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MainTitle

Evaluating the Safety and Effectiveness of Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Individuals With Latent Tuberculosis Infection

This study is ongoing, but not recruiting participants.
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)


Information provided by (Responsible Party)
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier
NCT01404312

First received: July 26, 2011
Last updated: December 12, 2016
Last Verified: December 2016
History of Changes
Purpose

Purpose

HIV-infected people have an increased risk of developing active tuberculosis (TB). The standard course of treatment for TB is 6 to 9 months of isoniazid (INH). A shorter course of treatment may be as effective and potentially increase treatment adherence. This study will compare the safety and effectiveness of a 4-week regimen of rifapentine (RPT) plus INH versus a standard 9-month regimen of INH in HIV-infected people who are at risk of developing active TB.

Condition Intervention Phase
Tuberculosis
HIV Infections

Drug : Rifapentine (RPT)
Drug : Isoniazid (INH)
Dietary Supplement : Pyridoxine (Vitamin B6)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Individuals With Latent Tuberculosis Infection

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures

  • Time from randomization to first diagnosis of active TB [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
Secondary Outcome Measures:
  • Occurrence of one or more serious adverse events (SAEs) versus no SAEs [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
  • Highest reported grade of each new Grade 3 or 4 laboratory value or sign or symptom that is at least one grade increase from baseline for targeted events [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
    Examples include: nausea and vomiting; cutaneous, drug-associated fever; elevated aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]), or bilirubin; and peripheral neuropathy
  • Ordered categorical variable indicating most stringent level of study drug management due to toxicity that was required over the treatment period [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
    Ordered categorical variables include: Premature permanent treatment discontinuation Treatment hold for more than 7 consecutive days None of the above
  • Time from randomization to death from any cause [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
  • Time from randomization to death due to a non-TB event [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
  • Efavirenz (EFV) plasma concentrations at Weeks 0, 2, and 4 [ Time Frame: Measured at Weeks 0, 2, and 4 ]
    Only measured in the first 90 participants randomized to Arm A who enter the study taking EFV and who meet dose timing criteria; and, under Version 2.0 of the protocol, at Weeks 0, 2, 4, and 16 in the first 30 participants randomized to Arm A who enter the study taking EFV and who meet dose timing criteria.
  • Nevirapine (NVP) plasma concentrations at Weeks 0, 2, and 4 [ Time Frame: Measured at Weeks 0, 2, and 4 ]
    Only measured in the first 90 participants randomized to Arm A who enter the study taking NVP and who meet dose timing criteria
  • Adherence to TB treatment [ Time Frame: Measured through Week 36 ]
    Self-reported number of pills missed since last visit and pill count while on study drug
  • Antibiotic resistance pattern of Mycobacterium tuberculosis (MTB) isolates in participants who develop active TB [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
  • HIV-1 RNA changes from baseline to Week 8 [ Time Frame: Measured at Week 8 ]
    Measured in the first 90 participants entering the study taking EFV and who meet pharmacokinetic (PK) analysis dose timing criteria and in the first 90 participants entering the study taking NVP and who meet PK analysis dose timing criteria (may be evaluated only in a subset, e.g., those with very low EFV or NVP levels)
  • Polymorphisms in host genes involved in metabolism or transport of EFV, NVP, and RPT [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
    Polymorphisms include: CYP2B6, CYP3A4/5, SLCO1B1, CYP2A6, UGT2B7, PXR (pregnane X receptor), CAR (constitutive androstane receptor), and HNF4A (hepatocyte nuclear factor)
  • Cost-effectiveness measures [ Time Frame: Measured through participants' last follow-up visit (3 years after last participant is enrolled) ]
  • EFV plasma concentrations at Weeks 0, 2, and 4 [ Time Frame: Measured through Week 4 ]
    For Version 2.0 of the protocol only, measured in the first 90 participants randomized to Arm B who enter the study taking EFV and who meet dose timing criteria.

Estimated Enrollment: 3000
Study Start Date: May 2012
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: RPT plus INH Regimen (Arm A)
Participants will receive RPT (dosage based on their weight), 300 mg of INH, and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 4. During Weeks 5 to 36, participants will not receive any study medications.
Drug: Rifapentine (RPT)
    RPT dosing will be based on participants' weight:
    • Participants who weigh 30 kg to less than 35 kg will receive 300 mg once daily (administered as two 150-mg tablets).
    • Participants who weigh 35 kg to less than 45 kg will receive 450 mg once daily (administered as three 150-mg tablets).
    • Participants who weigh greater than 45 kg will receive 600 mg once daily (administered as four 150-mg tablets).

    Drug: Isoniazid (INH)

    Participants will receive one 300-mg tablet or three 100-mg tablets of INH once daily.

    Dietary Supplement: Pyridoxine (Vitamin B6)
    • Participants will receive 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines.
    • Participants receiving 25 mg of pyridoxine will take one 25-mg tablet once daily with INH.
    • Participants receiving 50 mg of pyridoxine will take two 25-mg tablets once daily with INH.

    Active Comparator: INH Regimen (Arm B)
    Participants will receive 300 mg of INH and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 36.
    Drug: Isoniazid (INH)

    Participants will receive one 300-mg tablet or three 100-mg tablets of INH once daily.

    Dietary Supplement: Pyridoxine (Vitamin B6)
    • Participants will receive 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines.
    • Participants receiving 25 mg of pyridoxine will take one 25-mg tablet once daily with INH.
    • Participants receiving 50 mg of pyridoxine will take two 25-mg tablets once daily with INH.

    Detailed Description:

    The World Health Organization (WHO) estimates that in 2009 there were 9.4 million new cases of TB, and 1.68 million people died as a result of TB. Among new TB cases, 1.1 million occurred in people who were HIV-coinfected, and 35% of TB deaths were among HIV-coinfected individuals. In Africa, TB is the leading AIDS-related opportunistic infection. Latent TB infection occurs when people are infected with the bacteria that cause TB, but they do not have any symptoms of TB infection. Latent TB can develop into active TB, and HIV-infected people have an increased risk of progressing from latent TB to active TB. INH is a medication that is prescribed for people with latent TB to help prevent active TB from developing. The standard INH treatment regimen is 6 to 9 months; a shorter treatment regimen may prove to be as effective and may improve adherence. The purpose of this study is to compare the safety and effectiveness of a 4-week daily regimen of RPT plus INH to a standard 9-month daily INH regimen for TB prevention in HIV-infected individuals.
    This study will enroll HIV-infected people who do not have evidence of active TB but who are at high risk of developing active TB. Participants will be randomly assigned to receive RPT and INH once a day for 4 weeks or INH once a day for 9 months. All participants will receive pyridoxine (vitamin B6) with each dose of INH to help prevent possible side effects. Study visits will occur at baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and 36. At select study visits, participants will undergo a physical exam, clinical assessment, blood collection, and a chest radiograph or chest computed tomography (CT) scan (if needed). Some participants will have their blood stored for future testing. Follow-up study visits will occur every 12 weeks starting at Week 48 and will continue for 3 years after the last participant is enrolled.

    Eligibility

    Eligibility

    Ages Eligible for Study: 13 Years and older  
    Sexes Eligible for Study: All  
    Accepts Healthy Volunteers: No  

    Criteria

    Inclusion Criteria:

    • HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of greater than 1,000 copies/mL are also acceptable as documentation of HIV infection. More information on this criterion can be found in the protocol.
    • Tuberculin skin test (TST) reactivity greater than or equal to 5 mm or a positive interferon gamma release assay (IGRA) at any time prior to study entry, OR living in a high TB burden area. More information on this criterion can be found in the protocol.
    • Laboratory values obtained within 30 days prior to study entry:
      1. Absolute neutrophil count (ANC) greater than 750 cells/mm^3
      2. Hemoglobin greater than or equal to 7.4 g/dL
      3. Platelet count greater than or equal to 50,000/mm^3
      4. AST (SGOT) and ALT (SGPT) less than or equal to three times the upper limit of normal (ULN)
      5. Total bilirubin less than or equal to 2.5 times the ULN
    • Chest radiograph or chest CT scan without evidence of active tuberculosis, unless one has been performed within 30 days prior to entry
    • Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to study entry. More information on this criterion can be found in the protocol.
    • All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization) while receiving RPT and for 6 weeks after stopping this drug
    • Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (i.e., condoms, intrauterine device [IUD]), diaphragm with spermicide, or cervical cap with spermicide) while receiving RPT and for 6 weeks after stopping this drug. More information on this criterion can be found in the protocol.
    • Weight of greater than or equal to 30 kg
    • Participant or legal guardian is able and willing to provide informed consent


    Exclusion Criteria:
    • Treatment for active or latent TB (pulmonary or extrapulmonary) within 2 years prior to study entry or, at screening, presence of any confirmed or probable TB based on criteria listed in the current ACTG Diagnosis Appendix
    • History of multi-drug resistant (MDR) or extensively-drug resistant (XDR) TB at any time prior to study entry
    • Known exposure to MDR or XDR TB (e.g., household member of a person with MDR or XDR TB) at any time prior to study entry
    • Treatment for more than 14 consecutive days with a rifamycin or more than 30 consecutive days with INH at any time during the 2 years prior to enrollment
    • For participants taking antiretroviral therapy (ART) at study entry, only approved nucleoside reverse transcriptase inhibitors (NRTIs) with efavirenz (EFV) or nevirapine (NVP) for at least 4 weeks are permitted. Any other regimens at entry are exclusionary. A list of approved antiretroviral drugs is located on the A5279 protocol-specific webpage (PSWP). Participants on NVP must be dosed at 200 mg twice daily (BID). NOTE A: NVP trough levels will be evaluated in the first 90 participants in Arm A who are receiving NVP at entry and who meet other criteria in Section 10.0 of the protocol, after which enrolment for participants on NVP may be temporarily halted. NVP PK data will be evaluated to determine whether standard NVP dosing results in adequate PK drug exposure in the presence of RPT treatment. If the A5279 team determines that concomitant dosing of NVP and RPT results in adequate drug exposure, the study may continue enrollment of participants receiving NVP. NOTE B: Participants randomized to Arm A may initiate any ART regimen after completing 4 weeks of RPT/INH. Participants randomized to Arm B may initiate any ART regimen after study entry.
    • History of liver cirrhosis at any time prior to study entry
    • Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to study entry
    • Diagnosis of porphyria at any time prior to study entry
    • Peripheral neuropathy greater than or equal to Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry
    • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation
    • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
    • Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry
    • Breastfeeding

    contacts and locations

    Contacts and Locations

    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, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT01404312

    Locations

    United States, California
    University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
    La Jolla, California, United States, 92093-0672
    University of Southern California CRS
    Los Angeles, California, United States, 90033-1079
    UCSD Antiviral Research Center CRS
    San Diego, California, United States, 92103
    Ucsf Hiv/Aids Crs
    San Francisco, California, United States, 94110
    Harbor-UCLA CRS
    Torrance, California, United States, 90502
    United States, Colorado
    University of Colorado Hospital CRS
    Aurora, Colorado, United States, 80045
    Denver Public Health CRS
    Denver, Colorado, United States, 80204
    United States, Florida
    The University of Miami AIDS Clinical Research Unit (ACRU) CRS
    Miami, Florida, United States, 33136
    United States, Illinois
    Northwestern University CRS
    Chicago, Illinois, United States, 60611
    United States, Massachusetts
    Boston Medical Center CRS
    Boston, Massachusetts, United States, 02118
    United States, Michigan
    Henry Ford Hosp. CRS
    Detroit, Michigan, United States, 48202
    United States, New Jersey
    Cooper Univ. Hosp. CRS
    Camden, New Jersey, United States, 08103
    New Jersey Medical School Clinical Research Center CRS
    Newark, New Jersey, United States, 07103
    United States, New York
    Bronx-Lebanon Hospital Center NICHD CRS
    Bronx, New York, United States, 10457
    Nyu Ny Nichd Crs
    New York, New York, United States, 10016
    Columbia P&S CRS
    New York, New York, United States, 10032-3732
    United States, North Carolina
    Chapel Hill CRS
    Chapel Hill, North Carolina, United States, 27599
    Duke University Medical Center CRS
    Durham, North Carolina, United States, 27710
    United States, Texas
    Trinity Health and Wellness Center CRS
    Dallas, Texas, United States, 75208
    Houston AIDS Research Team CRS
    Houston, Texas, United States, 77030
    United States, Washington
    University of Washington AIDS CRS
    Seattle, Washington, United States, 98104-9929
    Botswana
    Gaborone CRS
    Gaborone, Botswana
    Molepolole CRS
    Gaborone, Botswana
    Brazil
    Hospital Nossa Senhora da Conceicao CRS
    Porto Alegre, Rio Grande do Sul, Brazil, 91350-200
    Univ. of Sao Paulo Brazil NICHD CRS
    Sao Paulo, São Paulo, Brazil, 14049-900
    Hospital Federal dos Servidores do Estado NICHD CRS
    Rio de Janeiro, Brazil, 20221-903
    Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
    Rio de Janeiro, Brazil, 21040-360
    Hosp. Geral De Nova Igaucu Brazil NICHD CRS
    Rio de Janeiro, Brazil, 26030
    Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
    Sao Paulo, Brazil, 01246-900
    Haiti
    Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
    Port-au-Prince, Haiti, 6110
    GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
    Port-au-Prince, Haiti
    Kenya
    Kisumu Crs
    Kisumu, Nyanza, Kenya, 40100
    Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
    Kericho, Rift Valley, Kenya, 20200
    Moi University Clinical Research Center (MUCRC) CRS
    Eldoret, Kenya, 30100
    Malawi
    Blantyre CRS
    Blantyre, Malawi
    Malawi CRS
    Lilongwe, Central, Malawi
    Peru
    Barranco CRS
    Lima, Peru, 04
    San Miguel CRS
    Lima, Peru, 32
    South Africa
    Soweto ACTG CRS
    Johannesburg, Gauteng, South Africa, 1862
    Wits Helen Joseph Hospital CRS (Wits HJH CRS)
    Johannesburg, Gauteng, South Africa, 2092
    Durban International Clinical Research Site CRS
    Durban, KwaZulu-Natal, South Africa, 4013
    Thailand
    Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
    Bangkok, Thailand, 10330
    Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
    Chiang Mai, Thailand, 50200
    Chonburi Hosp. CRS
    Chonburi, Thailand, 20000
    Zimbabwe
    Parirenyatwa CRS
    Harare, Zimbabwe

    Sponsors and Collaborators

    National Institute of Allergy and Infectious Diseases (NIAID)

    Investigators

    Study Chair: Richard E. Chaisson, MD Johns Hopkins University
    Study Chair: Susan Swindells, MBBS University of Nebraska
    More Information

    More Information


    Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)  
    ClinicalTrials.gov Identifier: NCT01404312   History of Changes  
    Other Study ID Numbers: A5279  
      10848  
      ACTG A5279  
    Study First Received: July 26, 2011  
    Last Updated: December 12, 2016  

    Additional relevant MeSH terms:
    Infection
    Communicable Diseases
    HIV Infections
    Tuberculosis
    Latent Tuberculosis
    Vitamins
    Vitamin B 6
    Pyridoxal
    Pyridoxine
    Vitamin B Complex
    Isoniazid
    Rifapentine
    Rifampin

    ClinicalTrials.gov processed this data on October 19, 2017
    This information is provided by ClinicalTrials.gov.