Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children
Recruitment status was Active, not recruiting
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The study involves use of isoniazid and cotrimoxazole as strategies for preventing infections in HIV-infected children and reducing mortality. Cotrimoxazole is well known to reduce mortality and infections in HIV-infected children and is currently the recommended standard of care. However, isoniazid has only been studied in HIV-infected adults (in whom it has been shown to substantially reduce the incidence of tuberculosis). In a randomised controlled study of isoniazid in HIV-infected children, the investigators found that INH reduced mortality and tuberculosis incidence in excess of 50%; the data safety monitoring board recommended termination of the placebo arm given the beneficial effects of INH. The investigators therefore aim to follow-up these children to compare the long term impact of two different INH and CTX preventive regimens (daily versus thrice weekly) on morbidity, mortality, adherence and incidence of adverse reactions. The investigators also aim to investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART as the benefit in this group is unknown.
Condition | Intervention | Phase |
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Tuberculosis |
Drug: Isoniazid Drug: Cotrimoxazole Drug: isoniazid Other: placebo |
Phase 3 |
Study Type: | Interventional |
Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Factorial Assignment Masking: Double-Blind Primary Purpose: Prevention |
Official Title: | Long Term Study of 2 Isoniazid (INH) Prophylactic Regimens With Concomitant Cotrimoxazole (CTX) in HIV-infected Children - Impact on Morbidity, Mortality, Bacterial Resistance and Incidence of Tuberculosis |
- TB incidence [ Time Frame: Jan 2003 to July 2011 ] [ Designated as safety issue: Yes ]
- Mortality [ Time Frame: Jan 2003 to July 2011 ] [ Designated as safety issue: Yes ]
- intercurrent infections [ Time Frame: Jan 2003 to July 2011 ] [ Designated as safety issue: No ]
- adherence [ Time Frame: Jan 2003 to July 2011 ] [ Designated as safety issue: No ]
- adverse events [ Time Frame: Jan 2003 to July 2011 ] [ Designated as safety issue: Yes ]
- antimicrobial resistance [ Time Frame: Jan 2003 to July 2011 ] [ Designated as safety issue: Yes ]
Enrollment: | 450 |
Study Start Date: | January 2003 |
Estimated Study Completion Date: | July 2011 |
Estimated Primary Completion Date: | July 2011 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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Experimental: Isoniazid preventive therapy
HIV infected children living in a high TB prevalence area receive isonaizid prophylaxis daily, together with cotrimoxazole prohpylaxis either 3 times a week or daily.
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Drug: Isoniazid
isoniazid 10mg/kg orally, daily, for study period
Drug: Cotrimoxazole
Cotrimoxazole given 3 times a week or daily, orally, for study period
Drug: isoniazid
Isoniazid, 10mg/kg daily for study period
|
Placebo Comparator: Placebo
HIV infected children living in a high TB prevalence area receive placebo once daily
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Drug: Cotrimoxazole
Cotrimoxazole given 3 times a week or daily, orally, for study period
Other: placebo
Placebo tablet identicle in appearance to intervention: isoniazid table
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Detailed Description:
Tuberculosis (TB) and HIV are dual pandemics occurring in South Africa. Prevention of TB and the subsequent decline in immune function in HIV-infected children is an important strategy to reduce mortality. Isoniazid (INH) prophylaxis reduces TB incidence in HIV-infected adults, but the efficacy in HIV-infected children has not been studied. In 2003, the investigators therefore began a double blind placebo controlled trial to investigate the impact of INH prophylaxis on mortality, morbidity and TB incidence in HIV-infected children. Interim analysis found a striking reduction in mortality and TB with a decrease in mortality in excess of 50% and 60% respectively, in children on INH. Based on this, the placebo arm was terminated; the study continued as a trial of thrice versus daily INH and cotrimoxazole (CTX). Although the results indicate an important benefit in children on INH, it is unknown what the long term efficacy and safety of INH prophylaxis is, what the optimal regime is and whether this pertains to children on HAART (who formed a minority of the cohort but who are still at risk for TB).
Aim To investigate the efficacy, safety and tolerability of INH and CTX as prophylactic strategies for HIV-infected children in a high TB prevalence area.
Objectives
- To compare the long term impact of two different INH preventive regimens (daily versus thrice weekly) on TB incidence, occurrence of INH resistance in patients with culture-confirmed TB, mortality, incidence of adverse reactions and adherence
- To compare the long term impact of two different CTX prophylactic regimens (daily versus thrice weekly) on mortality, frequency and duration of hospitalization, type of serious infections, nasopharyngeal carriage of bacteria and development of antimicrobial resistance, adherence and incidence of adverse reactions
- To investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART
Methods A prospective randomized double blind placebo controlled study of INH versus placebo in newly recruited HIV-infected children who are stable on HAART. In addition, an extended follow-up study of children already randomised to thrice weekly or daily INH and CTX. Children will be followed for 2 years with regular clinical evaluation, adherence assessment and laboratory monitoring. Outcomes measured will be mortality, TB incidence, morbidity, adherence and tolerability.
Ages Eligible for Study: | 8 Weeks to 15 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- HIV-infected children
- Resident in Cape Town
- Informed consent obtainable
- weight > 2.5kg
- Access to transport
- HAART use for not less than 2 months but not more than 12 months with no significant demonstrated toxicity and good adherence
Exclusion Criteria:
- Chronic diarrhoea
- Current use of INH prophylaxis
- Prior hypersensitivity to INH prior history of allergy to sulphur drugs
- Prior history of allergy to sulphur drugs
- Severe anaemia (haemoglobin less than 7 gm/dl)
- Neutropenia (absoloute neutrophil count less than 400 cells)
- Thrombocytopenia (platelet count < 50 000/uL)
- Non-reversible renal failure
- Clinical hepatitis
- Exposure to household TB contact, requiring INH prophylaxis
South Africa | |
Red Cross Childrens Hospital | |
Cape Town, Western Cape, South Africa, 7700 | |
Tygerberg Hospital | |
Cape Town, Western Cape, South Africa |
Principal Investigator: | Heather J Zar, MD PHd | University of Cape Town |
Principal Investigator: | Mark Cotton, Md PhD | Stellenbosch University |
No publications provided by University of Cape Town
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Professor HJ Zar, School of Child and Adolescent Health, University of Cape Town |
ClinicalTrials.gov Identifier: | NCT00330304 History of Changes |
Other Study ID Numbers: | 299/2005 |
Study First Received: | May 24, 2006 |
Last Updated: | September 7, 2010 |
Health Authority: | South Africa: Medicines Control Council |
Keywords provided by University of Cape Town:
Tuberculosis Child HIV prophylaxis mortality |
Additional relevant MeSH terms:
Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Isoniazid Trimethoprim-Sulfamethoxazole Combination Fatty Acid Synthesis Inhibitors Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action |
Pharmacologic Actions Antitubercular Agents Anti-Bacterial Agents Anti-Infective Agents Therapeutic Uses Lipid Regulating Agents Anti-Infective Agents, Urinary Renal Agents Antimalarials Antiprotozoal Agents Antiparasitic Agents |
ClinicalTrials.gov processed this record on March 03, 2013