Randomized Clinical Trial Comparing 4RIF vs. 9INH for LTBI Treatment-effectiveness

NCT00931736 | Completed Phase 3 DMC

• 2 other identifiers: MCT-94831ISRCTN05675547
• Study Type: interventional
• Target: 6,031
• Locations: 9 countries
• Sites: 12

Brief Summary

On a global scale, tuberculosis (TB) is the single most important infectious cause of morbidity and mortality. The World Health Organization has estimated that one-third of the entire world's population carries latent TB infection. A key TB control strategy is therapy of latent TB infection (LTBI). The current standard regimen is 9 months of Isoniazid (9INH). This regimen has excellent efficacy if taken regularly, but its effectiveness is substantially reduced by poor compliance. Serious side effects, such as hepato-toxicity can occur. Three shorter alternatives have been recommended: 6 months INH (6INH), 2 months Rifampin - Pyrazinamide (2RIF-PZA) and 4 months Rifampin (4RIF). The regimen of 6INH is less efficacious than 9INH, while 2RIF-PZA has been largely abandoned because of serious toxicity. Based on some evidence in treatment of LTBI, and extrapolating from extensive experience with treatment of active TB, it is believed that 4RIF has similar efficacy as 9INH. Therefore, the investigators are initiating the first multi-site international randomized trial that will compare the effectiveness of 4RIF and 9INH in preventing active tuberculosis.

Conditions

Latent Tuberculosis Infection

Keywords

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Confirmed active TB during 28 months after randomization

  Confirmed active TB during 28 months after randomization will be defined as a positive culture for M. tuberculosis, positive Nucleic acid amplification test for M TB complex, or caseating granulomas in a biopsy from any site. Positive AFB smears will be considered false positive if cultures are negative, but will be considered confirmatory, if cultures failed (for example if contamination or other technical problem occurs).

  7 years total with data analysis

Secondary Outcomes (5)

• Confirmed active TB in compliant participants

  7 years total with data analysis

• Probable and confirmed active TB

  7 years total with data analysis

• Rate of Grade 3 & 4 adverse events

  7 years including data analysis

• Comparative cost-effectiveness of regimens

  7 years including data analysis

• Occurrence of drug resistance in confirmed cases of active TB

  7 years including data analysis

Study Arms (2)

Isoniazid

ACTIVE COMPARATOR

The dosage of the medication is determined according to the weight of the subject. The dose is once per day, in pill format, for a total daily dose of 300mg if subject weighs ≥ 42 kg, otherwise 200 mg. Total duration of treatment is for 9 months.

Drug: Isoniazid

Rifampin

ACTIVE COMPARATOR

The dosage of the medication is determined according to the weight of the subject. The dose is once per day, in pill format, for a total daily dose of 600 mg if the subject weighs ≥ 50 kg, 450 mg if the subject weighs ≥ 36 kg and \< 50 kg, otherwise 300 mg for those weighing \< 36 kg. Total duration of treatment is for 4 months.

Drug: Rifampin

Interventions

Isoniazid DRUG

The dosage of the medication is determined according to the weight of the subject. The dose is once per day, in pill format, for a total daily dose of 300mg if subject weighs ≥ 42 kg, otherwise 200 mg. Total duration of treatment is for 9 months.

Isoniazid

Rifampin DRUG

The dosage of the medication is determined according to the weight of the subject. The dose is once per day, in pill format, for a total daily dose of 600 mg if the subject weighs ≥ 50 kg, 450 mg if the subject weighs ≥ 36 kg and \< 50 kg, otherwise 300 mg for those weighing \< 36 kg. Total duration of treatment is for 4 months.

Rifampin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (age 18 years and older) with documented positive TST (or in the absence of TST, a documented positive QFT) and prescribed 9 months of Isoniazid for LTBI, following authoritative recommendations.

You may not qualify if:

• Patients who were contacts of TB cases known to be resistant to Isoniazid, Rifampin, or both.
• Known HIV-infected individuals on anti-retroviral agents whose efficacy would be substantially reduced by Rifampin, unless therapy can safely be changed to agents not affected by Rifampin.
• Pregnant women - Rifampin and Isoniazid are considered safe in pregnancy but therapy is usually deferred until 2-3 months post-partum to avoid fetal risk and the potential for increased hepato-toxicity immediately post partum.
• Patients on any medication with clinically important drug interactions with Isoniazid or Rifampin, which their physician believes would make either arm contra-indicated.
• Patients with a history of allergy/hypersensitivity to Isoniazid or to Rifampin, Rifabutin or Rifapentine.
• Patients with active TB. Patients initially suspected to have active TB can be randomized once this has been excluded.
• Patients who have already started LTBI therapy.

Sponsors & Collaborators

• McGill University: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (12)

Woolcock Institute of Medical Research

Sydney, New South Wales, Australia

Location

Centre de Pneumophthysiologie

Cotonou, Benin

Location

Universidade Gama Filho, Centro de Ciências Biológicas e da Saúde

Rio de Janeiro, Brazil

Location

University of Alberta

Edmonton, Alberta, Canada

Location

British Columbia Centre for Disease Control

Vancouver, British Columbia, Canada

Location

Montreal Chest Institute

Montreal, Quebec, H2X 2P4, Canada

Location

Royal University Hospital

Saskatoon, Saskatchewan, Canada

Location

Research and Development Unit, Komfo Anokye Teaching Hospital

Kumasi, Ghana

Location

Service de Phtisiologie, Hopital National Ignace Deen

Conakry, Guinea

Location

Health Research Unit, Faculty of Medicine

Bandung, West Java, Indonesia

Location

King Fahad National Guard Hospital

Riyadh, Saudi Arabia

Location

Korean Institute of Tuberculosis

Seoul, South Korea

Location

Related Publications (5)

• Allard-Gray A, Boakye I, Camara A, Eisenbeis L, Guimaraes-Teixeira E, Sow O, Zielinski D, Campbell JR, Menzies D. Factors Associated With Discontinuation of Tuberculosis Preventive Treatment: Post Hoc Analysis of 2 Randomized, Controlled Trials. Clin Infect Dis. 2023 Jul 5;77(1):84-93. doi: 10.1093/cid/ciad164.

  PMID: 36949623 DERIVED

• Campbell JR, Al-Jahdali H, Bah B, Belo M, Cook VJ, Long R, Schwartzman K, Trajman A, Menzies D. Safety and Efficacy of Rifampin or Isoniazid Among People With Mycobacterium tuberculosis Infection and Living With Human Immunodeficiency Virus or Other Health Conditions: Post Hoc Analysis of 2 Randomized Trials. Clin Infect Dis. 2021 Nov 2;73(9):e3545-e3554. doi: 10.1093/cid/ciaa1169.

  PMID: 32785709 DERIVED

• Bastos ML, Campbell JR, Oxlade O, Adjobimey M, Trajman A, Ruslami R, Kim HJ, Baah JO, Toelle BG, Long R, Hoeppner V, Elwood K, Al-Jahdali H, Apriani L, Benedetti A, Schwartzman K, Menzies D. Health System Costs of Treating Latent Tuberculosis Infection With Four Months of Rifampin Versus Nine Months of Isoniazid in Different Settings. Ann Intern Med. 2020 Aug 4;173(3):169-178. doi: 10.7326/M19-3741. Epub 2020 Jun 16.

  PMID: 32539440 DERIVED

• Campbell JR, Trajman A, Cook VJ, Johnston JC, Adjobimey M, Ruslami R, Eisenbeis L, Fregonese F, Valiquette C, Benedetti A, Menzies D. Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled trials. Lancet Infect Dis. 2020 Mar;20(3):318-329. doi: 10.1016/S1473-3099(19)30575-4. Epub 2019 Dec 19.

  PMID: 31866327 DERIVED

• Menzies D, Adjobimey M, Ruslami R, Trajman A, Sow O, Kim H, Obeng Baah J, Marks GB, Long R, Hoeppner V, Elwood K, Al-Jahdali H, Gninafon M, Apriani L, Koesoemadinata RC, Kritski A, Rolla V, Bah B, Camara A, Boakye I, Cook VJ, Goldberg H, Valiquette C, Hornby K, Dion MJ, Li PZ, Hill PC, Schwartzman K, Benedetti A. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. N Engl J Med. 2018 Aug 2;379(5):440-453. doi: 10.1056/NEJMoa1714283.

  PMID: 30067931 DERIVED

MeSH Terms

Conditions

Latent Tuberculosis; Tuberculosis

Interventions

Isoniazid; Rifampin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Dick Menzies, MD

  McGill University / McGill University Health Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Respiratory Medicine

Study Record Dates

• First Submitted: July 1, 2009
• First Posted: July 2, 2009
• Study Start: August 1, 2009
• Primary Completion: April 1, 2017
• Study Completion: April 1, 2017
• Last Updated: December 19, 2017

Record last verified: 2017-12

Data Sharing

• IPD Sharing: Will share

Locations

CA (4); SA (1); ID (1); KR (1); AU (1); BE (1); GU (1); BR (1); GH (1)