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 currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01404312
First received: July 26, 2011
Last updated: September 29, 2014
Last verified: September 2014
  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: 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

Resource links provided by NLM:


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) ] [ Designated as safety issue: No ]

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) ] [ Designated as safety issue: Yes ]
  • 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) ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: No ]

    Ordered categorical variables include:

    1. Premature permanent treatment discontinuation
    2. Treatment hold for more than 7 consecutive days
    3. 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • Efavirenz (EFV) plasma concentrations at Weeks 0, 2, and 4 [ Time Frame: Measured at Weeks 0, 2, and 4 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
  • HIV-1 RNA changes from baseline to Week 8 [ Time Frame: Measured at Week 8 ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
  • EFV plasma concentrations at Weeks 0, 2, and 4 [ Time Frame: Measured through Week 4 ] [ Designated as safety issue: No ]
    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: December 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

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
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
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

  Show 75 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Richard E. Chaisson, MD Johns Hopkins University
Study Chair: Susan Swindells, MBBS University of Nebraska
  More Information

Publications:
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: September 29, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Infection
Communicable Diseases
HIV Infections
Acquired Immunodeficiency Syndrome
Tuberculosis
Latent Tuberculosis
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Vitamins
Vitamin B 6
Pyridoxine
Pyridoxal
Isoniazid
Rifapentine
Vitamin B Complex
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 30, 2014