Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2010 by University of Cape Town.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborators:
University of Stellenbosch
Medical Research Council
Rockefeller Foundation
Information provided by:
University of Cape Town
ClinicalTrials.gov Identifier:
NCT00330304
First received: May 24, 2006
Last updated: September 7, 2010
Last verified: September 2010
  Purpose

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
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

Resource links provided by NLM:


Further study details as provided by University of Cape Town:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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
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.
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
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

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

  1. 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
  2. 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
  3. 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.

  Eligibility

Ages Eligible for Study:   8 Weeks to 15 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00330304

Locations
South Africa
Red Cross Childrens Hospital
Cape Town, Western Cape, South Africa, 7700
Tygerberg Hospital
Cape Town, Western Cape, South Africa
Sponsors and Collaborators
University of Cape Town
University of Stellenbosch
Medical Research Council
Rockefeller Foundation
Investigators
Principal Investigator: Heather J Zar, MD PHd University of Cape Town
Principal Investigator: Mark Cotton, Md PhD University of Stellenbosch
  More Information

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
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Anti-Infective Agents, Urinary
Renal Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents

ClinicalTrials.gov processed this record on August 28, 2014