The use of randomisation-based efficacy estimators in non-inferiority trials

Gillespie, David; Farewell, Daniel; Barrett-Lee, Peter; Casbard, Angela; Hawthorne, A. B.; Hurt, Chris; Murray, Nick; Probert, Chris; Stenson, Rachel; Hood, Kerenza

doi:10.1186/s13063-017-1837-3

Cited by 5 publications

(4 citation statements)

References 24 publications

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Section: Resultsmentioning

confidence: 99%

“…This paper highlights the increase in variance experienced when fitting these models, something that can only be reduced when the models include strong predictors of adherence and outcome. 35 2. Extension of the approach to handle nonlinear outcome variables is also required 35 CACE analysis using propensity score approach (CACE) A propensity score is developed in the EXP group in order to predict the probability that those in the CON group would have been fully adherent if assigned to EXP.…”

Section: None Statedmentioning

confidence: 99%

“…35 2. Extension of the approach to handle nonlinear outcome variables is also required 35 CACE analysis using propensity score approach (CACE) A propensity score is developed in the EXP group in order to predict the probability that those in the CON group would have been fully adherent if assigned to EXP. CON group outcomes are re-weighted using these probabilities and compared with the outcomes of those who were fully adherent in the EXP group 1 (4)…”

Section: None Statedmentioning

confidence: 99%

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Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review

et al. 2022

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BackgroundIn non-inferiority trials with non-adherence to interventions (or non-compliance), intention-to-treat and per-protocol analyses are often performed; however, non-random non-adherence generally biases these estimates of efficacy.ObjectiveTo identify statistical methods that adjust for the impact of non-adherence and thus estimate the causal effects of experimental interventions in non-inferiority trials.DesignA systematic review was conducted by searching the Ovid MEDLINE database (31 December 2020) to identify (1) randomised trials with a primary analysis for non-inferiority that applied (or planned to apply) statistical methods to account for the impact of non-adherence to interventions, and (2) methodology papers that described such statistical methods and included a non-inferiority trial application.OutcomesThe statistical methods identified, their impacts on non-inferiority conclusions, and their advantages/disadvantages.ResultsA total of 24 papers were included (4 protocols, 13 results papers and 7 methodology papers) reporting relevant methods on 26 occasions. The most common were instrumental variable approaches (n=9), including observed adherence as a covariate within a regression model (n=3), and modelling adherence as a time-varying covariate in a time-to-event analysis (n=3). Other methods included rank preserving structural failure time models and inverse-probability-of-treatment weighting. The methods identified in protocols and results papers were more commonly specified as sensitivity analyses (n=13) than primary analyses (n=3). Twelve results papers included an alternative analysis of the same outcome; conclusions regarding non-inferiority were in agreement on six occasions and could not be compared on six occasions (different measures of effect or results not provided in full).ConclusionsAvailable statistical methods which attempt to account for the impact of non-adherence to interventions were used infrequently. Therefore, firm inferences about their influence on non-inferiority conclusions could not be drawn. Since intention-to-treat and per-protocol analyses do not guarantee unbiased conclusions regarding non-inferiority, the methods identified should be considered for use in sensitivity analyses.PROSPERO registration numberCRD42020177458.

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Section: Resultsmentioning

confidence: 99%

Section: None Statedmentioning

confidence: 99%

Section: None Statedmentioning

confidence: 99%

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Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review

et al. 2022

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“…We used instrumental variable methods to conduct these analyses, using randomisation as an instrument. [51][52][53] The models were fit using two-stage least squares instrumental variables regression, including those covariates used in the primary analysis model. The results were summarised using point estimates, and one-sided 95% CIs and NI p-values (in line with the sample size calculation).…”

Section: Sensitivity Analysesmentioning

confidence: 99%

Pragmatic randomised controlled trial of guided self-help versus individual cognitive behavioural therapy with a trauma focus for post-traumatic stress disorder (RAPID)

Bisson,

Ariti,

Cullen

et al. 2023

Health Technol Assess

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Background Guided self-help has been shown to be effective for other mental conditions and, if effective for post-traumatic stress disorder, would offer a time-efficient and accessible treatment option, with the potential to reduce waiting times and costs. Objective To determine if trauma-focused guided self-help is non-inferior to individual, face-to-face cognitive-behavioural therapy with a trauma focus for mild to moderate post-traumatic stress disorder to a single traumatic event. Design Multicentre pragmatic randomised controlled non-inferiority trial with economic evaluation to determine cost-effectiveness and nested process evaluation to assess fidelity and adherence, dose and factors that influence outcome (including context, acceptability, facilitators and barriers, measured qualitatively). Participants were randomised in a 1 : 1 ratio. The primary analysis was intention to treat using multilevel analysis of covariance. Setting Primary and secondary mental health settings across the United Kingdom’s National Health Service. Participants One hundred and ninety-six adults with a primary diagnosis of mild to moderate post-traumatic stress disorder were randomised with 82% retention at 16 weeks and 71% at 52 weeks. Nineteen participants and ten therapists were interviewed for the process evaluation. Interventions Up to 12 face-to-face, manualised, individual cognitive-behavioural therapy with a trauma focus sessions, each lasting 60–90 minutes, or to guided self-help using Spring, an eight-step online guided self-help programme based on cognitive-behavioural therapy with a trauma focus, with up to five face-to-face meetings of up to 3 hours in total and four brief telephone calls or e-mail contacts between sessions. Main outcome measures Primary outcome: the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, at 16 weeks post-randomisation. Secondary outcomes: included severity of post-traumatic stress disorder symptoms at 52 weeks, and functioning, symptoms of depression, symptoms of anxiety, alcohol use and perceived social support at both 16 and 52 weeks post-randomisation. Those assessing outcomes were blinded to group assignment. Results Non-inferiority was demonstrated at the primary end point of 16 weeks on the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [mean difference 1.01 (one-sided 95% CI −∞ to 3.90, non-inferiority p = 0.012)]. Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, score improvements of over 60% in both groups were maintained at 52 weeks but the non-inferiority results were inconclusive in favour of cognitive-behavioural therapy with a trauma focus at this timepoint [mean difference 3.20 (one-sided 95% confidence interval −∞ to 6.00, non-inferiority p = 0.15)]. Guided self-help using Spring was not shown to be more cost-effective than face-to-face cognitive-behavioural therapy with a trauma focus although there was no significant difference in accruing quality-adjusted life-years, incremental quality-adjusted life-years −0.04 (95% confidence interval −0.10 to 0.01) and guided self-help using Spring was significantly cheaper to deliver [£277 (95% confidence interval £253 to £301) vs. £729 (95% CI £671 to £788)]. Guided self-help using Spring appeared to be acceptable and well tolerated by participants. No important adverse events or side effects were identified. Limitations The results are not generalisable to people with post-traumatic stress disorder to more than one traumatic event. Conclusions Guided self-help using Spring for mild to moderate post-traumatic stress disorder to a single traumatic event appears to be non-inferior to individual face-to-face cognitive-behavioural therapy with a trauma focus and the results suggest it should be considered a first-line treatment for people with this condition. Future work Work is now needed to determine how best to effectively disseminate and implement guided self-help using Spring at scale. Trial registration This trial is registered as ISRCTN13697710. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/97) and is published in full in Health Technology Assessment; Vol. 27, No. 26. See the NIHR Funding and Awards website for further award information.

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Out-of-hospital cardiac arrest outcomes with “pit crew” resuscitation and scripted initiation of mechanical CPR

Gonzales

Oyler

Hayes

et al. 2019

The American Journal of Emergency Medicine

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The use of randomisation-based efficacy estimators in non-inferiority trials

Cited by 5 publications

References 24 publications

Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review

Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review

Pragmatic randomised controlled trial of guided self-help versus individual cognitive behavioural therapy with a trauma focus for post-traumatic stress disorder (RAPID)

Out-of-hospital cardiac arrest outcomes with “pit crew” resuscitation and scripted initiation of mechanical CPR

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