TBTC Study 31: Rifapentine-containing Tuberculosis Treatment Shortening Regimens (S31/A5349)
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| ClinicalTrials.gov Identifier: NCT02410772 |
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Recruitment Status :
Completed
First Posted : April 8, 2015
Results First Posted : September 28, 2021
Last Update Posted : September 28, 2021
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The purpose of this study is to determine whether one or two four-month regimens of tuberculosis treatment are as effective as a standard six-month regimen for treatment of pulmonary tuberculosis (TB). All three regimens are administered daily, seven days each week, with direct observation of each dose by a health-care worker at least five of the seven days of each week.
The standard six-month regimen is two months of isoniazid, rifampin, ethambutol, and pyrazinamide followed by four months of isoniazid and rifampin.
The first short regimen is a single substitution of rifapentine for rifampin: two months of isoniazid, rifapentine, ethambutol, and pyrazinamide, followed by two months of isoniazid and rifapentine.
The second short regimen is a double substitution of rifapentine for rifampin and moxifloxacin for ethambutol: two months of isoniazid, rifapentine, moxifloxacin, and pyrazinamide, followed by two months of isoniazid, rifapentine, and moxifloxacin.
Target enrollment is 2500 participants. Each study participant will remain in the study for 18 months in order to include at least 12 months of evaluation of whether the participant's TB recurs.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Tuberculosis | Drug: rifapentine Drug: rifapentine and moxifloxacin Drug: control | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 2516 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Rifapentine-containing Treatment Shortening Regimens for Pulmonary Tuberculosis: A Randomized, Open-label, Controlled Phase 3 Clinical Trial. TBTC Study 31, ACTG Study A5349 |
| Actual Study Start Date : | January 25, 2016 |
| Actual Primary Completion Date : | July 2020 |
| Actual Study Completion Date : | May 2021 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Regimen 1
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: control
standard six-month treatment |
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Experimental: Regimen 2
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
Regimen 2: Rifapentine is substituted for rifampin as the basis of 4-month treatment
Other Name: Priftin |
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Experimental: Regimen 3
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 and moxifloxacin
Regimen 3: In addition to the single substitution described for regimen 2, a second substitution is added, of moxifloxacin for ethambutol.
Other Name: Priftin and Avelox |
- TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) [ Time Frame: Twelve months after treatment assignment ]To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis A primary outcome status of "favorable", "unfavorable", or "not assessable" was assigned. For detailed definitions of outcomes please refer to: Dorman SE, at al. N Engl J Med. 2021 May 6;384(18):1705-1718.
- TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) [ Time Frame: Twelve months after treatment assignment ]
- To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis
- To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis A primary outcome status of "favorable", "unfavorable", or "not assessable" was assigned. For detailed definitions of outcomes please refer to: Dorman SE, at al. N Engl J Med. 2021 May 6;384(18):1705-1718.
- Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) [ Time Frame: Four months and up to 14 days after last does of after study treatment (Regimen 2 and 3) or Six months and up to 14 days after last does of after study treatment (Regimen 1) ]
- To evaluate the Safety of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis
- To evaluate the Safety of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis Grade 3 or higher Adverse Events are collected by Clinical sites in systematic way through the laboratory tests and physical exam during regular study follow up visits and also in a non-systematic way when it was self-reported by participants during the study visits. The events are graded by site investigators per Common Terminology Criteria for Adverse Events (CTCAE V4.03
- TB Disease-free Survival at Eighteen Months After Study Treatment Assignment [ Time Frame: eighteen months after treatment assignment ]
- Proportion of Participants Who Are Culture Negative at Eight Weeks [ Time Frame: eight weeks ]solid and liquid media considered separately
- Time to Stable Sputum Culture Conversion [ Time Frame: four or six months ]solid and liquid media considered separately
- Speed of Decline of Sputum Viable Bacilli by Automated MGIT Days to Detection [ Time Frame: four or six months ]
- TB Disease-free Survival at Twelve and Eighteen Months After Study Treatment Assignment Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome [ Time Frame: eighteen months after study treatment assignment ]Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have an unfavorable outcome
- TB Disease-free Survival at Twelve and Eighteen Months After Study Treatment Assignment Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome [ Time Frame: eighteen months after study treatment assignment ]Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have a favorable outcome
- Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility [ Time Frame: four or six months ]
- Efavirenz Maximum Concentration, Area Under the Time-concentration Curve, and Half Life [ Time Frame: four months ]Among participants with HIV infection receiving efavirenz-based antiretroviral therapy, these values will be used to estimate steady state efavirenz PK parameters including mid-dosing interval concentration
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 12 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Suspected pulmonary tuberculosis plus one or both of the following: a) at least one sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing, with semiquantitative result of 'medium' or 'high' and rifamycin resistance not detected.
- Age twelve (12) years or older
- A verifiable address or residence location that is readily accessible for visiting, and willingness to inform the study team of any change of address during the treatment and follow-up period.
- Women of child-bearing potential who are not surgically sterilized must agree to practice a barrier method of contraception or abstain from heterosexual intercourse during study drug treatment.
- Documentation of HIV infection status.
- For HIV-positive individuals, CD4 T cell count greater than or equal to 100 cells/mm3 based on testing performed at or within 30 days prior to screening.
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Laboratory parameters done at or within 14 days prior to screening:
- Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal
- Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of normal
- Serum or plasma creatinine level less than or equal to 2 times the upper limit of normal
- Serum or plasma potassium level greater than or equal to 3.5 meq/L
- Hemoglobin level of 7.0 g/dL or greater
- Platelet count of 100,000/mm3 or greater
- For women of childbearing potential, a negative pregnancy test at or within seven (7) days prior to screening
- Karnofsky score greater than or equal to 60
- Written informed consent
Exclusion Criteria:
- Pregnant or breast-feeding.
- Unable to take oral medications.
- Previously enrolled in this study.
- Received any investigational drug in the past 3 months.
- More than five (5) days of treatment directed against active tuberculosis within 6 months preceding initiation of study drugs.
- More than five (5) days of systemic treatment with any one or more of the following drugs within 30 days preceding initiation of study drugs: isoniazid, rifampin, rifabutin, rifapentine, ethambutol, pyrazinamide, kanamycin, amikacin, streptomycin, capreomycin, moxifloxacin, levofloxacin, gatifloxacin, ofloxacin, ciprofloxacin, other fluoroquinolones, ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, linezolid, clofazimine, delamanid or bedaquiline.
- Known history of prolonged QT syndrome.
- Suspected or documented tuberculosis involving the central nervous system and/or bones and/or joints, and/or miliary tuberculosis and/or pericardial tuberculosis.
- Current or planned use within six months following enrollment of one or more of the following medications: HIV protease inhibitors, HIV integrase inhibitors, HIV entry and fusion inhibitors, HIV non-nucleoside reverse transcriptase inhibitors other than efavirenz, quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine. Individuals who are currently taking efavirenz-based antiretroviral treatment or for whom initiation of efavirenz-based antiretroviral treatment is planned within 17 weeks following enrollment may participate.
- Weight less than 40.0 kg.
- Known allergy or intolerance to any of the study medications.
- Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any one or more of the following: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones.
- Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest.
- Current or planned incarceration or other involuntary detention.
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): NCT02410772
Show 33 study locations
| Study Chair: | Susan Dorman, MD | Medical University of South Carolina | |
| Study Chair: | Payam Nahid, MD, MPH | University of California at San Francisco | |
| Study Chair: | Susan Swindells, MBBS | University of Nebraska | |
| Study Chair: | Richard Chaisson, MD | Johns Hopkins University | |
| Study Chair: | Ekaterina V Kurbatova, MD, PhD, MPH | Centers for Disease Control and Prevention |
Documents provided by Centers for Disease Control and Prevention:
| Responsible Party: | Centers for Disease Control and Prevention |
| ClinicalTrials.gov Identifier: | NCT02410772 |
| Other Study ID Numbers: |
6655 |
| First Posted: | April 8, 2015 Key Record Dates |
| Results First Posted: | September 28, 2021 |
| Last Update Posted: | September 28, 2021 |
| Last Verified: | July 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Data being collected in CDISC format. |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Moxifloxacin Rifapentine Rifampin Anti-Bacterial Agents Anti-Infective Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors |
Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antibiotics, Antitubercular Antitubercular Agents Leprostatic Agents Nucleic Acid Synthesis Inhibitors Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C9 Inducers Cytochrome P-450 CYP3A Inducers |