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Letters to the Editor

In Reply: Short Intensified Treatment in Children With Drug-Susceptible Tuberculous Meningitis

van Toorn, Ronald FCP; Schaaf, H. Simon MD; Schoeman, Johan F. MD

Author Information
The Pediatric Infectious Disease Journal: September 2014 - Volume 33 - Issue 9 - p 993-994
doi: 10.1097/INF.0000000000000409
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We agree with the North London TB journal club about the importance of trials that would determine the most appropriate antimicrobial regimen for children with tuberculous meningitis (TBM). The study design advocated by the authors is a randomized controlled trial (RCT) of short intensified versus standard treatment (as advised by the World Health Organization).

Although a RCT would be the preferred study method, a large sample size would be required to separate out the effects of combination treatments. Wolbers et al1 addressed this question by comparing 2 approaches (RCT vs. 2 × 2 factorial design) using a design of a new trial in TBM as an example. In their trial example, the combination of 2 drugs added to standard treatment is assumed to reduce the hazard of death by 30% and the sample size of the combination trial to achieve 80% power was 750 patients. An adequately powered 2 × 2 factorial design (to detect effects of individual drugs) would require at least 8-fold the sample size (6000 patients) of the combination trial.

The short intensified TBM treatment regimen used in the Western Cape for nearly three decades is associated with a 3.8% mortality rate and a good outcome in greater than 80% of cases. A comparative superiority trial would require an even larger sample size than in the examples above.

Another issue is that of ethics: would it be ethically acceptable for a study site, which has a good outcome and low mortality amongst their TBM cases, to participate in a RCT comparing regimens that may be inferior to what they currently use? We have recently declined participation in a TBM study for this reason. Such a RCT would only be acceptable if another regimen (such as the World Health Organization 12-month regimen) has at least shown similar or better results in other study sites.

Ronald van Toorn, FCP

H. Simon Schaaf, MD

Johan F. Schoeman MD

Department of Pediatrics and Child Health

Stellenbosch University and Tygerberg

Children’s hospital

Western Cape, South Africa


1. Wolbers M, Heemskerk D, Chau TT, et al. Sample size requirements for separating out the effects of combination treatments: randomised controlled trials of combination therapy vs. standard treatment compared to factorial designs for patients with tuberculous meningitis. Trials. 2011;12:26
© 2014 by Lippincott Williams & Wilkins, Inc.