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:
Participant gender:
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
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