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Liana D Castel,1 Kenneth A Wallston,2 Benjamin R Saville,3 JoAnn R Alvarez,3 Bradley D Shields,4 Irene D Feurer,3 David Cella5 1Meharry-Vanderbilt Alliance, Nashville, TN, USA; 2Psychology in Nursing, Vanderbilt University School of Nursing, Nashville, TN, USA; 3Surgery and Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA; 4Medical Sciences, University of Arkansas School of Medicine, Little Rock, AR, USA; 5Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Background: There is a need for a survey instrument to measure arthralgia (joint pain) that has been psychometrically validated in the context of existing reference instruments. We developed the 16-item Patient-Reported Arthralgia Inventory (PRAI) to measure arthralgia severity in 16 joints, in the context of a longitudinal cohort study to assess aromatase inhibitor-associated arthralgia in breast cancer survivors and arthralgia in postmenopausal women without breast cancer. We sought to evaluate the reliability and validity of the PRAI instrument in these populations, as well as to examine the relationship of patient-reported morning stiffness and arthralgia. Methods: We administered the PRAI on paper in 294 women (94 initiating aromatase inhibitor therapy and 200 postmenopausal women without breast cancer) at weeks 0, 2, 4, 6, 8, 12, 16, and 52, as well as once in 36 women who had taken but were no longer taking aromatase inhibitor therapy. Results: Cronbach's alpha was 0.9 for internal consistency of the PRAI. Intraclass correlation coefficients of test-retest reliability were in the range of 0.87–0.96 over repeated PRAI administrations; arthralgia severity was higher in the non-cancer group at baseline than at subsequent assessments. Women with joint comorbidities tended to have higher PRAI scores than those without (estimated difference in mean scores: -0.3, 95% confidence interval [CI] -0.5, -0.2; P

OBJECTIVE: : To determine whether structured handover tool from operating room to pediatric cardiac intensive care unit following cardiac surgery is associated with a reduction in the loss of information transfer and an improvement in the quality of communication exchange. In addition, whether this tool is associated with a decrease in postoperative complications and an improvement in patient outcomes in the first 24 hrs of pediatric cardiac intensive care unit stay. DESIGN: : Prospective observational clinical study. SETTING: : Pediatric cardiac intensive care unit of an academic medical center. PATIENTS: : Pediatric cardiac surgery patients over a 3-yr period. Evaluation of communication and patients studied for two time periods: verbal handover (July 2007-June 2009) and structured handover (July 2009-June 2010). INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: : Two anonymous surveys administered to the entire clinical team of the pediatric cardiac intensive care unit evaluated loss of information transfer for each of the two handover processes. Quality of structured handover tool was evaluated by Likert scale responses in the second survey. Patient complications including cardiopulmonary resuscitation, mediastinal reexploration, placement on extracorporeal membrane oxygenation, development of severe metabolic acidosis, and number of early extubations in the first 24-hr pediatric cardiac intensive care unit stay were compared for the two time periods. Survey results showed the general opinion that the structured handover tool was of excellent quality to enhance communication (Likert scale: 4.4 ± 0.7). In addition, the tool was associated with a significant reduction (p < .001) in loss of information for every category of patient clinical care including patient, preoperative, anesthesia, operative, and postoperative details and laboratory values. Patient data revealed significant decrease (p < .05) for three of the four major complications studied and a significant increase (p < .04) in the number of early extubations following introduction of our standardized handover tool. CONCLUSIONS: : In this setting, a standardized handover tool is associated with a decrease in the loss of patient information, an improvement in the quality of communication during postoperative transfer, a decrease in postoperative complications, and an improvement in 24-hr patient outcomes. [ABSTRACT FROM AUTHOR]

While the majority of stroke researchers use frequentist statistics to analyze and present their data, Bayesian statistics are becoming more and more prevalent in stroke research. As opposed to frequentist approaches, which are based on the probability that data equal specific values given underlying unknown parameters, Bayesian approaches are based on the probability that parameters equal specific values given observed data and prior beliefs. The Bayesian paradigm allows researchers to update their beliefs with observed data to provide probabilistic interpretations of key parameters, for example, the probability that a treatment is effective. In this review, we outline the basic concepts of Bayesian statistics as they apply to stroke trials, compare them to the frequentist approach using exemplary data from a randomized trial, and explain how a Bayesian analysis is conducted and interpreted., Competing Interests: Dr Ospel is a consultant for Nicolab. Dr Goyal is a consultant for Mentice, Medtronic, MicroVention, and Stryker. Dr Brown reports compensation from MicroVention, Inc, for consultant services and compensation from the Faculty of Arts, University of Calgary, for consultant services. Dr Rinkel reports grants from the Niels Stensen Fellowship. Dr Ganesh reports compensation from Figure 1 for consultant services; grants from the Heart and Stroke Foundation of Canada; compensation from Atheneum for consultant services; grants from the Canadian Cardiovascular Society; compensation from Creative Research Designs for consultant services; grants from Campus Alberta Neuroscience; grants from the Government of Canada; stock options in TheRounds.com; compensation from DeepBench for consultant services; grants from the Alzheimer Society of Canada; grants from Rhodes Scholarships; grants from the Canadian Institutes of Health Research; compensation from the Canadian Association of Neuroscience Nurses for consultant services; grants from Alberta Innovates; stock holdings in Collavidence, Inc; grants from Wellcome Trust; travel support from the American Academy of Neurology; travel support from the American Heart Association; travel support from the University of Calgary; service as an editorial board member for the journal Stroke for American Heart Association; stock options in SnapDx, Inc; grants from MicroVention, Inc; service as a review editor for Stroke for Frontiers in Neurology; compensation from Alexion Pharmaceuticals for other services; grants from Panmure House; compensation from Biogen for other services; compensation from MD Analytics for consultant services; compensation from MyMedicalPanel for consultant services; compensation from CTC Communications Corporation for consultant services; service as an editorial board member for the journals Neurology and Neurology: Clinical Practice for the American Academy of Neurology; grants from the Fondation Brain Canada; and grants from the Sunnybrook Research Institute. Dr Hill reports grants from Boehringer Ingelheim, Medtronic, MicroVention, Inc, the Canadian Institutes of Health Research, NoNO, Inc, and Medtronic; compensation from Merck for end point review committee services; grants from Stryker Corporation; a patent issued for Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients licensed to Circle NVI; compensation from Brainsgate Ltd for consultant services; grants from Biogen, Inc, and Medtronic; and employment by the University of Calgary. The other authors report no conflicts.

Designing a clinical trial to evaluate the efficacy of an intervention is often complicated by uncertainty over aspects of the study population, potential treatment effects, most relevant outcomes, dropouts, and other factors. However, once participants begin to be enrolled and partial trial data become available, this level of uncertainty is reduced. Adaptive clinical trials are designed to take advantage of the accumulating data during the conduct of a trial to make changes according to prespecified decision rules to increase the likelihood of success or statistical efficiency. Common adaptive rules address early stopping for benefit or futility, sample size reestimation, adding or dropping treatment arms or altering randomization ratios, and changing the eligibility criteria to focus on responder patient subgroups. Adaptive clinical trials are gaining popularity for clinical stroke research. We provide an overview of the methods, practical considerations, challenges and limitations, and potential future role of adaptive clinical trials in advancing knowledge and practice in stroke., Competing Interests: Drs Crawford, Lorenzi, and Lewis report employment by Berry Consultants LLC. Dr Saville was previously employed by Berry Consultants LLC and is now the owner of Adaptix Trials LLC. Drs Crawford, Lorenzi, Saville, and Lewis and other staff of Berry Consultants LLC were involved in the design and operation of several of the clinical trials referenced in this review. Dr Lewis also reports funding from the National Institutes of Health; compensation from the National Academies of Sciences, Engineering, and Medicine for other services; and employment of the American Medical Association. Dr Anderson reports research grants from the National Health and Medical Research Council of Australia, the Medical Research Council and Medical Research Foundation of the United Kingdom, and Takeda and Penumbra. He has received consulting fees for being an Advisor to AstraZeneca Australia.

Over the past decade, the field of heart failure (HF) has witnessed remarkable progress in drug development, resulting in the approval of numerous groundbreaking drugs by the U.S. Food and Drug Administration. To address some of these challenges, the U.S. Food and Drug Administration has issued guidance documents that have been critical in contemporary HF drug development; however, there are still many challenges in need of investigation. This paper leverages efforts of the Heart Failure Collaboratory and the scientific community to discuss the critical need for innovative trial designs, important concepts in clinical trials in the modern era, and the utilization of big data to accelerate HF drug development. At this inflection point in HF drug development, it is imperative that, as a global scientific community, we foster increased collaboration among researchers, clinicians, patients, and regulatory bodies. Only through such unified efforts can we navigate the complexities of HF, accelerate the development process, and ultimately deliver effective therapies that transform patient outcomes., Competing Interests: Funding Support and Author Disclosures Dr Januzzi has a board position with Imbria Pharma; has received grant support from Abbott, Applied Therapeutics, AstraZeneca, BMS, and Novartis Pharmaceuticals; has received consulting income from Abbott Diagnostics, Beckman-Coulter, Jana Care, Janssen, Novartis, Prevencio, Quidel, and Roche Diagnostics; and has served on clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Medtronic, Pfizer, and Roche Diagnostics. Dr Lindenfeld has received consulting fees from Abbott, Adona, Axon, Alleviant, AstraZeneca, Boston Scienrific, CVRx, Cordio, Edwards Lifesciences, Medtronic, Merck, Orchestra Biomed, VWave, Whiteswell, and Vascular Dynamics; and has received grant funding from AstraZeneca and Volumetrix. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, Gossamer, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Bristow has been a consultant for ARCA Biopharma. Dr Abraham has received research grant support from the NHLBI (NIH 1 UG3/UH3 HL140144-01, 08/01/18-07/31/22, “Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Readmission/Mortality in Patients with Heart Failure and Central Sleep Apnea [LOFT-HF]”); has received consulting income from Abbott Vascular, Boehringer Ingelheim, and Zoll Respicardia; has received speaker honoraria from Impulse Dynamics; and has received salary support from V-Wave Medical. Dr O'Connor has done consulting for Abiomed and Merck. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Evidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited., Methods: In this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600 mg in divided doses on day one, then 800 mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome., Trial Registration: ISRCTN86534580., Findings: The primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n = 1829), usual care (n = 3256), and other treatments (n = 3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [-0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08])., Interpretation: In this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Saville, Berry, Detry, Fitzgerald and Saunders report grants from The University of Oxford, for the Sponsor's grant from the UK NIHR, for statistical design and analyses for the PRINCIPLE trial during the conduct of the study. Prof de Lusignan is Director of the Oxford-RCGP Research and Surveillance Centre and reports that through his University he has had grants outside the submitted work from AstraZeneca, GSK, Sanofi, Seqirus and Takeda for vaccine related research, and membership of advisory boards for AstraZeneca, Sanofi and Seqirus. Profs Hobbs and Butler reports grants from UKRI, during the conduct of the study. All other authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation., Methods: This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation., Findings: Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference -1·6% [-2·6% to -0·6%]; p(sup)=0·99; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference -1·4% [-2·3% to -0·4%]; p(sup)>0·99; NNT 71·4; 6 months: -0·5% [-1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up., Interpretation: In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat., Funding: UK Research and Innovation and National Institute for Health and Care Research., Competing Interests: Declaration of interests JSN-V-T was seconded to the Department of Health and Social Care, England from Oct 1, 2017, to March 31, 2022. On June 15, 2023, JSN-V-T completed one 3-h paid consultancy assignment for Merck Sharp & Dohme on a subject unrelated to COVID-19, and has given two paid lectures for Gilead who have manufactured COVID-19 treatments in 2022–23, and one paid lecture for AstraZeneca in 2022, who manufacture COVID-19 vaccines. JSN-V-T has consulted occasionally for Moderna (May 1, 2023 onwards) who manufacture COVID-19 vaccines. DML has received personal fees from Gilead for an educational video and from Merck for a roundtable discussion, speaker fees from Biotest, Takeda, and Astra Zeneca, and support to attend a conference from Octapharma. DML holds research grants from GlaxoSmithKline and Bristol Myers Squibb, has received consultancy fees from GlaxoSmithKline paid to his institution, all outside the current work, and reports giving lectures for Biotest, Takeda, and AstraZeneca. JFS has participated in a Data and Safety Monitoring Committee for the sotrovimab paediatric programme for GlaxoSmithKline (fee paid to the institution). JB reports being the Principle Investigator on The Medicines and Healthcare products Regulatory Agency commissioned study with GlaxoSmithKline to look at the evolution of variants in sotrovimab treated patients, and consulting fees from GlaxoSmithKline, hVIVO, Moderna, and Symbios (donated to UCL). SK has been a speaker for Pfizer and ViiV Healthcare. KH reports a grant to Cardiff University (via University of Oxford), and was on the National Institute for Health and Care Research (NIHR) Health Technology Assessment General Committee and Health Technology Assessment Funding Strategy Group until November, 2022, and is currently Deputy Chair of the Research Professors panel. BRS reports consulting fees were paid to his former employer (Berry Consultants) for tiral design and implementation. NPBT reports being on a single advisory board in July, 2021, with Merck & Co. OvH reports consulting fees from MindGap. AU reports honoria from Merck & Co, Gilead Sciences, Pfizer, and Astra Zeneca in relation to this disease area and manuscript. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members. The HFC (Heart Failure Collaboratory), a multidisciplinary public-private consortium of academics, trialists, patients, industry representatives, and government agencies, is working to improve the clinical trial ecosystem. The HFC aims to improve clinical trial efficiency and quality by standardizing concepts, and to help meet the demand for experienced individuals on DMCs by creating a standardized approach to training new members. This paper discusses the HFC's training workshop, and an apprenticeship model for new DMC members. It describes opportunities and challenges DMCs face, along with common myths and best practices learned through previous experiences, with an emphasis on data confidentiality and need for quality independent statistical reporting groups., Competing Interests: Funding Support and Author Disclosures Dr Fleming has received consulting fees from the National Institutes of Health, the World Health Organization, the Food and Drug Administration, and the pharmaceutical and biotech industry in the design, monitoring, and analysis of clinical trials; and he has received fees for serving on several industry-sponsored Data Monitoring Committees (DMCs). Dr Wittes has received compensation for her membership on several DMCs sponsored by industry, government, and not-for-profit organizations; and has received consulting fees from a variety of pharmaceutical and medical device companies. Dr Bristow is the President/CEO/Director at ARCA biopharma. Dr Rockhold has received consulting fees from Intercept, Clover, and Inventprise; has received compensation for serving on several industry-sponsored DMCs; and holds stock in Clover, GSK, Athira, Spence, Adaptic, and Doctor Evidence. Dr Claggett has received consulting fees from Alnylam, Axon, Cardior, Cardurion, CVRx, Cytokinetics, Intellia, and Rocket. Dr Abraham has received consulting fees from Boehringer Ingelheim, Cardionomic, Zoll Respicardia, scPharmaceuticals, Sensible Medical, and Vectorious; has received salary support from V-Wave Medical; and has served as a speaker for Edwards Lifesciences. Dr Lindenfeld has received consulting fees from Abbott, ADI, Alleviant, Amgen, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Cytokinetics, Edwards Lifesciences, Medtronic, Merck, VWave, Vascular Dynamics, Vectorious, and Whiteswell; and has received grants from Analog Devices Inc, AstraZeneca, and Volumetrix. Dr DeMets has received consulting fees from the National Institutes of Health, the U.S. Food and Drug Administration, and the pharmaceutical and medical device industry on the design, monitoring, and analysis of clinical trials; and he has received compensation for serving on several recent industry-sponsored data and safety monitoring committees or steering committees including AstraZeneca, Bristol Meyers Squib, GSK, Merck, Boston Scientific, Medtronic, USONA, LivaNova, AnthosTherapy, ARCA biopharma, Duke Clinical Research Institute, and the Population Health Research Institute of Hamilton Ontario. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known., Methods: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment., Results: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration., Conclusions: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.)., (Copyright © 2024 Massachusetts Medical Society.)

Importance: Left atrial appendage elimination may improve catheter ablation outcomes for atrial fibrillation., Objective: To assess the safety and effectiveness of percutaneous left atrial appendage ligation adjunctive to catheter pulmonary vein isolation for nonparoxysmal atrial fibrillation., Design, Setting, and Participants: This multicenter, prospective, open-label, randomized clinical trial evaluated the safety and effectiveness of percutaneous left atrial appendage ligation adjunctive to planned pulmonary vein isolation for nonparoxysmal atrial fibrillation present for less than 3 years. Eligible patients were randomized in a 2:1 ratio to undergo left atrial appendage ligation and pulmonary vein isolation or pulmonary vein isolation alone. Use of a 2:1 randomization ratio was intended to provide more device experience and safety data. Patients were enrolled from October 2015 to December 2019 at 53 US sites, with the final follow-up visit on April 21, 2021., Interventions: Left atrial appendage ligation plus pulmonary vein isolation compared with pulmonary vein isolation alone., Main Outcomes and Measures: A bayesian adaptive analysis was used for primary end points. Primary effectiveness was freedom from documented atrial arrythmias of greater than 30 seconds duration 12 months after undergoing pulmonary vein isolation. Rhythm was assessed by Holter monitoring at 6 and 12 months after pulmonary vein isolation, symptomatic event monitoring, or any electrocardiographic tracing obtained through 12 months after pulmonary vein isolation. Primary safety was a composite of predefined serious adverse events compared with a prespecified 10% performance goal 30 days after the procedure. Left atrial appendage closure was evaluated through 12 months after pulmonary vein isolation., Results: Overall, 404 patients were randomized to undergo left atrial appendage ligation plus pulmonary vein isolation and 206 were randomized to undergo pulmonary vein isolation alone. Primary effectiveness was 64.3% with left atrial appendage ligation and pulmonary vein isolation and 59.9% with pulmonary vein isolation only (difference, 4.3% [bayesian 95% credible interval, -4.2% to 13.2%]; posterior superiority probability, 0.835), which did not meet the statistical criterion to establish superiority (0.977). Primary safety was met, with a 30-day serious adverse event rate of 3.4% (bayesian 95% credible interval, 2.0% to 5.0%; posterior probability, 1.0) which was less than the prespecified threshold of 10%. At 12 months after pulmonary vein isolation, complete left atrial appendage closure (0 mm residual communication) was observed in 84% of patients and less than or equal to 5 mm residual communication was observed in 99% of patients., Conclusions and Relevance: Percutaneous left atrial appendage ligation adjunctive to pulmonary vein isolation did not meet prespecified efficacy criteria for freedom from atrial arrhythmias at 12 months compared with pulmonary vein isolation alone for patients with nonparoxysmal atrial fibrillation, but met prespecified safety criteria and demonstrated high rates of closure at 12 months., Trial Registration: ClinicalTrials.gov Identifier: NCT02513797.

Background: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials., Methods: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 μg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome., Trial Registration: ISRCTN86534580., Findings: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months., Interpretation: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted., Funding: UKRI/National Institute of Health Research (MC&#95;PC&#95;19079)., Competing Interests: Declaration of Competing Interest Drs. Saville, Berry, Detry, Fitzgerald and Saunders report grants from The University of Oxford, for the Sponsor's grant from the UK NIHR, for statistical design and analyses for the PRINCIPLE trial during the conduct of the study. Prof de Lusignan is Director of the Oxford-RCGP Research and Surveillance Centre and reports that through his University he has had grants outside the submitted work from AstraZeneca, GSK, Sanofi, Seqirus and Takeda for vaccine related research, and membership of advisory boards for AstraZeneca, Sanofi and Seqirus. Profs Hobbs and Butler report grants from UKRI, during the conduct of the study. All other authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The Breakthrough Devices Program of the US Food and Drug Administration has accelerated the development and evaluation of medical devices for patients with heart failure. One such device is the Optimizer Smart System, which the US Food and Drug Administration approved in 2019., Methods and Results: The Optimizer device was evaluated in a pivotal randomized clinical trial (FIX-HF-5C [Confirmatory Randomized Trial Evaluating the Optimizer System]) that leveraged Bayesian borrowing of external data to reduce the sample size and determine therapeutic device benefit versus continued medical therapy. Bayesian borrowing is explained in the context of the FIX-HF-5C trial, including an overview of the statistical methodologies, regulatory considerations, and interpretations of trial results., Conclusions: The US Food and Drug Administration Breakthrough Devices Program and novel Bayesian statistical methodology accelerated the path to regulatory approval and patient access to a potentially lifesaving device and may serve as a model for future clinical trials.

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a multifactorial Bayesian adaptive platform trial that aims to improve the way that S. aureus bloodstream infection, a globally common and severe infectious disease, is treated. In a world first, the SNAP trial will simultaneously investigate the effects of multiple intervention modalities within multiple groups of participants with different forms of S. aureus bloodstream infection. Here, we formalise the trial structure, modelling approach, and decision rules that will be used for the SNAP trial. By summarising the statistical principles governing the design, our hope is that the SNAP trial will serve as an adaptable template that can be used to improve comparative effectiveness research efficiency in other disease areas.Trial registration NCT05137119 . Registered on 30 November 2021., (© 2023. The Author(s).)

Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19., Methods and Analysis: PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid)., Eligibility Criteria: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18-49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial., Ethics and Dissemination: Ethical approval granted by South Central-Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals., Trial Registration Number: ISRCTN30448031; EudraCT number: 2021-005748-31., Competing Interests: Competing interests: JN-V-T was seconded to the Department of Health and Social Care, England (DHSC) from October 2017 to March 2022. The views expressed in this paper are those of its authors and not necessarily those of DHSC. JN-V-T reports a lecture fee from Gilead Sciences Ltd (manufacturer of remdesivir) and a paid Influenza Advisory Board for F. Hoffmann-La Roche (manufacturer of tocilizumab), both after March 2022. KH is a member of the following NIHR committees: HTA General Committee, HTA Funding Strategy Group, Research Professors Funding Committee. KH is co-investigator on the grant provided by UKRI/NIHR, Grant number NIHR135366 (subcontract from University of Oxford to Cardiff University). KH received a grant from AstraZeneca to support a trial of Evusheld for the prevention of COVID in high-risk individuals (to Cardiff University). KH is an independent member of the IDMC for the OCTAVE-DUO trial of vaccines for COVID in high-risk individuals (unpaid). DML has received grants/contracts from LifeArc, Medical Research Council, Bristol Myers Squibb and Blood Cancer UK. DML received personal fees/honoraria for a lecture from Biotest UK, for an educational video from Gilead and for a ‘round table’ discussion with Merck. SP is co-investigator on the grant provided by UKRI/NIHR, Grant number NIHR135366. DR has received consulting fees from OMASS therapeutics. DR has a leadership/fiduciary role in the Heal-COVID trial TMG. BRS reports grant money paid to his employer (Berry Consultants, LLC) from The University of Oxford, from the Sponsor’s grant from the UKRI/NIHR, per the statistical design and analyses for the PANORAMIC trial. GH reports that the NIHR funded this study. ML reports funding directly from the PANORAMIC trial (NIHR). ML reports being a RAPIS-TEST (NIHR EME) DMC member. JM reports that this is part of his consulting work for Berry Consultants. SK reports research funding from GSK, ViiV Healthcare, Ridgeback Biotherapeutics, Vir and Merck unrelated to this work. SK reports speaker’s fees from ViiV Healthcare and participation on ViiV Healthcare, Pfizer advisory boards. SK reports receiving donation of drugs for clinical studies from ViiV Healthcare, Toyama and GSK. JFS reports receiving research grants from MRC (MR/X004724/1), Wellcome, NIHR, DNDi, Gates and MRC (MR/W015560/1) paid to his institution. JFS reports receiving Pharmacometric consultancy fees from Adrenomed Ltd paid to his institution. JFS reports participation on a Data Safety Monitoring board/Advisory Board for GSK Sotrovimab paediatric programme. MIA reports receiving grants from BTRU – GEMS, Janssen – Cartography, Pfizer – Myst, Prenetics, Dunhill Medical Trust, BMA Trust – Kathleen Harper Fund and Antibiotic Research UK – all paid to the institution. MIA reports receiving consultancy fees from Prenetics and OxDx. MIA reports a planned patent for Ramanomics. MIA reports participation on a Data Safety Monitoring board/Advisory Board for Prenetics. MIA has an unpaid leadership/fiduciary role in the E3 Initiative. NPBT reports his current affiliations with RCGP and NIHR TVSM. NPBT reports a payment for a single episode of participation on the MSD advisory board in July 2021, prior to any knowledge or planning of this trial. OvH reports receiving an NIHR Development and Skills Personal Award. OvH reports receiving consulting fees for MINDGAP BV, with the fees paid to Oxford University lnnovation Limited. OvH reports unpaid participation on a Data Safety Monitoring board/Advisory Board for The CHIldren with COugh Cluster Randomised Controlled Trial (CHICO). OvH has an unpaid leadership/fiduciary role in the British Society of Antimicrobial Chemotherapy. CB reports full employment with the Nuffield Department of Primary Care Health Sciences. AU reports receiving consulting fees and payment/honoraria from Merck/MSD and Gilead Sciences. RH reports receiving expenses reimbursed for talks on COVID monoclonal antibodies. PL reports support from the NIHR for the grant to do the PANORAMIC study. NF reports receiving consulting fees from Abbott Diagnostics and GSK, a presentation fee from Abbott Diagnostics, and has stocks in Synairgen PLC., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Intracerebral hemorrhage (ICH) is a potentially devastating condition with elevated early mortality rates, poor functional outcomes, and high costs of care. Standard of care involves intensive supportive therapy to prevent secondary injury. To date, there is no randomized control study demonstrating benefit of early evacuation of supratentorial ICH., Methods: The Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH) Trial was designed to evaluate the minimally invasive trans-sulcal parafascicular surgery (MIPS) approach, a technique for safe access to deep brain structures and ICH removal using the BrainPath ® and Myriad ® devices (NICO Corporation, Indianapolis, IN). ENRICH is a multi-centered, two-arm, randomized, adaptive comparative-effectiveness study, where patients are block randomized by ICH location and Glasgow Coma Score (GCS) to early ICH evacuation using MIPS plus standard guideline-based management vs. standard management alone to determine if MIPS results in improved outcomes defined by the utility-weighted modified Rankin score (UWmRS) at 180 days as the primary endpoint. Secondary endpoints include clinical and economic outcomes of MIPS using cost per quality-adjusted life years (QALYs). The inclusion and exclusion criteria aim to capture a broad group of patients with high risk of significant morbidity and mortality to determine optimal treatment strategy., Discussion: ENRICH will result in improved understanding of the benefit of MIPS for both lobar and deep ICH affecting the basal ganglia. The ongoing study will lead to Level-I evidence to guide clinicians treatment options in the management of acute treatment of ICH., Trial Registration: This study is registered with clinicaltrials.gov (Identifier: NCT02880878)., Competing Interests: Authors BS and RL are employed by Berry Consultants LLC. Berry Consultants LLC supports the SLT with the study's adaptive clinical trial design. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ratcliff, Hall, Porto, Saville, Lewis, Allen, Frankel, Wright, Barrow and Pradilla.)

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population., Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031., Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir., Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community., Funding: UK National Institute for Health and Care Research., Competing Interests: Declaration of interests JSN-V-T was seconded to the Department of Health and Social Care, England from October, 2017, to March, 2022, and reports lecture fees from Gilead and fees for participation on an advisory board for F Hoffmann-La Roche. KH is a member of the Health Technology Assessment General Committee and Funding Strategy Group, and Research Professors Funding Committee at the UK National Institute for Health and Care Research (NIHR), received a grant from AstraZeneca (paid to their institution) to support a trial of Evusheld for the prevention of COVID-19 in high-risk individuals, and is an independent member of the independent data monitoring committee for the OCTAVE-DUO trial of vaccines in individuals at high risk of COVID-19. DML has received grants or contracts from LifeArc, the UK Medical Research Council, Bristol Myers Squibb, GlaxoSmithKline, the British Society for Antimicrobial Chemotherapy, and Blood Cancer UK, personal fees or honoraria from Biotest UK, Gilead, and Merck, consulting fees from GlaxoSmithKline (paid to their institution), and conference support from Octapharma. DBR has received consulting fees from OMASS Therapeutics and has a leadership and fiduciary role in the Heal-COVID trial TMG. BRS, JM, MAD, CTS, NSB, and MF report grant money paid to their employer from the University of Oxford for the statistical design and analyses of the PANORAMIC trial. JM has also participated on data and safety monitoring boards as part of his employment with Berry Consultants. ML is a member of the data monitoring and ethics committee of RAPIS-TEST (NIHR efficacy and mechanism evaluation). SK reports grants from GlaxoSmithKline, ViiV, Ridgeback Biotherapeutics, Vir, Merck, the UK Medical Research Council, and the Wellcome Trust (all paid to his institution), speaker's honoraria from ViiV, and donations of drugs for clinical studies from ViiV Healthcare, Toyama, and GlaxoSmithKline. JFS has participated on a data safety monitoring board for GlaxoSmithKline. MA has received grants from the Blood and Transplant Research Unit, Janssen, Pfizer, Prenetics, Dunhill Medical Trust, the BMA Trust (Kathleen Harper Fund), and Antibiotic Research UK (all of which were paid to their institution), and consultancy fees from Prenetics and OxDx. MA reports a planned patent for Ramanomics, has participated on data safety monitoring boards or advisory boards for Prenetics, and has an unpaid leadership or fiduciary role in the E3 Initiative. NPBT has received payment for participation on an advisory board from MSD (before any knowledge or planning of this trial). OvH has received consulting fees from MindGap (fees paid to Oxford University lnnovation), has participated on data safety monitoring boards or advisory boards for the CHICO trial, and has an unpaid leadership or fiduciary role in the British Society of Antimicrobial Chemotherapy. AU has received consulting fees and payment or honoraria from MSD, GlaxoSmithKline, and Gilead. NF has received consulting fees from Abbott Diagnostics and GlaxoSmithKline, is a member of the PRINCIPLE trial data safety monitoring board and the NIHR Health Technology Assessment General Funding Committee, and has stocks in Synairgen. JB has received consulting fees from GlaxoSmithKline (paid to her institution). All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background/aims: Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy., Methods: We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios., Results: Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis., Conclusion: The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Background: Multi-arm platform trials investigate multiple agents simultaneously, typically with staggered entry and exit of experimental treatment arms versus a shared control arm. In such settings, there is considerable debate whether to limit analyses for a treatment arm to concurrent randomized control subjects or to allow comparisons to both concurrent and non-concurrent (pooled) control subjects. The potential bias from temporal drift over time is at the core of this debate., Methods: We propose time-adjusted analyses, including a "Bayesian Time Machine," to model potential temporal drift in the entire study population, such that primary analyses can incorporate all randomized control subjects from the platform trial. We conduct a simulation study to assess performance relative to utilizing concurrent or pooled controls., Results: In multi-arm platform trials with staggered entry, analyses adjusting for temporal drift (either Bayesian or frequentist) have superior estimation of treatment effects and favorable testing properties compared to analyses using either concurrent or pooled controls. The Bayesian Time Machine generally provides estimates with greater precision and smaller mean square error than alternative approaches, at the risk of small bias and small Type I error inflation., Conclusions: The Bayesian Time Machine provides a compromise between bias and precision by smoothing estimates across time and leveraging all available data for the estimation of treatment effects. Prior distributions controlling the behavior of dynamic smoothing across time must be pre-specified and carefully calibrated to the unique context of each trial, appropriately accounting for the population, disease, and endpoints.

Mucopolysaccaridosis IIIA (MPS IIIA) is a rare genetic disease that afflicts children and leads to neurocognitive degeneration. We develop a Bayesian disease progression model (DPM) of MPS IIIA that characterizes the pattern of cognitive growth and decline in this disease. The DPM is a repeated measures model that incorporates a nonlinear developmental trajectory and shape-invariant random effects. This approach quantifies the pattern of cognitive development in MPS IIIA and addresses differences in biological age, length of follow-up, and clinical outcomes across natural history subjects. The DPM can be used in clinical trials to estimate the percent slowing in disease progression for treatment relative to natural history. Simulations demonstrate that the DPM provides substantial improvements in power relative to alternative analyses., (© 2022 John Wiley & Sons Ltd.)

Background: Colchicine has been proposed as a COVID-19 treatment., Aim: To determine whether colchicine reduces time to recovery and COVID-19-related admissions to hospital and/or deaths among people in the community., Design and Setting: Prospective, multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial (PRINCIPLE)., Method: Adults aged ≥65 years or ≥18 years with comorbidities or shortness of breath, and unwell for ≤14 days with suspected COVID-19 in the community, were randomised to usual care, usual care plus colchicine (500 µg daily for 14 days), or usual care plus other interventions. The co-primary endpoints were time to first self-reported recovery and admission to hospital/death related to COVID-19, within 28 days, analysed using Bayesian models., Results: The trial opened on 2 April 2020. Randomisation to colchicine started on 4 March 2021 and stopped on 26 May 2021 because the prespecified time to recovery futility criterion was met. The primary analysis model included 2755 participants who were SARS-CoV-2 positive, randomised to colchicine ( n = 156), usual care ( n = 1145), and other treatments ( n = 1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.92 (95% credible interval (CrI) = 0.72 to 1.16) and an estimated increase of 1.4 days in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. COVID-19-related admissions to hospital/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 (95% CrI = 0.28 to 1.89) and an estimated difference of -0.4% (95% CrI = -2.7 to 2.4)., Conclusion: Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community., (© The Authors.)

Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165-175., (© 2021 American Neurological Association.)

Background: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community., Methods: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 μg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing., Findings: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19)., Interpretation: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications., Funding: National Institute of Health Research and United Kingdom Research Innovation., Competing Interests: Declaration of interests MB reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, and GlaxoSmithKline; and is a member of advisory boards for Albus Health and ProAxsis, outside the submitted work. DR reports being a former employee of GlaxoSmithKline, outside the submitted work. BRS, NB, MAD, MF, and CS report grants from The University of Oxford, for the University of Oxford's grant from the UK National Institute for Health Research (NIHR) and for statistical design and analyses for the PRINCIPLE trial during the conduct of the study. SdL is Director of the Oxford–Royal College of General Practitioners (RCGP) Research and Surveillance Centre and reports that through his university he has had grants outside the submitted work from AstraZeneca, GlaxoSmithKline, Sanofi, Seqirus, and Takeda for vaccine-related research, and membership of advisory boards for AstraZeneca, Sanofi, and Seqirus. MIA reports grants and personal fees from Prenetics outside the submitted work. PJB reports grants and personal fees from AstraZeneca and Boehringer Ingelheim; and personal fees from Teva and Covis, during the conduct of the study. REKR reports grants from AstraZeneca and personal fees from Boehringer Ingelheim, Chiesi UK, and GlaxoSmithKline, during the conduct of the study. SR reports grants and non-financial support from Oxford respiratory NIHR Biomedical Research Centre (BRC), during the conduct of the study; and non-financial support from AstraZeneca and personal fees from the Australian Government Research Training Program, outside the submitted work. FDRH and CCB report grants from UK Research and Innovation, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Doxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. We aimed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes., Methods: We did a national, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centres in the UK. We included people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m 2 or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomisation to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalisation or death related to COVID-19, both measured over 28 days from randomisation and analysed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580., Findings: The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI -0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in the usual care plus doxycycline group and 43 (4·5%) in the usual care only group (estimated absolute percentage difference -0·5% [95% BCI -2·6 to 1·4]); there were five deaths (0·6%) in the usual care plus doxycycline group and two (0·2%) in the usual care only group., Interpretation: In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19., Funding: UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research., Competing Interests: Declaration of interests BRS, MAD, CS, MF, and NB report grants from University of Oxford, for the sponsor's grant from the UK National Institute for Health Research (NIHR), for statistical design and analyses for the trial, during the conduct of the study. RD reports grants and personal fees from Synairgen, during the conduct of the study; personal fees from TEVA Pharmaceuticals, Sanofi, Boehringer, and Novartis, outside of the submitted work; and grants from the Innovative Medicines Initiative, the UK Medical Research Council, and Novartis, outside of the submitted work. FDRH reports grants from UK Research and Innovation (UKRI), during the conduct of the study. OVH reports grants from UKRI, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications., Methods and Analysis: The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50-64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 'hot hubs' and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes., Ethics and Dissemination: Ethical approval Ref: 20/SC/0158 South Central - Berkshire Research Ethics Committee; IRAS Project ID: 281958; EudraCT Number: 2020-001209-22. Results will be presented to policymakers and at conferences and published in peer-reviewed journals., Trial Registration Number: ISRCTN86534580., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses., Competing Interests: Declaration of Competing Interest Johanna H van der Lee has no conflicts of interest. Jonathan Morton is an employee of Comradis, Oxford, UK, which received payment from conference funds managed by the US National MPS Society for the medical writing support provided during the development of this article, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Heather Adams has served as an advisory board member/consultant for Amicus Therapeutics, Beyond Batten Disease Foundation, Taylor’s Tale, ReGenXBio and Neurogene. She is a member of the Batten Disease Support & Research Association medical advisory board and the co-director of the Tourette Association of America Center of Excellence at University of Rochester. Lorne Clark has received honoraria for advisory boards and educational lectures from BioMarin, JCR Pharmaceutical, ReGenXBio and Sanofi Genzyme. Julie Eisengart has received research support from Lysogene, Sangamo and Shire/Takeda; consulting fees from ArmaGen, Denali Therapeutics, JCR Pharmaceutical, Orchard Therapeutics, ReGenXBio and Shire/Takeda; and honoraria for advisory boards for Amicus Therapeutics, bluebird bio, Orchard Therapeutics, ReGenXBio, Sanofi Genzyme and Shire/Takeda. Maria L Escolar has served as principal investigator and consultant on MPS trials for Abeona Therapeutics, Denali Therapeutics, ReGenXBio and Seelos Therapeutics. Roberto Giugliani has served on as speaker, consultant or advisory board member for Amicus Therapeutics, Abeona Therapeutics, BioMarin, Inventiva, Janssen, JCR Pharmaceuticals, Lysogene, PTC Therapeutics, ReGenXBio, Sanofi Genzyme, Sobi, Takeda and Ultragenyx; has received research grants from Allievex, Amicus Therapeutics, Armagen, BioMarin, GC Pharma, JCR Pharmaceuticals, Lysogene, ReGenXBio, Sanofi Genzyme and Takeda; and has received travel expenses to attend scientific meetings from Amicus Therapeutics, BioMarin, JCR Pharmaceuticals, Sanofi Genzyme, Takeda and Ultragenyx. Paul Harmatz has received research support for studies, served on scientific advisory boards, and provided consulting support for Aeglea Biotherapeutics, Alexion, Amicus Therapeutics, Armagen, Ascendis Pharma, BioMarin, Chiesi, Denali Therapeutics, Homology Medicines, Inventiva Pharma, JCR Pharmaceutical, Orphazyme, Paradigm BioPharma, PTC Therapeutics, QED, ReGenXbio, Sangamo, Sanofi Genzyme, Sobi and Shire/Takeda. Melissa Hogan is a principal consultant with Doulots, LLC through which she has received consulting fees from Denali Therapeutics and Seelos Therapeutics. She has also received stipends and expenses in accordance with her son's participation in a clinical trial and its extension sponsored by Shire (now Takeda). Shauna Kearney has received education and travel sponsorships from Actelion, BioMarin, Denali Therapeutics, Sanofi Genzyme and Shire/Takeda in connection with meetings. She has no conflicts of interest. Joseph Muenzer has received consulting fees from BioMarin, bluebird bio, Denali Therapeutics, Eloxx, Green Cross, JCR Pharmaceuticals, PTC Therapeutics, ReGenXBio, Sangamo, Sanofi Genzyme and Shire/Takeda. He is the principal investigator for Phase I/II and Phase II/III intrathecal enzyme replacement clinical trials for MPS II, a Phase I/II gene editing clinical trial for MPS II and a Phase I/II IV ERT clinical trial for MPS IIIA. Nicole Muschol has received consulting fees from BioMarin, Chiesi, Lysogene, Sanofi Genzyme, Shire/Takeda and Sobi; received grant/research support from BioMarin, Sanofi Genzyme and Shire/Takeda; and received honoraria/travel support from Actelion, Amicus Therapeutics, BioMarin, Sanofi Genzyme and Shire/Takeda. Stewart Rust has received travel grants, speaker fees and conference sponsorship from Takeda. Benjamin R Saville is employed by Berry Consultants, a statistical consulting company specializing in Bayesian adaptive clinical trials. The company has received consulting payments from Abeona Therapeutics in MPS-related trial design Margaret Semrud-Clikeman has no conflicts of interest. Raymond Wang is a principal investigator and has received travel support and honorarium for advisory board participation for Lysogene and ReGenXBio. Elsa Shapiro is the managing partner of Shapiro Neuropsychology Consulting through which she has received fees for providing consultation services on cognitive and behavioural endpoints for all the companies providing support for this conference., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigate multiple features of response adaptive randomization (RAR) in the context of a multiple arm randomized trial with control, where the primary goal is the identification of the best arm for use in a broader patient population. We maintain constant control allocation and vary the length of time until RAR is started, interim frequency, the underlying quantity used to calculate the randomization probabilities, and a threshold resulting in temporary arm dropping. We evaluate the designs on five metrics measuring benefit to the internal trial population, the future external population, and statistical estimation. Our results indicate these features have minimal interaction within the space explored, with preference for earlier activation of RAR, more frequent interim analyses, randomizing in proportion to the probability each arm is the best, and aggressive thresholding for temporarily dropping arms. The results illustrate useful principles for maximizing the benefit of RAR in practice., (© 2020 John Wiley & Sons Ltd.)

Background: Patients infected with the novel coronavirus (SARS-CoV-2) are being treated empirically with oseltamivir, but there is little evidence from randomised controlled trials to support the treatment of coronavirus infections with oseltamivir., Aim: To determine whether adding oseltamivir to usual care reduces time to recovery in symptomatic patients who have tested positive for coronavirus (not including SARS-CoV-2)., Design and Setting: Exploratory analysis of data from an open-label, pragmatic, randomised controlled trial during three influenza seasons, from 2016 to 2018, in primary care research networks, in 15 European countries., Method: Patients aged ≥1 year presenting to primary care with influenza-like illness (ILI), and who tested positive for coronavirus (not including SARS-CoV-2), were randomised to usual care or usual care plus oseltamivir. The primary outcome was time to recovery defined as a return to usual activities, with minor or absent fever, headache, and muscle ache., Results: Coronaviruses (CoV-229E, CoV-OC43, CoV-KU1 and CoV-NL63) were identified in 308 (9%) out of 3266 randomised participants in the trial; 153 of these were allocated to usual care and 155 to usual care plus oseltamivir; the primary outcome was ascertained in 136 and 147 participants, respectively. The median time to recovery was shorter in patients randomised to oseltamivir: 4 days (interquartile range [IQR] 3-6) versus 5 days (IQR 3-8; hazard ratio 1.31; 95% confidence interval = 1.03 to 1.66; P = 0.026)., Conclusion: Primary care patients with ILI testing positive for coronavirus (not including SARS-CoV-2) recovered sooner when oseltamivir was added to usual care compared with usual care alone. This may be of relevance to the primary care management of COVID-19., (©The Authors.)

Background and Purpose- EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods- Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results- The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P =0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P =0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P =0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions- There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02790632.

Background: Prior studies of cardiac contractility modulation (CCM) employed a 3-lead Optimizer system. A new 2-lead system eliminated the need for an atrial lead. This study tested the safety and effectiveness of this 2-lead system compared with the 3-lead system., Methods: Patients with New York Heart Association III/IVa symptoms despite medical therapy, left ventricular ejection fraction 25% to 45%, and not eligible for cardiac resynchronization therapy could participate. All subjects received an Optimizer 2-lead implant. The primary end point was the estimated difference in the change of peak VO 2 from baseline to 24 weeks between FIX-HF-5C2 (2-lead system) subjects relative to control subjects from the prior FIX-HF-5C (3-lead system) study. Changes in New York Heart Association were a secondary end point. The primary safety end point was a comparison of device-related adverse events between FIX-HF-5C2 and FIX-HF-5C subjects., Results: Sixty subjects, 88% male, 66±9 years old with left ventricular ejection fraction 34±6% were included. Baseline characteristics were similar between FIX-HF-5C and FIX-HF-5C2 subjects except that 15% of FIX-HF-5C2 subjects had permanent atrial fibrillation versus 0% in FIX-HF-5C. CCM delivery did not differ significantly between 2- and 3-lead systems (19 892±3472 versus 19 583±4998 CCM signals/day, CI of difference [-1228 to 1847]). The change of peak VO 2 from baseline to 24 weeks was 1.72 (95% Bayesian credible interval, 1.02-2.42) mL/kg per minute greater in the 2-lead device group versus controls. 83.1% of 2-lead subjects compared with 42.7% of controls experienced ≥1 class New York Heart Association improvement ( P <0.001). There were decreased Optimizer-related adverse events with the 2-lead system compared with the 3-lead system (0% versus 8%; P =0.03)., Conclusions: The 2-lead system effectively delivers comparable amount of CCM signals (including in subjects with atrial fibrillation) as the 3-lead system, is equally safe and improves peak VO 2 and New York Heart Association. Device-related adverse effects are less with the 2-lead system. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03339310.

Background/aims: Response adaptive randomization has many polarizing properties in two-arm settings comparing control to a single treatment. The generalization of these features to the multiple arm setting has been less explored, and existing comparisons in the literature reach disparate conclusions. We investigate several generalizations of two-arm response adaptive randomization methods relating to control allocation in multiple arm trials, exploring how critiques of response adaptive randomization generalize to the multiple arm setting., Methods: We perform a simulation study to investigate multiple control allocation schemes within response adaptive randomization, comparing the designs on metrics such as power, arm selection, mean square error, and the treatment of patients within the trial., Results: The results indicate that the generalization of two-arm response adaptive randomization concerns is variable and depends on the form of control allocation employed. The concerns are amplified when control allocation may be reduced over the course of the trial but are mitigated in the methods considered when control allocation is maintained or increased during the trial. In our chosen example, we find minimal advantage to increasing, as opposed to maintaining, control allocation; however, this result reflects an extremely limited exploration of methods for increasing control allocation., Conclusion: Selection of control allocation in multiple arm response adaptive randomization has a large effect on the performance of the design. Some disparate comparisons of response adaptive randomization to alternative paradigms may be partially explained by these results. In future comparisons, control allocation for multiple arm response adaptive randomization should be chosen to keep in mind the appropriate match between control allocation in response adaptive randomization and the metric or metrics of interest.

Background: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups., Methods: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921., Findings: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group., Interpretation: Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner., Funding: European Commission's Seventh Framework Programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The purpose of late phase clinical trials is to generate evidence of sufficient validity and generalisability to be translated into practice and policy to improve health outcomes. It is therefore crucial that the chosen endpoints are meaningful to the clinicians, patients and policymakers that are the end-users of evidence generated by these trials. The choice of endpoints may be improved by understanding their characteristics and properties. This narrative review describes the evolution, range and relative strengths and weaknesses of endpoints used in late phase trials. It is intended to serve as a reference to assist those designing trials when choosing primary endpoint(s), and for the end-users charged with interpreting these trials to inform practice and policy., Competing Interests: The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2019 Published by Elsevier Inc.)

Background: The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function., Methods: The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point-reduction in the composite of cardiovascular death or first HF hospitalization-and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score)., Conclusions: Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.

Clinicians and other decision makers in healthcare use results from clinical trials to inform practice. Interpretation of clinical trial results can be challenging, as weaknesses in trial design, data collection, analysis or reporting, can compromise the usefulness of results. A good working knowledge of clinical trial design is essential to expertly interpret and determine the validity and generalizability of the results. This manuscript will give a brief overview of clinical trial design including the strengths and limitations of various approaches. The focus will be on confirmatory clinical trials., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cystic fibrosis is a genetic disease typically characterized by progressive lung damage and premature mortality. Pulmonary exacerbations, or flare-ups of the lung disease, often require hospitalization for intensive treatment. Approximately 25% of patients with cystic fibrosis do not recover their baseline lung function after pulmonary exacerbations. There is a relative paucity of evidence to inform treatment strategies for exacerbations. Compounding this lack of evidence, there are a large number of treatment options already as well as becoming available. This results in significant variability between medication regimens prescribed by different physicians, treatment centers and regions with potentially adverse impact to patients. The conventional strategy is to undertake essential randomized clinical trials to inform treatment decisions and improve outcomes for patients with exacerbations. However, over the past several decades, clinical trials have generally failed to provide information critical to improved treatment and management of exacerbations. Bayesian adaptive platform trials hold the promise of addressing clinical uncertainties and informing treatment. Using modeling and response adaptive randomization, they allow for the evaluation of multiple treatments across different management domains, and progressive improvement in patient outcomes throughout the course of the trial. Bayesian adaptive platform trials require substantial amounts of preparation. Basic preparation includes extensive stakeholder involvement including elicitation of consumer preferences and clinician understanding of the research topic, defining the research questions, determining the best outcome measures, delineating study sub-groups, in depth statistical modeling, designing end-to-end digital solutions seamlessly supporting clinicians, researchers and patients, constructing randomisation algorithms and importantly, defining pre-determined intra-study end-points. This review will discuss the motivation and necessary steps required to embark on a Bayesian adaptive platform trial to optimize medication regimens for the treatment of pulmonary exacerbations of cystic fibrosis.

Background: Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration., Results: A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2-4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral nimodipine., Conclusions: The primary endpoint is the proportion of subjects with favorable outcome (6-8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.

Approximately one fourths of infant fractures are due to abuse. Recognition of abuse is important to avoid further morbidity/mortality. There is limited knowledge regarding how frequently pediatric emergency department clinicians consider abuse in infants with fractures. Our primary objective was to estimate the percentage of infants with fractures for whom abuse was considered, and to examine characteristics associated with abuse consideration. We performed a retrospective review of infants <1 year of age presenting to a pediatric emergency department. Our primary outcome variable was consideration of abuse. Our secondary outcome measures were identification of predictor variables associated with consideration of abuse. We identified 509 infants meeting study criteria. Pediatric emergency physicians considered abuse in approximately two thirds of infants with fractures. Consideration was more likely to occur in younger infants, in the presence of no history or unwitnessed injury mechanism, when evaluated by male physicians, and emergency department encounters from 12 am to 6 am.

ALIC 4 E is the first publicly funded, multicountry, pragmatic study determining whether antivirals should be routinely prescribed for influenza-like illness in primary care. The trial aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of participant characteristics (age, symptom duration, illness severity, and comorbidities). It is one of the first platform, response-adaptive, open trial designs implemented in primary care, and this article aims to provide an accessible description of key aspects of the study design. 1) The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatment arms. 2) Response adaptation allows the proportion of participants with key characteristics allocated to study arms to be altered during the course of the trial according to emerging outcome data, so that participants' information will be most useful, and increasing their chances of receiving the trial intervention that will be most effective for them. 3) Because the possibility of taking placebos influences participant expectations about their treatment, and determining effects of the interventions on patient help seeking and adherence behaviour in real-world care is critical to estimates of cost-effectiveness, ALIC 4 E is an open-label trial., Competing Interests: Conflict of interest: M. de Jong reports advisory board, travel and fees from Janssen, MedImmune and Shionogi. He also reports Independent Data and Safety Monitoring Board (IDSMB) and fees from Janssen, and IDSMB, travel and fees from GSK and Vertex, outside the submitted work. Conflict of interest: P. Beutels reports grants from European Commission project “PREPARE” during the conduct of the study, and an unrestricted gift for part-time research from Pfizer and GSK, outside the submitted work.

Pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF-TAP) is often based on cardiac MRI (CMR) right ventricular (RV) volumes indexed to body surface area (BSA). Weight extremes result in increased patient morbidity and affect indexed measurements. We hypothesized that patients with rTOF-TAP at extremes of weight have (1) over- or underestimated indexed volumes and (2) altered parameters of cardiac function. CMRs in patients with rTOF-TAP were retrospectively reviewed; analysis included right and left ventricular (LV) volumes and ejection fractions (EF) and peak global LV circumferential strain (ε cc ) from myocardial tagged images. Indexed volumes were recalculated using ideal BSA. Weight categories were assigned: underweight, appropriate weight, overweight, and obese. Linear regression models with weight category, spline of age, and gender were created to assess the association of weight and parameters of volume and function. When RV volumes were corrected for ideal BSA, 11 (31%) additional overweight and obese patients met published criteria for PVR and 3 (38%) underweight patients no longer met criteria. Obese and overweight patients had larger absolute LV and RV diastolic volumes, but no difference in volumes indexed to ideal BSA. Modeling demonstrated no difference in LVEF or RVEF by weight categories but significant differences in global LV ε cc . Extremes of body weight may result in inappropriate timing of PVR. Extremes of weight lead to abnormalities in global LV ε cc . Although clinical implications of abnormal ε cc are unclear, these patients may be at higher risk for early ventricular dysfunction.

Response adaptive randomization (RAR) methods for clinical trials are susceptible to imbalance in the distribution of influential covariates across treatment arms. This can make the interpretation of trial results difficult, because observed differences between treatment groups may be a function of the covariates and not necessarily because of the treatments themselves. We propose a method for balancing the distribution of covariate strata across treatment arms within RAR. The method uses odds ratios to modify global RAR probabilities to obtain stratum-specific modified RAR probabilities. We provide illustrative examples and a simple simulation study to demonstrate the effectiveness of the strategy for maintaining covariate balance. The proposed method is straightforward to implement and applicable to any type of RAR method or outcome., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objective: Athletes have a higher risk of infection with Staphylococcus aureus than the general population. Most studies in athletes have included primarily male contact sports participants and have not assessed S. aureus carriage over time. We aimed to examine the epidemiology and risk factors of S. aureus carriage in a cohort of male and female collegiate athletes., Study Design: We conducted a prospective cohort study of 377 varsity collegiate athletes from August 2008 to April 2010. A baseline questionnaire ascertained risk factors for colonization. Nasal and oropharyngeal swabs were obtained at enrollment and monthly thereafter to detect S. aureus colonization. The primary outcome was S. aureus colonization, both with methicillin-susceptible and methicillin-resistant S. aureus, as defined by bacterial culture and molecular confirmation. Secondary outcomes were time to colonization with S. aureus and carriage profile, defined as non-carrier, intermittent carrier, or persistent carrier., Results: Overall, 224 contact sports and 153 non-contact sports athletes were enrolled. Contact sports athletes had a higher risk of carrying S. aureus over time: They had higher odds of being colonized with MRSA (OR 2.36; 95 % CI 1.13-4.93) and they tended to carry S. aureus for longer periods of time (intermittent carriage OR 3.60; 95 % CI 2.02-6.40; persistent carriage OR 2.39; 95 % CI 1.21-4.72). Athletes engaged in contact sports also acquired S. aureus more quickly (HR 1.61; 95 % CI 1.02-2.55)., Conclusions: Staphylococcus aureus carriage was common in contact sports athletes. These findings suggest that efforts to prevent transmission of S. aureus among athletes should be focused on contact sports teams.