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 Data-sharing recommendations in biomedical journals and randomised controlled trials: an audit of journals following the ICMJE recommendations

BMJ Open ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. e038887
Author(s):  
Maximilian Siebert ◽  
Jeanne Fabiola Gaba ◽  
Laura Caquelin ◽  
Henri Gouraud ◽  
Alain Dupuy ◽  
...  
Keyword(s):  
Medical Journal ◽  
Data Sharing ◽  
Randomised Controlled Trials ◽  
Primary Outcome ◽  
Controlled Trials ◽  
Cross Sectional Survey ◽  
Eligibility Criteria ◽  
Cross Sectional ◽  
Data Set ◽  
Randomised Controlled

ObjectiveTo explore the implementation of the International Committee of Medical Journal Editors (ICMJE) data-sharing policy which came into force on 1 July 2018 by ICMJE-member journals and by ICMJE-affiliated journals declaring they follow the ICMJE recommendations.DesignA cross-sectional survey of data-sharing policies in 2018 on journal websites and in data-sharing statements in randomised controlled trials (RCTs).SettingICMJE website; PubMed/Medline.Eligibility criteriaICMJE-member journals and 489 ICMJE-affiliated journals that published an RCT in 2018, had an accessible online website and were not considered as predatory journals according to Beall’s list. One hundred RCTs for member journals and 100 RCTs for affiliated journals with a data-sharing policy, submitted after 1 July 2018.Main outcome measuresThe primary outcome for the policies was the existence of a data-sharing policy (explicit data-sharing policy, no data-sharing policy, policy merely referring to ICMJE recommendations) as reported on the journal website, especially in the instructions for authors. For RCTs, our primary outcome was the intention to share individual participant data set out in the data-sharing statement.ResultsEight (out of 14; 57%) member journals had an explicit data-sharing policy on their website (three were more stringent than the ICMJE requirements, one was less demanding and four were compliant), five (35%) additional journals stated that they followed the ICMJE requirements, and one (8%) had no policy online. In RCTs published in these journals, there were data-sharing statements in 98 out of 100, with expressed intention to share individual patient data reaching 77 out of 100 (77%; 95% CI 67% to 85%). One hundred and forty-five (out of 489) ICMJE-affiliated journals (30%; 26% to 34%) had an explicit data-sharing policy on their website (11 were more stringent than the ICMJE requirements, 85 were less demanding and 49 were compliant) and 276 (56%; 52% to 61%) merely referred to the ICMJE requirements. In RCTs published in affiliated journals with an explicit data-sharing policy, data-sharing statements were rare (25%), and expressed intentions to share data were found in 22% (15% to 32%).ConclusionThe implementation of ICMJE data-sharing requirements in online journal policies was suboptimal for ICMJE-member journals and poor for ICMJE-affiliated journals. The implementation of the policy was good in member journals and of concern for affiliated journals. We suggest the conduct of continuous audits of medical journal data-sharing policies in the future.RegistrationThe protocol was registered before the start of the research on the Open Science Framework (https://osf.io/n6whd/).

scholarly journals Inequity in rehabilitation interventions after hip fracture: a systematic review

2019 ◽  
Vol 48 (4) ◽  
pp. 489-497 ◽  
Author(s):  
K J Sheehan ◽  
L Fitzgerald ◽  
S Hatherley ◽  
C Potter ◽  
S Ayis ◽  
...  
Keyword(s):  
Nursing Home ◽  
Cognitive Impairment ◽  
Hip Fracture ◽  
Randomised Controlled Trials ◽  
Care Pathway ◽  
Data Extraction ◽  
Risk Of Bias ◽  
Controlled Trials ◽  
Eligibility Criteria ◽  
Randomised Controlled

Abstract Objective to determine the extent to which equity factors contributed to eligibility criteria of trials of rehabilitation interventions after hip fracture. We define equity factors as those that stratify healthcare opportunities and outcomes. Design systematic search of MEDLINE, Embase, CINHAL, PEDro, Open Grey, BASE and ClinicalTrials.gov for randomised controlled trials of rehabilitation interventions after hip fracture published between 1 January 2008 and 30 May 2018. Trials not published in English, secondary prevention or new models of service delivery (e.g. orthogeriatric care pathway) were excluded. Duplicate screening for eligibility, risk of bias (Cochrane Risk of Bias Tool) and data extraction (Cochrane’s PROGRESS-Plus framework). Results twenty-three published, eight protocol, four registered ongoing randomised controlled trials (4,449 participants) were identified. A total of 69 equity factors contributed to eligibility criteria of the 35 trials. For more than 50% of trials, potential participants were excluded based on residency in a nursing home, cognitive impairment, mobility/functional impairment, minimum age and/or non-surgical candidacy. Where reported, this equated to the exclusion of 2,383 out of 8,736 (27.3%) potential participants based on equity factors. Residency in a nursing home and cognitive impairment were the main drivers of these exclusions. Conclusion the generalisability of trial results to the underlying population of frail older adults is limited. Yet, this is the evidence base underpinning current service design. Future trials should include participants with cognitive impairment and those admitted from nursing homes. For those excluded, an evidence-informed reasoning for the exclusion should be explicitly stated. PROSPERO CRD42018085930.

scholarly journals Explaining temporal trends in annualised relapse rates in placebo groups of randomised controlled trials in relapsing multiple sclerosis: systematic review and meta-regression

2013 ◽  
Vol 19 (12) ◽  
pp. 1580-1586 ◽  
Author(s):  
Simon M Steinvorth ◽  
Christian Röver ◽  
Simon Schneider ◽  
Richard Nicholas ◽  
Sebastian Straube ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Randomised Controlled Trials ◽  
Controlled Trials ◽  
Eligibility Criteria ◽  
Patient Age ◽  
Meta Regression ◽  
Randomised Controlled ◽  
Relapsing Multiple Sclerosis ◽  
Relapse Rates ◽  
Over Time

Background: Recent studies have shown a decrease in annualised relapse rates (ARRs) in placebo groups of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS). Methods: We conducted a systematic literature search of RCTs in RMS. Data on eligibility criteria and baseline characteristics were extracted and tested for significant trends over time. A meta-regression was conducted to estimate their contribution to the decrease of trial ARRs over time. Results: We identified 56 studies. Patient age at baseline ( p < 0.001), mean duration of multiple sclerosis (MS) at baseline ( p = 0.048), size of treatment groups ( p = 0.003), Oxford Quality Scale scores ( p = 0.021), and the number of eligibility criteria ( p<0.001) increased significantly, whereas pre-trial ARR ( p = 0.001), the time span over which pre-trial ARR was calculated ( p < 0.001), and the duration of placebo-controlled follow-up ( p = 0.006) decreased significantly over time. In meta-regression of trial placebo ARR, the temporal trend was found to be insignificant, with major factors explaining the variation: pre-trial ARR, the number of years used to calculate pre-trial ARR and study duration. Conclusion: The observed decline in trial ARRs may result from decreasing pre-trial ARRs and a shorter time period over which pre-trial ARRs were calculated. Increasing patient age and duration of illness may also contribute.

scholarly journals Incidence and prognostic factors of knee extension deficits following anterior cruciate ligament reconstruction: A systematic review and meta-analysis of randomised controlled trials

2020 ◽  
Author(s):  
Nalan Ektas ◽  
Corey Scholes ◽  
Meredith Harrison-Brown ◽  
Maha Jegatheesan ◽  
Ashwin Rajesh ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Randomised Controlled Trials ◽  
Acl Injury ◽  
Knee Extension ◽  
Cochrane Library ◽  
Controlled Trials ◽  
Extension Deficit ◽  
Eligibility Criteria ◽  
Randomised Controlled

ABSTRACTBackground and aimsKnee extension deficits complicate recovery from ACL injury and reconstruction, however the incidence of knee extension loss is not well defined. The aim of this review was to identify the incidence of loss of extension (LOE) following ACL rupture and reconstruction, explore the definitions of knee extension deficits reported and identify prognostic factors affecting LOE incidence.Methods and analysisA systematic search was conducted in Medline, Cochrane Library and PEDro for studies in publication up to September 2019, with no restrictions on publication year. References were screened and assessed for inclusion using predetermined eligibility criteria. Randomised controlled trials (RCTs) that quantified knee angle, loss of extension or incidence of extension deficit were included for quality assessment and data extraction. Statistical summaries were generated and meta-analyses performed in two parts to examine: (i) the probability of a datapoint being zero incidence compared to a non-zero incidence, and (ii) the relationship between the predictors and non-zero LOE incidence.ResultsA sample of 8594 papers were retrieved using the search criteria, with 48 studies meeting eligibility criteria. Pooled results from 4065 participants were included for analysis, with 3965 participants who had undergone ACLR. The proportion of included studies judged at an overall low risk of bias was small (6%). The analysis revealed median LOE incidence of 15.9% (IQR 1.4 - 46.5) at a median follow up from treatment of 4.9 months (IQR 1.9 - 24). Median LOE incidence was 23 % (IQR 8.4 - 50.0) for the subset of studies reporting up to 12 months of follow up. The observed group and study were the most important predictors for whether a datapoint reported an incidence of extension deficit. Time to follow up (P < 0.001) and graft type (P = 0.02) were found to have a significant influence on non-zero LOE incidence (%).ConclusionsThis review examined the definitions for the measurement and interpretation of postoperative knee extension, and established the trajectory of knee extension deficit after ACL injury and reconstruction. While factors associated with loss of extension were identified, the trajectory of knee extension deficits were difficult to infer due to discrepancies in measurement techniques and patient variation. Clinicians should expect up to 1 in 3 patients to present postoperatively with loss of extension of at least 3 degrees, which may partially resolve over time. Future work should focus on the development of a standardised framework for postoperative measurement and reporting of LOE.

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 Workplace programmes for supporting breast-feeding: a systematic review and meta-analysis

2020 ◽  
pp. 1-13
Author(s):  
Xueying Tang ◽  
Peta Patterson ◽  
Kristen MacKenzie-Shalders ◽  
Louise A van Herwerden ◽  
Jo Bishop ◽  
...  
Keyword(s):  
Systematic Review ◽  
Breast Feeding ◽  
Randomised Controlled Trials ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Eligibility Criteria ◽  
Positive Direction ◽  
The Usa ◽  
Expectant Fathers ◽  
Randomised Controlled

Abstract Objective: To critically review the literature regarding workplace breast-feeding interventions and to assess their impact on breast-feeding indicators. Design: A systematic review and meta-analysis was conducted. Electronic searches for workplace intervention studies to support breast-feeding, without restriction on language or study design, were performed in PubMed, CENTRAL, CINAHL, Embase, Web of Science, Business Source Complete, ProQuest-Sociology and ProQuest-Social Science to 13 April 2020. A meta-analysis of the pooled effect of the programmes on breast-feeding indicators was conducted. Results: The search identified 10 215 articles; fourteen studies across eighteen publications met eligibility criteria. Programmes were delivered in the USA (n 10), Turkey (n 2), Thailand (n 1) or Taiwan (n 1). There were no randomised controlled trials. The pooled OR for exclusive breast-feeding at 3 or 6 months for participants v. non-participants of three non-randomised controlled studies was 3·21 (95 % CI 1·70, 6·06, I2 = 22 %). Despite high heterogeneity, other pooled outcomes were consistently in a positive direction with acceptable CI. Pooled mean duration of breast-feeding for five single-arm studies was 9·16 months (95 % CI 8·25, 10·07). Pooled proportion of breast-feeding at 6 months for six single-arm studies was 0·76 (95 % CI 0·66, 0·84) and breast-feeding at 12 months for three single-arm studies was 0·41 (95 % CI 0·22, 0·62). Most programmes were targeted at mothers; two were targeted at expectant fathers. Conclusions: Workplace programmes may be effective in promoting breast-feeding among employed mothers and partners of employed fathers. However, no randomised controlled trials were identified, and better-quality research on workplace interventions to improve breast-feeding is needed.

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 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.

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