Tuberculosis Infections and Infestations Tuberculosis
Conditions
Interventions
1. The standard therapy will be daily self-administered INH,10-15 mg/kg/day for children (max=300mg/day) for 9 months (9INH)
2. As currently recommended vitamin B6 (pyridoxine) will be
Sponsors
Canadian Institutes of Health Research (Canada)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Children (age 5 mm or QFT +) 1.2. Age 5 or less (TST >5 mm or QFT +) 1.3. Other reason for immuno-compromised state - such as therapy for malignancy or post-transplant (TST >5 mm or QFT +) 1.4. Contact: with adult or adolescent with active contagious pulmonary TB TST >5 mm or QFT +) 1.5. Have both of the following factors if TST = 10-14mm or QFT + or one factor if TST >15mm : 1.5.1. Arrival in Canada, Australia, or Saudi Arabia in the past 2 years from countries with estimated annual incidence of active TB greater than 100 per 100,000 1.5.2. Body mass index (BMI) less than 10th percentile for their age 2. Interferon gamma release assays (IGRA's) are ex-vivo tests of immune response to TB antigens, that have been adopted in some centres as alternatives to the TST, although WHO has recently recommended IGRAs should not be used to replace the TST in low and middle-income countries 3. If an eligible child undergoes a commercially available IGRA (the Quantiferon-Gold or T-Spot.TB), instead of a TST, and the result is positive, then they will be considered eligible 4. If both TST and IGRA are done, then the TST result will be used to determine eligibility 5. The TST may be negative for up to 8 weeks after primary infection, before adequate cell mediated immunity develops 6. Because of this, current practice is to begin LTBI treatment therapy immediately for children < 5 years old, even if TST negative 7. After 8-10 weeks the TST is repeated; LTBI therapy is continued if now TST positive, and stopped if still negative 8. Providers may continue therapy in very young, HIV infected or malnourished children 9. We propose to enroll TST negative children aged < 5, if the treating physician prescribes LTBI therapy, because: 9.1. Primary endpoints are still relevant, and measurable in this group 9.2. Acceptability and completion in this sub-group are of particular interest 9.3. Children that have new primary TB are at particularly high risk to develop disease (this is the rationale for their treatment) 10. If the treating MD stops therapy because the TST is negative after 8-10 weeks, these children will be excluded from the analysis of treatment completion, but included in the incidence density analysis (person-time) of tolerability and safety
Exclusion criteria
Exclusion criteria: 1. Children who were contacts of TB cases known to be resistant to INH, RIF, or both (i.e. MDR) 2. Known HIV-infected individuals on anti-retroviral agents whose efficacy would be substantially reduced by Rifampin, unless therapy can safely be changed to agents not affected by Rifampin 3. Pregnant women - Rifampin and INH are considered safe in pregnancy, but therapy is usually deferred until 2-3 months post-partum to avoid fetal risk and the potential for increased hepato-toxicity immediately post partum 4. Children on any medication with clinically important drug interactions with INH or RIF, which their physician believes would make either arm contra-indicated. This includes women taking hormonal contraceptives who will not take alternative contraception 5. History of allergy/hypersensitivity to Isoniazid or to Rifampin, Rifabutin or Rifapentine 6. Active TB. Children initially suspected to have active TB can be randomized once this has been excluded 7. Prior complete LTBI therapy or if children have taken >1 week and are still taking the treatment.. Children will be eligible if they took an incomplete LTBI therapy (less than 80% of recommended total dose) but > 6 months ago
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To compare the rates of premature discontinuation of study therapy because of adverse events of all grades judged probably related to 4RIF or 9INH, by the majority of an independent panel of 3 reviewers, blinded to study drug | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. To compare the rates of study drug completion of all children randomized to 4RIF or 9INH. Completion will be defined as taking at least 80% of total planned doses within 23 weeks for 4RIF, or within 52 weeks for 9INH 2. To compare the rates of clinically diagnosed active TB as judged by an independent panel of paediatricians, up to 16 months post randomization in children who complete study therapy per protocol (efficacy) 3. To describe the occurrence of drug resistant microbiologically confirmed active TB among children randomized to the two arms, during 16 months post randomization | — |
Countries
Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia
Outcome results
None listed