Evaluation of High-Dose Rifampicin Safety in Adult Patients with Complex Drug-Susceptible Pulmonary and Extrapulmonary Tuberculosis Using a Drug Combination

The primary objective of this study is to evaluate the **safety** of high-dose rifampicin (35 mg/kg/day) when used in conjunction with standard doses of isoniazid, pyrazinamide, and ethambutol over an 8-week period in adult subjects with pulmonary or extrapulmonary drug-susceptible tuberculosis (DS-TB) who belong to difficult-to-treat subgroups. Safety is assessed by comparing the proportion of participants experiencing severe adverse events (grade 3 or higher according to the Common Terminology Criteria for Adverse Events, CTCAE version 5) with historical controls receiving 10 mg/kg/day of rifampicin. This evaluation is clinically relevant as it aims to determine the feasibility of using higher doses of rifampicin to potentially improve treatment outcomes in challenging patient populations.

Secondary objectives include:

• Evaluating the tolerability of the high-dose rifampicin regimen based on the proportion of all adverse events (grade 1-4) and treatment dropout rates.
• Assessing the efficacy of high-dose rifampicin by measuring early sterilizing activity in the sputum of pulmonary TB subjects, with efficacy determined by culture conversion in liquid media at 8 weeks.
• Describing the bactericidal activity as the proportion of sputum smear conversion at 8 weeks.
• Describing the time dynamics of sputum smear bacterial load decline, smear, and culture conversion.
• Comparing the relapse rate 1 year after treatment completion.
• Describing the pharmacokinetics-pharmacodynamics (PK/PD) of rifampicin at high doses in difficult-to-treat TB.
• Describing the association between genetic polymorphisms and differences in the area under the curve (AUC) of rifampicin.
• Analyzing the correlation between rifampicin’s AUC/minimum inhibitory concentration (MIC) values and efficacy outcomes.
• Evaluating the response to treatment as measured by exhaled volatile organic compounds (VOCs).
• Describing tuberculosis-associated costs and the quality of life of DS-TB participants.

The clinical trial involves a total of **85 participants** diagnosed with **tuberculosis** (TB), specifically targeting those with pulmonary or extrapulmonary drug-sensitive TB (DS-TB) who belong to difficult-to-treat subgroups. The study population includes both male and female subjects, with an age range starting from 18 years and above, with a particular focus on individuals aged 60 years or older. Participants were selected based on confirmed or probable TB diagnosis, with additional criteria including a positive smear, Xpert MTB/RIF test, or M. tuberculosis culture, among other diagnostic indicators. The trial does not specifically target a vulnerable population. Relevant lifestyle considerations include a body mass index of 18.5 or lower, HIV infection, diabetes mellitus, hepatitis C or B virus infection, daily alcohol intake of two or more units, and chronic liver disease. Female participants of childbearing age are required to have a negative pregnancy test at baseline. The selection process ensures that participants provide informed consent and meet the outlined inclusion criteria.

The clinical trial is designed to evaluate the safety of high-dose **rifampicin** (35 mg/kg/day) in combination with standard doses of isoniazid, pyrazinamide, and ethambutol over an 8-week period in adult subjects with pulmonary or extrapulmonary drug-susceptible **tuberculosis** (DS-TB). This study is a phase IV, randomized, double-blind, controlled trial. The primary objective is to assess the proportion of participants experiencing severe adverse events (SAEs) of grade 3 or higher, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 5, compared to historical controls receiving 10 mg/kg/day of rifampicin. Secondary endpoints include the efficacy of the treatment, measured by the proportion of participants with a favorable outcome at 8 weeks, time to sputum culture conversion, and changes in quality of life and tuberculosis-associated costs.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as confirmed or probable DS-TB, informed consent, and specific health conditions. Female participants of childbearing age must have a negative pregnancy test at baseline. Participants will be involved in the study for a maximum of 8 weeks, with regular follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will conclude the trial, assessing the final health status and any adverse events experienced by the participants.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is expected to end by September 2026, with recruitment having started in September 2022. The study is conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **Rifampicin 150 mg Capsules**, which are hard capsules containing the active substance **rifampicin**. This medication is administered orally. The maximum daily dose is 3150 mg, with a total maximum dose of 176400 mg over a treatment period of 8 weeks. The capsules are manufactured by GENERICS [UK] LIMITED and are not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another treatment used in the trial is **RIMSTAR®, COMPRIMIDOS RECUBIERTOS CON PELÍCULA**, which are film-coated tablets containing a combination of active substances: **isoniazid**, **pyrazinamide**, **rifampicin**, and **ethambutol hydrochloride**. These tablets are also administered orally. The maximum daily dose is 10 mg/kg, with a total maximum dose of 560 mg/kg over the same 8-week treatment period. This product is manufactured by SANDOZ GMBH and is not intended for pediatric use. Compliance with the dosing regimen will be closely monitored.

The trial also includes the use of **Rifampicin 300 mg Capsules**, which are hard capsules containing **rifampicin** as the active substance. These capsules are administered orally, with a maximum daily dose of 3150 mg and a total maximum dose of 176400 mg over the 8-week treatment period. Like the 150 mg capsules, these are produced by GENERICS [UK] LIMITED and are not designed for pediatric patients. Participant adherence to the dosing schedule will be assessed regularly.

All treatments are administered orally, and the trial aims to evaluate the safety of high-dose rifampicin in combination with standard doses of isoniazid, pyrazinamide, and ethambutol. The primary objective is to assess the safety profile based on the occurrence of severe adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 5, in comparison to historical controls receiving 10 mg/kg/day of rifampicin.

The efficacy of the clinical trial will be assessed using several key endpoints. The primary efficacy endpoint is the proportion of participants with a favorable outcome at 8 weeks of treatment. Secondary efficacy endpoints include the time to sputum culture conversion from positive to negative and the correlation of the area under the curve/minimum inhibitory concentration (AUC/MIC) values with time to sputum culture conversion, adjusted with other explanatory covariates. Additionally, changes in quality of life questionnaires and tuberculosis-associated costs from all sites will be evaluated.

Data collection for these endpoints will occur at specified timepoints, including the 8-week mark of treatment. The analysis will involve comparing the outcomes of participants receiving high-dose **rifampicin** with historical controls. The trial will utilize validated laboratory tests to measure sputum culture conversion and assess the correlation of pharmacokinetic parameters with clinical outcomes. Patient-reported outcomes will be gathered through quality of life questionnaires to provide a comprehensive evaluation of the treatment's impact on participants' well-being and associated costs.