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Evaluation of the Effect of 3HP vs Periodic 3HP vs 6H in HIV-Positive Individuals (WHIP3TB)

This study is currently recruiting participants.
Verified December 2016 by KNCV Tuberculosis Foundation
Sponsor:
ClinicalTrials.gov Identifier:
NCT02980016
First Posted: December 2, 2016
Last Update Posted: December 2, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Aurum Institute
London School of Hygiene and Tropical Medicine
Johns Hopkins University
Information provided by (Responsible Party):
KNCV Tuberculosis Foundation
  Purpose
This study is a parallel, two part, open label, individually randomized, pragmatic trial among HIV-positive individuals. Part A compares a single round of weekly high dose rifapentine plus isoniazid for three months (3HP) to six months of daily isoniazid (6H). Part B compares periodic 3HP (p3HP) to a single round of 3HP.

Condition Intervention Phase
Tuberculosis HIV Drug: rifapentine + isoniazid Drug: Isoniazid Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Randomised, Pragmatic, Open-Label Trial To Evaluate The Effect Of Three Months Of High Dose Rifapentine Plus Isoniazid Administered As A Single Round Or Given Annually In HIV-Positive Individuals

Resource links provided by NLM:


Further study details as provided by KNCV Tuberculosis Foundation:

Primary Outcome Measures:
  • Treatment completion (part A) [ Time Frame: 1 year ]

    Number of participants without evidence of active TB at enrollment who complete treatment, defined as:

    Proportion of participants in 3HP group self-reporting treatment completion of ≥11 doses in a 16-week period

    ; Proportion or participants in 6H group self-reporting treatment completion of ≥167 doses over an 34 week (8-month) period


  • TB incidence (part B) [ Time Frame: 2 years ]
    Number of participants without evidence of active TB at enrollment who are diagnosed with active TB meeting the definition: Confirmed tuberculosis: Culture-positive, Xpert MTB/RIF-positive, or smear-positive for M. tuberculosis from any site in adults and children OR Clinical tuberculosis: Started on treatment for TB in adults and children


Secondary Outcome Measures:
  • TB incidence (part A) [ Time Frame: 1 year ]
    Number of participants without evidence of active TB at enrollment who are diagnosed with active TB meeting the definition: Confirmed tuberculosis: Culture-positive, Xpert MTB/RIF-positive, or smear-positive for M. tuberculosis from any site in adults and children OR Clinical tuberculosis: Started on treatment for TB in adults and children

  • All-cause mortality (part A) [ Time Frame: 1 year ]
    Number of participants without evidence of active TB at enrollment who die from any cause

  • Permanent discontinuation of therapy due to treatment-related adverse events (part A) [ Time Frame: 1 year ]
    Number of participants without evidence of active TB at enrollment who permanently discontinue therapy due to an adverse drug reaction

  • TB incidence (part B) [ Time Frame: 1 year ]
    Number of participants without evidence of active TB during enrollment who are diagnosed with active TB meeting during the second year of follow-up. The definition of active TB is: Confirmed tuberculosis: Culture-positive, Xpert MTB/RIF-positive, or smear-positive for M. tuberculosis from any site in adults and children OR Clinical tuberculosis: Started on treatment for TB in adults and children

  • Treatment completion (part B) [ Time Frame: 2 years ]
    Number of participants without evidence of active TB at enrollment who complete treatment, defined as: Proportion of participants in 3HP group self-reporting treatment completion of ≥11 doses in a 16-week period; Proportion or participants in p3HP group self-reporting treatment completion of ≥22 doses over two annual 16-week periods

  • All-cause mortality (part B) [ Time Frame: 2 years ]
    Number of participants without evidence of active TB at enrollment who die from any cause

  • Permanent discontinuation of therapy due to treatment-related adverse events (part B) [ Time Frame: 2 years ]
    Number of participants without evidence of active TB at enrollment who permanently discontinue therapy due to an adverse drug reaction

  • Cost per TB case prevented [ Time Frame: 2 years ]
    Cost per TB case prevented

  • Cost per death averted [ Time Frame: 2 years ]
    Cost per death averted

  • Cost per disability adjusted life year (DALY) averted by study arm [ Time Frame: 2 years ]
    Cost per disability adjusted life year (DALY) averted by study arm


Other Outcome Measures:
  • IGRA conversions (part A) [ Time Frame: 1 year ]
    Number of IGRA-negative participants without evidence of active TB at enrollment with the occurrence of IGRA conversions at the end of year 1

  • IGRA reversions (part A) [ Time Frame: 1 year ]
    Number of IGRA-positive participants without evidence of active TB at enrollment with the occurrence of IGRA reversions at the end of year 1

  • Incidence of TB resistant to isoniazid and/or rifapentine [ Time Frame: 2 years ]
    Number of individuals without evidence of active TB at enrollment who are diagnosed with active TB resistant to isoniazid and/or rifapentine


Estimated Enrollment: 4000
Study Start Date: November 2016
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 3HP (rifapentine + isoniazid)
Once weekly rifapentine (at a dose of 900 mg) plus isoniazid (at a dose of 900 mg), (with adjustment for participants weighing ≤50 kg) given for 12 weeks in Study Year 1
Drug: rifapentine + isoniazid
Rifapentine + isoniazid Once weekly rifapentine (at a dose of 900 mg) plus isoniazid (at a dose of 900 mg), with adjustment for participants weighing ≤50 kg
Other Name: Priftin (rifapentine)
Active Comparator: p3HP (rifapentine + isoniazid)
Once weekly rifapentine (at a dose of 900 mg) plus isoniazid (at a dose of 900 mg), (with adjustment for participants weighing ≤50 kg) given for 12 weeks in Study Years 1 and 2
Drug: rifapentine + isoniazid
Rifapentine + isoniazid Once weekly rifapentine (at a dose of 900 mg) plus isoniazid (at a dose of 900 mg), with adjustment for participants weighing ≤50 kg
Other Name: Priftin (rifapentine)
Active Comparator: 6H
Daily self-administered isoniazid (at a dose of 300 mg/daily) (with adjustment for participants weighing ≤24 kg) given for 26 weeks (6 months) in Study Year 1
Drug: Isoniazid
Daily self-administered isoniazid (at a dose of 300 mg/daily), with adjustment for participants weighing ≤24 kg
Other Name: Winthrop (isoniazid)

Detailed Description:

Part A: A randomised controlled trial of 3HP vs 6H [enrollment starts concurrently with Part B]

Justification: The World Health Organization (WHO) recommends at least six months of isoniazid (6H) for persons living with HIV. However, 6H remains poorly implemented in most high burden tuberculosis (TB) countries. In its 2015 guidelines, WHO includes 3HP as an latent tuberculosis infection (LTBI) treatment option for high-income and upper middle-income countries with TB incidence rates <100/100,000. One trial comparing 3HP to 6H in a high burden country suggests that a single round of 3HP has less toxicity, better treatment completion rates, and similar efficacy in preventing TB. The purpose of comparing a single round of 3HP to 6H is to demonstrate the feasibility of implementing 3HP in high burden countries, to explore its safety and effectiveness, and to generate evidence to guide a WHO recommendation for the use of 3HP in high burden settings.

Sample size: If we assume 85% of patients in the 6H arm complete treatment as defined above, with 400 patients in the 6H arm and 3600 patients in the 3HP arm we will have 82% power to detect an increase in treatment completion of 5% (To -90%) in the 3HP arm. If treatment completion in the 6H arm is 75%, we will have approximately 90% power to detect an increase in treatment completion of 7% in the 3HP arm.

Analysis: Treatment completion will be compared by study arm using Fishers Exact test, and associated risk difference and 95% confidence interval (CI).

Part B: A randomised controlled trial of 3HP vs p3HP [enrollment starts concurrently with Part A]

Justification: A single round of 3HP has been shown to be non-inferior to 9 months of isoniazid (9H) in persons at high risk of developing TB in low and middle TB burden settings. Similarly, a single round of 3HP has demonstrated similar efficacy in preventing active TB when compared to 6H among HIV-positive, tuberculin skin test (TST)-positive adults in the high burden setting of South Africa. In high burden settings, 6H and 3HP provide protection of limited duration probably due to high ongoing transmission and reinfection. Continuous isoniazid preventive therapy has been shown to provide more durable protection in high burden settings, but is not currently policy outside of a handful of countries, and the actual uptake is poor. Giving 3HP periodically may provide durable protection, be easier for health systems to implement, and may be associated with better adherence and fewer side effects.

Sample size: Assuming a cumulative TB incidence of 5% over 2 years in the control (3HP) arm, an overall loss to follow-up of 10% by year 2, a two-sided type I error of 5%, 1:1 randomisation, a superiority comparison and 1800 participants per arm, we have 80% power to detect a 40% reduction in cumulative TB incidence from months 0 to 24.

Analysis: The analysis will compare 3HP and p3HP with two years of follow up. Cumulative TB incidence will be determined by combining incident TB cases identified over the 24 months of follow up AND prevalent TB cases identified at the 12 and 24 month culture survey. Data will be reported as a risk difference and odds ratio and their associated 95% CIs, adjusting for randomisation strata. The secondary outcome comparing the effectiveness of p3HP to 3HP from month 13 to 24 (during which time the greatest effect is likely to be evident) will be conducting using the same analytic methods. The results of Part B will be disseminated subsequent to the results of Part A.

  Eligibility

Information from the National Library of Medicine

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:   2 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • At least two years of age
  • Known HIV infection
  • Antiretroviral therapy (ART) ineligible or on ART for ≥3 months

Exclusion Criteria:

  • Confirmed or suspected TB disease
  • Likely to move from the study area during the study period
  • Known exposure to TB cases with known or suspected resistance to isoniazid or rifampicin in the source case
  • TB treatment within the past year
  • TB preventive therapy within the last year
  • Sensitivity or intolerance to isoniazid or rifamycins
  • Suspected acute hepatitis or known chronic liver disease
  • ALT/AST >5 times the upper limit of normal (regardless of symptoms of hepatitis)
  • Pregnancy or breastfeeding
  • Women of childbearing potential who are unable or unwilling to use contraception
  • Self-reported alcohol use exceeding 28 units per week for men, or 21 units for women
  Contacts and Locations
Information from the National Library of Medicine

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): NCT02980016


Contacts
Contact: Vicky Cardenas, PhD, JD +1-301-770-4706 vcardenas@auruminstitute.org
Contact: Rene Wills +27 (0) 10 590 1399 rwills@auruminstitute.org

Locations
South Africa
The Aurum Institute NPC Recruiting
Johannesburg, Gauteng, South Africa, 2193
Contact: Gavin GJ Churchyard, MBBCh    +27 10 590 1300 ext 1300    gchurchyard@auruminstitute.org   
Contact: Vicky V Cardenas, BS Biology    +1-301-770-4706    vcardenas@auruminstitute.org   
Principal Investigator: Gavin GJ Churchyard, MBBCh         
Sponsors and Collaborators
KNCV Tuberculosis Foundation
Aurum Institute
London School of Hygiene and Tropical Medicine
Johns Hopkins University
Investigators
Principal Investigator: Gavin Churchyard, MBBCh, PhD Aurum Institute
  More Information

Publications:
Sterling TR, Benson CA, Shang N. Tolerability among HIV-infected persons of three months of once-weekly rifapentine + INH (3HP) vs. 9 months of daily INH (9H) for treatment of latent tuberculosis infection. In: International AIDS Society Conference. Washington, DC.; 2012.

Responsible Party: KNCV Tuberculosis Foundation
ClinicalTrials.gov Identifier: NCT02980016     History of Changes
Other Study ID Numbers: 3HP-AUR1-1-170
First Submitted: November 21, 2016
First Posted: December 2, 2016
Last Update Posted: December 2, 2016
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Isoniazid
Rifapentine
Rifampin
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Antibiotics, Antitubercular
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme 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