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TuberculosisPhase 3WHIP3TBNCT02980016

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

A Phase 3 study testing rifapentine + isoniazid and Isoniazid in people with Tuberculosis and HIV, run by The Aurum Institute NPC at 1 site in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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). Read more about this study

Who is it for?
Ages 2 years and olderHealthy volunteers can take part
Conditions the study is for
Tuberculosis, HIV
What is being tested?
rifapentine + isoniazid and Isoniazid
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4,027 participants
Where
1 siteSouth Africa
Study dates
Nov 2016to 18 Oct 2019
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 years and older
  • All sexes
  • Healthy volunteers accepted
  • Child, Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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
Show all 11Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

South Africa1 site
  • The Aurum Institute NPC

    Johannesburg, Gauteng, 2193

Other trials in South Africa

About this study

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

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.

Read the 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.

Conditions
Tuberculosis, HIV
Being tested
rifapentine + isoniazid, Isoniazid
Medical subject headings
Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • rifapentine + isoniazidDrug

    Also called Priftin (rifapentine)

    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

  • IsoniazidDrug

    Also called Winthrop (isoniazid)

    Daily self-administered isoniazid (at a dose of 300 mg/daily), with adjustment for participants weighing ≤24 kg

Study groups in NCT02980016
Study groupRoleWhat they receive
3HP (rifapentine + isoniazid)Active comparatorOnce 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
Receives: Drug: rifapentine + isoniazid
p3HP (rifapentine + isoniazid)Active comparatorOnce 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
Receives: Drug: rifapentine + isoniazid
6HActive comparatorDaily 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
Receives: Drug: Isoniazid

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Treatment completion (part A)

    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

    Measured: 1 year

  2. TB incidence (part B)

    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

    Measured: 2 years

Secondary outcomes (10)
  1. TB incidence (part A)

    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

    Measured: 1 year

  2. All-cause mortality (part A)

    Number of participants without evidence of active TB at enrollment who die from any cause

    Measured: 1 year

  3. Permanent discontinuation of therapy due to treatment-related adverse events (part A)

    Number of participants without evidence of active TB at enrollment who permanently discontinue therapy due to an adverse drug reaction

    Measured: 1 year

  4. TB incidence (part B)

    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

    Measured: 1 year

  5. Treatment completion (part B)

    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

    Measured: 2 years

  6. All-cause mortality (part B)

    Number of participants without evidence of active TB at enrollment who die from any cause

    Measured: 2 years

  7. Permanent discontinuation of therapy due to treatment-related adverse events (part B)

    Number of participants without evidence of active TB at enrollment who permanently discontinue therapy due to an adverse drug reaction

    Measured: 2 years

  8. Cost per TB case prevented

    Cost per TB case prevented

    Measured: 2 years

  9. Cost per death averted

    Cost per death averted

    Measured: 2 years

  10. Cost per disability adjusted life year (DALY) averted by study arm

    Cost per disability adjusted life year (DALY) averted by study arm

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Dec 2016 (estimated)
  2. Study startNov 2016
  3. Primary completion18 Oct 2019
  4. Study completion18 Oct 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
4,027 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02980016
Sponsor's protocol ID
3HP-AUR1-1-170
Acronym
WHIP3TB
Status last verified
Oct 2019
First submitted
21 Nov 2016
Last updated
30 Oct 2019
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Undecided

Publications

  • Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, Hackman J, Hamilton CD, Menzies D, Kerrigan A, Weis SE, Weiner M, Wing D, Conde MB, Bozeman L, Horsburgh CR Jr, Chaisson RE; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8;365(23):2155-66. doi: 10.1056/NEJMoa1104875.

    PubMed 22150035
  • Sterling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME; Tuberculosis Trials Consortium. Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study. Clin Infect Dis. 2015 Aug 15;61(4):527-35. doi: 10.1093/cid/civ323. Epub 2015 Apr 22.

    PubMed 25904367
  • 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.

  • Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, McIntyre JA, Gray GE, Chaisson RE. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med. 2011 Jul 7;365(1):11-20. doi: 10.1056/NEJMoa1005136.

    PubMed 21732833
  • Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, Nachman S, Oliveira R, Moro RN, Shang N, Goldberg SV, Sterling TR; International Maternal Pediatric and Adolescents AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr. 2015 Mar;169(3):247-55. doi: 10.1001/jamapediatrics.2014.3158.

    PubMed 25580725
  • Churchyard G, Cardenas V, Chihota V, Mngadi K, Sebe M, Brumskine W, Martinson N, Yimer G, Wang SH, Garcia-Basteiro AL, Nguenha D, Masilela L, Waggie Z, van den Hof S, Charalambous S, Cobelens F, Chaisson RE, Grant AD, Fielding KL; WHIP3TB Study Team. Annual Tuberculosis Preventive Therapy for Persons With HIV Infection : A Randomized Trial. Ann Intern Med. 2021 Oct;174(10):1367-1376. doi: 10.7326/M20-7577. Epub 2021 Aug 24.

    PubMed 34424730

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing rifapentine + isoniazid and Isoniazid in people with Tuberculosis and HIV, run by The Aurum Institute NPC at 1 site in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Treatment completion (part A) (time frame: 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02980016, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2019.

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