HIV Clinical Trial
Official title:
A Randomised, Pragmatic, Open-Label Trial To Evaluate The Effect Of Three Months Of High Dose Rifapentine Plus Isoniazid Administered As A Single Round Or Given Annually In HIV-Positive Individuals
This study is a parallel, two part, open label, individually randomized, pragmatic trial among HIV-positive individuals. Part A compares a single round of weekly high dose rifapentine plus isoniazid for three months (3HP) to six months of daily isoniazid (6H). Part B compares periodic 3HP (p3HP) to a single round of 3HP.
Part A: A randomised controlled trial of 3HP vs 6H [enrollment starts concurrently with Part
B]
Justification: The World Health Organization (WHO) recommends at least six months of
isoniazid (6H) for persons living with HIV. However, 6H remains poorly implemented in most
high burden tuberculosis (TB) countries. In its 2015 guidelines, WHO includes 3HP as an
latent tuberculosis infection (LTBI) treatment option for high-income and upper middle-income
countries with TB incidence rates <100/100,000. One trial comparing 3HP to 6H in a high
burden country suggests that a single round of 3HP has less toxicity, better treatment
completion rates, and similar efficacy in preventing TB. The purpose of comparing a single
round of 3HP to 6H is to demonstrate the feasibility of implementing 3HP in high burden
countries, to explore its safety and effectiveness, and to generate evidence to guide a WHO
recommendation for the use of 3HP in high burden settings.
Sample size: If we assume 85% of patients in the 6H arm complete treatment as defined above,
with 400 patients in the 6H arm and 3600 patients in the 3HP arm we will have 82% power to
detect an increase in treatment completion of 5% (To -90%) in the 3HP arm. If treatment
completion in the 6H arm is 75%, we will have approximately 90% power to detect an increase
in treatment completion of 7% in the 3HP arm.
Analysis: Treatment completion will be compared by study arm using Fishers Exact test, and
associated risk difference and 95% confidence interval (CI).
Part B: A randomised controlled trial of 3HP vs p3HP [enrollment starts concurrently with
Part A]
Justification: A single round of 3HP has been shown to be non-inferior to 9 months of
isoniazid (9H) in persons at high risk of developing TB in low and middle TB burden settings.
Similarly, a single round of 3HP has demonstrated similar efficacy in preventing active TB
when compared to 6H among HIV-positive, tuberculin skin test (TST)-positive adults in the
high burden setting of South Africa. In high burden settings, 6H and 3HP provide protection
of limited duration probably due to high ongoing transmission and reinfection. Continuous
isoniazid preventive therapy has been shown to provide more durable protection in high burden
settings, but is not currently policy outside of a handful of countries, and the actual
uptake is poor. Giving 3HP periodically may provide durable protection, be easier for health
systems to implement, and may be associated with better adherence and fewer side effects.
Sample size: Assuming a cumulative TB incidence of 5% over 2 years in the control (3HP) arm,
an overall loss to follow-up of 10% by year 2, a two-sided type I error of 5%, 1:1
randomisation, a superiority comparison and 1800 participants per arm, we have 80% power to
detect a 40% reduction in cumulative TB incidence from months 0 to 24.
Analysis: The analysis will compare 3HP and p3HP with two years of follow up. Cumulative TB
incidence will be determined by combining incident TB cases identified over the 24 months of
follow up AND prevalent TB cases identified at the 12 and 24 month culture survey. Data will
be reported as a risk difference and odds ratio and their associated 95% CIs, adjusting for
randomisation strata. The secondary outcome comparing the effectiveness of p3HP to 3HP from
month 13 to 24 (during which time the greatest effect is likely to be evident) will be
conducting using the same analytic methods. The results of Part B will be disseminated
subsequent to the results of Part A.
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