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A multi-arm multi-stage clinical trial design for binary outcomes with application to tuberculosis.

ABSTRACT: Randomised controlled trials are becoming increasingly costly and time-consuming. In 2011, Royston and colleagues proposed a particular class of multi-arm multi-stage (MAMS) designs intended to speed up the evaluation of new treatments in phase II and III clinical trials. Their design, which controls the type I error rate and power for each pairwise comparison, discontinues randomisation to poorly performing arms at interim analyses if they fail to show a pre-specified level of benefit over the control arm. Arms in which randomisation is continued to the final stage of the trial are compared against the control on a definitive time-to-event outcome measure. To increase efficiency, interim comparisons can be made on an intermediate time-to-event outcome which is on the causal pathway to the definitive outcome.We adapt Royston's MAMS design to binary outcomes observed at the end of a fixed follow-up period and analysed using an absolute difference in proportions. We apply the design to tuberculosis (TB), an area where many new drugs are in development, and demonstrate how it can greatly accelerate the evaluation of new TB regimens. We use simulations to support the extensions to the methodology and to investigate the amount of bias in the estimated treatment effects of arms in which randomisation is ceased at the first interim analysis and arms which continue to the final stage of the trial.The proposed seamless phase II/III TB trial designs are shown to greatly reduce sample size requirements and trial duration compared to conducting separate phase II and III trials. The bias in the estimated treatment effects for the definitive outcome is shown to be small, especially when treatment selection is based on an intermediate outcome or when a reanalysis is performed at the planned end of the trial after all recruited patients have completed follow-up.The proposed designs are practical and could be used in a variety of disease areas. They hold considerable promise for speeding up the evaluation of new treatments particularly in TB where many new regimens will soon be available for testing in phase II and phase III trials.

SUBMITTER: Bratton DJ

PROVIDER: S-EPMC3840569 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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A multi-arm multi-stage clinical trial design for binary outcomes with application to tuberculosis.

Bratton Daniel J DJ Phillips Patrick P J PP Parmar Mahesh K B MK

BMC medical research methodology 20131114

<h4>Background</h4>Randomised controlled trials are becoming increasingly costly and time-consuming. In 2011, Royston and colleagues proposed a particular class of multi-arm multi-stage (MAMS) designs intended to speed up the evaluation of new treatments in phase II and III clinical trials. Their design, which controls the type I error rate and power for each pairwise comparison, discontinues randomisation to poorly performing arms at interim analyses if they fail to show a pre-specified level o ...[more]

PMID: 24229079

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Project description:BackgroundTuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis.MethodsWe did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15-20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15-20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186).FindingsBetween May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22-2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3-5 adverse events, with similar proportions in each arm.InterpretationA dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost.FundingThe study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).

Project description:BackgroundMulti-Arm Multi-Stage designs aim at comparing several new treatments to a common reference, in order to select or drop any treatment arm to move forward when such evidence already exists based on interim analyses. We redesigned a Bayesian adaptive design initially proposed for dose-finding, focusing our interest in the comparison of multiple experimental drugs to a control on a binary criterion measure.MethodsWe redesigned a phase II clinical trial that randomly allocates patients across three (one control and two experimental) treatment arms to assess dropping decision rules. We were interested in dropping any arm due to futility, either based on historical control rate (first rule) or comparison across arms (second rule), and in stopping experimental arm due to its ability to reach a sufficient response rate (third rule), using the difference of response probabilities in Bayes binomial trials between the treated and control as a measure of treatment benefit. Simulations were then conducted to investigate the decision operating characteristics under a variety of plausible scenarios, as a function of the decision thresholds.ResultsOur findings suggest that one experimental treatment was less efficient than the control and could have been dropped from the trial based on a sample of approximately 20 instead of 40 patients. In the simulation study, stopping decisions were reached sooner for the first rule than for the second rule, with close mean estimates of response rates and small bias. According to the decision threshold, the mean sample size to detect the required 0.15 absolute benefit ranged from 63 to 70 (rule 3) with false negative rates of less than 2 % (rule 1) up to 6 % (rule 2). In contrast, detecting a 0.15 inferiority in response rates required a sample size ranging on average from 23 to 35 (rules 1 and 2, respectively) with a false positive rate ranging from 3.6 to 0.6 % (rule 3).ConclusionAdaptive trial design is a good way to improve clinical trials. It allows removing ineffective drugs and reducing the trial sample size, while maintaining unbiased estimates. Decision thresholds can be set according to predefined fixed error decision rates.Trial registrationClinicalTrials.gov Identifier: NCT01342692 .

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A multi-arm multi-stage clinical trial design for binary outcomes with application to tuberculosis.

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A multi-arm multi-stage clinical trial design for binary outcomes with application to tuberculosis.

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