Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children - Full Text View

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:

MedlinePlus related topics: HIV/AIDS Tuberculosis

Drug Information available for: Isoniazid

Genetic and Rare Diseases Information Center resources: Tuberculosis

U.S. FDA Resources

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

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.

Eligibility


Ages Eligible for Study:	8 Weeks to 15 Years (Child)
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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Amlabu V, Mulligan C, Jele N, Evans A, Gray D, Zar HJ, McIlleron H, Smith P. Isoniazid/acetylisoniazid urine concentrations: markers of adherence to isoniazid preventive therapy in children. Int J Tuberc Lung Dis. 2014 May;18(5):528-30. doi: 10.5588/ijtld.13.0730.

Gray DM, Workman LJ, Lombard CJ, Jennings T, Innes S, Grobbelaar CJ, Cotton MF, Zar HJ. Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study. Int J Tuberc Lung Dis. 2014 Mar;18(3):322-7. doi: 10.5588/ijtld.13.0354. Erratum in: Int J Tuberc Lung Dis. 2014 Jun;18(6):754.

Frigati LJ, Kranzer K, Cotton MF, Schaaf HS, Lombard CJ, Zar HJ. The impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with HIV in a high tuberculosis incidence setting. Thorax. 2011 Jun;66(6):496-501. doi: 10.1136/thx.2010.156752. Epub 2011 Apr 2.

le Roux SM, Cotton MF, Golub JE, le Roux DM, Workman L, Zar HJ. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules. BMC Med. 2009 Nov 3;7:67. doi: 10.1186/1741-7015-7-67.

Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. Epub 2006 Nov 3.


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 Drug Combination Antitubercular Agents Anti-Bacterial Agents Anti-Infective Agents	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 September 23, 2016