligible for BE-PEP, i.e. children below 5 years of age and/or with a weight below 20 kg. A Poisson model will be fit with village nested in island as random effect and controlled for distance to the nearest index case at baseline. In addition the investigators will compute incidence rate ratios between the entire BE-PEP and SDR-PEP arms over the period 2023-2026, also based on a Poisson model with village nested in island as random effect. Throughout the BE-PEOPLE trial the investigators will continue sampling leprosy patients identified (a skin biopsy from the edge of non-facial lesions), with the aim of using molecular assays for M. leprae as quality assurance mechanism. If sufficient DNA is available Deeplex-MycLep will be used for typing the strains, which will allow to perform highly sensitive surveillance for (traces of) resistance to rifampicin and bedaquiline. As part of BE-PEOPLE, the investigators will moreover enroll all microbiologically confirmed tuberculosis patients on all islands of Comoros (Moheli, Anjouan, and Grande Comore, where bedaquiline will not be introduced, maximum 100 patients/ year) and assess whether they ever received (BE-)PEP or leprosy treatment. The investigators will genotype their sputum with Deeplex-MycTB XL, which includes all M. tuberculosis genes (potentially) involved in resistance to rifampicin and bedaquiline, to be able to detect the earliest traces of acquired resistance to these drugs, which is unexpected after single dose administration.The overall goal of BE-PEOPLE is to validate a robust and safe leprosy PEP regimen, and its optimal administration, that prevents leprosy in the individual and interrupts transmission at the village level.If BE-PEP turns out to be safe and successful, the investigators aim to adjust national guidelines in Comoros towards island wide implementation on Anjouan and Moheli, allowing to sustainably eliminate leprosy.

Eligibility criteria: Inclusion Criteria:

1. Living in one of the study clusters (34 on Anjouan, 10 on Mohéli), in good state of health
2. Aged 2 years and above, as leprosy is very rare among infants and young toddlers. Children age 2-4 years or weighing less than 20 kg will not be given bedaquiline. If eligible they will receive only rifampicin.
3. Able and willing to provide informed consent for leprosy and tuberculosis screening, and PEP administration (as applicable in the different arms)

Exclusion Criteria:

1. Signs of active leprosy
2. Signs of active pulmonary tuberculosis (cough ≥2 weeks duration and without a negative TB test)
3. Signs of active extra-pulmonary tuberculosis (bluish-red nodules that cover the lymph nodes, bones or joints, or cervical glands with discharge)
4. Having received rifampicin or bedaquiline (if applicable) in the last 2-year period
5. Self-reported (suspected) pregnancy or breastfeeding
6. Concurrent (within the last three week period before D0) use of medications not included in the safe list (for bedaquiline only)

Primary outcomes:
measure: To evaluate effectiveness of PEP based on a combination of rifampicin and bedaquiline (BE-PEP), in preventing leprosy among contacts of incident cases.
timeFrame: Through study completion, an average of 4 years
Secondary outcomes:
measure: To assess effectiveness of the BE-PEP regimen at village level.
timeFrame: Through study completion, an average of 4 years
measure: To quantify frequency of potential adverse events such as gastro-intestinal (nausea, vomiting), nervous system-related (headache, dizziness) and cutaneous reactions
timeFrame: Until day 30 after treatment administration. 2026 final analyses
measure: To assess anti-PGL-I sero surveys as a tool to monitor leprosy transmission
timeFrame: Through study completion, an average of 4 years
measure: To monitor rifampicin and bedaquiline resistance among leprosy and tuberculosis patients
timeFrame: Through study completion, an average of 4 years
measure: To assess cost-effectiveness of the BE-PEP regimen compared to SDR-PEP.
timeFrame: Through study completion, an average of 4 years
measure: To evaluate the viability of Mycobacterium tuberculosis during and after treatment among TB patients on Grande Comore.
timeFrame: Through study completion, an average of 4 years
Other outcomes:
Locations:
city: Moroni
country: Comoros
facility: Fondation Damien
Study officials:
affiliation: Damien Foundation Comoros
name: Younoussa Assoumani
role: PRINCIPAL_INVESTIGATOR
References: