An Adaptive Trial to Find the Safest And Shortest TB Preventive Regimens.
NCT Number: NCT06498414
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2|PHASE3
Conditions: Tuberculosis Infection, Latent
Interventions: DRUG: rifampin standard arm|DRUG: rifampin double dose|DRUG: levofloxacin and rifapentine
Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Collaborators: Canadian Institutes of Health Research (CIHR)
Sex: ALL
Age: CHILD, ADULT, OLDER_ADULT
Enrollment: 1800
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: SINGLE (OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT
Start Date: 2024-10-01
Completion Date: 2029-06-01
Locations: Centre National Hospitalier Universitaire de Pneumo Phtisiologie de Cotonou (CNHU-PPC), Cotonou, Benin|Manaus, Manaus, Brazil|Unviversity of Calgary, Calgary, Alberta, Canada|The Governors of the University of Alberta, Edmonton, Alberta, T6G 2C8, Canada|BCCDC TB clinic, Vancouver, British Columbia, Canada|University of Manitoba, Winnipeg, Manitoba, Canada|University of Ottawa, Ottawa, Ontario, Canada|University Health Network, Toronto, Ontario, M6M2J5, Canada|MUHC, Montreal, Quebec, H4A 3J1, Canada|Hopital du Sacré-Coeur de Montreal, Montreal, Quebec, H4J 1C5, Canada|Universitas Padjadjaran, Klinik Penelitian Tuberculosis (TB research clinic), Bandung, Indonesia|Vietnam, Ho Chi Minh City, Vietnam

Summary:
Our study rationale is based on:

1. Tuberculosis Preventive Treatment (TPT) is given to healthy people and needs to be safe;
2. Tuberculosis Preventive Treatment (TPT) with shorter regimens are superior with respect to acceptance, completion, and costs;
3. 4 months of Rifampin 10mg/kg (4R10) is the safest regimen, but is completed by \<80% of patients;
4. The safety of 2 months of Rifampin 20mg/kg (2R20) is similar to that of 4 months of Rifampin 10mg/kg (4R10), but completion is a concern;
5. 1-month regimens have promising efficacy;
6. Safety and tolerability must be carefully assessed with comparisons to 4 months of Rifampin 10mg/kg (4R10), and head-to-head with each other.

OBJECTIVES: The investigator will use a Bayesian adaptive Phase 2 randomized open-label trial design to test at least three experimental Tuberculosis Preventive Treatment (TPT) regimens to identify at least one regimen of ≤2 months duration that has non-inferior safety, completion, and tolerability in adults and children relative to the reference Tuberculosis Preventive Treatment (TPT) regimen. The shortest, safest, and best tolerated regimen identified in this Phase 2 trial will be tested for effectiveness and efficacy in a Phase 3 trial.

Specific Tuberculosis Preventive Treatment (TPT) regimens (All are daily and self-administered) Reference: Rifampin at a dose of 10 mg/kg/day for 4 months (4R10); Experimental: 1) Rifampin at 20 mg/kg/day for 2 months (2R20); (2) one month Levofloxacin and Rifapentine (1LP). At a later stage a 3rd experimental regimen will be selected and added: one another novel 1-2-month regimen identified from pre-clinical and clinical studies. When selected, this will be explained fully including preliminary data on safety and efficacy in an amended protocol and consent - which will be submitted for ethics and regulatory approval at that time).

Primary Outcome Measures: Severe treatment-related Adverse Events (AE), The investigators wish to capture all clinically relevant Adverse Event (AEs) defined as events that are possibly or probably treatment-related and result in death, hospitalization, or investigators' decision to discontinue study drug. These are defined as Grade 3-5 Adverse Event (AEs) of any type, plus Grade 1-2 rash/allergy. Because allergic reactions that are often detected by participants at an early stage carry the risk of progressing to more advanced manifestations if therapy is continued, stopping study drug is mandated with any Grade allergic reaction. If a suspected treatment-related Adverse Event (AE), or any hospitalization or death occurs during treatment phase (up to 2 weeks after the last dose of study drug taken), the site will file initial and final Adverse Event (AE) reports that will be sent for adjudication by the Adverse Event (AE) panel who will be blinded to study arm., From the start of the treatment until 2 weeks after the treatment completion
Secondary Outcome Measures: Completion, Completion will be defined as taking at least 80% of prescribed doses within 150% of allowed time. This outcome will be based on the number of pills dispensed and counted during treatment follow-up visits, along with time from randomization until the date that ≥80% of doses of study drug are taken. This threshold is derived from a large-scale trial in which efficacy was significantly greater in persons who took at least 80% of doses., at the end of the treatment (1 month, 2 months or 4 months)|Tuberculosis Preventive Treatment (TPT)-related symptoms - Tolerability, The investigators found that reporting symptoms at the time of routine treatment phase follow-up visits, which the patient's provider did not consider an AE and so did not discontinue treatment, occurred significantly more frequently with 2 months of Rifampin 30mg/kg (2R30) than 2 months of Rifampin 20mg/kg (2R20) or 4 months of Rifampin 10mg/kg (4R10); this was associated with subsequent patient decision to stop Tuberculosis Preventive Treatment (TPT) in our 2R2 trial and our 4v9 trial. Thus, symptoms will be captured with a questionnaire, assessing the 10 most commonly reported symptoms at the time of routine follow-up visits in these previous trials., 2 weeks after the treatment has started in all arms|Patient preferences and acceptability of Tuberculosis Preventive Treatment (TPT), The impacts of different Tuberculosis Preventive Treatment (TPT) regimens on adherence, quality of life, and perceived trade-offs between pill burden, tolerability, and duration will be explored using qualitative methods informed by treatment acceptability frameworks, including those used in discrete choice experiments and the evaluation of broader disease prevention interventions. A purposive sample will include approximately 10 participants per arm in each country, with equal representation from men and women, key affected populations in each country, and participants who completed or decided to stop early. For pediatric participants we will interview their adult caregivers. They will be recruited for two private semi-structured, audio-recorded interviews. The first interview (10-15 min), after two weeks of treatment, will inquire on first impressions of treatment, including tolerability, impact on daily life, and early adherence issues., 2 weeks after the treatment has started in all arms|Plasma drug exposures, Pharmacokinetics (PK) of rifampin, levofloxacin, and rifapentine will be assessed after two weeks of therapy in all arms. An intensive Pharmacokinetics (PK) sub-study will be performed at sites with facilities and trained personnel to characterize peak concentrations (Cmax) and total drug exposures over the dosing interval (AUC). Serial venous blood samples will be collected at 0, 0.5, 1, 2, 4, 8, and 12 h after drug intake in 10 participants per sub-group in younger children aged 5-9 years, in adults, and also in people living with HIV on antiretroviral (30 total per arm). A population PK sub-study (e.g., either at 1, or 2, or 3, or 4, or 6 h after drug intake) will also be performed in consenting participants at all sites to assess determinants of Pharmacokinetics (PK) variability and the association of drug exposure on study outcomes., 2 weeks after the treatment has started in all arms|Assess both health system and patient/family costs, The investigators will assess both health system and patient/family costs using a bottom-up micro-costing approach and patient questionnaires. The investigators will perform activity-based costing informed by all relevant health services used by participants including visits, medications, tests, and hospitalizations (all collected in study case report forms (CRFs), and cost these items based on previous work. To estimate patient/family costs during treatment phase, the investigators will administer a questionnaire that we have used previously about out-of-pocket costs (e.g., transport, food) and time taken for Tuberculosis Preventive Treatment (TPT) related activities; this will be assessed in 20 participants per country and study arm. For employed persons, the investigators will value indirect costs of time using the mean wage in their jurisdiction (province or country) for their job title; for unemployed persons, the investigators will use the mean wage in the same jurisdiction., 2 weeks after the treatment has started in all arms|Active TB is suspected within 26 months of randomization, If active TB is suspected within 26 months of randomization, this will be investigated, managed, and reported in accordance with detailed standard operating procedures (SOPs). The final diagnosis will be based on microbiological confirmation. If not confirmed, the diagnosis will be based on the judgement of probable tuberculosis (TB) disease by the majority of a blinded 3-member independent panel that will review clinical information, microbiologic and radiologic results, and treatment response., From start of the treatment until 26 months after the randomization