Randomized Clinical Trial Comparing 4RIF vs. 9INH for LTBI Treatment-effectiveness
|First Submitted Date ICMJE||July 1, 2009|
|First Posted Date ICMJE||July 2, 2009|
|Last Update Posted Date||June 7, 2017|
|Actual Start Date ICMJE||August 2009|
|Primary Completion Date||April 2017 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Confirmed active TB during 28 months after randomization [ Time Frame: 7 years total with data analysis ]
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).
|Original Primary Outcome Measures ICMJE
||To compare the cumulative incidence during 28 months following randomization, of confirmed active tuberculosis among all persons randomized to 4RIF and 9INH (effectiveness). [ Time Frame: 7 years ]|
|Change History||Complete list of historical versions of study NCT00931736 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
||To compare the cumulative incidence of probable, as well as confirmed active TB between patients randomized to the two regimens during 28 months following randomization. [ Time Frame: 7 years ]|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Randomized Clinical Trial Comparing 4RIF vs. 9INH for LTBI Treatment-effectiveness|
|Official Title ICMJE||A Randomized Clinical Trial of 4 Months of Rifampin vs. 9 Months of Isoniazid for Latent Tuberculosis Infection. Part 3 - Effectiveness|
|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.|
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. Of these 8 million develop active disease, and 2 million die from TB each year. In Canada, and most other industrialized countries, the incidence of TB fell dramatically from 1900 until the late 1970's, but since then decline has slowed, and TB continues to cause significant morbidity, and mortality in disadvantaged populations.
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). 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.
The investigators have initiated a research program to evaluate the compliance, safety, costs and effectiveness of 4RIF for the treatment of LTBI. In the initial study of 116 patients, 4RIF was associated with significantly higher completion rates (90% vs 70%). The second phase of this study, conducted in Montreal, Toronto, Kingston, Saskatoon, Calgary, and Edmonton, plus Brazil and Saudi Arabia, compared the rates of serious adverse events (SAE) with the two regimens. These were adjudicated by an independent three member review panel, blinded to study drug. In this phase, among 420 subjects randomized to 4RIF overall rate of Grade 3-4 SAE was 2.4% compared to 5.6% among the 427 taking 9INH (p=.02). Grade 3-4 hepatotoxicity was very significantly lower (0.7% vs 3.8%; p=.003). Health system costs were also significantly lower, and completion rates significantly higher with 4RIF Therefore the conditions have been met to conduct the first randomized trial that will compare effectiveness of 4RIF and 9INH in preventing tuberculosis. Among the moderate to high risk subjects that will be eligible, the anticipated cumulative risk of active TB, if untreated, will be at least 3% during a follow-up of 28 months after randomization. We anticipate 50% completion rate with 9INH, providing an effectiveness of 45% (based on known efficacy of 90%). To detect superior effectiveness of 4RIF, assuming 80% completion, and 10% loss in follow-up, plus accounting for cluster randomization of household contacts we would require enrolment of 3283 subjects per arm, or a total of 6,566 subjects. This is reduced to 5720, because the 847 already randomized in Phase 2, were randomized, treated and followed for 28 months post-randomization to determine occurrence of active TB - using the same methods described in this proposal.
Eligible consenting subjects will be randomized in equal numbers to 9INH or 4RIF, by a web-based registration and randomization program, stratified by site in blocks of variable size (2-8 subjects). Subjects will be followed by their usual providers during therapy and then every 3 months up to 28 months post-randomization or the occurrence of a study end-point. The primary study outcome is the occurrence, during the 28 months after randomization, of microbiologically or histologically confirmed active TB. The final diagnosis will be based on the majority opinion of an independent 3-member clinical review panel, who will review all subjects investigated for TB, without knowledge of study drug, nor the clinical diagnosis. Planned sub-group analysis will compare rates of active TB in those who complete treatment per protocol (efficacy). Secondary outcomes include occurrence of confirmed plus probable active TB, Grade 3-4 adverse events (judged by another blinded, independent 3-member panel as in Phase 2), occurrence of drug resistant active TB, and costs - from the health system perspective. To accomplish this, in Canada one site has been added in Vancouver, the site in Brazil is doubled, and new sites in Korea, Australia, Indonesia, Benin, Guinea and Ghana (West Africa) have been added.
In addition to the parent trial, the investigators will include an additional component called "the Biomarker Study". For this part of the study the investigators will take an additional 10 mls of blood pre-treatment, as well as at four and nine months after starting treatment. In total an extra 30ml of blood (equal to 2 tablespoons) will be required over 9 months, and two additional veni-punctures, since veni-punctures will not be routinely performed at the 4 and 9 month time points. Three of the 10 ml will be used for the QFT-GIT test, the remaining 7 ml will have the serum separated and stored at -80°C for future biomarker studies. For subjects who were randomized to 4RIF, the blood draw at nine months will require an extra visit to the clinic, for which study subjects will be compensated. No specimens will be stored for future genetic testing. For the present time only the Montreal site will participate in this component. Other sites will join once funding is secured. All lab assays will be performed in the final year of the study, to enhance cost-effectiveness.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Latent Tuberculosis Infection|
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||April 2017|
|Primary Completion Date||April 2017 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Korea, Republic of, Saudi Arabia|
|Removed Location Countries|
|NCT Number ICMJE||NCT00931736|
|Other Study ID Numbers ICMJE||MCT-94831
ISRCTN05675547 ( Other Grant/Funding Number: MCT-94831 )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||Dr. Dick Menzies, McGill University|
|Study Sponsor ICMJE||McGill University|
|Collaborators ICMJE||Canadian Institutes of Health Research (CIHR)|
|PRS Account||McGill University|
|Verification Date||June 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP