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Background Safe, highly curative, short course, direct acting antiviral (DAA) therapies are now available to treat chronic hepatitis C. DAA therapy is freely available to all adults chronically infected with the hepatitis C virus (HCV) in Australia. If left untreated, hepatitis C may lead to progressive hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Australia is committed to eliminating hepatitis as a public health threat by 2030 set by the World Health Organization. However, since the introduction of funded DAA treatment, uptake has been suboptimal. Australia needs improved strategies for testing, treatment uptake and treatment completion to address the persisting hepatitis C public health problem. PLATINUM C is a HCV treatment registry and research platform for assessing the comparative effectiveness of alternative interventions for achieving virological cure. Methods PLATINUM C will prospectively enrol people with active HCV infection confirmed by recent detection of HCV ribonucleic acid (RNA) in blood. Those enrolled will agree to allow standardised collection of demographic, lifestyle, treatment, virological outcome and other relevant clinical data to better inform the future management of HCV infection. The primary outcome is virological cure evidenced by sustained virological response (SVR), which is defined as a negative HCV PCR result 6 to 18 months after initial prescription of DAA therapy and no less than 12 weeks after the completion of treatment. Study participants will be invited to opt-in to medication adherence monitoring and quality of life assessments using validated self-reported instruments (EQ-5D-5L). Discussion PLATINUM C is a treatment registry and platform for nesting pragmatic trials. Data collected will inform the design, development and implementation of pragmatic trials. The digital infrastructure, study procedures and governing systems established by the registry will allow PLATINUM C to support a wider research platform in the management of hepatitis C in primary care. Trial registration The trial is registered with the Australia and New Zealand Clinical Trials Register (ACTRN12619000023156). Date of registration: 10/01/2019.

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) is promising but unproven. We developed a concept for a randomized Bayesian adaptive clinical trial to define the interval after arrest during which patients derive benefit. Hypotheses: We hypothesized that the simulated design characteristics of the adaptive design would efficiently confirm or refute the existence of a therapeutic window for ECPR in a future trial. Methods: Through iterative simulation and design modification, we developed a Bayesian adaptive trial of ECPR for adults with OHCA. The goals of the trial design were to address the uncertainty surrounding the OHCA-to-ECPR interval within which clinical benefit might be preserved and the difference in prognosis between patients with non-shockable vs shockable rhythms. The treatment effect was defined as the mean 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval. The trial adaptively lengthens or contracts the estimated CA-to-ECPR eligibility window depending on the probability of benefit from ECPR. We simulated trial performance under six potential ECPR efficacy scenarios. We compared the adaptive design to a fixed design. Results: The trial had 91-100% power to detect a benefit from ECPR for non-shockable rhythms and 69-98% power for shockable rhythms under the scenarios simulated (figure). The design had a high probability of identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. In null scenarios, the 97-99% of the simulated trials ended early declaring futility. Conclusions: The adaptive trial design helps to ensure the patient population most likely to benefit from treatment—as defined by rhythm subgroup and estimated CA-to-ECPR interval—are enrolled. The design also promotes early termination of the trial if continuation is likely to be futile.

Objective The purpose of this double-blind, randomised, placebo-controlled, adaptive design trial with frequent interim analyses is to determine if Australian Indigenous children, who receive an additional (third) dose of human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to < 12 months, would improve protection against clinically significant all-cause gastroenteritis. Participants Up to 1000 Australian Aboriginal and Torres Strait Islander (hereafter Indigenous) infants aged 6 to < 12 months will be recruited from all regions of the Northern Territory. Interventions The intervention is the addition of a third scheduled dose of human monovalent rotavirus vaccine. Co-primary and secondary outcome measures ORVAC has two co-primary outcomes: (1) anti-rotavirus IgA seroconversion, defined as serum anti-rotavirus IgA ≥ 20 U/ml 28 to 55 days post Rotarix/placebo, and (2) time from randomisation to medical attendance for which the primary reason for presentation is acute gastroenteritis or acute diarrhoea illness before age 36 months. Secondary outcomes include (1) change in anti-rotavirus IgA log titre, (2) time from randomisation to hospitalisation with primary admission code presumed or confirmed acute diarrhoea illness before age 36 months, (3) time from randomisation to hospitalisation for which the admission is rotavirus confirmed diarrhoea illness before age 36 months and (4) time from randomisation to rotavirus infection (not necessarily requiring hospitalisation) meeting the jurisdictional definition before age 36 months. Discussion A detailed, prospective statistical analysis plan is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptative elements, decision thresholds, statistical methods and the simulations used to evaluate the operating characteristics of the trial. As at August 2020, four interim analyses have been run, but no stopping rules have been triggered. Application of this SAP will minimise bias and supports transparent and reproducible research. Trial registration Clinicaltrials.gov NCT02941107. Registered on 21 October 2016 Original protocol for the study 10.1136/bmjopen-2019-032549

BACKGROUND Extracorporeal cardiopulmonary resuscitation (ECPR) is a promising therapy for out-of-hospital cardiac arrest (OHCA) that is refractory to standard therapy, but no multicenter randomized clinical trials have been conducted to establish its efficacy. We report the design and operating characteristics of a proposed randomized Bayesian adaptive “enrichment” clinical trial designed to determine whether ECPR is effective for refractory OHCA and, if effective, to define the interval after arrest during which patients derive benefit. METHODS Through iterative trial simulation and trial design modification, we developed a Bayesian adaptive trial of ECPR for adults who experience non-traumatic out-of-hospital cardiac arrest. Our proposed trial design addresses the threats to trial success identified during the design process, which were (1) the uncertainty surrounding the cardiac arrest (CA)-to-ECPR interval within which clinical benefit might be preserved (2) the difference in prognosis between patients with an initial rhythm that is non-shockable vs. shockable. Trial subjects will be randomized 1:1 to receive either standard care or expedited transport to a hospital for potential ECPR. The CA-to-ECPR interval will be estimated in real time based on the sum of the estimated paramedic response time (911 call to scene arrival), paramedic scene time, and transport time to hospital. A Bayesian decreasing step function will be used to estimate the efficacy of the treatment with an outcome of the 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval at pre-specified interims. The trial will adaptively lengthen the estimated CA-to-ECPR eligibility window if the treatment appears effective at the upper limit of initial eligibility window. If ECPR appears ineffective at longer estimated CA-to-ECPR intervals, the upper limit of the window for enrollment eligibility will be shortened. The analysis will be stratified by rhythm subgroup. RESULTS With a maximum total sample size of 400, and a cap on the maximum sample size of 300 for the non-shockable rhythm subgroup, the trial design has power ranging from 91–100% to detect a benefit from ECPR for non-shockable rhythms under the various efficacy scenarios simulated and power ranging from 69–98% for shockable rhythms under the same scenarios. The trial design also has a high probability of correctly identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. If ECPR is equivalent to standard CA care, the type I error is 2.5% with a 99% probability of stopping enrollment early for futility in the non-shockable subgroup and a 97% probability of stopping enrollment early for futility in the shockable subgroup. CONCLUSION This proposed adaptive trial design helps to ensure the population of patients who are most likely to benefit from treatment—as defined both by rhythm subgroup and estimated CA-to-ECPR interval—is enrolled. The design promotes early termination of the trial if continuation is likely to be futile.

BACKGROUND The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (= 80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P = 0.50), nor did 90-day mortality (19% and 18%, respectively; P = 1.00). CONCLUSIONS Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283.)

Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock—Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two-part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equa...

Rationale Efficacy of mechanical thrombectomy for acute stroke due to large vessel occlusion initiated beyond 6 h of time last seen well has not been demonstrated in randomized trials. Aim To establish whether subjects considered to have substantial areas of salvageable brain based on age-adjusted clinical core mismatch who can undergo endovascular treatment within 6–24 h from time last seen well (TLSW) have better outcomes at three months compared to subjects treated with standard medical therapy alone. Age-adjusted clinical core mismatch is defined by age (≤80 or >80 years), baseline National Institutes of Health Stroke Scale (NIHSS) (10–20 or ≥21), and core size (0–20 cm3 in subjects older than 80 and, in subjects younger than 80, 0–30 cm3 with NIHSS 10–20 and 31–50 cm3 with NIHSS ≥21). Design Prospective, randomized, multicenter, Bayesian adaptive-enrichment, open label trial with blinded endpoint assessment. For the purpose of enrolment, ischemic core size will be evaluated by CT perfusion or magnetic resonance imaging-diffusion-weighted imaging measured by automated software (RAPID). Procedures Subjects with acute ischemic stroke due to computed tomography angiography- or magnetic resonance angiogram-proven arterial occlusion of the intracranial internal carotid and/or proximal middle cerebral artery (M1) with age-adjusted clinical core mismatch in whom treatment can be initiated between 6 and 24 h from TSLW are randomized in a 1:1 ratio to receive mechanical embolectomy with the Trevo device or medical management alone. Sequential interim analyses allowing adaptation of enrolment criteria or stopping new enrolment for futility or predicted success will occur in every 50 randomized patients starting at 150 to a maximum of 500 patients. Study outcomes The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is stroke-related mortality at 90 days. Analysis The primary endpoint, expressed as a utility-weighted modified Rankin Scale score is analyzed using a Bayesian posterior probability with adjustment for ischemic core size. For regulatory reasons, a nested co-primary endpoint analysis was added consisting of the proportion of subjects with modified Rankin Scale 0–2 between the active and control groups also analyzed using a Bayesian model.

Background and Purpose— Although the modified Rankin Scale (mRS) is the most commonly used primary end point in acute stroke trials, its power is limited when analyzed in dichotomized fashion and its indication of effect size challenging to interpret when analyzed ordinally. Weighting the 7 Rankin levels by utilities may improve scale interpretability while preserving statistical power. Methods— A utility-weighted mRS (UW-mRS) was derived by averaging values from time-tradeoff (patient centered) and person-tradeoff (clinician centered) studies. The UW-mRS, standard ordinal mRS, and dichotomized mRS were applied to 11 trials or meta-analyses of acute stroke treatments, including lytic, endovascular reperfusion, blood pressure moderation, and hemicraniectomy interventions. Results— Utility values were 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. For trials with unidirectional treatment effects, the UW-mRS paralleled the ordinal mRS and outperformed dichotomous mRS analyses. Both the UW-mRS and the ordinal mRS were statistically significant in 6 of 8 unidirectional effect trials, whereas dichotomous analyses were statistically significant in 2 to 4 of 8. In bidirectional effect trials, both the UW-mRS and ordinal tests captured the divergent treatment effects by showing neutral results, whereas some dichotomized analyses showed positive results. Mean utility differences in trials with statistically significant positive results ranged from 0.026 to 0.249. Conclusions— A UW-mRS performs similar to the standard ordinal mRS in detecting treatment effects in actual stroke trials and ensures the quantitative outcome is a valid reflection of patient-centered benefits.

In an attempt to identify needed mental health skills, many professional organizations have or are in the process of establishing core competency standards for their professions. The AAMFT identified 128 core competencies for the independent practice of MFT. The aim of this study was to learn the opinions of AAMFT Approved Supervisors as to how well prepared postgraduate trainees are when compared to the core competencies. One hundred thirty-five AAMFT Approved Supervisors provided their perspectives on (a) which competencies are most commonly learned in MFT graduate programs, (b) how well the graduates have mastered these competencies, and (c) the level to which the supervisors need the competencies to be mastered prior to entering advanced training. Results suggest that a gap exists between the level of mastery that the postgraduate trainees exhibit and the level desired by supervisors. Implications are suggested for closing this gap.

Traditional phase 3 clinical trials compare an experimental arm with control. They inefficiently use patients, time, and finances. Dramatic and rapid changes in biology makes such trials untenable. We describe an alternative drug development strategy that we are using in a particular setting, the trial GBM AGILE (Glioblastoma Multiforme Adaptive Global Innovative Learning Environment). The trial’s design employs many innovations. Some aspects are similar to those of I-SPY 2 (see 4 articles in July 7, 2016 NEJM) but GBM AGILE extends I-SPY 2 in many ways. (1) It is a Bayesian platform trial that simultaneously evaluates many treatment arms (including combinations) from many companies. (2) Arms are added to the trial at any time and leave when they have been evaluated, whether positively or negatively. (3) An arm’s sample size is adaptive and based on frequent analyses of the trial results. (4) Every arm has an initial stage in which it is randomized adaptively: arms performing better in disease subtypes are assigned with higher probability to such patients. (5) An arm that performs sufficiently well in a disease subset moves seamlessly into a small (50-patient) confirmatory, registration stage in the same subset, with equal randomization against control. (6) All experimental arms are compared against a common control arm that is assigned to 20% of patients in every subtype; a bridging model takes advantage of having many arms in the trial and many comparisons among arms, and enables indirect randomization comparisons of all arms with all controls. (7) Patient subtypes are defined by line of therapy, MGMT methylation status for newly diagnosed patients, and biomarkers associated with targeted therapies, although adaptive randomization enables us to draw conclusions about off-target effects. The many possible subtypes means that there are many possible drug indications. So there are many possible “error types” and no single definition of statistical power. For example, the trial may conclude that a drug’s indication is “recurrent, biomarker-positive” disease when in truth it is “all recurrent” disease. We show how the design addresses this issue and we define “pure type I error.” GBM AGILE’s primary endpoint is overall survival (OS). To make the design more efficient we incorporate evaluations of patients’ statuses over time using a longitudinal model based on periodic MRI assessments and performance status. The longitudinal model and its components are not end points but rather provide auxiliary information that enables multiply imputing OS for surviving patients. We represent the trial’s coordinating committees that are made up of more than 150 enthusiastic and devoted disease experts and advocates from around the globe, including from Australia and China. The U.S. FDA has been enormously helpful in designing GBM AGILE, especially as regards its potential for drug and biomarker registration. Our approach provides a model for other diseases, including those outside of cancer. Citation Format: Donald A. Berry, Todd Graves, Jason Connor, Brian Alexander, Timothy Cloughesy, Anna Barker, Scott M. Berry, for the GBM AGILE Global Alliance. Adaptively randomized seamless-phase multiarm platform trial: Glioblastoma Multiforme Adaptive Global Innovative Learning Environment (GBM AGILE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3594. doi:10.1158/1538-7445.AM2017-3594