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Detailed statistical analysis plan for a cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP), a novel school-based intervention to prevent obesity in school children.
Creanor, S, Lloyd, J, Hillsdon, M, Dean, S, Green, C, Taylor, RS, Ryan, E, Wyatt, K, ,
Trials. 2016;(1):599
Abstract
BACKGROUND The Healthy Lifestyles Programme (HeLP) trial is being conducted to determine whether a novel school-based intervention is effective and cost-effective in preventing obesity in 9-10 year-old children. This article describes the detailed statistical analysis plan for the HeLP trial, including an amendment (and rationale for amendment) made to originally planned sensitivity analyses. METHODS AND DESIGN The HeLP trial is a definitive, pragmatic, superiority, cluster randomised controlled trial with two parallel groups and blinded outcome assessment. This update article describes in detail (1) the primary and secondary outcomes, (2) the statistical analysis principles (including which children will be included in each analysis, how the clustered nature of the study design will be accounted for, which covariates will be included in each analysis, how the results will be presented), (3) planned sensitivity analyses, planned subgroup analyses and planned adherence-adjusted analyses for the primary outcome, (4) planned analyses for the secondary outcomes and (e) planned longitudinal analyses. TRIAL REGISTRATION International Standard Randomised Controlled Trial Number (ISRCTN) register: ISRCTN15811706 . Registered on 1 May 2012.
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Modelling variable dropout in randomised controlled trials with longitudinal outcomes: application to the MAGNETIC study.
Kolamunnage-Dona, R, Powell, C, Williamson, PR
Trials. 2016;(1):222
Abstract
BACKGROUND Clinical trials with longitudinally measured outcomes are often plagued by missing data due to patients withdrawing or dropping out from the trial before completing the measurement schedule. The reasons for dropout are sometimes clearly known and recorded during the trial, but in many instances these reasons are unknown or unclear. Often such reasons for dropout are non-ignorable. However, the standard methods for analysing longitudinal outcome data assume that missingness is non-informative and ignore the reasons for dropout, which could result in a biased comparison between the treatment groups. METHODS In this article, as a post hoc analysis, we explore the impact of informative dropout due to competing reasons on the evaluation of treatment effect in the MAGNETIC trial, the largest randomised placebo-controlled study to date comparing the addition of nebulised magnesium sulphate to standard treatment in acute severe asthma in children. We jointly model longitudinal outcome and informative dropout process to incorporate the information regarding the reasons for dropout by treatment group. RESULTS The effect of nebulised magnesium sulphate compared with standard treatment is evaluated more accurately using a joint longitudinal-competing risk model by taking account of such complexities. The corresponding estimates indicate that the rate of dropout due to good prognosis is about twice as high in the magnesium group compared with standard treatment. CONCLUSIONS We emphasise the importance of identifying reasons for dropout and undertaking an appropriate statistical analysis accounting for such dropout. The joint modelling approach accounting for competing reasons for dropout is proposed as a general approach for evaluating the sensitivity of conclusions to assumptions regarding missing data in clinical trials with longitudinal outcomes. TRIAL REGISTRATION EudraCT number 2007-006227-12 . Registration date 18 Mar 2008.
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Detailed statistical analysis plan for the pulmonary protection trial.
Buggeskov, KB, Jakobsen, JC, Secher, NH, Jonassen, T, Andersen, LW, Steinbrüchel, DA, Wetterslev, J
Trials. 2014;:510
Abstract
BACKGROUND Pulmonary dysfunction complicates cardiac surgery that includes cardiopulmonary bypass. The pulmonary protection trial evaluates effect of pulmonary perfusion on pulmonary function in patients suffering from chronic obstructive pulmonary disease. This paper presents the statistical plan for the main publication to avoid risk of outcome reporting bias, selective reporting, and data-driven results as an update to the published design and method for the trial. RESULTS The pulmonary protection trial is a randomized, parallel group clinical trial that assesses the effect of pulmonary perfusion with oxygenated blood or Custodiol™ HTK (histidine-tryptophan-ketoglutarate) solution versus no pulmonary perfusion in 90 chronic obstructive pulmonary disease patients. Patients, the statistician, and the conclusion drawers are blinded to intervention allocation. The primary outcome is the oxygenation index from 10 to 15 minutes after the end of cardiopulmonary bypass until 24 hours thereafter. Secondary outcome measures are oral tracheal intubation time, days alive outside the intensive care unit, days alive outside the hospital, and 30- and 90-day mortality, and one or more of the following selected serious adverse events: pneumothorax or pleural effusion requiring drainage, major bleeding, reoperation, severe infection, cerebral event, hyperkaliemia, acute myocardial infarction, cardiac arrhythmia, renal replacement therapy, and readmission for a respiratory-related problem. CONCLUSIONS The pulmonary protection trial investigates the effect of pulmonary perfusion during cardiopulmonary bypass in chronic obstructive pulmonary disease patients. A preserved oxygenation index following pulmonary perfusion may indicate an effect and inspire to a multicenter confirmatory trial to assess a more clinically relevant outcome. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01614951, registered on 6 June 2012.
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The Active for Life Year 5 (AFLY5) school-based cluster randomised controlled trial protocol: detailed statistical analysis plan.
Lawlor, DA, Peters, TJ, Howe, LD, Noble, SM, Kipping, RR, Jago, R
Trials. 2013;:234
Abstract
BACKGROUND The Active For Life Year 5 (AFLY5) randomised controlled trial protocol was published in this journal in 2011. It provided a summary analysis plan. This publication is an update of that protocol and provides a detailed analysis plan. UPDATE This update provides a detailed analysis plan of the effectiveness and cost-effectiveness of the AFLY5 intervention. The plan includes details of how variables will be quality control checked and the criteria used to define derived variables. Details of four key analyses are provided: (a) effectiveness analysis 1 (the effect of the AFLY5 intervention on primary and secondary outcomes at the end of the school year in which the intervention is delivered); (b) mediation analyses (secondary analyses examining the extent to which any effects of the intervention are mediated via self-efficacy, parental support and knowledge, through which the intervention is theoretically believed to act); (c) effectiveness analysis 2 (the effect of the AFLY5 intervention on primary and secondary outcomes 12 months after the end of the intervention) and (d) cost effectiveness analysis (the cost-effectiveness of the AFLY5 intervention). The details include how the intention to treat and per-protocol analyses were defined and planned sensitivity analyses for dealing with missing data. A set of dummy tables are provided in Additional file 1. DISCUSSION This detailed analysis plan was written prior to any analyst having access to any data and was approved by the AFLY5 Trial Steering Committee. Its publication will ensure that analyses are in accordance with an a priori plan related to the trial objectives and not driven by knowledge of the data. TRIAL REGISTRATION ISRCTN50133740.
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Use of dexmedetomidine for prophylactic analgesia and sedation in delayed extubation patients after craniotomy: a study protocol and statistical analysis plan for a randomized controlled trial.
Zhao, LH, Shi, ZH, Yin, NN, Zhou, JX
Trials. 2013;:251
Abstract
BACKGROUND Pain and agitation are common in patients after craniotomy. They can result in tachycardia, hypertension, immunosuppression, increased catecholamine production and increased oxygen consumption. Dexmedetomidine, an alpha-2 agonist, provides adequate sedation without respiratory depression, while facilitating frequent neurological evaluation. METHODS/DESIGN The study is a prospective, randomized, double-blind, controlled, parallel-group design. Consecutive patients are randomly assigned to one of the two treatment study groups, labeled 'Dex group' or 'Saline group.' Dexmedetomidine group patients receive a continuous infusion of 0.6 μg/kg/h (10 ug/ml). Placebo group patients receive a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. The mean percentages of time in optimal sedation, vital signs, various and adverse events, the percentage of patients requiring propofol for rescue to achieve/maintain targeted sedation (Sedation-Agitation Scale, SAS 3 to 4) and total dose of propofol required throughout the study drug infusion are collected. The percentage of patients requiring fentanyl for additional rescue to analgesia and total dose of fentanyl required are recorded. The effects of dexmedetomidine on hemodynamic and recovery responses during extubation are measured. Intensive care unit and hospital length of stay also are collected. Plasma levels of epinephrine, norepinephrine, dopamine, cortisol, neuron-specific enolase and S100-B are measured before infusion (T1), at two hours (T2), four hours (T3) and eight hours (T4) after infusion and at the end of infusion (T5) in 20 patients in each group. DISCUSSION The study has been initiated as planned in July 2012. One interim analysis advised continuation of the trial. The study will be completed in July 2013. TRIAL REGISTRATION ClinicalTrials (NCT): ChiCTR-PRC-12002903.
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Genetic Risk and Outcome of Psychosis (GROUP), a multi-site longitudinal cohort study focused on gene-environment interaction: objectives, sample characteristics, recruitment and assessment methods.
Korver, N, Quee, PJ, Boos, HB, Simons, CJ, de Haan, L, ,
International journal of methods in psychiatric research. 2012;(3):205-21
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Abstract
OBJECTIVE A longitudinal focus on gene-environment vulnerability and resilience in both patients, their unaffected family members and non-related controls offers the opportunity to elucidate etiological and pathogenetic factors influencing the onset and course of psychotic disorders. The current paper delineates the objectives, sample characteristics, recruitment and assessment procedures of the Genetic Risk and Outcome of Psychoses (GROUP) study. METHODS A naturalistic longitudinal cohort study with assessments at baseline, after three and six years of follow-up. The study is conducted by a consortium of four university psychiatric centres, with their affiliated mental health care institutions in the Netherlands covering more than 7.5 million inhabitants. Extensive assessment of genetic factors, environmental factors, (endo)phenotypes, and outcome. RESULTS At baseline, 1120 patients, 1057 siblings, 919 parents and 590 healthy controls were included. CONCLUSION The GROUP study will contribute to insight in risk and protective factors in the aetiology of non-affective psychotic disorders, and in the variation in their course and outcome.
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A feasibility study exploring the role of Chinese herbal medicine in the treatment of endometriosis.
Flower, A, Lewith, GT, Little, P
Journal of alternative and complementary medicine (New York, N.Y.). 2011;(8):691-9
Abstract
BACKGROUND Endometriosis is a common and disabling gynecologic condition affecting between 5% and 15% of women of childbearing age. Conventional medical intervention has unpleasant side-effects, and symptoms frequently return after treatment. Preliminary evidence suggests Chinese herbal medicine (CHM) may contribute to the treatment of endometriosis. OBJECTIVES The aims of this study were to test the feasibility of a novel methodology for investigating individualized decoctions of CHM rigorously and to gather preliminary data on the treatment effect of CHM for a larger definitive trial. DESIGN This was a 16-week prospective, double blinded, randomized controlled trial of 40 women with laparoscopically confirmed endometriosis. SETTINGS The trial was conducted at a private CHM clinic in Hove (U.K.) and at a National Health Service outpatient clinic in London (U.K.). INTERVENTIONS Participants were initially randomized to either wait-list control (WLC) or treatment groups to receive either individualized CHM decoctions or a therapeutically inert placebo decoction. OUTCOME MEASURES Four 10-cm visual analogue scales (VAS) were used to measure menstrual pain, daily pain, and pain on intercourse and bowel movement; these measurements were recorded weekly. The Endometriosis Health Profile-30 (EHP-30) endometriosis-specific quality-of-life questionnaire was completed at the beginning and at the end of the trial. The Measure Yourself Medical Outcomes Profile (MYMOP) a patient-centered health questionnaire was completed monthly. Liver and renal function was measured at 0, 4, 8, and 16 weeks. RESULTS Twenty-eight (28) women completed the trial. High dropout rates led to the suspension of the WLC. Randomization, double blinding, and allocation concealment was achieved successfully. Adjusted mean differences favored the active treatment in the EHP-30 and MYMOP scores. VAS scores favored the active treatment for relief of menstrual pain and the placebo group for reduction of daily pain. CONCLUSIONS the methodology successfully allowed individualized CHM decoctions to be tested rigorously. There are nonspecific contextual effects from CHM that require further investigation. Provisional data were generated to warrant a larger, more-definitive study.