Tuberculosis
Conditions
Keywords
Pharmacokinetics
Brief summary
The Tuberculosis Trials Consortium (TBTC) Study 31 is a phase 3 trial evaluating rifapentine-containing regimens for treatment-shortening of drug-susceptible pulmonary tuberculosis. This pharmacokinetic/pharmacodynamic (PK/PD) substudy evaluates rifapentine and moxifloxacin exposure-response relationships for efficacy and safety outcomes. Intensive and sparse PK sampling are performed among participants receiving rifapentine-containing regimens. PK and clinical outcomes data are used to characterize population pharmacokinetics and assess relationships between drug exposure, culture conversion, treatment failure or relapse, and adverse events.
Detailed description
This pharmacokinetic/pharmacodynamic (PK/PD) substudy is conducted within TBTC Study 31, a phase 3 randomized trial evaluating rifapentine-containing regimens for treatment-shortening of drug-susceptible pulmonary tuberculosis. The substudy evaluates population pharmacokinetics and exposure-response relationships for rifapentine and moxifloxacin administered in rifapentine-containing multidrug regimens. Rifapentine is administered at a daily dose of 1200 mg with food, with or without moxifloxacin. Participants undergo intensive and sparse pharmacokinetic sampling between Weeks 2 and 8 of treatment. Intensive PK sampling includes serial plasma collections over approximately 24 hours in a subset of participants, with additional later sampling performed after at least 14 days. Sparse PK sampling is performed in the remaining Study 31 participants. Population PK models are developed using nonlinear mixed-effects methods to estimate individual exposure parameters including area under the concentration-time curve (AUC0-24) and maximum concentration (Cmax). PK/PD analyses evaluate relationships between drug exposure and efficacy outcomes, including culture conversion and treatment failure or relapse, as well as safety outcomes including grade 3 or higher adverse events. The study also evaluates the effect of covariates including demographic and clinical factors on rifapentine and moxifloxacin pharmacokinetics.
Interventions
DRUGRifapentine
A rifamycin with activity against Mycobacterium tuberculosis
DRUGMoxifloxacin
A fluoroquinolone
DRUGRifampin
A rifamycin with activity against Mycobacterium tuberculosis
DRUGIsoniazid
An anti-tuberculosis agent
DRUGPyrazinamide
An anti-tuberculosis agent
DRUGEthambutol
An anti-tuberculosis agent
DIETARY_SUPPLEMENTPyridoxine
An essential vitamin
Sponsors
Centers for Disease Control and Prevention
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rifapentine Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) | Plasma concentrations measured at approximately 0.5, 3, 5, 9, 12, and 24 hours after the pharmacokinetic reference dose during Weeks 2-8 after treatment initiation. | To characterize rifapentine exposure (AUC0-24) using population pharmacokinetics. |
| Rifapentine Maximum Plasma Concentration (Cmax) | Plasma concentrations measured during 0-24 hours following the pharmacokinetic reference dose; PK sampling performed during Weeks 2-8 after treatment initiation. | To characterize rifapentine peak concentration using population pharmacokinetic modeling. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With TB-Related Unfavorable Outcomes in the Rifapentine-Moxifloxacin Regimen | Efficacy assessed through 12 months after treatment initiation; pharmacokinetics assessed during Weeks 2-8. | Number of microbiologically eligible participants with TB-related unfavorable outcomes in the rifapentine-moxifloxacin regimen through 12 months after treatment initiation. Associations with rifapentine and moxifloxacin exposures are reported in separate Statistical Analyses. |
| Number of Participants With Grade 3 or Higher Adverse Events | Pharmacokinetics assessed Weeks 2-8; Safety assessed from randomization through treatment period, up to 14 days after last dose. | Number of participants with grade 3 or higher adverse events during the treatment period in each rifapentine-containing treatment arm. Associations with rifapentine and moxifloxacin exposures are reported in separate Statistical Analyses. |
| Moxifloxacin Area Under the Concentration-Time Curve at Steady State | Weeks 2 through 8 after treatment initiation. | To characterize moxifloxacin pharmacokinetics when moxifloxacin was administered 400 mg daily with rifapentine 1200 mg daily. |
| Number of Participants With Grade 3 or Higher Adverse Events in the Rifapentine-Moxifloxacin Regimen | Pharmacokinetics assessed Weeks 2-8; Safety assessed from randomization through treatment period, up to 14 days after last dose. | Number of participants with grade 3 or higher adverse events in the rifapentine-moxifloxacin regimen during the treatment period. The association between moxifloxacin exposure and safety outcomes was evaluated using multivariable logistic regression and is reported in the Statistical Analysis section. |
Countries
Uganda, United States, Vietnam
Contacts
STUDY_CHAIRRada Savic, PhD
University of San Francisco School of Pharmacy, San Francisco, CA
Participant flow
Recruitment details
Participants were enrolled at 34 clinical research sites in 13 countries between January 2016 and October 2018. First participant was enrolled on 25 January 2016. Last participant was enrolled on 30 October 2018
Pre-assignment details
Of 5124 patients screened, 2516 underwent randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 63 Participants |
| Age, Categorical >=65 years | 27 Participants |
| Age, Categorical Between 18 and 65 years | 2253 Participants |
| Age, Continuous | 31 years |
| Cavitation status at baseline Cavitation on chest radiograph | 1703 Participants |
| Cavitation status at baseline No cavitation on chest radiograph | 204 Participants |
| Cavitation status at baseline Unknown | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 74 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 867 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 454 Participants |
| HIV status at baseline HIV Negative | 716 Participants |
| HIV status at baseline HIV Positive | 62 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 86 Participants |
| Race (NIH/OMB) Black or African American | 1676 Participants |
| Race (NIH/OMB) More than one race | 357 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Region of Enrollment Africa | 1716 participants |
| Region of Enrollment East Asia | 86 participants |
| Region of Enrollment South America | 339 participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 673 Participants |
| Sex: Female, Male Male | 544 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 825 | 4 / 835 | 3 / 846 |
| other Total, other adverse events | 74 / 825 | 61 / 835 | 94 / 846 |
| serious Total, serious adverse events | 56 / 825 | 39 / 835 | 37 / 846 |
Outcome results
None listed