Isoniazid Plus Antiretroviral Therapy to Prevent Tuberculosis in HIV-infected Persons

NCT ID: NCT00463086

Last Updated: 2012-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 1368 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-11-30
• Study Completion Date: 2011-11-30

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

1.Isoniazid (INH)

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)

Group Type: EXPERIMENTAL

isoniazid

Intervention Type: DRUG

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)

2. Placebo

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)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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)

Interventions

isoniazid

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

Placebo

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)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. 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.

2. Willingness to participate

3. Able to engage in informed consent procedures

Exclusion Criteria

1. Evidence of active TB or suspicion of active TB as determined by a symptoms screening algorithm.

2. Current TB chemotherapy ( TB treatment completed in the preceding 30 days will not be an exclusion)

3. Current or previous treatment of latent TB infection since HIV infection (any duration)

4. Current treatment with fluoroquinolones or other antibiotics with significant anti-tuberculous activity currently being used to treat TB in South Africa

5. Past reaction/intolerance to INH.

6. Acute hepatitis or existing Grade III-IV peripheral neuropathy.

7. Pregnancy or < 6weeks post-partum period (Due to increased risk of hepatotoxicity).

8. Grade III or higher baseline abnormal liver function. (Note: toxicity grades are all according to ACTG toxicity tables for persons on ART).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medecins Sans Frontieres, Netherlands

OTHER

Sponsor Role: collaborator

Imperial College London

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: collaborator

University of Cape Town

OTHER

Sponsor Role: lead

Responsible Party

Prof Gary Maartens

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gary Maartens (overall PI), FCP

Role: PRINCIPAL_INVESTIGATOR

University of Cape Town

Eric Goemaere (co-investigator), MBBS

Role: STUDY_DIRECTOR

Medecins Sans Frontieres, Netherlands

Molebogeng X Rangaka (Lead Investigator), MBChB

Role: STUDY_DIRECTOR

University of Cape Town

Gilles van Cutsem co-investigator), MBBS

Role: STUDY_DIRECTOR

Medecins Sans Frontieres, Netherlands

Andrew Boulle co-investigator), FCP

Role: STUDY_DIRECTOR

University of Cape Town

Robert J Wilkinson (PI:Immunology Studies), FRCP

Role: STUDY_DIRECTOR

Wellcome Trust

Shahied Mathee (Ubuntu PMO), MBChB

Role: STUDY_DIRECTOR

Provincial Government of Western Cape

Locations

Ubuntu Clinic,Site B Khayelitsha

Cape Town, Western Cape, South Africa

Countries

South Africa

References

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.

Reference Type: DERIVED

PMID: 24835842 (View on PubMed)

Other Identifiers

HAARTIPT07

Identifier Type: -

Identifier Source: org_study_id