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

Purpose

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	Intervention	Phase
Latent Tuberculosis Infection	Drug: Isoniazid Drug: Rifampin	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: No masking 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

Resource links provided by NLM:

MedlinePlus related topics: Tuberculosis

Drug Information available for: Isoniazid Rifampin

Genetic and Rare Diseases Information Center resources: Tuberculosis

U.S. FDA Resources

Further study details as provided by Dr. Dick Menzies, McGill University:

Primary Outcome Measures:

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:

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 ).
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.
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.
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.
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.


Enrollment:	6031
Actual Study Start Date:	August 2009
Study Completion Date:	April 2017
Primary Completion Date:	April 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

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Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
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

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: NCT00931736

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


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 )
Study First Received:	July 1, 2009
Last Updated:	June 6, 2017
Individual Participant Data
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

ClinicalTrials.gov processed this record on June 23, 2017