Isoniazid Plus Antiretroviral Therapy to Prevent Tuberculosis in HIV-infected Persons (HAART-IPT)
Primary Purpose
Tuberculosis, Latent Tuberculosis Infection, HIV Infections
Status
Completed
Phase
Not Applicable
Locations
South Africa
Study Type
Interventional
Intervention
isoniazid
Placebo
Sponsored by
About this trial
This is an interventional prevention trial for Tuberculosis focused on measuring Tuberculosis, TB, Mycobacteria, HIV, Human immunodeficiency virus, Latent tuberculosis infection, HAART, Highly active anti-retroviral therapy, Isoniazid preventive therapy, INH, Opportunistic infections, HIV-1, Treatment Experienced, AIDS, Mycobacterium Tuberculosis
Eligibility Criteria
Inclusion Criteria:
- Male and female attendees (age ≥18yo) of the Ubuntu HIV and ARV Clinic identified as eligible for the ARV programme will be invited to participate.
- Willingness to participate
- Able to engage in informed consent procedures
Exclusion Criteria:
- Evidence of active TB or suspicion of active TB as determined by a symptoms screening algorithm.
- Current TB chemotherapy ( TB treatment completed in the preceding 30 days will not be an exclusion)
- Current or previous treatment of latent TB infection since HIV infection (any duration)
- Current treatment with fluoroquinolones or other antibiotics with significant anti-tuberculous activity currently being used to treat TB in South Africa
- Past reaction/intolerance to INH.
- Acute hepatitis or existing Grade III-IV peripheral neuropathy.
- Pregnancy or < 6weeks post-partum period (Due to increased risk of hepatotoxicity).
- Grade III or higher baseline abnormal liver function. (Note: toxicity grades are all according to ACTG toxicity tables for persons on ART).
Sites / Locations
- Ubuntu Clinic,Site B Khayelitsha
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
1.Isoniazid (INH)
2. Placebo
Arm Description
A self-administered daily dose of 5mg/kg of Isoniazid (300mg if weight is more than or equal to 50kg and 200mg if weight is less than 50kg)
A self-administered daily dose of 5mg/kg of placebo for 12months (300mg if weight is more than or equal to 50kg and 200mg if weight is less than 50kg)
Outcomes
Primary Outcome Measures
Rate of development of TB (microbiologically confirmed TB or highly probable TB) during the 36 month risk period
Secondary Outcome Measures
Rate of drug toxicity (specifically, peripheral neuropathy, hepatitis +/-raised ALT grade III or worse and allergic rashes grade III or worse
Proportions adhering to study drug and HAART at the end of each study year as measured by pharmacy refills
Rate of development of INH monoresistance during the 36 month risk period.
Death
Worsening ART outcomes (virological and immunological failure)
Full Information
NCT ID
NCT00463086
First Posted
April 19, 2007
Last Updated
July 16, 2012
Sponsor
University of Cape Town
Collaborators
Medecins Sans Frontieres, Netherlands, Imperial College London, Johns Hopkins University, London School of Hygiene and Tropical Medicine
1. Study Identification
Unique Protocol Identification Number
NCT00463086
Brief Title
Isoniazid Plus Antiretroviral Therapy to Prevent Tuberculosis in HIV-infected Persons
Acronym
HAART-IPT
Official Title
A Randomized-controlled Trial of Isoniazid Plus Highly Active Antiretroviral Therapy Against Placebo to Prevent Tuberculosis in HIV-infected Persons
Study Type
Interventional
2. Study Status
Record Verification Date
July 2012
Overall Recruitment Status
Completed
Study Start Date
November 2007 (undefined)
Primary Completion Date
November 2011 (Actual)
Study Completion Date
November 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cape Town
Collaborators
Medecins Sans Frontieres, Netherlands, Imperial College London, Johns Hopkins University, London School of Hygiene and Tropical Medicine
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to evaluate whether isoniazid can safely (and further) reduce the risk of tuberculosis in HIV infected people receiving HAART.
Detailed Description
The incidence of Tuberculosis (TB) in poor settlements around Cape Town continues to rise despite highly-active-anti-retroviral therapy (HAART) roll-out and DOTS. In Khayelitsha district, where this project will be conducted, TB incidence is about 1600/100000. There is an equally high HIV prevalence, currently 33%. Over 50% of adults presenting with active TB are co-infected with HIV and a third of all patients starting HAART have active TB. Although HAART has been shown to reduce the overall risk of TB by 59-80%, this risk still far exceeds the general risk. In the Khayelitsha HAART cohort, the risk of developing TB whilst on HAART is ~12 per 100 p-y. In the nearby community of Gugulethu, there is a 14% risk of active TB with at least half of the cases occurring within the first 3months on HAART. In a region where RD1-detected prevalence of latent TB infection is at least 80%, there is a real concern that TB will likely undo the benefit of HAART in the long run. Additional measures are therefore required to reduce the risk of TB in those already receiving or starting HAART. Isoniazid preventive therapy (IPT) represents an option but there is insufficient evidence to determine whether IPT can further (and safely) reduce the risk of TB in the HAART era. In a RCT, we propose to evaluate whether IPT can reduce the risk of active TB in patients receiving HAART.
A total minimum sample size of 1204 is required for the study to detect a 35% reduction in the hazard rates for tuberculosis in the intervention group (h1= 0.052) compared to the control group (h0=0.085) at a power of 80% and a Type II error of 0.05. Our maximum targeted sample size when losses to follow-up and subgroup analyses are considered is 1445. Development of TB will be the primary endpoint.
Additional information (on 10 August 2010):
Recruitment and enrolment into the study was completed in October 2009. We have screened over 2000 patients already on ART and those newly starting ART. However, instead of enrolling our desired maximum sample size of 1445, a revised minimum total of 1368 were instead randomized to the study drug. This followed an amendment to the sample size necessitated by new information on the clinical site; primarily higher rates of patients lost to follow-up at the clinical site than previously anticipated. The amendment to our sample size was reported to, and acknowledged by, the Research Ethics Committee of the University of Cape Town. Follow-up of participants will continue until Oct/November 2011.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Latent Tuberculosis Infection, HIV Infections
Keywords
Tuberculosis, TB, Mycobacteria, HIV, Human immunodeficiency virus, Latent tuberculosis infection, HAART, Highly active anti-retroviral therapy, Isoniazid preventive therapy, INH, Opportunistic infections, HIV-1, Treatment Experienced, AIDS, Mycobacterium Tuberculosis
7. Study Design
Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1368 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1.Isoniazid (INH)
Arm Type
Experimental
Arm Description
A self-administered daily dose of 5mg/kg of Isoniazid (300mg if weight is more than or equal to 50kg and 200mg if weight is less than 50kg)
Arm Title
2. Placebo
Arm Type
Placebo Comparator
Arm Description
A self-administered daily dose of 5mg/kg of placebo for 12months (300mg if weight is more than or equal to 50kg and 200mg if weight is less than 50kg)
Intervention Type
Drug
Intervention Name(s)
isoniazid
Intervention Description
A self-administered daily dose of 5mg/kg of Isoniazid or placebo for 12months(300mg if weight is more than or equal to 50kg and 200mg if weight is less than 50kg)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
A self-administered dose of 5mg/kg of placebo (300mg if weight is more than or equal to 50kg and 200mg if weight is less than 50kg)
Primary Outcome Measure Information:
Title
Rate of development of TB (microbiologically confirmed TB or highly probable TB) during the 36 month risk period
Time Frame
Patients are assessed for TB one two monthly at each ART re-fill appointment
Secondary Outcome Measure Information:
Title
Rate of drug toxicity (specifically, peripheral neuropathy, hepatitis +/-raised ALT grade III or worse and allergic rashes grade III or worse
Time Frame
during the intervention period (ALT determined at baseline, 1, 2 and 3 months and then 3-monthly. the last safety determination is at 12 months post initiation of the study drug)
Title
Proportions adhering to study drug and HAART at the end of each study year as measured by pharmacy refills
Time Frame
1 month to two monthly, depending on the individual patient's clinic appointment
Title
Rate of development of INH monoresistance during the 36 month risk period.
Time Frame
36 months
Title
Death
Time Frame
36 months
Title
Worsening ART outcomes (virological and immunological failure)
Time Frame
CD4+count and viral load are assessed as per clinic protocol (6 monthly post ART initiation)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male and female attendees (age ≥18yo) of the Ubuntu HIV and ARV Clinic identified as eligible for the ARV programme will be invited to participate.
Willingness to participate
Able to engage in informed consent procedures
Exclusion Criteria:
Evidence of active TB or suspicion of active TB as determined by a symptoms screening algorithm.
Current TB chemotherapy ( TB treatment completed in the preceding 30 days will not be an exclusion)
Current or previous treatment of latent TB infection since HIV infection (any duration)
Current treatment with fluoroquinolones or other antibiotics with significant anti-tuberculous activity currently being used to treat TB in South Africa
Past reaction/intolerance to INH.
Acute hepatitis or existing Grade III-IV peripheral neuropathy.
Pregnancy or < 6weeks post-partum period (Due to increased risk of hepatotoxicity).
Grade III or higher baseline abnormal liver function. (Note: toxicity grades are all according to ACTG toxicity tables for persons on ART).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gary Maartens (overall PI), FCP
Organizational Affiliation
University of Cape Town
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Eric Goemaere (co-investigator), MBBS
Organizational Affiliation
Medecins Sans Frontieres, Netherlands
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Molebogeng X Rangaka (Lead Investigator), MBChB
Organizational Affiliation
University of Cape Town
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Gilles van Cutsem co-investigator), MBBS
Organizational Affiliation
Medecins Sans Frontieres, Netherlands
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Andrew Boulle co-investigator), FCP
Organizational Affiliation
University of Cape Town
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Robert J Wilkinson (PI:Immunology Studies), FRCP
Organizational Affiliation
Wellcome Trust
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Shahied Mathee (Ubuntu PMO), MBChB
Organizational Affiliation
Provincial Government of Western Cape
Official's Role
Study Director
Facility Information:
Facility Name
Ubuntu Clinic,Site B Khayelitsha
City
Cape Town
State/Province
Western Cape
Country
South Africa
12. IPD Sharing Statement
Citations:
PubMed Identifier
24835842
Citation
Rangaka MX, Wilkinson RJ, Boulle A, Glynn JR, Fielding K, van Cutsem G, Wilkinson KA, Goliath R, Mathee S, Goemaere E, Maartens G. Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. Lancet. 2014 Aug 23;384(9944):682-90. doi: 10.1016/S0140-6736(14)60162-8. Epub 2014 May 13.
Results Reference
derived
Learn more about this trial
Isoniazid Plus Antiretroviral Therapy to Prevent Tuberculosis in HIV-infected Persons
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