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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00931736




Registration number
NCT00931736
Ethics application status
Date submitted
1/07/2009
Date registered
1/07/2009
Date last updated
15/12/2017

Titles & IDs
Public title
Randomized Clinical Trial Comparing 4RIF vs. 9INH for LTBI Treatment-effectiveness
Scientific title
A Randomized Clinical Trial of 4 Months of Rifampin vs. 9 Months of Isoniazid for Latent Tuberculosis Infection. Part 3 - Effectiveness
Secondary ID [1] 0 0
ISRCTN05675547
Secondary ID [2] 0 0
MCT-94831
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Latent Tuberculosis Infection 0 0
Latent Tuberculosis Infection 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases
Infection 0 0 0 0
Studies of infection and infectious agents
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Isoniazid
Treatment: Drugs - Rifampin
Treatment: Drugs - Isoniazid
Treatment: Drugs - Rifampin

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.

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.

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.

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.


Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Confirmed active TB during 28 months after randomization - 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).
Timepoint [1] 0 0
7 years total with data analysis
Primary outcome [2] 0 0
Confirmed active TB during 28 months after randomization - 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).
Timepoint [2] 0 0
7 years total with data analysis
Secondary outcome [1] 0 0
Confirmed active TB in compliant participants - 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 ).
Timepoint [1] 0 0
7 years total with data analysis
Secondary outcome [2] 0 0
Probable and confirmed active TB - Compare the cumulative incidence of probable, as well as confirmed, active TB between patients randomized to the two regimens during 28 months following randomization.
Timepoint [2] 0 0
7 years total with data analysis
Secondary outcome [3] 0 0
Rate of Grade 3 & 4 adverse events - Compare rates of Grades 3 &4 adverse events during treatment between subjects randomized to the two regimens.
Timepoint [3] 0 0
7 years including data analysis
Secondary outcome [4] 0 0
Comparative cost-effectiveness of regimens - Compare health system costs, and cost-effectiveness of the two regimens, in the different sites.
Timepoint [4] 0 0
7 years including data analysis
Secondary outcome [5] 0 0
Occurrence of drug resistance in confirmed cases of active TB - Describe occurrence of drug resistance (to INH or RIF) among subjects who develop confirmed active TB.
Timepoint [5] 0 0
7 years including data analysis
Secondary outcome [6] 0 0
Confirmed active TB in compliant participants - 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 ).
Timepoint [6] 0 0
7 years total with data analysis
Secondary outcome [7] 0 0
Probable and confirmed active TB - Compare the cumulative incidence of probable, as well as confirmed, active TB between patients randomized to the two regimens during 28 months following randomization.
Timepoint [7] 0 0
7 years total with data analysis
Secondary outcome [8] 0 0
Rate of Grade 3 & 4 adverse events - Compare rates of Grades 3 &4 adverse events during treatment between subjects randomized to the two regimens.
Timepoint [8] 0 0
7 years including data analysis
Secondary outcome [9] 0 0
Comparative cost-effectiveness of regimens - Compare health system costs, and cost-effectiveness of the two regimens, in the different sites.
Timepoint [9] 0 0
7 years including data analysis
Secondary outcome [10] 0 0
Occurrence of drug resistance in confirmed cases of active TB - Describe occurrence of drug resistance (to INH or RIF) among subjects who develop confirmed active TB.
Timepoint [10] 0 0
7 years including data analysis

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Woolcock Institute of Medical Research - Sydney
Recruitment postcode(s) [1] 0 0
- Sydney
Recruitment outside Australia
Country [1] 0 0
Benin
State/province [1] 0 0
Cotonou
Country [2] 0 0
Brazil
State/province [2] 0 0
Rio de Janeiro
Country [3] 0 0
Canada
State/province [3] 0 0
Alberta
Country [4] 0 0
Canada
State/province [4] 0 0
British Columbia
Country [5] 0 0
Canada
State/province [5] 0 0
Quebec
Country [6] 0 0
Canada
State/province [6] 0 0
Saskatchewan
Country [7] 0 0
Ghana
State/province [7] 0 0
Kumasi
Country [8] 0 0
Guinea
State/province [8] 0 0
Conakry
Country [9] 0 0
Indonesia
State/province [9] 0 0
West Java
Country [10] 0 0
Korea, Republic of
State/province [10] 0 0
Seoul
Country [11] 0 0
Saudi Arabia
State/province [11] 0 0
Riyadh

Funding & Sponsors
Primary sponsor type
Other
Name
McGill University
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Canadian Institutes of Health Research (CIHR)
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Canadian Institutes of Health Research (CIHR)
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/show/NCT00931736
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Dick Menzies, MD
Address 0 0
McGill University / McGill University Health Centre
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications