Phase II Randomized Study on Pharmacokinetics and Safety of High-Dose Rifampicin and Pyrazinamide in Shortened Treatment of Drug-Sensitive Pulmonary Tuberculosis

The primary objective of this study is to evaluate strategies for reducing the duration of treatment for **tuberculosis** by examining the pharmacokinetics and safety of higher doses of **rifampicin** and **pyrazinamide** in a shortened treatment regimen for patients with mild-to-moderate, drug-sensitive pulmonary tuberculosis. This is clinically relevant as it aims to improve patient compliance and outcomes by potentially decreasing the treatment period, which is traditionally lengthy and can lead to issues with adherence and resistance.

The clinical trial focuses on a population diagnosed with **tuberculosis**, specifically targeting individuals with confirmed active pulmonary tuberculosis. The study includes both male and female participants, with an age range encompassing adults and adolescents. The trial does not involve a vulnerable population. Participants were selected based on their confirmed diagnosis through positive culture or PCR test for M. tuberculosis-complex and have not yet commenced first-line TB treatment. The sponsor has not provided information regarding the total number of participants. The study aims to explore strategies for reducing the length of TB treatment by examining a shorter regimen with higher doses of RIF and PZA for those with drug-sensitive pulmonary TB. Participants have provided written consent to partake in the study. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, prospective phase II study to evaluate the pharmacokinetics and safety of higher doses of **rifampicin** and **pyrazinamide** in the treatment of mild-to-moderate **tuberculosis**. The trial aims to assess whether a shortened treatment regimen can be effective compared to the standard of care. The study will involve participants with confirmed active pulmonary tuberculosis, who have not yet started treatment and have provided written consent. The trial will be conducted over an estimated period ending on December 31, 2028, with recruitment having commenced on November 23, 2020.

Participants will be randomly assigned to receive either the investigational regimen or the standard treatment. The trial is **double-blind** and controlled to ensure unbiased results. The primary endpoint is the area under the concentration-time curve (AUC0-24h) for high-dose rifampicin in combination with high-dose pyrazinamide, measured on day 1 after the first dose and at week 2. The maximum treatment period for participants is four weeks, with the medications administered orally.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy. The end-of-study visit will conclude the participant's involvement, which is expected to last up to four weeks. Conditions that may lead to early termination from the study include adverse reactions to the medication, withdrawal of consent, or any other medical reasons deemed necessary by the investigator.

The clinical trial involves the administration of **pyrazinamide**, an antibiotic used in the treatment of tuberculosis. Pyrazinamide is provided in an oral pharmaceutical form, designated as PHF00245MIG. The maximum daily dose of pyrazinamide is 3750 mg, with a total maximum dose of 450,000 mg over the treatment period. The treatment duration is set for a maximum of 4 months. The administration route is oral, and the medication is not formulated for pediatric use. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

Another experimental medication used in the trial is **rifampicin**, also an antibiotic for tuberculosis treatment. Rifampicin is administered orally in the pharmaceutical form PHF00170MIG. The maximum daily dose for rifampicin is 3300 mg, with a total maximum dose of 396,000 mg over the treatment period, which is also set for a maximum of 4 months. The oral route is employed for administration, and similar to pyrazinamide, rifampicin is not formulated for pediatric use. Participant compliance is closely monitored to maintain the integrity of the study results.

Both pyrazinamide and rifampicin are chemically derived substances and are utilized in this study to explore the pharmacokinetics and safety of higher doses in a shortened treatment regimen for mild-to-moderate tuberculosis. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy and safety of the higher doses of these antibiotics in reducing the length of tuberculosis treatment.

Efficacy in this clinical trial will be assessed primarily through the measurement of the **area under the concentration and time curve (AUC0-24h)** for high-dose **Rifampicin (RIF)** in combination with high-dose **Pyrazinamide (PZA)**. This primary endpoint will be evaluated on day 1 after the first dose and at week 2. The trial aims to investigate the pharmacokinetics and safety aspects of higher doses of these antibiotics in a shortened treatment regimen for mild-to-moderate tuberculosis, compared to the standard of care. The study will focus on patients with confirmed active pulmonary tuberculosis who have not yet started treatment. The efficacy parameters will be collected and analyzed at specified time points to determine the potential for reducing the length of tuberculosis treatment through the use of higher doses of RIF and PZA.