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Pharmacokinetic and Pharmacodynamic Study of High-Dose Rifapentine and Moxifloxacin for Treatment of Tuberculosis (S31PK/PD)

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ClinicalTrials.gov Identifier: NCT02563327
Recruitment Status : Recruiting
First Posted : September 30, 2015
Last Update Posted : March 1, 2017
Sponsor:
Collaborator:
AIDS Clinical Trials Group
Information provided by (Responsible Party):
Centers for Disease Control and Prevention

Brief 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.


Condition or disease Intervention/treatment Phase
Tuberculosis Drug: Rifapentine Drug: Moxifloxacin Drug: Rifampin Drug: Isoniazid Drug: Pyrazinamide Drug: Ethambutol Dietary Supplement: Pyridoxine Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: TBTC Study 31 PK/PD: Population Pharmacokinetic and Pharmacodynamic Study of Efficacy and Safety of High-Dose Rifapentine and Moxifloxacin for Treatment of Tuberculosis in the Study 31 Treatment Trial: Intensive PK Sampling
Actual Study Start Date : May 30, 2016
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Active Comparator: Standard Therapy

Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by Eighteen weeks of daily treatment with rifampin and isoniazid. All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose.

Study drug doses: rifampin, 600 mg; isoniazid, 300 mg; pyrazinamide, < 55kg 1000 mg, >= 55-75 kg 1500 mg, >75 kg 2000 mg; ethambutol, < 55kg 800 mg, >= 55-75 kg 1200 mg, >75 kg 1600 mg.

Drug: Rifampin
A rifamycin with activity against Mycobacterium tuberculosis

Drug: Isoniazid
An anti-tuberculosis agent

Drug: Pyrazinamide
An anti-tuberculosis agent

Drug: Ethambutol
An anti-tuberculosis agent

Dietary Supplement: Pyridoxine
An essential vitamin
Other Name: Vitamin B6

Experimental: Rifapentine-containing Regimen

Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by Nine weeks of daily treatment with rifapentine and isoniazid. All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose.

Study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, < 55kg 1000 mg, >= 55-75 kg 1500 mg, >75 kg 2000 mg; ethambutol, < 55kg 800 mg, >= 55-75 kg 1200 mg, >75 kg 1600 mg.

Drug: Rifapentine
A rifamycin with activity against Mycobacterium tuberculosis
Other Name: Priftin

Drug: Isoniazid
An anti-tuberculosis agent

Drug: Pyrazinamide
An anti-tuberculosis agent

Drug: Ethambutol
An anti-tuberculosis agent

Dietary Supplement: Pyridoxine
An essential vitamin
Other Name: Vitamin B6

Experimental: Rifapentine- and Moxifloxacin-containing Regimen

Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin. All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose.

Study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, < 55kg 1000 mg, >= 55-75 kg 1500 mg, >75 kg 2000 mg; moxifloxacin, 400 mg.

Drug: Rifapentine
A rifamycin with activity against Mycobacterium tuberculosis
Other Name: Priftin

Drug: Moxifloxacin
A fluoroquinolone

Drug: Isoniazid
An anti-tuberculosis agent

Drug: Pyrazinamide
An anti-tuberculosis agent

Dietary Supplement: Pyridoxine
An essential vitamin
Other Name: Vitamin B6




Primary Outcome Measures :
  1. TB disease-free survival at twelve months after study treatment assignment [ Time Frame: Twelve months after treatment assignment ]
  2. Proportion of participants with grade 3 or higher adverse events during study drug treatment [ Time Frame: Four or six months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02563327


Contacts
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Contact: Deron C. Burton, MD, JD, MPH 404-639-1506 akq7@cdc.gov
Contact: Stefan Goldberg, MD 404-639-5339 ssg3@cdc.gov

Locations
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Uganda
Mulago Hospital Recruiting
Kampala, Uganda
Contact: Principal Investigator       jlj@case.edu   
Sponsors and Collaborators
Centers for Disease Control and Prevention
AIDS Clinical Trials Group
Investigators
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Study Chair: Marc Weiner, MD Audie L. Murphy VA Hospital, San Antonio, TX
Study Chair: Rada Savic, PhD University of San Francisco School of Pharmacy, San Francisco, CA

Publications:

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Responsible Party: Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier: NCT02563327     History of Changes
Other Study ID Numbers: CDC-NCHHSTP-6719
First Posted: September 30, 2015    Key Record Dates
Last Update Posted: March 1, 2017
Last Verified: February 2017

Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Vitamins
Vitamin B 6
Pyridoxal
Pyridoxine
Moxifloxacin
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Rifapentine
Norgestimate, ethinyl estradiol drug combination
Vitamin B Complex
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral