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).
Adults, and children aged ≥5 years with weight of > 15Kg.
Positive test for TB infection: either Tuberculin test (>5mm, or >10mm, based on epidemiologic and clinical factors and interpreted following local guidelines) or interferon gamma release assay based on Manufacturer's criteria; and,
Recommended for Tuberculosis Preventive Treatment (TPT), following Canadian guidelines (for Canadian sites), and World Health Organization (WHO) guidelines (for international sites).
Current tuberculosis (TB) disease - detected pre-enrolment with symptom screen, chest x-ray, and confirmatory microbiological (culture or genotypic) testing as needed; Prior to referral to research staff (research clinic) for consideration as potential participants, all persons must undergo symptoms screen and a chest Xray. If chest Xray is not available, then a negative results from a GeneXpert MTb RIF Ultra of spontaneous (expectorated) sputum will be considered sufficient to exclude TB disease pre-referral. If Chest Xray is abnormal or symptoms consistent with TB disease are present then at least two AFB smears and mycobacterial cultures must be done, and must be negative, or one GeneXpert MTb Rif Ultra must be negative before enrolment
Children aged 0-4 years;
Persons weighing <15 kg.
Women who are pregnant or breast-feeding;
Parallel
rifampin standard arm
Drug120 doses daily self-administered rifampin at 10mg/kg/day (max 600mg/day)
rifampin double dose
Drug60 doses daily self-administered rifampin at 20 mg/kg (max. 1200 mg/day)
levofloxacin and rifapentine
Drug30 doses daily self-administered levofloxacin (15 mg/kg, max 750mg/day and rifapentine (10mg/kg, max: 600mg)
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.
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.
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.
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.
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. A separate sub-study in breastfeeding women will be performed to assess PK profiles of a single dose of RIF, LFX, INH, RPT, and BDQ (PRiMe study).
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McGill University Health Centre/Research Institute of the McGill University Health Centre
Lead sponsor
Canadian Institutes of Health Research (CIHR)
Collaborator