Adaptive Designs for Non-inferiority Trials with Multiple Experimental Treatments

Xu, Wenfu; Hu, Feifang; Cheung, Siu Hung

doi:10.1177/0962280217695579

Cited by 6 publications

(4 citation statements)

References 34 publications

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“…Sample size calculation and optimization is done with regard to the considered definition of study success. Even though there exists extensive literature and recent research on three-arm non-inferiority trials, [12][13][14][15][16][17][18][19] we are not aware of a similar suggestion in the literature.…”

Section: Reject H Nmentioning

confidence: 89%

Single‐stage, three‐arm, adaptive test strategies for non‐inferiority trials with an unstable reference

Brannath

Scharpenberg

Schmidt

2022

Statistics in Medicine

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For indications where only unstable reference treatments are available and use of placebo is ethically justified, three-arm "gold standard" designs with an experimental, reference and placebo arm are recommended for non-inferiority trials.In such designs, the demonstration of efficacy of the reference or experimental treatment is a requirement. They have the disadvantage that only little can be concluded from the trial if the reference fails to be efficacious. To overcome this, we investigate novel single-stage, adaptive test strategies where non-inferiority is tested only if the reference shows sufficient efficacy and otherwise 𝛿-superiority of the experimental treatment over placebo is tested. With a properly chosen superiority margin, 𝛿-superiority indirectly shows non-inferiority. We optimize the sample size for several decision rules and find that the natural, data driven test strategy, which tests non-inferiority if the reference's efficacy test is significant, leads to the smallest overall and placebo sample sizes. We proof that under specific constraints on the sample sizes, this procedure controls the family-wise error rate. All optimal sample sizes are found to meet this constraint. We finally show how to account for a relevant placebo drop-out rate in an efficient way and apply the new test strategy to a real life data set.

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Section: Reject H Nmentioning

confidence: 89%

Single‐stage, three‐arm, adaptive test strategies for non‐inferiority trials with an unstable reference

Brannath

Scharpenberg

Schmidt

2022

Statistics in Medicine

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“…Another measure was considered by Xu et. al., 22 in which total variance is defined by T V normal′ = ∑ i = 1 G − 1 V i + false( G − 1 false) V G. This particular definition of total variance matches the optimal allocation proposal discussed by Dunnett 23 for trials in which there are homogeneous variances of responses.…”

Section: Response-adaptive Treatment Allocationmentioning

confidence: 58%

Response-adaptive treatment randomization for multiple comparisons of treatments with recurrent event responses

Gao

Cheung

et al. 2022

Stat Methods Med Res

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Recurrent event responses are frequently encountered during clinical trials of treatments for certain diseases, such as asthma. The recurrence rates of different treatments are often compared by applying the negative binomial model. In addition, a balanced treatment-allocation procedure that assigns the same number of patients to each treatment is often applied. Recently, a response-adaptive treatment-allocation procedure has been developed for trials with recurrent event data, and has been shown to be superior to balanced treatment allocation. However, this response-adaptive treatment allocation procedure is only applicable for the comparison of two treatments. In this paper, we derive response-adaptive treatment-allocation procedures for trials which comprise several treatments. As pairwise comparisons and multiple comparisons with a control are two common multiple-testing scenarios in trials with more than two treatments, corresponding treatment-allocation procedures for these scenarios are also investigated. The redesign of two clinical studies illustrates the clinical benefits that would be obtained from our proposed response-adaptive treatment-allocation procedures.

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“…Sample size calculation and optimization is done with regard to the considered definition of study success. Even though there exists extensive literature and recent research on three-arm non-inferiority trials, [17,18,20,13,19,12] we are not aware of a similar suggestion in the literature.…”

Section: Introductionmentioning

confidence: 85%

Single-stage, three-arm, adaptive test strategies for non-inferiority trials with an unstable reference

Brannath¹,

Scharpenberg²,

Schmidt³

2021

Preprint

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For indications where only unstable reference treatments are available and use of placebo is ethically justified, three-arm 'gold standard' designs with an experimental, reference and placebo arm are recommended for non-inferiority trials. In such designs, the demonstration of efficacy of the reference or experimental treatment is a requirement. They have the disadvantage that only little can be concluded from the trial if the reference fails to be efficacious. To overcome this, we investigate novel single-stage, adaptive test strategies where non-inferiority is tested only if the reference shows sufficient efficacy and otherwise δ-superiority of the experimental treatment over placebo is tested. With a properly chosen superiority margin, δ-superiority indirectly shows noninferiority. We optimize the sample size for several decision rules and find that the natural, data driven test strategy, which tests non-inferiority if the reference's efficacy test is significant, leads to the smallest overall and placebo sample sizes. We proof that under specific constraints on the sample sizes, this procedure controls the family-wise error rate. All optimal sample sizes are found to meet this constraint. We finally show how to account for a relevant placebo drop-out rate in an efficient way and apply the new test strategy to a real life data set.

show abstract

Adaptive Designs for Non-inferiority Trials with Multiple Experimental Treatments

Cited by 6 publications

References 34 publications

Single‐stage, three‐arm, adaptive test strategies for non‐inferiority trials with an unstable reference

Single‐stage, three‐arm, adaptive test strategies for non‐inferiority trials with an unstable reference

Response-adaptive treatment randomization for multiple comparisons of treatments with recurrent event responses

Single-stage, three-arm, adaptive test strategies for non-inferiority trials with an unstable reference

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