Trial reportTrials2011
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.
Trial report in Trials, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Fluoroquinolones for treating tuberculosis (presumed drug-sensitive).The Cochrane database of systematic reviews · 2013Pooled it
- Successful Optimization of Tobacco Dependence Treatment in the Emergency Department: A Randomized Controlled Trial Using the Multiphase Optimization Strategy.Annals of emergency medicine · 2023Trial
- Trial
- When should factorial designs be used for late-phase randomised controlled trials?Clinical trials (London, England) · 2024Review
- Application of Cerebrospinal Fluid Host Protein Biosignatures in the Diagnosis of Tuberculous Meningitis in Children from a High Burden Setting.Mediators of inflammation · 2019Article
- Tobacco dependence treatment in the emergency department: A randomized trial using the Multiphase Optimization Strategy.Contemporary clinical trials · 2018Article
- A systematic approach to designing statistically powerful heteroscedastic 2 × 2 factorial studies while minimizing financial costs.BMC medical research methodology · 2016Article
- Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis.BMC infectious diseases · 2016Article
- Factorial experiments: efficient tools for evaluation of intervention components.American journal of preventive medicine · 2014Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors.
Funding
Abstract
backgroundIn certain diseases clinical experts may judge that the intervention with the best prospects is the addition of two treatments to the standard of care. This can either be tested with a simple randomized trial of combination versus standard treatment or with a 2 x 2 factorial design.
methodsWe compared the two approaches using the design of a new trial in tuberculous meningitis as an example. In that trial 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 is 750 patients. We calculated the power of corresponding factorial designs with one- to sixteen-fold the sample size of the combination trial depending on the contribution of each individual drug to the combination treatment effect and the strength of an interaction between the two.
resultsIn the absence of an interaction, an eight-fold increase in sample size for the factorial design as compared to the combination trial is required to get 80% power to jointly detect effects of both drugs if the contribution of the less potent treatment to the total effect is at least 35%. An eight-fold sample size increase also provides a power of 76% to detect a qualitative interaction at the one-sided 10% significance level if the individual effects of both drugs are equal. Factorial designs with a lower sample size have a high chance to be underpowered, to show significance of only one drug even if both are equally effective, and to miss important interactions.
conclusionsPragmatic combination trials of multiple interventions versus standard therapy are valuable in diseases with a limited patient pool if all interventions test the same treatment concept, it is considered likely that either both or none of the individual interventions are effective, and only moderate drug interactions are suspected. An adequately powered 2 x 2 factorial design to detect effects of individual drugs would require at least 8-fold the sample size of the combination trial.
trial registrationCurrent Controlled Trials ISRCTN61649292.
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