scholarly journals Improving analysis practice of continuous adverse event outcomes in randomised controlled trials - a distributional approach

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anca Chis Ster ◽  
Rachel Phillips ◽  
Odile Sauzet ◽  
Victoria Cornelius
Keyword(s):  
Adverse Event ◽  
Randomised Controlled Trials ◽  
Statistical Power ◽  
Biological Data ◽  
Controlled Trials ◽  
Reference Ranges ◽  
Clinical Interpretation ◽  
Continuous Outcomes ◽  
Distributional Method ◽  
Randomised Controlled

Abstract Background Randomised controlled trials (RCTs) provide valuable information for developing harm profiles but current analysis practices to detect between-group differences are suboptimal. Drug trials routinely screen continuous clinical and biological data to monitor participant harm. These outcomes are regularly dichotomised into abnormal/normal values for analysis. Despite the simplicity gained for clinical interpretation, it is well established that dichotomising outcomes results in a considerable reduction in information and thus statistical power. We propose an automated procedure for the routine implementation of the distributional method for the dichotomisation of continuous outcomes proposed by Peacock and Sauzet, which retains the precision of the comparison of means. Methods We explored the use of a distributional approach to compare differences in proportions based on the comparison of means which retains the power of the latter. We applied this approach to the screening of clinical and biological data as a means to detect ‘signals’ for potential adverse drug reactions (ADRs). Signals can then be followed-up in further confirmatory studies. Three distributional methods suitable for different types of distributions are described. We propose the use of an automated approach using the observed data to select the most appropriate distribution as an analysis strategy in a RCT setting for multiple continuous outcomes. We illustrate this approach using data from three RCTs assessing the efficacy of mepolizumab in asthma or COPD. Published reference ranges were used to define the proportions of participants with abnormal values for a subset of 10 blood tests. The between-group distributional and empirical differences in proportions were estimated for each blood test and compared. Results Within trials, the distributions varied across the 10 outcomes demonstrating value in a practical approach to selecting the distributional method in the context of multiple adverse event outcomes. Across trials, there were three outcomes where the method chosen by the automated procedure varied for the same outcome. The distributional approach identified three signals (eosinophils, haematocrit, and haemoglobin) compared to only one when using the Fisher’s exact test (eosinophils) and two identified by use of the 95% confidence interval for the difference in proportions (eosinophils and potassium). Conclusion When dichotomisation of continuous adverse event outcomes aids clinical interpretation, we advocate use of a distributional approach to retain statistical power. Methods are now easy to implement. Retaining information is especially valuable in the context of the analysis of adverse events in RCTs. The routine implementation of this automated approach requires further evaluation.

scholarly journals A nested randomised controlled trial of a newsletter and Post-it® note did not increase postal questionnaire response rates in a falls prevention trial

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1083
Author(s):  
Sara Rodgers ◽  
Illary Sbizzera ◽  
Sarah Cockayne ◽  
Caroline Fairhurst ◽  
Sarah E. Lamb ◽  
...  
Keyword(s):  
Randomised Controlled Trials ◽  
Statistical Power ◽  
Controlled Trial ◽  
Meta Analysis ◽  
Response Rates ◽  
Postal Questionnaire ◽  
Falls Prevention ◽  
Controlled Trials ◽  
Questionnaire Response ◽  
Randomised Controlled

Background: Attrition (i.e. when participants do not return the questionnaires) is a problem for many randomised controlled trials. The resultant loss of data leads to a reduction in statistical power and can lead to bias. The aim of this study was to assess whether a pre-notification newsletter and/or a handwritten or printed Post-it® note sticker, as a reminder, increased postal questionnaire response rates for participants of randomised controlled trials. Method: This study was a factorial trial embedded within a trial of a falls-prevention intervention among men and women aged ≥65 years under podiatric care. Participants were randomised into one of six groups: newsletter plus handwritten Post-it®; newsletter plus printed Post-it®; newsletter only; handwritten Post-it® only; printed Post-it® only; or no newsletter or Post-it®. The results were combined with those from previous embedded randomised controlled trials in a meta-analysis. Results: The 12-month response rate was 803/826 (97.2%) (newsletter 95.1%, no newsletter 99.3%, printed Post-it® 97.5%, handwritten Post-it® 97.1%, no Post-it® 97.1%). Pre-notification with a newsletter had a detrimental effect on response rates (adjusted odds ratio (OR), 0.14; 95% CI, 0.04 to 0.48; p<0.01) and time to return the questionnaire (adjusted hazard ratio, 0.86; 95% CI, 0.75 to 0.99; p=0.04). No other statistically significant differences were observed between the intervention groups on response rates, time to response, and the need for a reminder. Conclusions: Post-it® notes have been shown to be ineffective in three embedded trials, whereas the evidence for newsletter reminders is still uncertain.

scholarly journals Exclusion of enrolled participants in randomised controlled trials: what to do with ineligible participants?

BMJ Open ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. e039546
Author(s):  
Andrea M Rehman ◽  
Rashida Ferrand ◽  
Elizabeth Allen ◽  
Victoria Simms ◽  
Grace McHugh ◽  
...  
Keyword(s):  
Lung Function ◽  
Randomised Controlled Trials ◽  
Statistical Power ◽  
Human Error ◽  
Trial Steering Committee ◽  
Controlled Trials ◽  
Primary Analysis ◽  
Intervention Effect ◽  
Eligibility Criteria ◽  
Randomised Controlled

ObjectivePost-randomisation exclusions in randomised controlled trials are common and may include participants identified as not meeting trial eligibility criteria after randomisation. We report how a decision might be reached and reported on, to include or exclude these participants. We illustrate using a motivating scenario from the BREATHE trial (Trial registration ClinicalTrials.gov, NCT02426112) evaluating azithromycin for the treatment of chronic lung disease in people aged 6–19 years with HIV in Zimbabwe and Malawi.Key pointsIncluding all enrolled and randomised participants in the primary analysis of a trial ensures an unbiased estimate of the intervention effect using intention-to-treat principles, and minimises the effects of confounding through balanced allocation to trial arm. Ineligible participants are sometimes enrolled, due to measurement or human error. Of 347 participants enrolled into the BREATHE trial, 11 (3.2%) were subsequently found to be ineligible based on lung function criteria. We assumed no safety risk of azithromycin treatment; their inclusion in the trial and subsequent analysis of the intervention effect therefore mirrors clinical practice. Senior trial investigators considered diurnal variations in the measurement of lung function, advantages of retaining a higher sample size and advice from the Data Safety and Monitoring Board and Trial Steering Committee, and decided to include these participants in primary analysis. We planned and reported analyses including and excluding these participants, and in our case the interpretation of treatment effect was consistent.ConclusionThe decision, by senior investigators, on whether to exclude enrolled participants, should reflect issues of safety, treatment efficacy, statistical power and measurement error. As long as decisions are made prior to finalising the statistical analysis plan for the trial, the risk of exclusions creating bias should be minimal. The decision taken should be transparently reported and a sensitivity analysis can present the opposite decision.

scholarly journals The impact of equol-producing status in modifying the effect of soya isoflavones on risk factors for CHD: a systematic review of randomised controlled trials

2016 ◽  
Vol 5 ◽  
Author(s):  
Rahel L. Birru ◽  
Vasudha Ahuja ◽  
Abhishek Vishnu ◽  
Rhobert W. Evans ◽  
Yoshihiro Miyamoto ◽  
...  
Keyword(s):  
Risk Factors ◽  
Randomised Controlled Trials ◽  
Statistical Power ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Ovid Medline ◽  
Central Register ◽  
Bacterial Action ◽  
Randomised Controlled ◽  
The Impact

AbstractRecent studies suggest that the ability to produce equol, a metabolite of the soya isoflavone daidzein, is beneficial to coronary health. Equol, generated by bacterial action on isoflavones in the human gut, is biologically more potent than dietary sources of isoflavones. Not all humans are equol producers. We investigated whether equol-producing status is favourably associated with risk factors for CHD following an intervention by dietary soya isoflavones. We systematically reviewed randomised controlled trials (RCT) that evaluated the effect of soya isoflavones on risk factors for CHD and that reported equol-producing status. We searched PubMed, EMBASE, Ovid Medline and the Cochrane Central Register for Controlled Trials published up to April 2015 and hand-searched bibliographies to identify the RCT. Characteristics of participants and outcomes measurements were extracted and qualitatively analysed. From a total of 1671 studies, we identified forty-two articles that satisfied our search criteria. The effects of equol on risk factors for CHD were mainly based on secondary analyses in these studies, thus with inadequate statistical power. Although fourteen out of the forty-two studies found that equol production after a soya isoflavone intervention significantly improved a range of risk factors including cholesterol and other lipids, inflammation and blood pressure variables, these results need further verification by sufficiently powered studies. The other twenty-eight studies primarily reported null results. RCT of equol, which has recently become available as a dietary supplement, on CHD and its risk factors are awaited.

scholarly journals Sample size requirements for pilot randomised controlled trials with continuous outcomes: a simulation study

Trials ◽  
2013 ◽  
Vol 14 (Suppl 1) ◽  
pp. P46 ◽  
Author(s):  
Marion Teare ◽  
Alexandra Hayman ◽  
Munya Dimairo ◽  
Neil Shephard ◽  
Amy Whitehead ◽  
...  
Keyword(s):  
Sample Size ◽  
Simulation Study ◽  
Randomised Controlled Trials ◽  
Controlled Trials ◽  
Continuous Outcomes ◽  
Randomised Controlled

Adverse event reporting in randomised controlled trials of neuropathic pain: Considerations for future practice

Pain ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 213-220 ◽  
Author(s):  
Victoria R. Cornelius ◽  
Odile Sauzet ◽  
John E. Williams ◽  
Salma Ayis ◽  
Paul Farquhar-Smith ◽  
...  
Keyword(s):  
Adverse Event ◽  
Neuropathic Pain ◽  
Randomised Controlled Trials ◽  
Adverse Event Reporting ◽  
Controlled Trials ◽  
Event Reporting ◽  
Randomised Controlled ◽  
Future Practice

scholarly journals Endocrinology trial design: adverse event reporting in randomised controlled trials of recombinant human GH in GH-deficient adults

2002 ◽  
Vol 175 (2) ◽  
pp. 545-552 ◽  
Author(s):  
J Bryant ◽  
E Loveman ◽  
C Cave ◽  
D Chase ◽  
R Milne
Keyword(s):  
Quality Of Life ◽  
Adverse Event ◽  
Adverse Effects ◽  
Adverse Events ◽  
Randomised Controlled Trials ◽  
Controlled Trials ◽  
Number Of Patients ◽  
Randomised Controlled ◽  
The Impact

We have evaluated the reporting of withdrawals due to adverse effects and specific adverse effects in randomised controlled trials of recombinant human GH in adults. A systematic review was carried out of randomised controlled trials of the clinical effectiveness of recombinant human GH in adults with GH deficiency in relation to impact on quality of life. Trials were identified from searching electronic databases, bibliographies of related articles and consulting experts. There was reporting of withdrawals due to adverse effects and specific adverse effects. Rates of oedema and arthralgia were reported in included trials. Seventeen randomised controlled trials, published between 1990 and 1999, met the inclusion criteria for the review. Nine trials reported data on the effectiveness of GH on quality of life in adults. Only five trials (29%) reported both withdrawals from the study because of adverse events and specific adverse events with numbers per study arm and per type. Six further trials (35%) reported either withdrawal details or specific adverse event details or partial data on specific adverse events. Six trials (35%), however, did not report information on either withdrawals or specific adverse events. Ten of the 17 studies (59%) reported the number of patients who withdrew from the study due to adverse events per study arm and type of adverse event per study arm. Seven of the 17 trials (41%) reported the number of specific adverse events per study arm and six (35%) reported the type per study arm. The reporting of adverse events in randomised controlled trials of GH is variable and not consistent across trials. It is not possible to assess the impact that adverse events may have had on unblinding patients, and therefore the extent to which the effects of GH may have been overestimated. Therefore those conducting endocrinology trials in the future need to pay attention to the reporting of withdrawals due to adverse events and specific adverse events.

scholarly journals A study update newsletter or Post-it® note did not increase postal questionnaire response rates in a falls prevention trial: an embedded randomised factorial trial

F1000Research ◽  
2019 ◽  
Vol 7 ◽  
pp. 1083
Author(s):  
Sara Rodgers ◽  
Illary Sbizzera ◽  
Sarah Cockayne ◽  
Caroline Fairhurst ◽  
Sarah E. Lamb ◽  
...  
Keyword(s):  
Randomised Controlled Trials ◽  
Statistical Power ◽  
Controlled Trial ◽  
Response Rates ◽  
Postal Questionnaire ◽  
Falls Prevention ◽  
Controlled Trials ◽  
Questionnaire Response ◽  
Factorial Trial ◽  
Randomised Controlled

Background: Participants not returning data collection questionnaires is a problem for many randomised controlled trials. The resultant loss of data leads to a reduction in statistical power and can result in bias. The aim of this study was to assess whether the use of a study update newsletter and/or a handwritten or printed Post-it® note sticker increased postal questionnaire response rates for participants of a randomised controlled trial. Method: This study was a factorial trial embedded within a host trial of a falls-prevention intervention among men and women aged ≥65 years under podiatric care. Participants were randomised into one of six groups: newsletter plus handwritten Post-it®; newsletter plus printed Post-it®; newsletter only; handwritten Post-it® only; printed Post-it® only; or no newsletter or Post-it®. The results were combined with those from previous embedded randomised controlled trials in meta-analyses. Results: The overall 12-month response rate was 803/826 (97.2%) (newsletter 95.1%, no newsletter 99.3%, printed Post-it® 97.5%, handwritten Post-it® 97.1%, no Post-it® 97.1%). The study update newsletter had a detrimental effect on response rates (adjusted odds ratio 0.14, 95% CI 0.04 to 0.48, p<0.01) and time to return the questionnaire (adjusted hazard ratio 0.86, 95% CI 0.75 to 0.99, p=0.04). No other statistically significant differences were observed between the intervention groups on response rates, time to response, and the need for a reminder. Conclusions: Post-it® notes have been shown to be ineffective in three embedded trials, whereas the evidence for newsletter reminders is still uncertain.

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