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

• Sponsor: McGill University
• Collaborator: Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): Dr. Dick Menzies, McGill University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Latent Tuberculosis Infection	Drug: Isoniazid; Drug: Rifampin	Phase 3

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Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6031 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Clinical Trial of 4 Months of Rifampin vs. 9 Months of Isoniazid for Latent Tuberculosis Infection. Part 3 - Effectiveness
• Actual Study Start Date: August 2009
• Actual Primary Completion Date: April 2017
• Actual Study Completion Date: April 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Isoniazid; 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; 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.
Active Comparator: Rifampin; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Confirmed active TB during 28 months after randomization [ Time Frame: 7 years total with data analysis ]
   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).

Secondary Outcome Measures :

1. Confirmed active TB in compliant participants [ Time Frame: 7 years total with data analysis ]
   Compare the cumulative incidence of confirmed active TB among those who took at least 80% of doses of the LTBI treatment to which they were randomized, in less than 120% of the allowed time (i.e. efficacy ).
2. Probable and confirmed active TB [ Time Frame: 7 years total with data analysis ]
   Compare the cumulative incidence of probable, as well as confirmed, active TB between patients randomized to the two regimens during 28 months following randomization.
3. Rate of Grade 3 & 4 adverse events [ Time Frame: 7 years including data analysis ]
   Compare rates of Grades 3 &4 adverse events during treatment between subjects randomized to the two regimens.
4. Comparative cost-effectiveness of regimens [ Time Frame: 7 years including data analysis ]
   Compare health system costs, and cost-effectiveness of the two regimens, in the different sites.
5. Occurrence of drug resistance in confirmed cases of active TB [ Time Frame: 7 years including data analysis ]
   Describe occurrence of drug resistance (to INH or RIF) among subjects who develop confirmed active TB.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Contacts and Locations

Locations

Australia, New South Wales

Woolcock Institute of Medical Research

Sydney, New South Wales, Australia

Benin

Centre de Pneumophthysiologie

Cotonou, Benin

Brazil

Universidade Gama Filho, Centro de Ciências Biológicas e da Saúde

Rio de Janeiro, Brazil

Canada, Alberta

University of Alberta

Edmonton, Alberta, Canada

Canada, British Columbia

British Columbia Centre for Disease Control

Vancouver, British Columbia, Canada

Canada, Quebec

Montreal Chest Institute

Montreal, Quebec, Canada, H2X 2P4

Canada, Saskatchewan

Royal University Hospital

Saskatoon, Saskatchewan, Canada

Ghana

Research and Development Unit, Komfo Anokye Teaching Hospital

Kumasi, Ghana

Guinea

Service de Phtisiologie, Hopital National Ignace Deen

Conakry, Guinea

Indonesia

Health Research Unit, Faculty of Medicine

Bandung, West Java, Indonesia

Korea, Republic of

Korean Institute of Tuberculosis

Seoul, Korea, Republic of

Saudi Arabia

King Fahad National Guard Hospital

Riyadh, Saudi Arabia

Sponsors and Collaborators

McGill University

Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: Dick Menzies, MD; McGill University / McGill University Health Centre

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Dr. Dick Menzies, Director of Respiratory Medicine, McGill University
• ClinicalTrials.gov Identifier: NCT00931736 History of Changes
• Other Study ID Numbers: MCT-94831; ISRCTN05675547 ( Other Grant/Funding Number: MCT-94831 )
• First Posted: July 2, 2009
• Last Update Posted: December 19, 2017
• Last Verified: December 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Keywords provided by Dr. Dick Menzies, McGill University:

Tuberculosis

Additional relevant MeSH terms:

Infection; Tuberculosis; Latent Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Rifampin; Isoniazid; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Leprostatic Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; 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; Fatty Acid Synthesis Inhibitors; Hypolipidemic Agents; Antimetabolites; Lipid Regulating Agents