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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT00931736
Registration number
NCT00931736
Ethics application status
Date submitted
1/07/2009
Date registered
2/07/2009
Titles & IDs
Public title
Randomized Clinical Trial Comparing 4RIF vs. 9INH for LTBI Treatment-effectiveness
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Scientific title
A Randomized Clinical Trial of 4 Months of Rifampin vs. 9 Months of Isoniazid for Latent Tuberculosis Infection. Part 3 - Effectiveness
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Secondary ID [1]
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ISRCTN05675547
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Secondary ID [2]
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MCT-94831
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Latent Tuberculosis Infection
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Condition category
Condition code
Infection
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Studies of infection and infectious agents
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Infection
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Other infectious diseases
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Respiratory
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Other respiratory disorders / diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
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.
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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Confirmed active TB during 28 months after randomization
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Assessment method [1]
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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).
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Timepoint [1]
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7 years total with data analysis
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Secondary outcome [1]
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Confirmed active TB in compliant participants
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Assessment method [1]
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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 ).
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Timepoint [1]
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7 years total with data analysis
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Secondary outcome [2]
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Probable and confirmed active TB
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Assessment method [2]
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Compare the cumulative incidence of probable, as well as confirmed, active TB between patients randomized to the two regimens during 28 months following randomization.
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Timepoint [2]
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7 years total with data analysis
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Secondary outcome [3]
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Rate of Grade 3 & 4 adverse events
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Assessment method [3]
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Compare rates of Grades 3 \&4 adverse events during treatment between subjects randomized to the two regimens.
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Timepoint [3]
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7 years including data analysis
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Secondary outcome [4]
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Comparative cost-effectiveness of regimens
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Assessment method [4]
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Compare health system costs, and cost-effectiveness of the two regimens, in the different sites.
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Timepoint [4]
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7 years including data analysis
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Secondary outcome [5]
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Occurrence of drug resistance in confirmed cases of active TB
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Assessment method [5]
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Describe occurrence of drug resistance (to INH or RIF) among subjects who develop confirmed active TB.
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Timepoint [5]
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7 years including data analysis
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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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/08/2009
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/04/2017
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Sample size
Target
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Accrual to date
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Final
6031
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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Woolcock Institute of Medical Research - Sydney
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Recruitment postcode(s) [1]
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- Sydney
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Recruitment outside Australia
Country [1]
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Benin
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State/province [1]
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Cotonou
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Country [2]
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Brazil
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State/province [2]
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Rio de Janeiro
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Canada
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State/province [3]
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Alberta
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Country [4]
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Canada
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State/province [4]
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British Columbia
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Country [5]
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Canada
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Quebec
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Canada
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State/province [6]
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Saskatchewan
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Country [7]
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Ghana
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State/province [7]
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Kumasi
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Country [8]
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Guinea
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State/province [8]
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Conakry
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Country [9]
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Indonesia
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State/province [9]
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West Java
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Country [10]
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Korea, Republic of
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State/province [10]
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Seoul
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Country [11]
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Saudi Arabia
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State/province [11]
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Riyadh
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Funding & Sponsors
Primary sponsor type
Other
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Name
McGill University
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Address
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Country
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Other collaborator category [1]
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Government body
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Name [1]
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Canadian Institutes of Health Research (CIHR)
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Address [1]
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Ethics approval
Ethics application status
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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.
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Trial website
https://clinicaltrials.gov/study/NCT00931736
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Trial related presentations / publications
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. 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. 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. Menzies D, Adjobimey M, Ruslami R, Trajman A, Sow O, Kim H, Obeng Baah J, Marks GB, Long R, Hoeppner V, Elwood K, Al-Jahdali H, Gninafon M, Apriani L, Koesoemadinata RC, Kritski A, Rolla V, Bah B, Camara A, Boakye I, Cook VJ, Goldberg H, Valiquette C, Hornby K, Dion MJ, Li PZ, Hill PC, Schwartzman K, Benedetti A. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. N Engl J Med. 2018 Aug 2;379(5):440-453. doi: 10.1056/NEJMoa1714283.
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Public notes
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Contacts
Principal investigator
Name
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Dick Menzies, MD
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Address
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McGill University / McGill University Health Centre
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT00931736