scholarly journals Update to the FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical analysis plan for the trials and for the individual patient data meta-analysis

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Gillian Elizabeth Mead ◽  
◽  
Catriona Graham ◽  
Laurent Billot ◽  
Per Näsman ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Individual Patient Data ◽  
Statistical Analysis Plan ◽  
Trial Registration ◽  
Stroke Recovery ◽  
Search Query ◽  
Two Stage ◽  
Data Set ◽  
Link Type ◽  
The Individual

Abstract Background Three large trials of fluoxetine for stroke recovery (FOCUS (fluoxetine or control under supervision), AFFINITY (the Assessment oF FluoxetINe In sTroke recovery) and EFFECTS (Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke)) have been collaboratively designed with the same basic protocol to facilitate an individual patient data analysis (IPDM). The statistical analysis plan for the three individual trials has already been reported in Trials, including a brief description of the IPDM. In this protocol, we describe in detail how we will perform the IPDM. Methods/design Data from EFFECTS and AFFINITY will be transferred securely to the FOCUS statistician, who will perform a one-stage IPDM and a two-stage IPDM. For the one-stage IPDM, data will be combined into a single data set and the same analyses performed as described for the individual trials. For the two-stage IPDM, the results for the three individual trials will be combined using fixed effects meta-analyses. The primary and secondary outcome domains for the IPDM are the same as for individual trials. We will also perform analyses according to several subgroups including country of recruitment, ethnicity and trial. We will also explore the effects of fluoxetine on our primary and secondary outcomes in subgroups defined by combinations of characteristics. We also describe additional research questions that will be addressed using the combined data set, and published subsequently, including predictors of important post-stroke problems such as seizures, low mood and bone fractures. Discussion An IPDM of our three large trials of fluoxetine for stroke recovery will allow us to provide the most precise estimates of any risks and benefits of fluoxetine vs placebo, to detect reliably a smaller overall effect size than those detectable by the individual trials, to better determine the effects of fluoxetine vs placebo in subgroups of patients and outcomes and to broaden the generalisability of the results. Also, we may identify differences in treatment effects between studies. Trial registration FOCUS: ISRCTN ISRCTN83290762. Registered on 23 May 2012. EudraCT 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry ACTRN12611000774921. Registered on 22 July 2011. EFFECTS: ISRCTN ISRCTN13020412. Registered on 19 December 2014. ClinicalTrials.gov NCT02683213. Registered on 2 February 2016. EudraCT 2011-006130-16. Registered on 8 August 2014.

scholarly journals The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis

Trials ◽  
2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Catriona Graham ◽  
Steff Lewis ◽  
John Forbes ◽  
Gillian Mead ◽  
Maree L. Hackett ◽  
...  
Keyword(s):  
New Zealand ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Patient Data ◽  
Trial Registration ◽  
The Core ◽  
Link Type ◽  
Routine Administration ◽  
The Individual

Abstract Background Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients’ functional outcome. Methods/Design The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2–15 days after stroke onset. Patients are randomised centrally via each trials’ web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. Discussion Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020. Trial registration FOCUS: ISRCTN, ISRCTN83290762. Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Registered on 22 July 2011. EFFECTS: ISRCTN, ISRCTN13020412. Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213. Registered on 2 February 2016. EudraCT, 2011-006130-16. Registered on 8 August 2014.

Empirical comparison of subgroup effects in conventional and individual patient data meta-analyses

2008 ◽  
Vol 24 (03) ◽  
pp. 358-361 ◽  
Author(s):  
Laura Koopman ◽  
Geert J. M. G. van der Heijden ◽  
Arno W. Hoes ◽  
Diederick E. Grobbee ◽  
Maroeska M. Rovers
Keyword(s):  
Individual Patient Data ◽  
Meta Analysis ◽  
Acute Otitis Media ◽  
Patient Data ◽  
Published Data ◽  
Summary Statistics ◽  
Two Stage ◽  
Data Set ◽  
Meta Analyses ◽  
Subgroup Effects

Objectives:Individual patient data (IPD) meta-analyses have been proposed as a major improvement in meta-analytic methods to study subgroup effects. Subgroup effects of conventional and IPD meta-analyses using identical data have not been compared. Our objective is to compare such subgroup effects using the data of six trials (n= 1,643) on the effectiveness of antibiotics in children with acute otitis media (AOM).Methods:Effects (relative risks, risk differences [RD], and their confidence intervals [CI]) of antibiotics in subgroups of children with AOM resulting from (i) conventional meta-analysis using summary statistics derived from published data (CMA), (ii) two-stage approach to IPD meta-analysis using summary statistics derived from IPD (IPDMA-2), and (iii) one-stage approach to IPD meta-analysis where IPD is pooled into a single data set (IPDMA-1) were compared.Results:In the conventional meta-analysis, only two of the six studies were included, because only these reported on relevant subgroup effects. The conventional meta-analysis showed larger (age < 2 years) or smaller (age ≥ 2 years) subgroup effects and wider CIs than both IPD meta-analyses (age < 2 years: RDCMA-21 percent, RDIPDMA-1-16 percent, RDIPDMA-2-15 percent; age ≥2 years: RDCMA-5 percent, RDIPDMA-1-11 percent, RDIPDMA-2-11 percent). The most important reason for these discrepant results is that the two studies included in the conventional meta-analysis reported outcomes that were different both from each other and from the IPD meta-analyses.Conclusions:This empirical example shows that conventional meta-analyses do not allow proper subgroup analyses, whereas IPD meta-analyses produce more accurate subgroup effects. We also found no differences between the one- and two-stage meta-analytic approaches.

scholarly journals The effectiveness and safety of antifibrinolytics in patients with acute intracranial haemorrhage: statistical analysis plan for an individual patient data meta-analysis

2017 ◽  
Vol 2 ◽  
pp. 120 ◽  
Author(s):  
Katharine Ker ◽  
David Prieto-Merino ◽  
Nikola Sprigg ◽  
Abda Mahmood ◽  
Philip Bath ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Intracranial Haemorrhage ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Statistical Analysis Plan ◽  
Patient Data ◽  
Time To Treatment ◽  
Logistic Regression Models ◽  
Secondary Outcomes

Introduction: The Antifibrinolytic Trialists Collaboration aims to increase knowledge about the effectiveness and safety of antifibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of antifibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42016052155). We will conduct an individual patient data meta-analysis of randomised controlled trials with 1000 patients or more assessing the effects of antifibrinolytics in acute intracranial haemorrhage. We will assess the effect on two co-primary outcomes: 1) death in hospital at end of trial follow-up, and 2) death in hospital or dependency at end of trial follow-up. The co-primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of antifibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of antifibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of antifibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.

scholarly journals The effectiveness and safety of antifibrinolytics in patients with acute intracranial haemorrhage: statistical analysis plan for an individual patient data meta-analysis

2018 ◽  
Vol 2 ◽  
pp. 120
Author(s):  
Katharine Ker ◽  
David Prieto-Merino ◽  
Nikola Sprigg ◽  
Abda Mahmood ◽  
Philip Bath ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Intracranial Haemorrhage ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Statistical Analysis Plan ◽  
Patient Data ◽  
Time To Treatment ◽  
Logistic Regression Models ◽  
Intention To Treat ◽  
Secondary Outcomes

Introduction: The Antifibrinolytic Trialists Collaboration aims to increase knowledge about the effectiveness and safety of antifibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of antifibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42016052155). We will conduct an individual patient data meta-analysis of randomised controlled trials with 1000 patients or more assessing the effects of antifibrinolytics in acute intracranial haemorrhage. We will assess the effect on two co-primary outcomes: 1) Death in hospital within 30 days of randomisation, and 2) Death  or dependency at final follow-up within 90 days of randomisation. The co-primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of antifibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of antifibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of antifibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.

scholarly journals An Internet-based emotion regulation intervention versus no intervention for non-suicidal self-injury in adolescents: a statistical analysis plan for a feasibility randomised clinical trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Markus Harboe Olsen ◽  
Britt Morthorst ◽  
Anne Katrine Pagsberg ◽  
Michella Heinrichsen ◽  
Bo Møhl ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Emotion Regulation ◽  
Statistical Analysis ◽  
Randomised Clinical Trial ◽  
Statistical Analysis Plan ◽  
Feasibility Trial ◽  
Treatment As Usual ◽  
Link Type ◽  
Self Injury ◽  
Statistical Report

Abstract Background Non-suicidal self-injury (NSSI) has a lifetime prevalence of 17% in adolescents in the general population and up to 74% in adolescents with psychiatric disorders. NSSI is one of the most important predictors of later suicidal behaviour and death by suicide. The TEENS feasibility trial was initiated to assess the feasibility and safety of Internet-based Emotion Regulation Individual Therapy for Adolescents (ERITA) as an add-on to treatment as usual in 13–17-year-old patients with NSSI referred to the Child and Adolescent Mental Health Services. Methods The TEENS feasibility trial is a randomised clinical trial with a parallel-group design. The trial intervention is an 11-week online therapy which is tested as an add-on to treatment as usual versus treatment as usual. The primary feasibility outcomes are the fraction of participants who (1) completed 12 weeks of follow-up interview or assessment, (2) consented to inclusion and randomisation out of all eligible participants, and (3) were compliant with the experimental intervention, assessed as completion of at least six out of eleven modules in the programme. Since this is a feasibility trial, we did not predefine a required sample size. The exploratory clinical outcome, the frequency of NSSI episodes, assessed using Deliberate Self-Harm Inventory – Youth version (DSHI-Y), at the end of intervention, is planned to be the future primary outcome in a larger pragmatic definitive randomised clinical trial. After completion of the feasibility trial, blinded data will be analysed by two independent statisticians blinded to the intervention, where ‘A’ and ‘B’ refer to the two groups. A third party will compare these reports, and discrepancies will be discussed. The statistical report with the analyses chosen for the manuscript is being tracked using a version control system, and both statistical reports will be published as a supplementary material. Based on the final statistical report, two blinded conclusions will be drawn by the steering group. Discussion We present a pre-defined statistical analysis plan for the TEENS feasibility trial, which limits bias, p-hacking, data-driven interpretations. This statistical analysis plan is accompanied by a pre-programmed version-controlled statistical report with simulated data, which increases transparency and reproducibility. Trial registration ClinicalTrials.govNCT04243603. Registered on 28 January 2020

scholarly journals Statistical analysis plan for the COMPARE trial: a 3-arm randomised controlled trial comparing the effectiveness of Constraint-induced Aphasia Therapy Plus and Multi-modality Aphasia Therapy to usual care in chronic post-stroke aphasia (COMPARE)

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Miranda L. Rose ◽  
Tapan Rai ◽  
David Copland ◽  
Lyndsey Nickels ◽  
Leanne Togher ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Usual Care ◽  
Relative Effectiveness ◽  
Random Effect ◽  
Statistical Analysis Plan ◽  
Trial Registration ◽  
Post Intervention ◽  
Post Stroke ◽  
Aphasia Therapy

Abstract Background While high-quality meta-analyses have confirmed the effectiveness of aphasia therapy after stroke, there is limited evidence for the comparative effectiveness of different aphasia interventions. Two commonly used interventions, Constraint-induced Aphasia Therapy Plus (CIAT Plus) and Multi-modality Aphasia Therapy (M-MAT), are hypothesised to rely on diverse underlying neural mechanisms for recovery and may be differentially responsive to aphasia severity. COMPARE is a prospective randomised open-blinded end-point trial designed to determine whether, in people with chronic post-stroke aphasia living in the community, CIAT Plus and M-MAT provide greater therapeutic benefit compared to usual care, are differentially effective according to aphasia severity, and are cost-effective. This paper details the statistical analysis plan for the COMPARE trial developed prior to data analysis. Methods Participants (n = 216) are randomised to one of three arms, CIAT Plus, M-MAT or usual care, and undertake therapy with a study trained speech pathologist in groups of three participants stratified by aphasia severity. Therapy occurs for 3 h blocks per day for 10 days across 2 weeks. The primary clinical outcome is aphasia severity as measured by the Western Aphasia Battery-Revised Aphasia Quotient (WAB-R-AQ) immediately post intervention. Secondary outcomes include WAB-R-AQ at 12-week follow-up, and functional communication, discourse efficiency, multimodal communication, and health-related quality of life immediately post intervention and at 12-week follow-up. Results Linear mixed models (LMMs) will be used to analyse differences between M-MAT and UC, and CIAT-Plus and UC on each outcome measure immediately and at 12 weeks post-intervention. The LMM for WAB-R-AQ will assess the differences in efficacy between M-MAT and CIAT-Plus. All analyses will control for baseline aphasia severity (fixed effect) and for the clustering effect of treatment groups (random effect). Discussion This trial will provide relative effectiveness data for two common interventions for people with chronic post-stroke aphasia, and highlight possible differential effects based on aphasia severity. Together with the health economic analysis data, the results will enable more informed personalised prescription for aphasia therapy after stroke. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN 12615000618550. Registered on 15 June 2016

scholarly journals Statistical analysis plan for the Prophylactic Melatonin for Delirium in Intensive Care (ProMEDIC): a randomised controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Bradley Wibrow ◽  
F. Eduardo Martinez ◽  
Andrew Ford ◽  
Erin Kelty ◽  
Kevin Murray ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Statistical Analysis ◽  
Controlled Trial ◽  
Statistical Analysis Plan ◽  
Brain Dysfunction ◽  
Primary Objective ◽  
Trial Registration ◽  
Clinical Trial Registry ◽  
Randomised Controlled

Abstract Rationale Delirium is defined as acute organic brain dysfunction characterised by inattention and disturbance of cognition. It is common in the intensive care unit and is associated with poorer outcomes. Good quality sleep is important in the prevention and management of delirium. Melatonin is a natural hormone secreted by the pineal gland which helps in the regulation of the sleep-wake cycle. It is possible that melatonin supplementation in intensive care improves sleep and prevents delirium. Methods and design The ‘Prophylactic Melatonin for Delirium in Intensive Care’ study is a multi-centre, randomised, double-blinded, placebo-controlled trial. The primary objective of this study is to determine whether melatonin given prophylactically decreases delirium in critically ill patients. A total of 850 ICU patients have been randomised (1:1) to receive either melatonin or a placebo. Participants were monitored twice daily for symptoms of delirium. Results This paper and the attached additional files describe the statistical analysis plan (SAP) for the trial. The SAP has been developed and submitted for publication before the database has been locked and before the treatment allocation has been unblinded. The SAP contains details of analyses to be undertaken, which will be reported in the primary and secondary publications. Discussion The SAP details the analyses that will be done to avoid bias coming from knowledge of the results in advance. This trial will determine whether prophylactic melatonin administered to intensive care unit patients helps decrease the rate and the severity of delirium. Trial registration Australian and New Zealand Clinical Trial Registry (ANZCTR) ACTRN1261600043647, registration date: 06 April 2016. WHO Trial Number – U1111-1175-1814

scholarly journals Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): protocol and statistical analysis plan for a randomized controlled trial

2016 ◽  
Vol 1 ◽  
pp. 31 ◽  
Author(s):  
Haleema Shakur ◽  
Bukola Fawole ◽  
Modupe Kuti ◽  
Oladapo O. Olayemi ◽  
Adenike Bello ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Statistical Analysis ◽  
Tranexamic Acid ◽  
Postpartum Haemorrhage ◽  
Controlled Trial ◽  
Statistical Analysis Plan ◽  
Trial Protocol ◽  
Randomized Controlled ◽  
Link Type ◽  
Trial Participants

Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. Methods: Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo.  Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. Discussion: This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. Trial registration:The trial was registered:ClinicalTrials.gov, Identifier NCT00872469https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190http://www.isrctn.com/ISRCTN76912190(Registration date: 22/03/2012).

scholarly journals Implementing two-stage consent pathway in neonatal trials

2021 ◽  
pp. fetalneonatal-2021-322960
Author(s):  
Eleanor Mitchell ◽  
Sam J Oddie ◽  
Jon Dorling ◽  
Chris Gale ◽  
Mark John Johnson ◽  
...  
Keyword(s):  
Critical Period ◽  
Trial Registration ◽  
Two Stage ◽  
Trial Team ◽  
Link Type ◽  
National Guidance ◽  
Registration Number ◽  
Time Critical

Perinatal trials sometimes require rapid recruitment processes to facilitate inclusion of participants when interventions are time-critical. A two-stage consent pathway has been used in some trials and is supported by national guidance. This pathway includes seeking oral assent for participation during the time-critical period followed by informed written consent later. This approach is being used in the fluids exclusively enteral from day one (FEED1) trial where participants need to be randomised within 3 hours of birth. There is some apprehension about approaching parents for participation via the oral assent pathway. The main reasons for this are consistent with previous research: lack of a written record, lack of standardised information and unfamiliarity with the process. Here, we describe how the pathway has been implemented in the FEED1 trial and the steps the trial team have taken to support sites. We provide recommendations for future trials to consider if they are considering implementing a similar pathway. Trial registration number: ISRCTN89654042.

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