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ACTG 5311: Phase I Clinical Trial of the Pharmacokinetics of High-dose Daily Rifapentine, Given as a Single Dose or in Divided Doses to Healthy Volunteers
Last Updated: 24-Jul-2012

Overview

PI / Study Chair
Kelly Dooley

Network / CTU /
ACTG

Current Study Status
Pending as of 02/29/2012

Anticipated Start Date


Target Accural
48


Downloads

Protocol Synopsis

Number Phase Study Type Population
A5311 Phase I RX - Treatment
 Healthy Adult

Trial Design

A5311 is a prospective, phase I, open label, randomized crossover trial in healthy volunteers to investigate the PK of RPT at a dose of 20 mg/kg given as a single daily dose or in two divided doses with either low-fat meals or a low-fat breakfast, and of RPT at a dose of 15 mg/kg in a single daily dose with either a low-fat breakfast or a single boiled egg. The focus will be on PK, safety, and tolerability. 


Safety and tolerability will be evaluated throughout the trial, and safety evaluations including targeted history and physical examination, will be conducted once weekly during the drug treatment periods of the trial and twice during the washout period. Pregnancy tests will be performed on women of childbearing potential.

At entry, the first 12 volunteers who indicate during screening that they are willing to remain on study for up to 12 weeks will be assigned to Arm 2A; all others will be randomized to Arms 1A, 1B, or 2B. See section 6.0 for dosing and sampling schedules.

All volunteers will participate in two 2-week periods of drug administration. Periods 1 and 2 will be separated by a 4-week washout period. Volunteers in Arm 2A will continue RPT dosing for an additional 2 weeks after Period 2 so that RPT concentrations after 4 weeks of daily dosing at 15 mg/kg can be evaluated.



Objectives

Primary:
  1. To compare the intra-individual AUC0-24h of RPT after multiple doses of 10 mg/kg twice daily (BID) versus after multiple doses of 20 mg/kg once daily (QD) (Group 1).

    (Section 1.2)
  2. To compare the intra-individual AUC0-24h of RPT after multiple doses of 15 mg/kg QD taken with a low-fat breakfast versus after multiple doses of 15 mg/kg QD taken with a single boiled egg (Group 2). 

    (Section 1.2)
  3. To evaluate the safety and tolerability of each dosing regimen.

    (Section 1.2)

Secondary:
  1. To compare the intra-individual pharmacokinetic (PK) parameters Cmax, Cmin, T1/2, and CL/F of RPT and its metabolite, desacetylrifapentine (desRPT), after multiple doses of 10 mg/kg BID versus after multiple doses of 20 mg/kg QD (Group 1).
  2. To compare the intra-individual PK parameters Cmax, Cmin, T1/2, and CL/F of RPT and its metabolite, desRPT, after multiple doses of 15 mg/kg QD with a low-fat breakfast versus after multiple doses of 15 mg/kg QD with a single boiled egg (Group 2).
  3. To determine the time to steady state of RPT (all arms). 
  4. To compare RPT and desRPT PK parameters AUC0-24h, Cmax, Cmin, CL/F, and T1/2 among volunteers taking 15 mg/kg of RPT daily with a low-fat meal versus 20 mg/kg of RPT daily with a low-fat meal (Group 2 vs Group 1). 
  5. To evaluate for evidence of autoinduction (or time-dependence) of pharmacokinetics of RPT by estimating the mean ratio of the intra-individual multiple-dose AUC0-tau to the single-dose AUC0-inf (AUC0-24hss/AUC0-infsd). In addition, the PK parameters CL/F and T1/2 after a single dose versus after multiple doses will be compared (both groups).
  6. To explore whether human genetic variants known to predict altered PK of rifamycin are associated with differences in RPT PK.

    (Section 1.3)


Primary Endpoints

Primary, Pharmacokinetics:
  1. RPT PK parameter AUC0-24h, on study Days 14 and 56 in Group 1, when given at a dose of 20 mg/kg once daily and when given at a dose of 10 mg/kg twice daily.

    (Section 9.2.1)
  2. RPT PK parameter AUC0-24h on study Days 14 and 56 in Group 2, when given at a dose of 15 mg/kg once daily with a boiled egg and when given at a dose of 15 mg/kg once daily with a low-fat meal.

    (Section 9.2.1)

Primary, Safety:
  1. Grade 2 or higher signs and symptoms observed while on study beginning with the first dose of study drug and continuing through the follow-up period. Laboratory results of chemistries and hematologies with toxicity grades evaluated while on study beginning with the first dose of study drug and continuing through the follow-up period.

    (Section 9.2.1)


Secondary Endpoints

  1. RPT PK parameters Cmax, Cmin, CL/F, and T1/2, and RPT metabolite desRPT PK parameters AUC0-24h, Cmax, Cmin, CL/F, and T1/2, on study Days 14 and 56 in Group 1, when RPT is given at a dose of 20 mg/kg once daily and when given at a dose of 10 mg/kg twice daily
  2. RPT PK parameters Cmax, Cmin, CL/F, and T1/2, and RPT metabolite desRPT PK parameters AUC0-24h, Cmax, Cmin, CL/F, and T1/2, on study Days 14 and 56 in Group 2 ,when RPT is given at a dose of 15 mg/kg once daily with a boiled egg and when given at a dose of 15 mg/kg once daily with a low-fat meal
  3. Cmin (trough) values on Days 1, 7, 14, 43, 49, 56, 64, and 70 among volunteers in Arm 2A and Days 1, 7, 14, 43, 49, and 56 among volunteers in Arms 1A,1B, and 2B
  4. RPT and its metabolite desRPT PK parameters AUC0-24h, Cmax, Cmin, CL/F, and T1/2 at steady state when given at a dose of 20 mg/kg once daily (Group 1) and when given at a dose of 15 mg/kg once daily (Group 2).
  5. RPT and its metabolite desRPT PK parameters AUC0-inf, CL/F, and T1/2 obtained after single dose on Days 1 and 43 and AUC0-24h, CL/F, and T1/2 obtained after multiple-dose on Days 14 and 56.
  6. Human genetic variants/polymorphisms in gene SLCO1B1 and possibly other genes that are thought to affect PK of RIF.


Links

ACTG Website Listing
WHO Clinical Trials Registry Listing
ClinicalTrials.gov Listing