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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Dr. Dick Menzies, McGill University
ClinicalTrials.gov Identifier:
NCT00170209
First received: September 12, 2005
Last updated: January 20, 2014
Last verified: January 2014
  Purpose

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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by McGill University:

Primary Outcome Measures:
  • Adverse events of all grades [ Time Frame: Treatment duration ] [ Designated as safety issue: Yes ]
    The outcome of intolerability/adverse events (or the 'inverse' of safety) will include adverse events of all levels of severity (Grades 1 to 4) 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:
  • Rates of drug completion (compliance) [ Time Frame: Treatment duration ] [ Designated as safety issue: No ]
    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.

  • Confirmed active TB during 16 months after randomization (efficacy) [ Time Frame: 16 months post-randomization ] [ Designated as safety issue: No ]
    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.

  • Occurrence of drug resistance in confirmed cases of active TB [ Time Frame: 16 months post-randomization ] [ Designated as safety issue: No ]
    To describe the occurrence of drug-resistant, microbiologically confirmed active TB among children randomized to the two arms, during 16 months post-randomization.


Estimated Enrollment: 822
Study Start Date: August 2011
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 standard therapy will be daily self-administered INH, 5 mg/kg/day (max=300mg/day) for 9 months (9INH). Dosage will be adjusted if weight is less than 42 kg at 200mg/day for 9 months.
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 mg/kg/day for 4 months (4RIF). Dosage will be adjusted if weight is 36-49 kg at 450 mg/day or at 300 mg/day for weight of 35 kg and less.
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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  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: NCT00170209

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 Children's Hospital
Montreal, Quebec, Canada, H2X 2P4
Ghana
Research and Development Unit, Komfo Anokye Teaching Hospital
Kumasi, Ghana
Guinea
Service de Pneumo-Phtisiologie, Hopital National Ignace Deen
Conakry, Africa, Guinea
Indonesia
Health Research Unit, Faculty of Medicine
Bandung, West Java, Indonesia
Sponsors and Collaborators
McGill University
Canadian Institutes of Health Research (CIHR)
Investigators
Principal Investigator: Dick Menzies, MD, MSc McGill University Health Center
  More Information

No publications provided by McGill University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dr. Dick Menzies, Director of Respiratory Medicine, McGill University
ClinicalTrials.gov Identifier: NCT00170209     History of Changes
Other Study ID Numbers: MCT-44154
Study First Received: September 12, 2005
Last Updated: January 20, 2014
Health Authority: Canada: Canadian Institutes of Health Research

Keywords provided by McGill University:
Tuberculosis
Children

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

ClinicalTrials.gov processed this record on July 22, 2014