TBTC Study 31: Rifapentine-containing Tuberculosis Treatment Shortening Regimens

Tuberculosis Clinical Trial

— S31/A5349  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02410772
• Other study ID #: 6655
• Status: Completed
• Phase: Phase 3
• Start date: January 25, 2016
• Est. completion date: May 2021

Study information

• Verified date: July 2021
• Source: Centers for Disease Control and Prevention
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

Title:

Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled, phase 3 clinical trial

Hypotheses:

A) Seventeen (17) week rifapentine-based regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), pyrazinamide (Z) and ethambutol (E) followed by nine weeks of rifapentine plus isoniazid, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin (R), isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.

B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine, isoniazid, pyrazinamide and moxifloxacin (M), followed by nine weeks of rifapentine, isoniazid, and moxifloxacin, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.

Phase: 3

Design: This will be an international, multicenter, randomized, controlled, open-label, 3-arm, phase 3 non-inferiority trial.

Population: Patients with newly diagnosed, previously untreated pulmonary tuberculosis.

Number of Sites: Multiple international sites, primarily sites of the Tuberculosis Trials Consortium and the AIDS Clinical Trials Group.

Study Duration: Duration per participant is approximately 18 months.

Description of Agent or Intervention: After written informed consent, participants will be randomly assigned to receive one of the following oral regimens:

Regimen 1 (control regimen): 2RHZE/4RH

• Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by

• Eighteen weeks of daily treatment with rifampin and isoniazid

Regimen 2 (investigational regimen): 2PHZE/2PH

• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by

• Nine weeks of daily treatment with rifapentine and isoniazid

Regimen 3 (investigational regimen): 2PHZM/2PHM

• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by

• Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin

Objectives:

Primary:

• 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

Secondary:

• To evaluate the safety of the investigational regimens

• To evaluate the tolerability of the investigational regimens

• To collect and store biospecimens from consenting participants for the purpose of future research on discovery and validation of TB biomarkers

• To determine the correlation of mycobacterial and clinical markers with time to culture conversion, culture status at completion of eight weeks of treatment, treatment failure, and relapse.

• To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs. The main objectives of the PK/PD study are to characterize study drug PK parameters and to determine relationships between treatment outcomes and PK parameters.

• To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with rifapentine

Endpoints:

Primary Endpoints:

• Efficacy: TB disease-free survival at twelve months after study treatment assignment.

• Safety: Proportion of participants with grade 3 or higher adverse events during study drug treatment

Secondary Endpoints:

• TB disease-free survival at eighteen months after study treatment assignment

• Time to stable sputum culture conversion (solid and liquid media considered separately)

• Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection

• Proportion of participants who are culture negative at completion of eight weeks of treatment (solid and liquid media considered separately)

• Sensitivity analyses assuming all participants classified as 'not assessable' have a favorable outcome

• Discontinuation of assigned treatment for a reason other than microbiological ineligibility

• Estimated steady state efavirenz PK parameters including mid-dosing interval concentration

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2516
• Est. completion date: May 2021
• Est. primary completion date: July 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

• 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.

Related Conditions & MeSH terms

• Tuberculosis

Intervention

Drug:
• rifapentine
Regimen 2: Rifapentine is substituted for rifampin as the basis of 4-month treatment
• rifapentine and moxifloxacin
Regimen 3: In addition to the single substitution described for regimen 2, a second substitution is added, of moxifloxacin for ethambutol.
• control
standard six-month treatment

Locations

Country	Name	City	State
Brazil	TBTC Site 94/ ACTG Site 12201 Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	TBTC Site 91/ ACTG Site 12101 Insituto Nacional de Pesquisa Clínica Evandro Chagas	Rio de Janeiro
China	TBTC Site 36 TB and Chest Service of Hong Kong, China	Hong Kong
Haiti	TBTC Site 45/ ACTG Site 30022: Les Centres Gheskio (INLR)	Port au Prince	Ouest
Haiti	TBTC Site 67/ ACTG Site 31730 GHESKIO centers IMIS	Port-au-Prince	Ouest
India	TBTC Site 44/ ACTG Site 11701 CART CRS, YRGCARE Medical Centre VHS	Chennai	Tamilnadu
India	TBTC Site 43/ ACTG Site 31441 BJ Medical College	Pune	Maharashtra
Kenya	TBTC Site 03/ ACTG Site 12601 Moi University Clinical Research Site	Eldoret
Kenya	TBTC Site 02/ ACTG 12501 Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS	Kericho	Kericho County
Kenya	TBTC Site 39/ ACTG Site 31460 Kisumu CRS	Kisumu	Nyanza Province
Malawi	TBTC Site 04/ ACTG Site 30301 Blantyre CRS (or College of Medicine - Johns Hopkins Research Project, COM-JHP)	Blantyre
Malawi	TBTC Site 05/ ACTG Site 12001 UNC Project Tidziwe Centre	Lilongwe
Peru	TBTC Site 90/ ACTG Site 11301 Asociacion Civil Impacta Salud y Educacion	Lima
Peru	TBTC Site 93/ ACTG Site 11302 CRS San Miguel	Lima
South Africa	TBTC Site 10/ ACTG Site 31718 TASK Applied Science	Bellville	Cape Town
South Africa	TBTC Site 08/ ACTG Site 31793 South African Tuberculosis Vaccine Initiative (SATVI)	Cape Town	Western Province
South Africa	TBTC Site 06/ ACTG Site 11201 Durban International Clinical Research Site	Durban	KwaZulu Natal
South Africa	TBTC Site 07/ ACTG Site 11101 Wits Helen Joseph CRS	Johannesburg
South Africa	TBTC Site 09/ ACTG Site 31792 University of Cape Town Lung Institute (Pty) Ltd	Mowbray	Cape Town
South Africa	TBTC Site 01/ACTG Site 8950 FAM CRU	Parow Valley	Western Cape
South Africa	TBTC Site 34 Wits Health Consortium Perinatal HIV Research Unit (PHRU)	Soweto	Gauteng
South Africa	TBTC Site 49/ ACTG Site 12301 Soweto ACTG CRS	Soweto	Johannesburg
Thailand	TBTC Site 69/ ACTG Site 31784 Thai-CTIU, CMU HIV Treatment CRS	Muang Chiang Mai	Chiang Mai
Thailand	TBTC Site 42/ ACTG Site 31802 The Thai Red Cross AIDS Research Centre	Pathumwan	Bangkok
Uganda	TBTC Site 11/ ACTG Site 12401 Joint Clinical Research Centre, Kampala Clinical Research Site	Kampala
Uganda	TBTC Site 30 Uganda-Case Western Reserve Research Collaboration	Kampala
United States	TBTC Site 20 UNTHSC (University of North Texas Health Science Center)	Fort Worth	Texas
United States	TBTC Site 62 Baylor College of Medicine & Affiliated Hospitals/VA	Houston	Texas
United States	TBTC Site 24 Columbia Unversity	New York	New York
United States	TBTC Site 63 San Antonio VA Medical Center (South Texas Group)	San Antonio	Texas
United States	TBTC Site 82/ ACTG Site 801 USCF AIDS CRS	San Francisco	California
Vietnam	TBTC Site 37 Vietnam NTP/UCSF Research Collaboration	Hanoi
Zimbabwe	TBTC Site 41/ ACTG Site 30313 Parirenyatwa Clinical Research Site	Harare

Sponsors (2)

Lead Sponsor	Collaborator
Centers for Disease Control and Prevention	AIDS Clinical Trials Group

Countries where clinical trial is conducted

United States,  Vietnam,  Zimbabwe,  Brazil,  China,  Haiti,  India,  Kenya,  Malawi,  Peru,  South Africa,  Thailand,  Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	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.	Twelve months after treatment assignment
Primary	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)	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.	Twelve months after treatment assignment
Primary	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)	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	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)
Secondary	TB Disease-free Survival at Eighteen Months After Study Treatment Assignment		eighteen months after treatment assignment
Secondary	Proportion of Participants Who Are Culture Negative at Eight Weeks	solid and liquid media considered separately	eight weeks
Secondary	Time to Stable Sputum Culture Conversion	solid and liquid media considered separately	four or six months
Secondary	Speed of Decline of Sputum Viable Bacilli by Automated MGIT Days to Detection		four or six months
Secondary	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	Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have an unfavorable outcome	eighteen months after study treatment assignment
Secondary	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	Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have a favorable outcome	eighteen months after study treatment assignment
Secondary	Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility		four or six months
Secondary	Efavirenz Maximum Concentration, Area Under the Time-concentration Curve, and Half Life	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	four months