. 2017 Aug 29;2017(8):CD006418. doi: 10.1002/14651858.CD006418.pub3

Zar 2007.

Methods	Trial design: double‐blind, placebo‐controlled trial. Follow‐up: children underwent a tuberculin skin test and chest radiography if clinically indicated. Adverse events: alanine transaminase were measured one and three months after randomization and thereafter six‐monthly or more frequently if clinically indicated.
Participants	Number of participants: 277 Median (IQR) age at baseline: 25 months (9 to 52) Inclusion criteria: age > 8 weeks, weight > 2.5 kg, access to transport, informed consent, children stable on ART for two to three months. Exclusion criteria: chronic diarrhoea, current use of or need for isoniazid prophylaxis, previous hypersensitivity to isoniazid or sulphur containing drugs, haemoglobin < 70 g/L, neutrophil count < 400 cell/uL, platelet count < 50,000 x10⁹/L, non‐reversible renal failure.
Interventions	Isoniazid: 10 mg/kg/dose with a variability of 8 mg/kg to 12 mg/kg, either daily or three times a week on Monday, Wednesday, and Friday for a median duration of 5.7 months. Placebo, identical in appearance to isoniazid tablets, either daily or three times a week on Monday, Wednesday, and Friday for a median duration of 5.7 months. ART was not widely available. Some children obtained treatment through participation in pharmaceutical trials or charitable donations. 23 of 263 (9%) were on ART at enrolment and 58 (22%) started treatment during the trial.
Outcomes	Active TB Death Adverse events Not included in this review: none
Notes	Definitions: ‐ Definite TB: a microbiological or histological identification of Mycobacterium tuberculosis. ‐ Probable TB: based on a combination of typical clinical symptoms and signs, tuberculin skin testing, chest radiography, a history of close TB contact, and a documented response to antimycobacterial therapy. Cotrimoxazole (5 mg/kg/dose of the trimethoprim component): Given to all children < 12 months and those older with clinical CDC category B or C disease, in those with severe immunological impairment (CD4 count of < 15% of total lymphocyte count), or in those with previous episode of Pneumocystis jirovecii pneumonia. Study was planned to run for 2 years, however, the placebo arm was terminated early on the recommendation of the data safety monitoring board on the basis of the results of interim analyses. About 30% of the children received ART during the trial with similar percentages in isoniazid and placebo groups. Adverse events were graded 1 to 4 according to the toxicity criteria of the National Institutes of Health's division of AIDS (DAIDS). Grade 3 and 4 events were reported. Country: South Africa Prevalence of isoniazid resistance: 0% Positive tuberculin test: 9% Funding: The study was supported by Rockefeller Foundation, USA.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A variable block random list was used. Generation of allocation sequence was achieved by variable blocked randomization lists prepared by the trial statistician and sent to each trial site pharmacist in a sealed opaque envelope.
Allocation concealment (selection bias)	Low risk	Central allocation (pharmacists labelled trial drugs with sequential numbers). The participants were allocated study numbers sequentially by the study nurse at enrolment. They were then sequentially allocated to treatment group by the pharmacist according to the prepared list.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Placebo was manufactured to have an identical appearance to isoniazid, participants and personnel were blinded to study assignment.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Investigators assessing the outcome and were blinded, the diagnosis of probable TB was subject to independent review by a blinded investigator.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition rate was very low, < 20%.
Selective reporting (reporting bias)	Low risk	All outcomes stated in the study protocol were the same as those in the published manuscript.
Other bias	Unclear risk	The data safety monitoring board recommended randomization into placebo to be stopped after 277 of the planned 432 were enrolled. The placebo arm was ended on 17 May 2004 on the recommendation of the data safety monitoring board on the basis of the results of interim analyses.

Abbreviations:

ALT/SGPT: Alanine aminotransferase (serum glutamic pyruvic transaminase)  ANC: Absolute neutrophil count  ART: Antiretroviral therapy  AST/SGOT: Aspartate aminotransferase (serum glutamic‐oxaloacetic transaminase)  CDC: Centers for Diseases Control and Prevention  CXR: Chest x‐rays  INH: Isoniazid  SMX/TMP: Trimethoprim/Sulfamethoxazole  TB: Tuberculosis  WHO: World Health Organization