Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b/c Trial

Abstract

Previous clinical trials for drug-susceptible tuberculosis (DS-TB) have shown that first-line treatment with doses of rifampicin up to 40 mg/kg are safe and increase the early treatment response for young adults with pulmonary tuberculosis. This may lead to a shorter treatment duration for those persons with TB and a good baseline prognosis, or increased treatment success for vulnerable subgroups (age > 60, diabetes, malnutrition, HIV, hepatitis B or hepatitis C coinfection, TB meningitis, stable chronic liver diseases). Here, we describe the design of a phase 2b/c clinical study under the hypothesis that rifampicin at 35 mg/kg is as safe for these vulnerable groups as for the participants included in previous clinical trials. RIAlta is an interventional, open-label, multicenter, prospective clinical study with matched historical controls comparing the standard DS-TB treatment (isoniazid, pyrazinamide, and ethambutol) with rifampicin at 35 mg/kg (HR35ZE group) vs. rifampicin at 10 mg/kg (historical HR10ZE group). The primary outcome is the incidence of grade ≥ 3 Adverse Events or Severe Adverse Events. A total of 134 participants will be prospectively included, and compared with historical matched controls with at least a 1:1 proportion. This will provide a power of 80% to detect non-inferiority with a margin of 8%. This study will provide important information for subgroups of patients that are more vulnerable to TB bad outcomes and/or treatment toxicity. Despite limitations such as non-randomized design and the use of historical controls, the results of this trial may inform the design of future more inclusive clinical trials, and improve the management of tuberculosis in subgroups of patients for whom scientific evidence is still scarce. Trial registration: EudraCT 2020-003146-36, NCT04768231.

Development and Validation of a UPLC-MS/MS Method for Therapeutic Drug Monitoring, Pharmacokinetic and Stability Studies of First-Line Antituberculosis Drugs in Urine

“…Up to now, no LC-MS/MS method has been reported for simultaneous analysis of RIF-Q, 3-F-RIF, or PZA in urine. Our method enabled an excellent chromatographic separation of RIF from its degradation products ( Figure 1 ), which may be particularly important given the numerous clinical trials underway for higher-dose rifamycins in different forms of TB disease [ 42 , 43 , 44 ]. The method accurately quantified all the analytes, including RIF-Q, which other authors observed in clinical samples in plasma [ 45 , 46 ].…”

Dried Blood Spot Sampling to Assess Rifampicin Exposure and Treatment Outcomes among Native and Non-Native Tuberculosis Patients in Paraguay: An Exploratory Study

“…Currently, our group, the EUSAT-RCS consortium (https://www.eusattb.net/), is preparing a multinational, multicenter phase IIb clinical trial evaluating the safety and efficacy of high-dose rifampicin (35 mg/kg) in adult subjects with pulmonary or extrapulmonary DS-TB belonging to difficult to treat subgroups (such as patients older than 60 years and/or with significant comorbidities with active tuberculosis) [28]. The results from this scheduled phase II trial will generate solid evidence on if the optimized dose will be feasible in the clinical practice for the whole population.…”