Strategic use of new generation antidepressants for depression: SUN(^_^) D protocol update and statistical analysis plan.
ABSTRACT: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken.This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results.ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).
Project description:For critically ill patients treated in intensive care units (ICU), two feeding strategies are currently being advocated, one by American/Canadian and the other by European expert guidelines. These guidelines differ particularly in the timing of initiating parenteral nutrition (PN) in patients for whom enteral nutrition (EN) does not reach caloric targets.The EPaNIC trial is an investigator-initiated, non-commercial, multi-center, randomized, controlled, clinical trial with a parallel group design. This study compares early (European guideline) versus late (American/Canadian guideline) initiation of PN when EN fails to reach a caloric target. In the early PN group, PN is initiated within 24-48 hours after ICU admission to complete early enteral nutrition (EN) up to a calculated nutritional target. In the late PN group, PN completing EN is initiated when the target is not reached on day 8. In both groups, the same early EN protocol is applied. The study is designed to compare clinical outcome (morbidity and mortality) in the 2 study arms as well as to address several mechanistical questions. We here describe the EPaNIC study protocol and the statistical analysis plan for the primary report of the clinical results.The study has been initiated as planned on august 01 2007. One interim analysis advised continuation of the trial. The study will be completed in February 2011.ClinicalTrials (NCT): NCT00512122.
Project description:<h4>Background</h4>Paracetamol (acetaminophen) is recommended in most clinical practice guidelines as the first choice of treatment for low back pain, however there is limited evidence to support this recommendation. The PACE trial is the first placebo controlled trial of paracetamol for acute low back pain. This article describes the statistical analysis plan.<h4>Results</h4>PACE is a randomized double dummy placebo controlled trial that investigates and compares the effect of paracetamol taken in two regimens for the treatment of low back pain. The protocol has been published. The analysis plan was completed blind to study group and finalized prior to initiation of analyses. All data collected as part of the trial were reviewed, without stratification by group, and classified by baseline characteristics, process of care and trial outcomes. Trial outcomes were classified as primary and secondary outcomes. Appropriate descriptive statistics and statistical testing of between-group differences, where relevant, have been planned and described.<h4>Conclusions</h4>A standard analysis plan was developed for the results of the PACE study. This plan comprehensively describes the data captured and pre-determined statistical tests of relevant outcome measures. The plan demonstrates transparent and verifiable use of the data collected. This a priori plan will be followed to ensure rigorous standards of data analysis are strictly adhered to.<h4>Trial registration</h4>Australia and New Zealand Clinical Trials Registry ACTRN12609000966291.
Project description:BACKGROUND:Fluid accumulation frequently coexists with acute kidney injury (AKI) and is associated with increased risk for AKI progression and mortality. Among septic shock patients, restricted use of resuscitation fluid has been reported to reduce the risk of worsening of AKI. Restrictive fluid therapy, however, has not been studied in the setting of established AKI. Here, we present the protocol and statistical analysis plan of the REstricted fluid therapy VERsus Standard trEatment in Acute Kidney Injury-the REVERSE-AKI trial that compares a restrictive fluid therapy regimen to standard therapy in critically ill patients with AKI. METHODS:REVERSE-AKI is an investigator-initiated, multinational, open-label, randomized, controlled, feasibility pilot trial conducted in seven ICUs in five countries. We aim to randomize 100 critically ill patients with AKI to a restrictive fluid treatment regimen vs standard management. In the restrictive fluid therapy regimen, the daily fluid balance target is neutral or negative. The primary outcome is the cumulative fluid balance assessed after 72 hours from randomization. Secondary outcomes include safety, feasibility, duration, and severity of AKI, and outcome at 90 days (mortality and dialysis dependence). CONCLUSIONS:This is the first multinational trial investigating the feasibility and safety of a restrictive fluid therapy regimen in critically ill patients with AKI. TRIAL REGISTRATION:clinical.trials.gov NCT03251131.
Project description:It is well known that competing demands exist between the control of important covariate imbalance and protection of treatment allocation randomness in confirmative clinical trials. When implementing a response-adaptive randomization algorithm in confirmative clinical trials designed under a frequentist framework, additional competing demands emerge between the shift of the treatment allocation ratio and the preservation of the power. Based on a large multicenter phase III stroke trial, we present a patient randomization scheme that manages these competing demands by applying a newly developed minimal sufficient balancing design for baseline covariates and a cap on the treatment allocation ratio shift in order to protect the allocation randomness and the power. Statistical properties of this randomization plan are studied by computer simulation. Trial operation characteristics, such as patient enrollment rate and primary outcome response delay, are also incorporated into the randomization plan.
Project description:OBJECTIVE: To assess adjustment practices for primary outcomes of randomized controlled trials and their impact on the results. DESIGN: Meta-epidemiologic study. DATA SOURCES: 25 biomedical journals with the highest impact factor according to Journal Citation Reports 2009. STUDY SELECTION: Randomized controlled trials published in print in 2009 that reported primary outcomes. The search yielded 684 eligible papers of randomized controlled trials, of which 200 were randomly selected. DATA EXTRACTION: Two researchers independently extracted data on study population, intervention, primary outcome, and the adjustment plan for primary outcomes. They also recorded the magnitude and statistical significance of the intervention effect with and without adjustments, and estimated whether adjustment made a difference in the level of nominal significance. They also compared the analysis plan for model adjustment in the published trial versus the trial protocol with information on the protocol collected from registries, design papers, and communication with all corresponding authors. RESULTS: 54% of the trials used stratified randomization, 96% presented baseline characteristics in the compared arms, and 46% also evaluated differences in baseline factors with statistical testing. Half of the trials performed adjusted analyses for the main outcome, as the sole analysis (29%) or along with unadjusted analyses (21%). Adjustment for stratification variables and for baseline variables was performed in 39% (42/108) and 42% (84/199) of the trials, respectively. Among 40 comparisons with both adjusted and unadjusted analyses, 43% had statistically significant effects, 40% had non-significant effects, and 18% had significant effects with only one of the two analyses, but not with the other. Information on analysis plan regarding model adjustment was available in 6% (9/162) of trial registry entries, 78% (21/27) of design papers, and 74% (40/54) of protocols obtained from authors. The analysis plan disagreed between the published trial and the registry, protocol, or design paper in 47% (28/60) of the studies. CONCLUSIONS: There is large diversity on whether and how analyses of primary outcomes are adjusted in randomized controlled trials and these choices can sometimes change the nominal significance of the results. Registered protocols should explicitly specify adjustments plans for main outcomes and analysis should follow these plans.
Project description:BACKGROUND:ANDROMEDA-SHOCK is an international, multicenter, randomized controlled trial comparing peripheral perfusion-targeted resuscitation to lactate-targeted resuscitation in patients with septic shock in order to test the hypothesis that resuscitation targeting peripheral perfusion will be associated with lower morbidity and mortality. OBJECTIVE:To report the statistical analysis plan for the ANDROMEDA-SHOCK trial. METHODS:We describe the trial design, primary and secondary objectives, patients, methods of randomization, interventions, outcomes, and sample size. We describe our planned statistical analysis for the primary, secondary and tertiary outcomes. We also describe the subgroup and sensitivity analyses. Finally, we provide details for presenting our results, including mock tables showing baseline characteristics, the evolution of hemodynamic and perfusion variables, and the effects of treatments on outcomes. CONCLUSION:According to the best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and initiating the analyses. We anticipate that this procedure will prevent analysis bias and enhance the utility of the reported results.
Project description:<h4>Background</h4>Statistical analysis plans describe the planned data management and analysis for clinical trials. This supports transparent reporting and interpretation of clinical trial results. This paper reports the statistical analysis plan for the RESOLVE clinical trial. The RESOLVE trial assigned participants with chronic low back pain to graded sensory-motor precision training or sham-control.<h4>Results</h4>We report the planned data management and analysis for the primary and secondary outcomes. The primary outcome is pain intensity at 18-weeks post randomization. We will use mixed-effects models to analyze the primary and secondary outcomes by intention-to-treat. We will report adverse effects in full. We also describe analyses if there is non-adherence to the interventions, data management procedures, and our planned reporting of results.<h4>Conclusion</h4>This statistical analysis plan will minimize the potential for bias in the analysis and reporting of results from the RESOLVE trial.<h4>Trial registration</h4>ACTRN12615000610538 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368619).
Project description:OBJECTIVE:The objective of the Dutch Sildenafil therapy in dismal prognosis early onset fetal growth restriction (STRIDER) randomised clinical trial is to assess the beneficial and harmful effects of sildenafil versus placebo on fetal and neonatal mortality in pregnant women with severe early-onset fetal growth restriction. The objective of this detailed statistical analysis plan is to minimize the risks of selective reporting and data-driven analysis. SETTING:The setting is 10 tertiary care hospitals and one secondary care hospital in The Netherlands. PARTICIPANTS:The participants will be 360 pregnant women with severe early-onset fetal growth restriction. INTERVENTIONS:The intervention is sildenafil 25?mg or placebo orally three times a day. PRIMARY AND SECONDARY OUTCOME MEASURES:The primary outcome is a composite of death or major neonatal morbidity assessed at hospital discharge. The secondary outcomes are neurodevelopmental impairment; mean scores of the Bayley III cognitive and motor assessment; the proportion of patients experiencing either preeclampsia or haemolysis, elevated liver enzymes, and low platelets syndrome; pulsatility index of uterine arteries, umbilical artery, and middle cerebral artery; birthweight; and gestational age at either delivery or intra-uterine death. RESULTS:A detailed statistical analysis is presented, including pre-defined exploratory outcomes and planned subgroup analyses. One interim analysis after 180 patients had completed the study was planned and a strategy to minimise the risks of type I errors due to repetitive testing is presented. During review of this manuscript the interim analysis was performed by the Data Safety Monitoring Board and early stopping of the trial was recommended. Final analyses will be conducted independently by two statistically qualified persons following the present plan. CONCLUSION:This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data and updated after stopping of the trial at interim analysis. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02277132 . Registered on 29 September 2014. Original protocol for the study: doi: https://doi.org/10.5281/zenodo.56148.
Project description:Preoperative airway assessment in Denmark is based on a non-specific clinical assessment left to the discretion of the responsible anesthesiologist. The DIFFICAIR trial compares the effect of using a systematic and consistent airway assessment versus a non-specific clinical assessment on the frequency of unanticipated difficult airway management.To prevent outcome bias and selective reporting, we hereby present a detailed statistical analysis plan as an amendment (update) to the previously published protocol for the DIFFICAIR trial.The DIFFICAIR trial is a stratified, parallel group, cluster (cluster?=?department) randomized multicenter trial involving 28 departments of anesthesia in Denmark randomized to airway assessment either by the Simplified Airway Risk Index (SARI) or by a usual non-specific assessment. Data from patients' preoperative airway assessment are registered in the Danish Anesthesia Database. An objective score for intubation grading the severity, that is the severity of the intubations, as well as the frequency of unanticipated difficult intubation, is measured for each group.Primary outcome measures are the fraction of unanticipated difficult and easy intubations.The database is programmed so that the registration of the SARI is mandatory for the intervention group but invisible to controls.Data recruitment was commenced in October 2012 and ended in ultimo December 2013.We intend to increase the transparency of the data analyses regarding the DIFFICAIR trial by an a priori publication of a statistical analysis plan.ClinicalTrials.gov: NCT01718561.
Project description:BACKGROUND:The Pneumatic CompREssion for Preventing VENous Thromboembolism (PREVENT) trial evaluates the effect of adjunctive intermittent pneumatic compression (IPC) with pharmacologic thromboprophylaxis compared to pharmacologic thromboprophylaxis alone on venous thromboembolism (VTE) in critically ill adults. METHODS/DESIGN:In this multicenter randomized trial, critically ill patients receiving pharmacologic thromboprophylaxis will be randomized to an IPC or a no IPC (control) group. The primary outcome is "incident" proximal lower-extremity deep vein thrombosis (DVT) within 28 days after randomization. Radiologists interpreting the lower-extremity ultrasonography will be blinded to intervention allocation, whereas the patients and treating team will be unblinded. The trial has 80% power to detect a 3% absolute risk reduction in the rate of proximal DVT from 7% to 4%. DISCUSSION:Consistent with international guidelines, we have developed a detailed plan to guide the analysis of the PREVENT trial. This plan specifies the statistical methods for the evaluation of primary and secondary outcomes, and defines covariates for adjusted analyses a priori. Application of this statistical analysis plan to the PREVENT trial will facilitate unbiased analyses of clinical data. TRIAL REGISTRATION:ClinicalTrials.gov , ID: NCT02040103 . Registered on 3 November 2013; Current controlled trials, ID: ISRCTN44653506 . Registered on 30 October 2013.