Study of Daily Rifapentine for Pulmonary Tuberculosis

• ClinicalTrials.gov Identifier: NCT00814671
• Recruitment Status: Completed
• First Posted: December 25, 2008
• Results First Posted: September 28, 2016
• Last Update Posted: February 6, 2018
• Sponsor: Johns Hopkins University
• Collaborators: University of Cape Town Lung Institute; University of Cape Town
• Information provided by (Responsible Party): Johns Hopkins University

Tracking Information

• First Submitted Date: December 24, 2008
• First Posted Date: December 25, 2008
• Results First Submitted Date: August 3, 2016
• Results First Posted Date: September 28, 2016
• Last Update Posted Date: February 6, 2018
• Study Start Date: April 2010
• Actual Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 8, 2018)

• Percentage of Participants With Negative Lowenstein Jensen Cultures at Week 8 [ Time Frame: 8 weeks ]
• Tolerability [ Time Frame: 10 weeks ]
  percentage of participants discontinuing assigned treatment

Original Primary Outcome Measures (submitted: December 24, 2008)

• To Estimate the Microbiological Activity of Rifapentine Administered at Once Daily Doses of 450 mg and 600 mg Based on Proportion of Participants With Culture Conversion [ Time Frame: 8 weeks ]
• To Estimate the Frequency of Side Effects of Rifapentine Administered at Once Daily Doses of 450 mg and 600 mg in the Context of Multidrug Intensive Phase TB Treatment [ Time Frame: 10 weeks ]

Current Secondary Outcome Measures (submitted: January 8, 2018)

• Time to Stable Culture Conversion on Solid Medium [ Time Frame: 12 weeks ]
  Time to stable culture conversion (in days) on Lowenstein Jensen solid medium
• Time to Stable Culture Conversion on Liquid MGIT Media [ Time Frame: 12 weeks ]
  Time (in days) to stable culture conversion on liquid MGIT media
• Pharmacokinetics of Rifapentine [ Time Frame: 8 weeks ]
  area under the concentration time curve (AUC[0-24]) for rifapentine administered once daily at doses of 450 mg or 600 mg in the context of multi drug intensive phase TB treatment

Original Secondary Outcome Measures (submitted: December 24, 2008)

• To Evaluate the Microbiological Activity of Rifapentine Administered at Once Daily Doses of 450 mg and 600 mg in the Context of Multidrug Intensive Phase TB Treatment, Based on Time to Sputum Culture Conversion [ Time Frame: 8 weeks ]
• To Evaluate the Microbiological Activity of Rifapentine Administered at Once Daily Doses of 450 mg and 600 mg in the Context of Multidrug Intensive Phase TB Treatment, Based on Time to Culture Growth in MGIT Liquid Media [ Time Frame: 8 weeks ]
• To Describe the Pharmacokinetics of Rifapentine Administered at Once Daily Doses of 450 mg and 600 mg in the Context of Multidrug Intensive Phase TB Treatment [ Time Frame: 4 weeks ]
• To Determine if Rifapentine Exposures Are Associated With Microbiological Activity [ Time Frame: 8 weeks ]
• To Determine if Rifapentine Exposures Are Associated With Safety [ Time Frame: 10 weeks ]
• To Compare Lowenstein Jensen and Bactec MGIT Media With Respect to Proportion of Participants With 8-week Culture Conversion and Time to Culture Conversion [ Time Frame: 8 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Daily Rifapentine for Pulmonary Tuberculosis
• Official Title: A Phase 2 Randomized, Open-label Trial of Daily Rifapentine 450mg or 600mg in Place of Rifampicin 600mg for Intensive Phase Treatment of Smear-positive Pulmonary Tuberculosis

Brief Summary

The goal of this Phase 2 study is to determine the microbiological activity and safety of rifapentine when given as a component of multidrug intensive phase treatment of smear-positive pulmonary tuberculosis (TB).

Funding Source- FDA Office of Orphan Products Development (OOPD)

Detailed Description

Prospective phase II, open-label, single center study in which each experimental rifapentine regimen is evaluated using a two-stage design. Adults (HIV-negative, or HIV-positive with CD4 > 200 cells/cu mm) suspected to have pulmonary tuberculosis who meet eligibility criteria will be randomized to receive one of three intensive phase regimens. Intensive phase regimens will consist of once daily isoniazid, pyrazinamide, and ethambutol, plus one of the following: rifampin 600 mg once daily OR rifapentine 450 mg once daily OR rifapentine 600 mg once daily. Randomization will be stratified by presence/absence of cavitation on baseline chest radiograph. In Stage 1, 15 subjects will be randomized to each arm, following which there will be an enrollment pause for efficacy and safety assessment. Any rifapentine regimen for which fewer than 6 of 11 evaluable participants have week 8 culture conversion will be discarded.

Stage 2 will randomize subjects into the remaining "accepted arms" with a maximum of 36 additional subjects per arm.

All subjects will continue TB treatment with a conventional continuation phase treatment.

Study Site

Study subjects will be recruited from the University of Cape Town inpatient wards and outpatient clinics.

Estimated Study Duration

It is estimated that 18 months will be required for recruitment and enrollment of study subjects. The estimated duration of participation for each study subject is 18 months, including 2 months of experimental intensive phase TB treatment, 4 months of non-experimental conventional continuation phase TB treatment, and an additional 12 months for follow-up for TB relapse.

Study Management

Study subjects will have study visits on days 0, 7, 14, 21, 28, 35, 42, 49, and 56 for sputum collection and adverse event assessment. Safety laboratory monitoring will be performed on days 14, 28, 42, and 56 and will consist of complete blood count, serum alanine aminotransferase, serum total bilirubin, and serum creatinine. Steady state pharmacokinetic analysis will be performed on approximately day 28. Subjects will have additional study visits at week 10 and at months 4, 6, 12, and 18.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Tuberculosis

Intervention

• Drug: Rifapentine 450
  rifapentine 450 mg
  Other Name: Priftin
• Drug: Rifapentine 600
  rifapentine 600 mg
  Other Name: Priftin
• Drug: Rifampin
  rifampin 600 mg
  Other Name: Rifampacin

Study Arms

• Experimental: RPT450
  Rifapentine 450mg daily
  Intervention: Drug: Rifapentine 450
• Active Comparator: RIF 600
  Rifampin 600mg daily
  Intervention: Drug: Rifampin
• Experimental: RPT 600
  Rifapentine 600mg daily
  Intervention: Drug: Rifapentine 600

Publications *

• Rosenthal IM, Williams K, Tyagi S, Peloquin CA, Vernon AA, Bishai WR, Grosset JH, Nuermberger EL. Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. Am J Respir Crit Care Med. 2006 Jul 1;174(1):94-101. Epub 2006 Mar 30.
• Rosenthal IM, Williams K, Tyagi S, Vernon AA, Peloquin CA, Bishai WR, Grosset JH, Nuermberger EL. Weekly moxifloxacin and rifapentine is more active than the denver regimen in murine tuberculosis. Am J Respir Crit Care Med. 2005 Dec 1;172(11):1457-62. Epub 2005 Sep 1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 24, 2008): 153
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: September 2014
• Actual Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated sputum. Patients having extra-pulmonary manifestations of tuberculosis, in addition to smear-positive pulmonary disease, are eligible for enrollment.
2. No prior history of tuberculosis disease or tuberculosis treatment
3. No treatment with fluoroquinolones in the 2 months preceding initiation of study drugs.
4. Age > 18 years
5. Weight ≥ 50 kg and ≤ 80 kg
6. Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs; see Appendix)
7. Signed informed consent
8. Ability to adhere with study follow-up
9. Women with child-bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy.
10. HIV negative, or HIV-positive with CD4 > 200 cells/cu mm

11. Laboratory parameters done at, or 14 days prior to, screening (with results available for review by study personnel):

    • Serum alanine aminotransferase (ALT) activity ≤ 2 times the upper limit of normal
    • Serum total bilirubin level ≤ 2 times the upper limit of normal
    • Serum creatinine level less than or equal to the upper limit of normal
    • Hemoglobin level of at least 7.0 g/dL
    • Platelet count of at least 100,000/mm3
    • Negative pregnancy test (women of childbearing potential)

Exclusion Criteria:

1. Pregnant or breast-feeding
2. Known intolerance or allergy to any of the study drugs
3. Concomitant disorders or conditions for which isoniazid (INH), rifamycins, pyrazinamide (PZA), or ethambutol (EMB) are contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
4. Current or planned therapy, during the intensive phase of TB therapy with cyclosporine or tacrolimus, or HIV antiretroviral (ARV) therapy, which have unacceptable interactions with rifamycins.
5. Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable.
6. Pulmonary silicosis
7. Central nervous system TB

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: South Africa

Administrative Information

• NCT Number: NCT00814671
• Other Study ID Numbers: NA_00019095
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Johns Hopkins University
• Study Sponsor: Johns Hopkins University

Collaborators

• University of Cape Town Lung Institute
• University of Cape Town

Investigators

• Principal Investigator: Susan Dorman, MD; Johns Hopkins University

• PRS Account: Johns Hopkins University
• Verification Date: January 2018