Clinical trial NCT02410772: TBTC Study 31: Rifapentine-containing Tuberculosis Treatment Shortening Regimens
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
First posted: 2015-04-08
Enrollment: 2516
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Twelve months after treatment assignment
measure: 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)
timeFrame: Twelve months after treatment assignment
measure: 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)
timeFrame: 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 outcomes:
measure: Proportion of Participants Who Are Culture Negative at Eight Weeks
timeFrame: eight weeks
measure: Time to Stable Sputum Culture Conversion
timeFrame: four or six months
measure: Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility (Tolerability)
timeFrame: four or six months
measure: Estimated Steady State Efavirenz PK Parameters Including Mid-dosing Interval Concentration
timeFrame: four months
measure: TB Disease-free Survival at Eighteen Months After Study Treatment Assignment
timeFrame: Eighteen months after study treatment assignment.
measure: TB Disease-free Survival at Eighteen Months After Study Treatment Assignment
timeFrame: Eighteen months after treatment assignment
measure: Speed of Decline of Sputum Viable Bacilli by Automated Liquid MGIT Culture Days to Detection
timeFrame: 12 months
Other outcomes:
measure: Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome
timeFrame: 12 months
measure: Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome
timeFrame: 12 months
Locations:
city: San Francisco
country: United States
facility: TBTC Site 82/ ACTG Site 801 USCF AIDS CRS
state: California
city: New York
country: United States
facility: TBTC Site 24 Columbia Unversity
state: New York
city: Fort Worth
country: United States
facility: TBTC Site 20 UNTHSC (University of North Texas Health Science Center)
state: Texas
city: Houston
country: United States
facility: TBTC Site 62 Baylor College of Medicine & Affiliated Hospitals/VA
state: Texas
city: San Antonio
country: United States
facility: TBTC Site 63 San Antonio VA Medical Center (South Texas Group)
state: Texas
city: Porto Alegre
country: Brazil
facility: TBTC Site 94/ ACTG Site 12201 Hospital Nossa Senhora da Conceicao
state: RS
city: Rio de Janeiro
country: Brazil
facility: TBTC Site 91/ ACTG Site 12101 Insituto Nacional de Pesquisa Clínica Evandro Chagas
city: Hong Kong
country: China
facility: TBTC Site 36 TB and Chest Service of Hong Kong, China
city: Port au Prince
country: Haiti
facility: TBTC Site 45/ ACTG Site 30022: Les Centres Gheskio (INLR)
state: Ouest
city: Port-au-Prince
country: Haiti
facility: TBTC Site 67/ ACTG Site 31730 GHESKIO centers IMIS
state: Ouest
city: Pune
country: India
facility: TBTC Site 43/ ACTG Site 31441 BJ Medical College
state: Maharashtra
city: Chennai
country: India
facility: TBTC Site 44/ ACTG Site 11701 CART CRS, YRGCARE Medical Centre VHS
state: Tamilnadu
city: Kericho
country: Kenya
facility: TBTC Site 02/ ACTG 12501 Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
state: Kericho County
city: Kisumu
country: Kenya
facility: TBTC Site 39/ ACTG Site 31460 Kisumu CRS
state: Nyanza Province
city: Eldoret
country: Kenya
facility: TBTC Site 03/ ACTG Site 12601 Moi University Clinical Research Site
city: Blantyre
country: Malawi
facility: TBTC Site 04/ ACTG Site 30301 Blantyre CRS (or College of Medicine - Johns Hopkins Research Project, COM-JHP)
city: Lilongwe
country: Malawi
facility: TBTC Site 05/ ACTG Site 12001 UNC Project Tidziwe Centre
city: Lima
country: Peru
facility: TBTC Site 90/ ACTG Site 11301 Asociacion Civil Impacta Salud y Educacion
city: Lima
country: Peru
facility: TBTC Site 93/ ACTG Site 11302 CRS San Miguel
city: Bellville
country: South Africa
facility: TBTC Site 10/ ACTG Site 31718 TASK Applied Science
state: Cape Town
city: Mowbray
country: South Africa
facility: TBTC Site 09/ ACTG Site 31792 University of Cape Town Lung Institute (Pty) Ltd
state: Cape Town
city: Soweto
country: South Africa
facility: TBTC Site 34 Wits Health Consortium Perinatal HIV Research Unit (PHRU)
state: Gauteng
city: Soweto
country: South Africa
facility: TBTC Site 49/ ACTG Site 12301 Soweto ACTG CRS
state: Johannesburg
city: Durban
country: South Africa
facility: TBTC Site 06/ ACTG Site 11201 Durban International Clinical Research Site
state: KwaZulu Natal
city: Parow Valley
country: South Africa
facility: TBTC Site 01/ACTG Site 8950 FAM CRU
state: Western Cape
city: Cape Town
country: South Africa
facility: TBTC Site 08/ ACTG Site 31793 South African Tuberculosis Vaccine Initiative (SATVI)
state: Western Province
city: Johannesburg
country: South Africa
facility: TBTC Site 07/ ACTG Site 11101 Wits Helen Joseph CRS
city: Pathumwan
country: Thailand
facility: TBTC Site 42/ ACTG Site 31802 The Thai Red Cross AIDS Research Centre
state: Bangkok
city: Muang Chiang Mai
country: Thailand
facility: TBTC Site 69/ ACTG Site 31784 Thai-CTIU, CMU HIV Treatment CRS
state: Chiang Mai
city: Kampala
country: Uganda
facility: TBTC Site 11/ ACTG Site 12401 Joint Clinical Research Centre, Kampala Clinical Research Site
city: Kampala
country: Uganda
facility: TBTC Site 30 Uganda-Case Western Reserve Research Collaboration
city: Hanoi
country: Vietnam
facility: TBTC Site 37 Vietnam NTP/UCSF Research Collaboration
city: Harare
country: Zimbabwe
facility: TBTC Site 41/ ACTG Site 30313 Parirenyatwa Clinical Research Site
Study officials:
affiliation: Medical University of South Carolina
name: Susan Dorman, MD
role: STUDY_CHAIR
affiliation: University of California at San Francisco
name: Payam Nahid, MD, MPH
role: STUDY_CHAIR
affiliation: University of Nebraska
name: Susan Swindells, MBBS
role: STUDY_CHAIR
affiliation: Johns Hopkins University
name: Richard Chaisson, MD
role: STUDY_CHAIR
affiliation: Centers for Disease Control and Prevention
name: Ekaterina V Kurbatova, MD, PhD, MPH
role: STUDY_CHAIR
References:
citation: Podany AT, Pham M, Sizemore E, Martinson N, Samaneka W, Mohapi L, Badal-Faesen S, Dawson R, Johnson JL, Mayanja H, Lalloo U, Whitworth WC, Pettit A, Campbell K, Phillips PPJ, Bryant K, Scott N, Vernon A, Kurbatova EV, Chaisson RE, Dorman SE, Nahid P, Swindells S, Dooley KE, Fletcher CV. Efavirenz Pharmacokinetics and Human Immunodeficiency Virus Type 1 (HIV-1) Viral Suppression Among Patients Receiving Tuberculosis Treatment Containing Daily High-Dose Rifapentine. Clin Infect Dis. 2022 Sep 10;75(4):560-566. doi: 10.1093/cid/ciab1037.
citation: Dorman SE, Nahid P, Kurbatova EV, Phillips PPJ, Bryant K, Dooley KE, Engle M, Goldberg SV, Phan HTT, Hakim J, Johnson JL, Lourens M, Martinson NA, Muzanyi G, Narunsky K, Nerette S, Nguyen NV, Pham TH, Pierre S, Purfield AE, Samaneka W, Savic RM, Sanne I, Scott NA, Shenje J, Sizemore E, Vernon A, Waja Z, Weiner M, Swindells S, Chaisson RE; AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021 May 6;384(18):1705-1718. doi: 10.1056/NEJMoa2033400.
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citation: Bryant KE, Yuan Y, Engle M, Kurbatova EV, Allen-Blige C, Batra K, Brown NE, Chiu KW, Davis H, Elskamp M, Fagley M, Fedrick P, Hedges KNC, Narunsky K, Nassali J, Phan M, Phan H, Purfield AE, Ricaldi JN, Robergeau-Hunt K, Whitworth WC, Sizemore EE; AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis. Contemp Clin Trials. 2021 May;104:106355. doi: 10.1016/j.cct.2021.106355. Epub 2021 Mar 10.
citation: Dorman SE, Nahid P, Kurbatova EV, Goldberg SV, Bozeman L, Burman WJ, Chang KC, Chen M, Cotton M, Dooley KE, Engle M, Feng PJ, Fletcher CV, Ha P, Heilig CM, Johnson JL, Lessem E, Metchock B, Miro JM, Nhung NV, Pettit AC, Phillips PPJ, Podany AT, Purfield AE, Robergeau K, Samaneka W, Scott NA, Sizemore E, Vernon A, Weiner M, Swindells S, Chaisson RE; AIDS Clinical Trials Group and the Tuberculosis Trials Consortium. High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial. Contemp Clin Trials. 2020 Mar;90:105938. doi: 10.1016/j.cct.2020.105938. Epub 2020 Jan 22.