Pragmatic trial on the safety and tolerability of an optimized dose of rifampicin in tuberculosis patients

Each year approximately 10 million people get sick of tuberculosis and in 2020
1.3 million people died due to TB. This disease remains the deadliest
infectious disease in the world regardless of its cheap treatment and high cure
rates. Treatment for drug-susceptible TB consists of 2 months intensive
treatment with isoniazid, rifampicin, ethambutol and pyrazinamide, and
thereafter a continuation phase of 4 months with isoniazid and rifampicin
according to guidelines. Current treatment for drug-susceptible TB has to be
given for at least 6 months, which is long. It can lead to side-effects, which
can decrease medication adherence. The current TB treatment is suboptimal,
leading to favourable treatment outcomes in only 80% of the patients under
programmatic circumstances.
Drug resistance to the key first-line drugs rifampicin and isoniazid is
increasing. The aim of the WHO *End TB Strategy* is to end the global TB
pandemic by 2035. This ambitious goal is dependent on the achievement in
several areas before the year 2025: vaccines, new drugs and optimization of
standard drugs and point-of-care diagnostic tests. Rifampicin, a drug with a
well-known safety profile and efficacy data is currently dosed sub-optimal. The
dose was selected when introduced in the 1970s because of financial reasons,
fear for toxicity and because serum concentrations were well above the MIC.

There is substantial increasing evidence that higher doses of rifampicin are
more optimal in terms of efficacy, prevention of resistance and are better
tolerated than expected. The simple intervention to increase the dose and
induce better outcome, reduce resistance selection and shorten treatment can
have a major impact, contributing to WHO end TB strategy.

This study has been transitioned to CTIS with ID 2023-509885-39-00 check the CTIS register for the current data.

The primary objective is to describe and compare the incidence of
hepatotoxicity in standard care and in a regimen with an optimized dose of 1800
mg rifampicin in patients with rifampicin-susceptible tuberculosis. We
identified hypotheses for non-inferiority. The null hypothesis states that the
regimen with the optimized dose of rifampicin shows more hepatotoxicity than
the regimen with the standard rifampicin dose. The alternative hypothesis
states that there is no clinically relevant difference in hepatotoxicity
between the regimen with an optimized dose of rifampicin and the regimen with
the standard dose. In this case, the regimen with an optimized dose is
non-inferior to the regimen with a standard dose of rifampicin.

The secondary objectives are:
• To compare any adverse events in the optimized dose regimen versus the
standard dose regimen.
• To compare final treatment outcome at the end of treatment according to WHO
definitions of cure in the optimized dose regimen versus the standard dose
regimen.
• To compare two and three months culture conversion rates in the optimized
dose regimen versus the standard dose regimen.
• To describe and compare the steady-state plasma pharmacokinetics of the
optimized dose regimen versus the standard dose regimen. This will be performed
depending on the availability of pharmacological analyses.

This is a pragmatic randomized controlled open label non-inferiority phase III
trial, with balanced 1:1 stratified randomization.

We will compare a regimen with an optimized dose of rifampicin, to the standard
regimen, as described below:
• Experimental arm with daily 1800 mg rifampicin for 6 months: 2HR1800ZE/4HR1800
• Control arm with the daily standard regimen for 6 months: 2HRZE/4HR

As this is a pragmatic trial, which is performed as much as possible within
local standard of care, we expect there not to be much additional burden for
participants. The planned study visits (wk1, wk2, wk4, wk6, wk8, wk 12, wk 17,
wk 22 and wk 26) are adapted to the standard of care. Lab assessments, which
include blood samples, have to be performed four times during the study period.
The MAMS study of our group showed that a rifampicin dose of 35 mg/kg per day
for 12 weeks was safe. In the PanACEA HIGHRIF1 study higher doses up to 40 mg
rifampicin/kg were well tolerated for 7 days with monotherapy and additionally
7 days with combination therapy. However, we give a lower dose of rifampicin in
the experimental arm, as 1800 mg is closest to a dose of 35 mg/kg. According to
a retrospective cohort study a higher dose of rifampicin was safe and
well-tolerated in patients with severe disease and/or low rifampicin plasma
concentrations at the beginning. We have not seen flu-like syndrome in any of
our high dose rifampicin studies and no higher incidence of hepatotoxicity was
seen in our studies with pulmonary TB with higher doses of rifampicin up to 35
mg/kg.