Using Trial Sequential Analysis for estimating the sample sizes of further trials: example using smoking cessation intervention

Abstract Background Assessing benefits and harms of health interventions is resource-intensive and often requires feasibility and pilot trials followed by adequately powered randomised clinical trials. Data from feasibility and pilot trials are used to inform the design and sample size of the adequately powered randomised clinical trials. When a randomised clinical trial is conducted, results from feasibility and pilot trials may be disregarded in terms of benefits and harms. Methods We describe using feasibility and pilot trial data in the Trial Sequential Analysis software to estimate the required sample size for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using trial sequential analysis methods to assess the intervention’s effects. Results We provide a worked example to illustrate how we successfully used the Trial Sequential Analysis software to arrive at a sensible sample size for a new randomised clinical trial and use it in the argumentation for research funds for the trial. Conclusions Trial Sequential Analysis can utilise data from feasibility and pilot trials as well as other trials, to estimate a sample size for one or more, similarly designed, future randomised clinical trials. As this method uses available data, estimated sample sizes may be smaller than they would have been using conventional sample size estimation methods.

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Using Trial Sequential Analysis for estimating the sample sizes of further trials: example using smoking cessation intervention

10.21203/rs.3.rs-35669/v3 ◽

2020 ◽

Author(s):

Ravinder Claire ◽

Christian Gluud ◽

Ivan Berlin ◽

Tim Coleman ◽

Jo Leonardi-Bee

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Sample Size ◽

Sequential Analysis ◽

Randomised Clinical Trial ◽

Randomised Clinical Trials ◽

Trial Sequential Analysis ◽

Analysis Software ◽

Cessation Intervention ◽

Pilot Trials

Abstract Background Assessing benefits and harms of health interventions is resource-intensive and often requires feasibility and pilot trials followed by adequately powered randomised clinical trials. Data from feasibility and pilot trials are used to inform the design and sample size of the adequately powered randomised clinical trials. When a randomised clinical trial is conducted, results from feasibility and pilot trials may be disregarded in terms of benefits and harms.MethodsWe describe using feasibility and pilot trial data in the Trial Sequential Analysis software to estimate the required sample size for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using trial sequential analysis methods to assess the intervention’s effects.ResultsWe provide a worked example to illustrate how we successfully used the Trial Sequential Analysis software to arrive at a sensible sample size for a new randomised clinical trial and use it in the argumentation for research funds for the trial. ConclusionsTrial Sequential Analysis can utilise data from feasibility and pilot trials as well as other trials, to estimate a sample size for one or more, similarly designed, future randomised clinical trials. As this method uses available data, estimated sample sizes may be smaller than they would have been using conventional sample size estimation methods.

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Using Trial Sequential Analysis for estimating the sample sizes of further trials: example using smoking cessation intervention

10.21203/rs.3.rs-35669/v2 ◽

2020 ◽

Author(s):

Ravinder Claire ◽

Christian Gluud ◽

Ivan Berlin ◽

Tim Coleman ◽

Jo Leonardi-Bee

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Sample Size ◽

Sequential Analysis ◽

Randomised Clinical Trial ◽

Randomised Clinical Trials ◽

Trial Sequential Analysis ◽

Analysis Software ◽

Cessation Intervention ◽

Pilot Trials

Abstract Background: Assessing benefits and harms of health interventions is resource-intensive and often requires feasibility and pilot trials followed by adequately powered randomised clinical trials. Data from feasibility and pilot trials are used to inform the design and sample size of the adequately powered randomised clinical trials. When a randomised clinical trial is conducted, results from feasibility and pilot trials may be disregarded in terms of benefits and harms.Methods: We describe using feasibility and pilot trial data in the Trial Sequential Analysis software to estimate the required sample size for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using trial sequential analysis methods to assess the intervention's effects. Results: We provide a worked example to illustrate how we successfully used the Trial Sequential Analysis software to arrive at a sensible sample size for a new randomised clinical trial and use it in the argumentation for research funds for the trial. Conclusions: Trial Sequential Analysis can utilise data from feasibility and pilot trials as well as other trials, to estimate a sample size for one or more, similarly designed, future randomised clinical trials. As this method uses available data, estimated sample sizes may be smaller than they would have been using conventional sample size estimation methods.

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Using Trial Sequential Analysis for estimating the sample sizes of further trials: example using smoking cessation intervention

10.21203/rs.3.rs-35669/v1 ◽

2020 ◽

Author(s):

Ravinder Claire ◽

Christian Gluud ◽

Ivan Berlin ◽

Tim Coleman ◽

Jo Leonardi-Bee

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Smoking Cessation ◽

Sample Size ◽

Sequential Analysis ◽

Randomised Clinical Trial ◽

Randomised Clinical Trials ◽

Trial Sequential Analysis ◽

Cessation Intervention ◽

Pilot Trials

Abstract Background Assessing benefits and harms of health interventions is resource-intensive and often requires feasibility and pilot trials followed by adequately powered randomised clinical trials. Data from feasibility and pilot trials are used to inform the design and sample size of the adequately powered randomised clinical trials. When a randomised clinical trial is conducted, results from feasibility and pilot trials may be disregarded in terms of benefits and harms. Methods We describe using feasibility and pilot trial data in the Trial Sequential Analysis program to estimate the required sample size for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using Trial Sequential Analysis to assess the intervention’s effects. Results We provide a worked example to illustrate how we successfully used Trial Sequential Analysis methods to argue for the research funds needed to undertake a randomised clinical trial. Conclusions Trial Sequential Analysis can utilise data from feasibility and pilot trials as well as other trials, to estimate a sample size for one or more future randomised clinical trials. As this method uses available data, estimated sample sizes may be smaller than they would have been using conventional sample size estimation methods.

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Health apps targeting children with overweight—a protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

Systematic Reviews ◽

10.1186/s13643-020-1269-0 ◽

2020 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Rajeeb Rashid ◽

Paolo Perego ◽

Laura Condon ◽

Janus Christian Jakobsen ◽

Jane Lindschou ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Sequential Analysis ◽

Meta Analysis ◽

Randomised Clinical Trials ◽

Trial Sequential Analysis ◽

Health Apps

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Assessing gaps in cholesterol treatment guidelines for primary prevention of cardiovascular disease based on available randomised clinical trial evidence: The Rotterdam Study

European Journal of Preventive Cardiology ◽

10.1177/2047487317743352 ◽

2017 ◽

Vol 25 (4) ◽

pp. 420-431 ◽

Cited By ~ 6

Author(s):

Jelena Pavlović ◽

Philip Greenland ◽

Jaap W Deckers ◽

Maryam Kavousi ◽

Albert Hofman ◽

...

Keyword(s):

Cardiovascular Disease ◽

Clinical Trial ◽

Clinical Trials ◽

Primary Prevention ◽

Randomised Clinical Trial ◽

Lipid Lowering ◽

Randomised Clinical Trials ◽

Atherosclerotic Cardiovascular Disease ◽

Intermediate Risk ◽

Clinical Trial Evidence

Background The purpose of this study was to determine how American College of Cardiology/American Heart Association (ACC/AHA) 2013 and European Society of Cardiology 2016 guidelines for the primary prevention of atherosclerotic cardiovascular disease (CVD) compare in reflecting the totality of accrued randomised clinical trial evidence for statin treatment at population level. Methods From 1997–2008, 7279 participants aged 45–75 years, free of atherosclerotic cardiovascular disease, from the population-based Rotterdam Study were included. For each participant, we compared eligibility for each one of 11 randomised clinical trials on statin use in primary prevention of CVD, with recommendations on lipid-lowering therapy from the ACC/AHA and European Society of Cardiology (ESC) guidelines. Atherosclerotic cardiovascular disease incidence and cardiovascular disease mortality rates were calculated. Results The proportion of participants eligible for each trial ranged from 0.4% for ALLHAT-LLT to 30.8% for MEGA. The likelihood of being recommended for lipid-lowering treatment was lowest for those eligible for low-to-intermediate risk RCTs (HOPE-3, MEGA, and JUPITER), and highest for high-risk individuals with diabetes (MRC/BHF HPS, CARDS, and ASPEN) or elderly PROSPER. Eligibility for an increasing number of randomised clinical trials correlated with a greater likelihood of being recommended lipid-lowering treatment by either guideline ( p < 0.001 for both guidelines). Conclusion Compared to RCTs done in high risk populations, randomised clinical trials targeting low-to-intermediate risk populations are less well-reflected in the ACC/AHA, and even less so in the ESC guideline recommendations. Importantly, the low-to-intermediate risk population targeted by HOPE-3, the most recent randomised clinical trial in this field, is not well-captured by the current European prevention guidelines and should be specifically considered in future iterations of the guidelines.

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Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

BMJ ◽

10.1136/bmj.d6898 ◽

2011 ◽

Vol 343 (nov24 1) ◽

pp. d6898-d6898 ◽

Cited By ~ 203

Author(s):

B. Hemmingsen ◽

S. S. Lund ◽

C. Gluud ◽

A. Vaag ◽

T. Almdal ◽

...

Keyword(s):

Systematic Review ◽

Type 2 Diabetes ◽

Clinical Trials ◽

Glycaemic Control ◽

Sequential Analysis ◽

Meta Analysis ◽

Randomised Clinical Trials ◽

Trial Sequential Analysis ◽

Intensive Glycaemic Control

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Effects of adding ivabradine to usual care in patients with angina pectoris: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis

Open Heart ◽

10.1136/openhrt-2020-001288 ◽

2020 ◽

Vol 7 (2) ◽

pp. e001288

Author(s):

Mathias Maagaard ◽

Emil Eik Nielsen ◽

Naqash Javaid Sethi ◽

Liang Ning ◽

Si-hong Yang ◽

...

Keyword(s):

Clinical Trials ◽

Angina Pectoris ◽

Adverse Events ◽

Sequential Analysis ◽

Randomised Clinical Trials ◽

Trial Sequential Analysis ◽

Serious Adverse Events ◽

All Cause Mortality ◽

Artery Disease

ObjectiveTo determine the impact of ivabradine on outcomes important to patients with angina pectoris caused by coronary artery disease.MethodsWe conducted a systematic review. We included randomised clinical trials comparing ivabradine versus placebo or no intervention for patients with angina pectoris due to coronary artery disease published prior to June 2020. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Cochrane methodology, Trial Sequential Analysis, Grading of Recommendations Assessment, Development, and Evaluation, and our eight-step procedure. Primary outcomes were all-cause mortality, serious adverse events and quality of life.ResultsWe included 47 randomised clinical trials enrolling 35 797 participants. All trials and outcomes were at high risk of bias. Ivabradine compared with control did not have effects when assessing all-cause mortality (risk ratio [RR] 1.04; 95% CI 0.96 to 1.13), quality of life (standardised mean differences −0.05; 95% CI −0.11 to 0.01), cardiovascular mortality (RR 1.07; 95% CI 0.97 to 1.18) and myocardial infarction (RR 1.03; 95% CI 0.91 to 1.16). Ivabradine seemed to increase the risk of serious adverse events after removal of outliers (RR 1.07; 95% CI 1.03 to 1.11) as well as the following adverse events classified as serious: bradycardia, prolonged QT interval, photopsia, atrial fibrillation and hypertension. Ivabradine also increased the risk of non-serious adverse events (RR 1.13; 95% CI 1.11 to 1.16). Ivabradine might have a statistically significant effect when assessing angina frequency (mean difference (MD) 2.06; 95% CI 0.82 to 3.30) and stability (MD 1.48; 95% CI 0.07 to 2.89), but the effect sizes seemed minimal and possibly without any relevance to patients, and we identified several methodological limitations, questioning the validity of these results.ConclusionOur findings do not support that ivabradine offers significant benefits on patient important outcomes, but rather seems to increase the risk of serious adverse events such as atrial fibrillation and non-serious adverse events. Based on current evidence, guidelines need reassessment and the use of ivabradine for angina pectoris should be reconsidered.PROSPERO registration numberCRD42018112082.

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Ketamine for critically ill patients with severe acute brain injury: Protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

PLoS ONE ◽

10.1371/journal.pone.0259899 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0259899

Author(s):

Frederik Andreas Madsen ◽

Trine Hjorslev Andreasen ◽

Jane Lindschou ◽

Christian Gluud ◽

Kirsten Møller

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Brain Injury ◽

Functional Outcome ◽

Sequential Analysis ◽

Acute Brain Injury ◽

Randomised Clinical Trials ◽

Trial Sequential Analysis ◽

Secondary Brain Injury ◽

Serious Adverse Events

Introduction Intensive care for patients with severe acute brain injury aims both to treat the immediate consequences of the injury and to prevent and treat secondary brain injury to ensure a good functional outcome. Sedation may be used to facilitate mechanical ventilation, for treating agitation, and for controlling intracranial pressure. Ketamine is an N-methyl-D-aspartate receptor antagonist with sedative, analgesic, and potentially neuroprotective properties. We describe a protocol for a systematic review of randomised clinical trials assessing the beneficial and harmful effects of ketamine for patients with severe acute brain injury. Methods and analysis We will systematically search international databases for randomised clinical trials, including CENTRAL, MEDLINE, Embase, and trial registries. Two authors will independently review and select trials for inclusion, and extract data. We will compare ketamine by any regimen versus placebo, no intervention, or other sedatives or analgesics for patients with severe acute brain injury. The primary outcomes will be functional outcome at maximal follow up, quality of life, and serious adverse events. We will also assess secondary and exploratory outcomes. The extracted data will be analysed using Review Manager and Trials Sequential Analysis. Evidence certainty will be graded using GRADE. Ethics and dissemination The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice. PROSPERO no CRD42021210447.

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