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

NCT00170209 | Completed Phase 3 DMC

• 1 other identifier: MCT-44154
• Study Type: interventional
• Target: 844
• Locations: 7 countries
• Sites: 9

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.

Conditions

Latent Tuberculosis Infection

Keywords

Tuberculosis; Children

Outcome Measures

Primary Outcomes (1)

• Adverse events of all grades

  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.

  Treatment duration

Secondary Outcomes (3)

• Rates of drug completion (compliance)

  Treatment duration

• Confirmed active TB during 16 months after randomization (efficacy)

  16 months post-randomization

• Occurrence of drug resistance in confirmed cases of active TB

  16 months post-randomization

Study Arms (2)

Isoniazid

ACTIVE COMPARATOR

The standard therapy will be daily self-administered INH, 10-15 mg/kg/day (max=300mg/day) for 9 months (9INH).

Drug: Isoniazid

Rifampin

ACTIVE COMPARATOR

The experimental arm will be daily self-administered RIF 10-20 mg/kg/day for 4 months (4RIF).

Drug: Rifampin

Interventions

Isoniazid DRUG

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.

Isoniazid

Rifampin DRUG

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.

Rifampin

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:
• HIV positive (TST \>5 mm or QFT+)
• Age 5 or less (TST \>5 mm or QFT+)
• Other reason for immuno-compromised state - such as therapy for malignancy or post-transplant (TST \>5 mm or QFT+)
• Contact: with adult or adolescent with active contagious pulmonary TB. (TST \>5 mm or QFT +)
• Have both of the following factors if TST = 10-14mm or QFT + or one factor if TST \>15mm :
• 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
• Body mass index (BMI) less than 10th percentile for their age

You may not qualify if:

• 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.

Sponsors & Collaborators

• McGill University: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (9)

Woolcock Institute of Medical Research

Sydney, New South Wales, Australia

Location

Centre de Pneumophthysiologie

Cotonou, Benin

Location

Universidade Gama Filho, Centro de Ciências Biológicas e da Saúde

Rio de Janeiro, Brazil

Location

University of Alberta

Edmonton, Alberta, Canada

Location

British Columbia Centre for Disease Control

Vancouver, British Columbia, Canada

Location

Montreal Children's Hospital

Montreal, Quebec, H2X 2P4, Canada

Location

Research and Development Unit, Komfo Anokye Teaching Hospital

Kumasi, Ghana

Location

Service de Pneumo-Phtisiologie, Hopital National Ignace Deen

Conakry, Africa, Guinea

Location

Health Research Unit, Faculty of Medicine

Bandung, West Java, Indonesia

Location

Related Publications (7)

• Allard-Gray A, Boakye I, Camara A, Eisenbeis L, Guimaraes-Teixeira E, Sow O, Zielinski D, Campbell JR, Menzies D. Factors Associated With Discontinuation of Tuberculosis Preventive Treatment: Post Hoc Analysis of 2 Randomized, Controlled Trials. Clin Infect Dis. 2023 Jul 5;77(1):84-93. doi: 10.1093/cid/ciad164.

  PMID: 36949623 DERIVED

• Campbell JR, Al-Jahdali H, Bah B, Belo M, Cook VJ, Long R, Schwartzman K, Trajman A, Menzies D. Safety and Efficacy of Rifampin or Isoniazid Among People With Mycobacterium tuberculosis Infection and Living With Human Immunodeficiency Virus or Other Health Conditions: Post Hoc Analysis of 2 Randomized Trials. Clin Infect Dis. 2021 Nov 2;73(9):e3545-e3554. doi: 10.1093/cid/ciaa1169.

  PMID: 32785709 DERIVED

• Bastos ML, Campbell JR, Oxlade O, Adjobimey M, Trajman A, Ruslami R, Kim HJ, Baah JO, Toelle BG, Long R, Hoeppner V, Elwood K, Al-Jahdali H, Apriani L, Benedetti A, Schwartzman K, Menzies D. Health System Costs of Treating Latent Tuberculosis Infection With Four Months of Rifampin Versus Nine Months of Isoniazid in Different Settings. Ann Intern Med. 2020 Aug 4;173(3):169-178. doi: 10.7326/M19-3741. Epub 2020 Jun 16.

  PMID: 32539440 DERIVED

• Campbell JR, Trajman A, Cook VJ, Johnston JC, Adjobimey M, Ruslami R, Eisenbeis L, Fregonese F, Valiquette C, Benedetti A, Menzies D. Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled trials. Lancet Infect Dis. 2020 Mar;20(3):318-329. doi: 10.1016/S1473-3099(19)30575-4. Epub 2019 Dec 19.

  PMID: 31866327 DERIVED

• Diallo T, Adjobimey M, Ruslami R, Trajman A, Sow O, Obeng Baah J, Marks GB, Long R, Elwood K, Zielinski D, Gninafon M, Wulandari DA, Apriani L, Valiquette C, Fregonese F, Hornby K, Li PZ, Hill PC, Schwartzman K, Benedetti A, Menzies D. Safety and Side Effects of Rifampin versus Isoniazid in Children. N Engl J Med. 2018 Aug 2;379(5):454-463. doi: 10.1056/NEJMoa1714284.

  PMID: 30067928 DERIVED

• Lee SJ, Lee SH, Kim YE, Cho YJ, Jeong YY, Kim HC, Lee JD, Kim JR, Hwang YS, Kim HJ, Menzies D. Risk factors for latent tuberculosis infection in close contacts of active tuberculosis patients in South Korea: a prospective cohort study. BMC Infect Dis. 2014 Nov 18;14:566. doi: 10.1186/s12879-014-0566-4.

  PMID: 25404412 DERIVED

• Aspler A, Long R, Trajman A, Dion MJ, Khan K, Schwartzman K, Menzies D. Impact of treatment completion, intolerance and adverse events on health system costs in a randomised trial of 4 months rifampin or 9 months isoniazid for latent TB. Thorax. 2010 Jul;65(7):582-7. doi: 10.1136/thx.2009.125054.

  PMID: 20627913 DERIVED

MeSH Terms

Conditions

Latent Tuberculosis; Tuberculosis

Interventions

Isoniazid; Rifampin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Dick Menzies, MD, MSc

  McGill University Health Centre/Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Respiratory Medicine

Study Record Dates

• First Submitted: September 12, 2005
• First Posted: September 15, 2005
• Study Start: August 1, 2011
• Primary Completion: November 1, 2014
• Study Completion: May 1, 2015
• Last Updated: December 19, 2017

Record last verified: 2017-12

Locations

BE (1); BR (1); CA (3); GH (1); AU (1); GU (1); ID (1)