Pharmacokinetic and Pharmacodynamic Study of High-Dose Rifapentine and Moxifloxacin for Treatment of Tuberculosis

• Status: Unknown status
• Trial end date: 2020-03-01
• Target enrollment: 0
• Participant gender: All

Summary

The Tuberculosis Trials Consortium (TBTC) phase 3 treatment trial, Study 31, will investigate the efficacy and safety of daily rifapentine (1200 mg daily) with or without moxifloxacin as part of multidrug treatment regimens for drug-sensitive pulmonary TB. The proposed study (Study 31 PK/PD) will examine the population pharmacokinetics and pharmacodynamics (PK/PD) of high-dose daily rifapentine with and without moxifloxacin given for 17 weeks. Two different PK sampling procedures are required for the population PK/PD assessments involving rifapentine and moxifloxacin: (1) intensive sampling of 6 samples/participant on one occasion plus subsequent sparse sampling for a subset of Study 31 participants who are invited to co-enroll in Study 31 PK/PD; and (2) sparse sampling of 2-3 samples/participant for all other Study 31 trial participants (these data will be collected as part of the Study 31 treatment protocol). Herein, we describe the PK sampling to be conducted among those Study 31 participants who are co-enrolled to Study 31 PK/PD (n=60). Intensive PK sampling is needed in some participants to estimate the population PK model parameters with no bias and satisfactory precision (relative standard error < 20%). PK and outcomes data from all participants in Study 31 will be merged to build the population PK/PD models to evaluate PK/PD parameters. Details regarding these planned analyses are also provided in this Study 31 PK/PD protocol.

Primary Objectives:

1. Characterize the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine, using sparse PK data from Study 31 and intensive PK data from Study 31 PK/PD. Using the population PK model, determine post-hoc Bayesian estimates of individual-level PK parameters.

2. Examine the relationship between rifapentine PK parameters of interest and treatment efficacy. PK parameters will include area under the concentration time curve (AUC0-24), peak concentration (Cmax), time above the mean inhibitory concentration (MIC), and AUC/MIC. The treatment outcome of interest will be time to culture conversion and time to treatment failure or relapse.

Secondary Objectives:

3. Among the Study 31 participants in the lowest 10% for rifapentine AUC0-24, examine the PK/PD effect on culture conversion of sputa after completion of 4 months of daily rifapentine therapy.

4. Examine the relationship between safety outcomes (Grade 3 or higher adverse events) and rifapentine PK parameters (AUC0-24, Cmax, AUC0-24/MIC and time above MIC).

5. Characterize the population PK of moxifloxacin, and then estimate moxifloxacin AUC0-24 and Cmax when moxifloxacin is administered with rifapentine given at a daily dose of 1200 mg.

6. Examine the relationships between moxifloxacin PK and treatment outcomes (as described in objective 2 for rifapentine) and moxifloxacin PK and safety (as described in objective 4 for rifapentine).

Design:

In Study 31 PK/PD, among 60 participants with tuberculosis enrolled in a rifapentine-based treatment arm of Study 31, PK data will be collected on two occasions. At TBTC sites that have the capacity to perform this activity, participants will have 6 scheduled PK samples per participant collected to measure rifapentine (with or without moxifloxacin) concentrations over approximately 24 hours. In addition among these 60 participants, 2 to 3 scheduled PK samples will be obtained on a second "late" sampling at > 14 days after the first PK sampling.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centers for Disease Control and Prevention
• Collaborator: AIDS Clinical Trials Group
• Treatments: Ethambutol; Fluoroquinolones; Isoniazid; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination; Pyrazinamide; Pyridoxal; Pyridoxine; Rifampin; Rifapentine; Vitamin B 6; Vitamin B Complex; Vitamins

Criteria

Inclusion Criteria:

• Age 18 years or greater

• Enrolled in TBTC Study 31

• Randomized to receive one of the rifapentine treatment regimens.

• Willingness to be sampled 6 times during 1 PK sampling session and 2 - 3 times during another PK sampling session at an outpatient clinic, a clinical research center, or a hospital.

• Written informed consent given for the Study 31 PK/PD study

Exclusion Criteria:

• Hematocrit < 25% most recent value, measured within 30 days before PK/PD study enrollment