Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved]
Background: In randomized controlled trials (RCTs), the power is often ‘reverse engineered’ based on the number of participants that can realistically be achieved. An attractive alternative is planning a new trial conditional on the available evidence; a design of particular interest in RCTs that us...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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F1000 Research Ltd
2022-11-01
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| Series: | F1000Research |
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| Online Access: | https://f1000research.com/articles/11-85/v2 |
| _version_ | 1811225901922254848 |
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| author | George C.M. Siontis Georgia Salanti Adriani Nikolakopoulou Dimitris Mavridis Romy Sweda |
| author_facet | George C.M. Siontis Georgia Salanti Adriani Nikolakopoulou Dimitris Mavridis Romy Sweda |
| author_sort | George C.M. Siontis |
| collection | DOAJ |
| description | Background: In randomized controlled trials (RCTs), the power is often ‘reverse engineered’ based on the number of participants that can realistically be achieved. An attractive alternative is planning a new trial conditional on the available evidence; a design of particular interest in RCTs that use a sham control arm (sham-RCTs). Methods: We explore the design of sham-RCTs, the role of sequential meta-analysis and conditional planning in a systematic review of renal sympathetic denervation for patients with arterial hypertension. The main efficacy endpoint was mean change in 24-hour systolic blood pressure. We performed sequential meta-analysis to identify the time point where the null hypothesis would be rejected in a prospective scenario. Evidence-based conditional sample size calculations were performed based on fixed-effect meta-analysis. Results: In total, six sham-RCTs (981 participants) were identified. The first RCT was considerably larger (535 participants) than those subsequently published (median sample size of 80). All trial sample sizes were calculated assuming an unrealistically large intervention effect which resulted in low power when each study is considered as a stand-alone experiment. Sequential meta-analysis provided firm evidence against the null hypothesis with the synthesis of the first four trials (755 patients, cumulative mean difference -2.75 (95%CI -4.93 to -0.58) favoring the active intervention)). Conditional planning resulted in much larger sample sizes compared to those in the original trials, due to overoptimistic expected effects made by the investigators in individual trials, and potentially a time-effect association. Conclusions: Sequential meta-analysis of sham-RCTs can reach conclusive findings earlier and hence avoid exposing patients to sham-related risks. Conditional planning of new sham-RCTs poses important challenges as many surgical/minimally invasive procedures improve over time, the intervention effect is expected to increase in new studies and this violates the underlying assumptions. Unless this is accounted for, conditional planning will not improve the design of sham-RCTs. |
| first_indexed | 2024-04-12T09:15:08Z |
| format | Article |
| id | doaj.art-a1c0671ea8654ddf996c82119f98a68f |
| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-04-12T09:15:08Z |
| publishDate | 2022-11-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj.art-a1c0671ea8654ddf996c82119f98a68f2022-12-22T03:38:51ZengF1000 Research LtdF1000Research2046-14022022-11-0111140665Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved]George C.M. Siontis0https://orcid.org/0000-0003-2128-9205Georgia Salanti1https://orcid.org/0000-0002-3830-8508Adriani Nikolakopoulou2https://orcid.org/0000-0001-5884-4319Dimitris Mavridis3https://orcid.org/0000-0003-1041-4592Romy Sweda4Department of Cardiology, University Hospital of Bern, Bern, SwitzerlandInstitute of Social and Preventive Medicine (ISPM), University of Bern, Bern, SwitzerlandInstitute of Medical Biometry and Statistics, University of Freiburg, Freiburg, GermanyDepartment of Primary Education, University of Ioannina, Ioannina, GreeceDepartment of Cardiology, University Hospital of Bern, Bern, SwitzerlandBackground: In randomized controlled trials (RCTs), the power is often ‘reverse engineered’ based on the number of participants that can realistically be achieved. An attractive alternative is planning a new trial conditional on the available evidence; a design of particular interest in RCTs that use a sham control arm (sham-RCTs). Methods: We explore the design of sham-RCTs, the role of sequential meta-analysis and conditional planning in a systematic review of renal sympathetic denervation for patients with arterial hypertension. The main efficacy endpoint was mean change in 24-hour systolic blood pressure. We performed sequential meta-analysis to identify the time point where the null hypothesis would be rejected in a prospective scenario. Evidence-based conditional sample size calculations were performed based on fixed-effect meta-analysis. Results: In total, six sham-RCTs (981 participants) were identified. The first RCT was considerably larger (535 participants) than those subsequently published (median sample size of 80). All trial sample sizes were calculated assuming an unrealistically large intervention effect which resulted in low power when each study is considered as a stand-alone experiment. Sequential meta-analysis provided firm evidence against the null hypothesis with the synthesis of the first four trials (755 patients, cumulative mean difference -2.75 (95%CI -4.93 to -0.58) favoring the active intervention)). Conditional planning resulted in much larger sample sizes compared to those in the original trials, due to overoptimistic expected effects made by the investigators in individual trials, and potentially a time-effect association. Conclusions: Sequential meta-analysis of sham-RCTs can reach conclusive findings earlier and hence avoid exposing patients to sham-related risks. Conditional planning of new sham-RCTs poses important challenges as many surgical/minimally invasive procedures improve over time, the intervention effect is expected to increase in new studies and this violates the underlying assumptions. Unless this is accounted for, conditional planning will not improve the design of sham-RCTs.https://f1000research.com/articles/11-85/v2meta-analysis sequential methods power calculation renal sympathetic denervationeng |
| spellingShingle | George C.M. Siontis Georgia Salanti Adriani Nikolakopoulou Dimitris Mavridis Romy Sweda Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved] F1000Research meta-analysis sequential methods power calculation renal sympathetic denervation eng |
| title | Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved] |
| title_full | Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved] |
| title_fullStr | Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved] |
| title_full_unstemmed | Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved] |
| title_short | Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved] |
| title_sort | estimating the sample size of sham controlled randomized controlled trials using existing evidence version 2 peer review 2 approved |
| topic | meta-analysis sequential methods power calculation renal sympathetic denervation eng |
| url | https://f1000research.com/articles/11-85/v2 |
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