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Rifampin Versus Isoniazid for the Treatment of Latent Tuberculosis Infection in Children (P4v9)

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ClinicalTrials.gov Identifier: NCT00170209
Recruitment Status : Completed
First Posted : September 15, 2005
Last Update Posted : December 19, 2017
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Dr. Dick Menzies, McGill University

Brief Summary:

Tuberculosis (TB) is spread by airborne transmission from adults with active contiguous TB to children, especially those living in the same household. Once children are exposed and infected they are at very high risk to develop active TB - which can be lethal if not detected and treated promptly. This makes it very important to detect TB infection as soon as possible, and treat this while it is still latent or dormant. Current therapy for latent TB infection is 9 months of Isoniazid; this is very effective if taken properly but because treatment is so long many children do not finish this. Four months of Rifampin is a recommended alternative. In adults this has been shown to be safer with much higher completion rates. However the effectiveness of this treatment is unclear, and is being studied in an ongoing study. The investigators plan to compare the safety as well as the acceptability and effectiveness of 4 months Rifampin with 9 months Isoniazid (standard treatment) in children in several sites in Canada and other countries.

It is hypothesized that among children at high risk for development of active TB, intolerance/adverse events will not be worse (non-inferiority), among those randomized to 4RIF compared to those randomized to 9INH. In addition completion of latent tuberculosis infection (LTBI) therapy will be significantly greater (superiority), and subsequent rates of active TB will not be significantly higher (non-inferiority) in children taking 4RIF.

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

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Study Type : Interventional
Actual Enrollment : 844 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Trial to Compare Effectiveness of 4 Months Rifampin (4 RIF) With 9 Months Isoniazid (9 INH) in the Prevention of Active TB in Children: The P4v9 Trial
Study Start Date : August 2011
Actual Primary Completion Date : November 2014
Actual Study Completion Date : May 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Active Comparator: Isoniazid
The standard therapy will be daily self-administered INH, 10-15 mg/kg/day (max=300mg/day) for 9 months (9INH).
Drug: Isoniazid
The dosage of the medication is determined according to the weight of the child. The dose is once per day, 10-15 mg/kg/day (max=300mg/day). Total duration of treatment is 9 months. Both a detailed dose chart calculating doses by weight and age and protocols for preparation of medications (crushing pills, mixing suspensions) are available.

Active Comparator: Rifampin
The experimental arm will be daily self-administered RIF 10-20 mg/kg/day for 4 months (4RIF).
Drug: Rifampin
The dosage of the medication is determined according to the weight of the child. The dose is once per day, 10-20 mg/kg/day (max=600mg/day). Total duration of treatment is 4 months. Both a detailed dose chart calculating doses by weight and age and protocols for preparation of medications (crushing pills, mixing suspensions) are available.

Primary Outcome Measures :
  1. Adverse events of all grades [ Time Frame: Treatment duration ]
    The outcome of intolerability/adverse events (or the 'inverse' of safety) will include adverse events of all levels of severity (Grades 1 to 5) that resulted in permanent discontinuation of study drug, that were judged probably related to the study drug by a majority (2 out of 3) of the independent review panel members.

Secondary Outcome Measures :
  1. Rates of drug completion (compliance) [ Time Frame: Treatment duration ]
    To compare the rates of study drug completion of all children randomized to 4RIF or 9INH. Completion will be defined as taking at least 80% of total planned doses within 23 weeks for 4RIF, or within 52 weeks for 9INH.

  2. Confirmed active TB during 16 months after randomization (efficacy) [ Time Frame: 16 months post-randomization ]
    To compare the rates of clinically diagnosed active TB as judged by an independent panel of pediatricians, up to 16 months post-randomization in children who complete study therapy per protocol.

  3. Occurrence of drug resistance in confirmed cases of active TB [ Time Frame: 16 months post-randomization ]
    To describe the occurrence of drug-resistant, microbiologically confirmed active TB among children randomized to the two arms, during 16 months post-randomization.

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Children (age <18) with documented positive TST (or in the absence of TST, a positive QFT or T-Spot) and prescribed 9INH for LTBI for the following indications:

    1. HIV positive (TST >5 mm or QFT+)
    2. Age 5 or less (TST >5 mm or QFT+)
    3. Other reason for immuno-compromised state - such as therapy for malignancy or post-transplant (TST >5 mm or QFT+)
    4. Contact: with adult or adolescent with active contagious pulmonary TB. (TST >5 mm or QFT +)
    5. Have both of the following factors if TST = 10-14mm or QFT + or one factor if TST >15mm :

      1. Arrival in Canada, Australia, or Saudi Arabia in the past 2 years from countries with estimated annual incidence of active TB greater than 100 per 100,000
      2. Body mass index (BMI) less than 10th percentile for their age

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.
  • Prior complete LTBI therapy or if children have taken >1 week and are still taking the treatment. Children will be eligible if they took an incomplete LTBI therapy (less than 80% of recommended total dose) but > 6 months ago.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00170209

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Australia, New South Wales
Woolcock Institute of Medical Research
Sydney, New South Wales, Australia
Centre de Pneumophthysiologie
Cotonou, Benin
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 Children's Hospital
Montreal, Quebec, Canada, H2X 2P4
Research and Development Unit, Komfo Anokye Teaching Hospital
Kumasi, Ghana
Service de Pneumo-Phtisiologie, Hopital National Ignace Deen
Conakry, Africa, Guinea
Health Research Unit, Faculty of Medicine
Bandung, West Java, Indonesia
Sponsors and Collaborators
McGill University
Canadian Institutes of Health Research (CIHR)
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Principal Investigator: Dick Menzies, MD, MSc McGill University Health Centre/Research Institute of the McGill University Health Centre
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Dr. Dick Menzies, Director of Respiratory Medicine, McGill University
ClinicalTrials.gov Identifier: NCT00170209    
Other Study ID Numbers: MCT-44154
First Posted: September 15, 2005    Key Record Dates
Last Update Posted: December 19, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Dr. Dick Menzies, McGill University:
Additional relevant MeSH terms:
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Latent Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Latent Infection
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
Lipid Regulating Agents