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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by McGill University
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Dr. Dick Menzies, McGill University
ClinicalTrials.gov Identifier:
NCT00931736
First received: July 1, 2009
Last updated: January 20, 2014
Last verified: January 2014
  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
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by McGill University:

Primary Outcome Measures:
  • Confirmed active TB during 28 months after randomization [ Time Frame: 7 years total with data analysis ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Describe occurrence of drug resistance (to INH or RIF) among subjects who develop confirmed active TB.


Estimated Enrollment: 5720
Study Start Date: August 2009
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: December 2014 (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
Genders Eligible for Study:   Both
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

Contacts
Contact: Dick Menzies, MD (514) 934-1934 ext 32129 dick.menzies@mcgill.ca
Contact: Karen Hornby, BScN MScEpi (514) 934-1934 ext 32197 karen.hornby@mail.mcgill.ca

Locations
Australia, New South Wales
Woolcock Institute of Medical Research Recruiting
Sydney, New South Wales, Australia
Contact: Guy Marks, MD, PhD         
Principal Investigator: Guy Marks, MD, PhD         
Benin
Centre de Pneumophthysiologie Recruiting
Cotonou, Benin
Contact: Martin Gninafon, MD         
Principal Investigator: Martin Gninafon, MD         
Brazil
Universidade Gama Filho, Centro de Ciências Biológicas e da Saúde Recruiting
Rio de Janeiro, Brazil
Contact: Anete Trajman, MD, PhD         
Principal Investigator: Anete Trajman, MD, PhD         
Canada, Alberta
University of Alberta Completed
Edmonton, Alberta, Canada
Canada, British Columbia
British Columbia Centre for Disease Control Recruiting
Vancouver, British Columbia, Canada
Contact: Kevin Elwood, MD         
Principal Investigator: Kevin Elwood, MD         
Canada, Quebec
Montreal Chest Institute Completed
Montreal, Quebec, Canada, H2X 2P4
Canada, Saskatchewan
Royal University Hospital Suspended
Saskatoon, Saskatchewan, Canada
Ghana
Research and Development Unit, Komfo Anokye Teaching Hospital Recruiting
Kumasi, Ghana
Contact: Joseph Obeng Baah, MD         
Principal Investigator: Joseph Obeng Baah         
Guinea
Service de Phtisiologie, Hopital National Ignace Deen Recruiting
Conakry, Guinea
Contact: Oumou Bah-Sow, MD         
Principal Investigator: Oumou Sow-Bah, MD         
Indonesia
Health Research Unit, Faculty of Medicine Recruiting
Bandung, West Java, Indonesia
Contact: Rovina Ruslami, MD         
Principal Investigator: Philip Hill, MD, MPH         
Korea, Republic of
Korean Institute of Tuberculosis Recruiting
Seoul, Korea, Republic of
Contact: HeeJin Kim, MD, MPH, PhD         
Principal Investigator: HeeJin Kim, MD, MPH, PhD         
Saudi Arabia
King Fahad National Guard Hospital Recruiting
Riyadh, Saudi Arabia
Contact: Hamdan Al-Jahdali, MD, PhD         
Principal Investigator: Hamdan Al-Jahdali, MD, PhD         
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

No publications provided

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
Study First Received: July 1, 2009
Last Updated: January 20, 2014
Health Authority: Canada: Health Canada

Keywords provided by McGill University:
Tuberculosis

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

ClinicalTrials.gov processed this record on August 26, 2014