Statistical Analysis Plan Research Articles

Is Cerebrolysin effective in reducing symptoms of Diabetic Peripheral Neuropathy?

Aim This is an investigator initiated observational comparative medical program, to test the efficacy of Cerebrolysin® intake for 1 month versus 2 months, in patients clinically diagnosed with type 2 diabetes mellitus (T2DM) and suffering from peripheral neuropathy. Methods Patients aged ≥ 18 years old, clinically diagnosed with mild or moderate painful diabetic polyneuropathy, received Cerebrolysin® for 1 or 2 months according to investigators’ decision. Demographic data, detailed medical history, and laboratory results were collected at baseline. All enrolled patients were evaluated for Toronto Clinical Scoring System (TCSS), Visual Analogue Scale (VAS) and Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (LANSS) at baseline and end of the program (1 month/2 month). Results VAS, TCSS, and LANSS were significantly improved for all 136 enrolled patients at the end of their treatment with Cerebrolysin® for 1 or 2 months, regarding gender, duration since diagnosis of T2DM (more than or less than 10 years) and HbA1c ≤ 9% or ˃ 9%, with a very highly statistically significant difference (p-value ˂ 0.001). They were slightly improved more in patients received Cerebrolysin® for 1 month more than for 2 months. There was no statistically significant difference for gender, duration of diagnosis with diabetes mellitus less or more than 10 years, and HbA1c ≤ 9% & ˃ 9% regarding the change of VAS, TCSS, and LANSS as dependent variables, using Linear stepwise regression. While there was noticed improvement in VAS, TCSS, and LANSS with use of Cerebrolysin® for 1 month more than 2 months, Regression Coefficient (B (95% of Confidence interval)) B=0.794 (0.29-1.29), B=1.472 (0.87-2.074), B=2.143 (0.45-3.83) and p-value = 0.002, p-value ˂ 0.001, p-value = 0.13 respectively. There was no adverse event (AE) or serious adverse event (SAE) reported during the program. Conclusion: Cerebrolysin® is considered effective in the management of peripheral neuropathy in patients with T2DM Abbreviations: Adverse Event (AE), Advanced Glycation End products (AGE), Contract Research Organization (CRO), Diabetic Peripheral Neuropathy (DPN), Diacylglycerol (DAG), estimated Glomerular Filtration (eGFR), Fasting Blood Sugar (FBS), Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (LANSS), Peripheral Vascular Disease (PVD), Pin- Prick Threshold (PPT), Protein Kinase C (PKC), Statistical Analysis Plan (SAP), Serious Adverse Event (SAE), Standard Deviation (SD), Type 1 Diabetes Mellitus (T1DM), Type 2 Diabetes Mellitus (T2DM), Toronto Clinical Scoring System (TCSS), Traumatic Brain Injury (TBI), Visual Analogue Scale (VAS).

Implementing the WHO Labour Care Guide to reduce the use of Caesarean section in four hospitals in India: protocol and statistical analysis plan for a pragmatic, stepped-wedge, cluster-randomized pilot trial

abstractBackgroundThe World Health Organization (WHO) Labour Care Guide (LCG) is a paper-based labour monitoring tool designed to facilitate the implementation of WHO’s latest guidelines for effective, respectful care during labour and childbirth. Implementing the LCG into routine intrapartum care requires a strategy that improves healthcare provider practices during labour and childbirth. Such a strategy might optimize the use of Caesarean section (CS), along with potential benefits on the use of other obstetric interventions, maternal and perinatal health outcomes, and women’s experience of care. However, the effects of a strategy to implement the LCG have not been evaluated in a randomised trial. This study aims to: (1) develop and optimise a strategy for implementing the LCG (formative phase); and (2) To evaluate the implementation of the LCG strategy compared with usual care (trial phase).MethodsIn the formative phase, we will co-design the LCG strategy with key stakeholders informed by facility assessments and provider surveys, which will be field tested in one hospital. The LCG strategy includes a LCG training program, ongoing supportive supervision from senior clinical staff, and audit and feedback using the Robson Classification. We will then conduct a stepped-wedge, cluster-randomized pilot trial in four public hospitals in India, to evaluate the effect of the LCG strategy intervention compared to usual care (simplified WHO partograph). The primary outcome is the CS rate in nulliparous women with singleton, term, cephalic pregnancies in spontaneous labour (Robson Group 1). Secondary outcomes include clinical and process of care outcomes, as well as women’s experience of care outcomes. We will also conduct a process evaluation during the trial, using standardized facility assessments, in-depth interviews and surveys with providers, audits of completed LCGs, labour ward observations and document reviews. An economic evaluation will consider implementation costs and cost-effectiveness.DiscussionFindings of this trial will guide clinicians, administrators and policymakers on how to effectively implement the LCG, and what (if any) effects the LCG strategy has on process of care, health and experience outcomes. The trial findings will inform the rollout of LCG internationally.Trial registration: CTRI/2021/01/030695 (Protocol version 1.4, 25 April 2022).

Evaluating the feasibility and preliminary efficacy of a Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS): an update to the protocol for a feasibility cluster-randomised controlled trial

BackgroundCognitive difficulties experienced by people with multiple sclerosis (MS) impact on quality of life and daily functioning, from childcare and work to social and self-care activities. The Cognitive Occupation-Based programme for people with MS (COB-MS) was developed as a holistic, individualised cognitive rehabilitation intervention to address the wide-ranging symptoms and functional difficulties that present in MS, including the ability to maintain employment, social activities, home management and self-care. The aim of the research is to evaluate the feasibility and preliminary efficacy of COB-MS for people with MS.MethodsDue to the impacts of COVID-19, trial activities that were planned for in-person delivery were completed remotely. One hundred and twenty people with MS will be assigned to participate in either the COB-MS programme or a treatment-as-usual, wait-list control group as part of this single-blind, cluster-randomised controlled feasibility and preliminary efficacy trial of the COB-MS programme. The COB-MS group will participate in an eight-session occupational-based cognitive rehabilitation programme over 9 weeks. The COB-MS intervention was planned for in-person delivery but was delivered online by occupational therapists to small groups of people with MS. The primary outcome measure is the Goal Attainment Scaling at 12 weeks. Participants will be assessed pre-intervention, post-intervention, 12 weeks post-intervention and 6 months post-intervention. Qualitative evaluations of participants’ perspectives will also be examined as part of the feasibility study. Data, due to be collected in-person, was collected online or by post. The original study design, including the statistical analysis plan, remains unchanged despite the shift to a remote trial conduct.DiscussionResults will provide recommendations for a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy.Trial registrationISRCTN ISRCTN11462710. Registered on 9 September 2019 and updated on 23 September 2020 to account for changes outlined here.

Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART)

BackgroundMND-SMART is a platform, multi-arm, multi-stage, multi-centre, randomised controlled trial recruiting people with motor neuron disease. Initially, the treatments memantine and trazodone will each be compared against placebo, but other investigational treatments will be introduced into the trial later. The co-primary outcomes are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) functional outcome, which is assessed longitudinally, and overall survival.MethodsInitially in MND-SMART, participants are randomised 1:1:1 via a minimisation algorithm to receive placebo or one of the two investigational treatments with up to 531 to be randomised in total. The comparisons between each research arm and placebo will be conducted in four stages, with the opportunity to cease further randomisations to poorly performing research arms at the end of stages 1 or 2. The final ALS-FRS-R analysis will be at the end of stage 3 and final survival analysis at the end of stage 4. The estimands for the co-primary outcomes are described in detail. The primary analysis of ALS-FRS-R at the end of stages 1 to 3 will involve fitting a normal linear mixed model to the data to calculate a mean difference in rate of ALS-FRS-R change between each research treatment and placebo. The pairwise type 1 error rate will be controlled, because each treatment comparison will generate its own distinct and separate interpretation. This publication is based on a formal statistical analysis plan document that was finalised and signed on 18 May 2022.DiscussionIn developing the statistical analysis plan, we had to carefully consider several issues such as multiple testing, estimand specification, interim analyses, and statistical analysis of the repeated measurements of ALS-FRS-R. This analysis plan attempts to balance multiple factors, including minimisation of bias, maximising power and precision, and deriving clinically interpretable summaries of treatment effects.Trial registrationEudraCT Number, 2019–000099-41. Registered 2 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=mnd-smartClinicalTrials.gov, NCT04302870. Registered 10 March 2020.

Pain treatment after total hip arthroplasty: Detailed statistical analysis plan for the RECIPE randomised clinical trial.

The RECIPE trial systematically investigates effects of different combinations of paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty. To preserve transparency, minimize risk of bias, and to prevent data-driven analysis, we present this detailed statistical analysis plan. The RECIPE trial is a randomized, blinded, parallel four-group multicenter clinical trial for patients undergoing planned primary total hip arthroplasty. Interventions are initiated preoperatively and continued for 24 hours postoperatively. Primary outcome is total opioid consumption 0-24 hours after end of surgery. Primary analysis will be performed in the modified intention to treat population of all patients undergoing total hip arthroplasty, and all analyses will be stratified for site. We will perform pairwise comparisons between each of the four groups. The primary outcome will be analysed using the van Elteren test and we will present Hodges-Lehmann median differences and confidence intervals. Binary outcomes will be analysed using logistic regression. To preserve a family-wise error rate of <0.05, we will use a Bonferroni-adjusted alfa of 0.05/6=0.0083 for all six pairwise comparisons between groups when analysing the primary outcome. We will systematically assess the underlying statistical assumptions for each analysis. Data will be analysed by two blinded independent statisticians, and we will write abstracts covering all possible combinations of conclusions, before breaking the blind. The RECIPE trial will provide important information on benefit and harm of combinations of the most frequently used non-opioid analgesics for pain after primary hip arthroplasty.

Booster vaccination protection against SARS-CoV-2 infections in young adults during an Omicron BA.1-predominant period: A retrospective cohort study.

While booster vaccinations clearly reduce the risk of severe Coronavirus Disease 2019 (COVID-19) and death, the impact of boosters on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections has not been fully characterized: Doing so requires understanding their impact on asymptomatic and mildly symptomatic infections that often go unreported but nevertheless play an important role in spreading SARS-CoV-2. We sought to estimate the impact of COVID-19 booster doses on SARS-CoV-2 infections in a vaccinated population of young adults during an Omicron BA.1-predominant period. We implemented a cohort study of young adults in a college environment (Cornell University's Ithaca campus) from a period when Omicron BA.1 was the predominant SARS-CoV-2 variant on campus (December 5 to December 31, 2021). Participants included 15,800 university students who completed initial vaccination series with vaccines approved by the World Health Organization for emergency use, were enrolled in mandatory at-least-weekly surveillance polymerase chain reaction (PCR) testing, and had no positive SARS-CoV-2 PCR test within 90 days before the start of the study period. Robust multivariable Poisson regression with the main outcome of a positive SARS-CoV-2 PCR test was performed to compare those who completed their initial vaccination series and a booster dose to those without a booster dose. A total of 1,926 unique SARS-CoV-2 infections were identified in the study population. Controlling for sex, student group membership, date of completion of initial vaccination series, initial vaccine type, and temporal effect during the study period, our analysis estimates that receiving a booster dose further reduces the rate of having a PCR-detected SARS-CoV-2 infection relative to an initial vaccination series by 56% (95% confidence interval [42%, 67%], P < 0.001). While most individuals had recent booster administration before or during the study period (a limitation of our study), this result is robust to the assumed delay over which a booster dose becomes effective (varied from 1 day to 14 days). The mandatory active surveillance approach used in this study, under which 86% of the person-days in the study occurred, reduces the likelihood of outcome misclassification. Key limitations of our methodology are that we did not have an a priori protocol or statistical analysis plan because the analysis was initially done for institutional research purposes, and some analysis choices were made after observing the data. We observed that boosters are effective, relative to completion of initial vaccination series, in further reducing the rate of SARS-CoV-2 infections in a college student population during a period when Omicron BA.1 was predominant; booster vaccinations for this age group may play an important role in reducing incidence of COVID-19.

A Visual Tool to Help Develop a Statistical Analysis Plan for Randomized Trials in Palliative Care.

Collaboration with a statistician about the design of a statistical analysis plan can be enhanced by illustrating how statisticians conceptualize their task. This conceptualization can be represented by a directed acyclic graph (DAG), which illustrates the statistician's approach and also provides an actionable tool to assist in the development of the plan.

Effect of Jianpi Bushen formula for colon cancer patients who underwent adjuvant chemotherapy: Statistical analysis plan for a multicenter trial

Effect of Jianpi Bushen formula for colon cancer patients who underwent adjuvant chemotherapy: Statistical analysis plan for a multicenter trial

DirEct versus VIdeo LaryngosCopE (DEVICE): protocol and statistical analysis plan for a randomised clinical trial in critically ill adults undergoing emergency tracheal intubation

IntroductionAmong critically ill patients undergoing orotracheal intubation in the emergency department (ED) or intensive care unit (ICU), failure to visualise the vocal cords and intubate the trachea on the first...

Pneumococcal vaccine schedules (PVS) study: a cluster-randomised, non-inferiority trial of an alternative versus standard schedule for pneumococcal conjugate vaccination—statistical analysis plan

RationaleThe effectiveness of universal immunisation with pneumococcal conjugate vaccine (PCV) has been evident in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in several countries. Reducing the cost of PCV programmes may facilitate vaccine introduction in some countries and improve the sustainability of PCV in EPIs in low-income countries when they transition away from subsidised vaccine supply.Methods and designPVS is a real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative ‘1+1’ schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard ‘3+0’ schedule). Delivery of the interventions began in late 2019 in 68 geographic clusters and will continue for 4 years. The primary endpoint is the prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2–260 weeks with clinical pneumonia in year 4. Secondary endpoints are the prevalence of vaccine-type pneumococcal carriage among all ages in year 4 and the incidence of radiological pneumonia in children enrolled to receive the interventions. Additional disease and carriage endpoints are included.PurposeThis statistical analysis plan (SAP) describes the cohorts and populations, and follow-up criteria, to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe how analyses will account for the effect of clustering and stratified randomisation. The SAP defines the approach to non-inferiority and other analyses. Defining the SAP early in the trial will avoid bias in analyses that may arise from prior knowledge of trial findings.

Minimising Young Children’s Anxiety through Schools (MY-CATS): statistical analysis plan for a cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of an online parent-led intervention compared with usual school practice for young children identified as at risk for anxiety disorders

BackgroundThe Minimising Young Children’s Anxiety through Schools (MY-CATS) trial is being conducted to determine whether an online evidence-based parent-guided cognitive behavioural therapy intervention in addition to usual school practice is effective and cost-effective compared with usual school practice in reducing anxiety disorders in children aged 4–7 deemed ‘at risk’ of anxiety disorders. This update article describes the detailed statistical analysis plan for the MY-CATS trial and reports a review of the underpinning sample size assumptions.Methods and designThe MY-CATS study is a two-arm, definitive superiority pragmatic parallel group cluster randomised controlled trial in which schools will be randomised 1:1 to receive either the intervention (in addition to usual school practice) or the usual school practice only. This update to the (published) protocol provides a detailed description of the study methods, the statistical principles, the trial population and the planned statistical analyses, including additional analyses comprising instrumental variable regression and mediation analysis.Trial registrationISRCTN82398107. Prospectively registered on 14 January 2021

Final Results from a Phase2b Randomized, Placebo-Controlled Clinical Trial of RBX2660: A Microbiota-Based Drug for the Prevention of Recurrent Clostridioides difficile Infection.

Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented. The PUNCHCD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at least 18years of age and had at least three episodes of CDI and at least two rounds of standard antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Patients were randomized 1:1:1 to groupA, two doses of RBX2660; groupB, two doses of placebo; or groupC, one dose of RBX2660 and one dose of placebo; all administered 7 ± 2days apart. Treatment success was prevention of recurrence, defined as absence of diarrhea and no re-treatment for CDI any time after the first dose until 8weeks after the second dose of the study treatment. Safety was assessed by reports of adverse events and symptoms. The final efficacy and safety are reported for data available through 24months. For the primary endpoint, treatment success at 8weeks, 56.8% (25/45) of participants who received one dose of RBX2660 + one dose of placebo, 55.6% (25/45) of participants who received two doses of RBX2660, and 43.2% (19/44) of participants who received two doses of placebo in the final intention-to-treat (ITT) population were responders (both p = 0.2 vs placebo). In the per-protocol population, 87.5% (21/24) of participants who received one dose of RBX2660 + one dose of placebo and 58.1% (18/31) of those who received two doses of placebo had treatment success (p = 0.017; treatment difference, 29.4 [95%CI 7.6, 51.3]); 75.0% (21/28) of participants in the PP population who received two doses of RBX2660 were responders (p = 0.17 vs placebo). The safety profile of RBX2660, whether delivered as one or two doses, was similar to the placebo group. While the phase2b PUNCHCD2 clinical trial did not meet its pre-defined primary endpoint of treatment success at 8weeks after two doses of RBX2660 vs two doses of placebo, clinically meaningful data were obtained to justify proceeding with the single dose regimen in the phase3 clinical trial, PUNCHCD3, now complete. To date, the cumulative data for RBX2660 demonstrate consistent efficacy and safety outcomes for reduction of CDI recurrence in adults. ClinicalTrials.gov: NCT02299570.

Sanfu herbal patch applied at acupoints in patients with bronchial asthma: statistical analysis plan for a randomised controlled trial

BackgroundSanfu herbal patch (SHP) is widely used in the prevention and treatment of bronchial asthma in China, but its efficacy and mechanism of action are not completely clear. This trial aims to determine the efficacy of SHP and the underlying mechanism.Methods/designWe will conduct a multi-centre parallel randomised controlled trial consisting of 72 participants with bronchial asthma recruited and randomly allocated at a ratio of 1:1 into two groups. The patients in one group will receive three courses of SHP treatment, and the patients in the other group will receive placebo treatment, with 24 weeks of follow-up evaluation for both groups. The primary outcome, i.e. forced expiratory volume in the first second (FEV1), which refers to the change in FEV1 from the beginning of the baseline to the end of 3 treatment sessions (TSs), will be assessed and compared via Student’s t test or the Mann–Whitney U test. Other outcomes will include questionnaire surveys and laboratory indicators. Detailed and complete statistical analyses in a double-blinded fashion will be provided for evaluating this trial.DiscussionThe data we obtain will be examined based on the above statistical analysis, which will help to reduce the risk of external reporting bias and data-driven results.Trial registrationChinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR1900024616. Registered on 19 July 2019.

Inconsistent Outcome Reporting in Heart Failure Randomized Controlled Trials

Randomized controlled trials (RCTs) may report outcomes different from those prespecified on trial-registration websites, protocols and statistical analysis plans (SAPs). This study sought to investigate the prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified. MEDLINE via PubMed was searched to include phase II-IV HF RCTs in 9 high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with prespecified outcomes in protocols, registration websites and SAPs. We used the χ2 or Fisher exact test to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) to omission of prespecified secondary outcomes, 2 (6.3%) to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) to changing prespecified secondary outcomes to primary outcomes. Of the inconsistencies, 3 (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) to addition of new secondary outcomes, and 2 (6.3%,) to changes in the timing of assessment of primary outcomes. The majority of the inconsistencies favored statistically significant findings; 78 (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (β = -0.14; 95% CI, -0.22 - -0.01; P = 0.035). More than 1 in 10 trials reported outcomes inconsistent with those specified in trial registration websites, SAPs and protocols. An action plan is warranted to minimize selective reporting and improve transparency.

Detailed statistical analysis plan for the neurological complications in endoscopic versus open radial artery harvest (NEO) randomised clinical trial.

Coronary artery bypass grafting can be conducted using the radial artery as a bypass graft. However, it remains unclear which harvesting method is superior, i.e. endoscopic or open radial artery, and which site for proximal anastomosis of the radial artery has the greatest benefits? The NEO Trial is a single site randomised clinical trial with a 2 × 2 factorial design. The first comparison assesses endoscopic versus open radial artery harvest with a primary outcome of hand function and secondary outcomes of neurological deficits through clinical exams and neurophysiological studies. The primary outcome is postoperatively hand function at three months. We anticipate a mean difference of 3 points with a standard deviation of 8 points, a power of 90%, and a type I error of 5%, resulting in a required sample size of 300 participants randomised 1:1. Secondary outcomes are neurological deficits (based on nerve conduction measurements, algometry test and von Frey hair test), clinical neurological examination of cutaneous sensibility, and registration of complications in the donor arm (haematoma formation, wound dehiscence, and/or infection). The second comparison assesses two different proximal anastomotic sites, i.e. aorto-radial anastomosis versus mammario-radial anastomosis. The primary outcome is a composite of cerebrovascular events and the secondary outcome is graft patency evaluation by multi-slice computer tomography-scan. These outcomes will be assessed at 1year postoperatively, and the results of this comparison will be exploratory only. Both comparisons will be analysed using intention-to-treat and intervention groups will be compared using linear regression, logistic regression, or Mann-Whitney U test depending on data type. Two independent statisticians will follow the present plan and conduct the analyses which will hereafter be fused into a final analysis based on consensus. This detailed analysis plan will increase the validity of the NEO trial results by predefining the statistical analysis in detail. ClinicalTrials.gov identifier: NCT01848886 . Registered 25 February 2013. Danish Ethics committee number: H-3-2012-116. Danish Data Protection Agency: 2007-58-0015/jr. n:30-0838.

Protocolised REDUction of non-resuscitation fluids versus usual care in SEptic shock patients (REDUSE) - a statistical analysis plan for a multicentre feasibility trial

Protocolised REDUction of non-resuscitation fluids versus usual care in SEptic shock patients (REDUSE) - a statistical analysis plan for a multicentre feasibility trial

Study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-ll (HAS FLAIR-II) trial

Background: Fluid bolus therapy with 20% albumin may shorten the duration of vasopressor therapy in patients after cardiac surgery. Objective: To describe the study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial. Design, setting, participants and intervention: HAS FLAIR-II is a phase 2b, multicentre, parallel group, openlabel, randomised controlled trial that will be conducted at six Australian intensive care units. Patients requiring fluid bolus therapy after cardiac surgery will be randomly assigned in a 1:1 ratio to the intervention of fluid bolus therapy with 20% albumin or a comparator of fluid bolus therapy with a crystalloid solution. Main outcome measures: The primary outcome measure is the cumulative duration of vasopressor therapy. Secondary outcomes include vasopressor use, service utilisation, and mortality. All analyses will be conducted on an intention-to-treat basis. Results and conclusion: The study protocol and statistical analysis plan will guide the conduct and analysis of the HAS FLAIR-II trial, such that analytical and reporting biases are minimised. Trial registration: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN No. 12620000137998).

Crafting statistical analysis plans: A cross‐discipline approach

AbstractDeveloping a plan for data analysis at the beginning of a study is an important practice that is underutilized in many scientific fields. Several funding agencies and journals now require submission of statistical analysis plans in advance of scientific studies, particularly in the clinical sciences. Even when a plan is not required, it can be advantageous to the scientific process by improving reproducibility. An analysis plan allows researchers to organize their knowledge about their research questions and experimental design to more easily recognize and choose the appropriate statistical analyses. An analysis plan provides a roadmap for the analyses: Researchers can think through potential statistical decisions (e.g. to transform or not to transform? how to handle missing or censored data?) in advance and thoroughly document the justifications and trade‐offs for their intended analyses. Such decisions are not influenced by data when made before data collection, thus preventing pitfalls like p‐hacking, HARKing and non‐replicability of results. We describe a general framework for crafting an analysis plan—including essential components of any plan—and provide an example template that can be used by researchers. The analysis plan framework is presented for broad appeal to experienced statisticians, quantitative researchers and everyone in between.

In this Issue of CCR

Point of View: A four-step model to aid teaching, clinical assessment and communication of circulatory disorders amongst junior clinicians Editorial: Midodrine – why don't you just work better? Review: Midodrine Use in Critically Ill Patients – A Narrative Review Original Articles: Study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial Early sedation in traumatic brain injury: a multicentre international observational study The association between vital signs abnormalities during post-anaesthesia care unit stay and deterioration in the general ward following major abdominal cancer surgery assessed by continuous wireless monitoring Mortality associated with Acute Respiratory Distress Syndrome 2009-2019: A systematic review and meta-analysis The prevalence of post extubation dysphagia in critically ill adults: An Australian data linkage study ANTIPORT: adaptation of a transfusion prediction score to an Australian cardiac surgery population

Real-World Evidence (RWE) Studies Supported Hematologic Oncology United States Food and Drug Administration (US FDA) Approval: What Do They Look like?

Introduction/Background: Although randomized controlled trials are considered the gold standard of evidence for safety and efficacy of a drug, they are subject to several limitations such as difficulty in recruiting patients with rare diseases or randomization of patients to studies with treatments that lack an established standard of care owing to efficacy or toxicity concerns. RWE can help overcome these challenges. RWE collects patient data from historical trials or retrospective observational studies and compares or contextualizes these data to experimental treatments by using proper statistical adjustments. The 21st Century Cures Act inspired the framework for the US FDA to use RWE to assess product effectiveness of approved drugs to support regulatory decision-making. Consequently, RWE is increasingly used in New Drug Applications (NDAs) and Biologics License Applications (BLAs) for hematologic malignancies, and findings suggest that submissions using RWE may receive faster approval. However, data are lacking on adoption of RWE for regulatory submissions and its use in regulatory decision-making. Here, we outline RWE utilization and limitations of regulatory submissions for hematologic malignancy therapeutics, which received accelerated or full approval in the US. Methods: Between 2017 and 2021, all NDA and BLA approvals from the Division of Hematological Malignancies were reviewed for hematology/oncology drugs or indications. The FDA Oncology Drug Advisory Committee (ODAC) briefing and/or multidisciplinary review documents were evaluated to identify the drug approvals using RWE. This assessment was performed by 4 independent reviewers who evaluated FDA comments regarding RWE. RWE sources, study methodology, drug indications, pivotal trial information, statistical analyses, and results were summarized. Results: A total of 74 hematologic malignancy approvals were identified, of which 7 (9.4%) provided RWE that supported regulatory approval. Detailed analyses of the FDA ODAC briefing and/or multidisciplinary review documents for these 7 drug compounds including comparison of trial and RWE data source, patient population, clinical endpoints and outcomes, comparison strategy, and FDA comments are shown in the Table. The FDA identified several key considerations for RWE use for drug applications based on single-arm studies. These included pivotal trials that demonstrated a high response or large treatment effect, an improved drug toxicity profile, or a novel drug mechanism of action. The most common RWE sources included retrospective observational studies from medical records, data from other clinical trials, commercial electronic health record databases, and literature reviews. The most common hematologic indications for RWE submissions were relapsed/refractory (R/R) large B-cell lymphoma and R/R multiple myeloma. The most common endpoints for RWE included presence of measurable residual disease, complete response rate, and duration of response. In contrast, the most common endpoints in pivotal trials included survival endpoints (eg, progression-free survival). The most common statistical methods used to adjust for baseline imbalances included propensity-score matching and inverse-probability of treatment weighting. The FDA identified several areas that may compromise the reliability of RWE: lack of early engagement and discussion of the study design with the FDA, absence of a prespecified statistical analysis plan or protocol, lack of transparency in data collection methods, dissimilar inclusion/exclusion criteria, dissimilar study endpoints, and an inconsistent method or frequency of outcome assessments. Comparator arms often missed baseline covariates, had selection bias, and used different outcome assessment criteria. Conclusion: Good data quality, comparable patient populations, consistent endpoints, prespecified protocols, and the establishment of statistical analysis plans before the start of a study may be the most important factors in the FDA's approval of RWE regulatory submissions. Although the use of RWE to define a direct comparator was limited by flaws in study design and statistical analyses, RWE can be used to establish historical outcomes for patients with currently available treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal