Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

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.

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL-286, a novel retinoic acid receptor-ß agonist for treatment of spinal cord injury, in male healthy participants.

AIMS: KCL-286 is an orally available agonist that activates the retinoic acid receptor (RAR) ß2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL-286 in male healthy volunteers to establish dosing to be used in the SCI patient population. METHODS: The design was a double blind, randomized, placebo-controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARß2 mRNA expression was evaluated in white blood cells. RESULTS: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration-time curve up to 24 h showing a trend to subproportionality with dose. RARß2 was upregulated by the investigational medicinal product in white blood cells. CONCLUSION: KCL-286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL-286 as a novel oral treatment for SCI.

Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial.

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.

A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol.

BACKGROUND: Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma. METHODS/DESIGN: Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom. TRIAL REGISTRATION: ISRCTN84434175. Registered 12 November 2018.

Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples.

BACKGROUND: Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. METHODS: The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant's dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies. RESULTS: In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians' time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion. CONCLUSION: Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.

Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review.

BACKGROUND: Cancer prognostic biomarkers have shown disappointing clinical applicability. The objective of this study was to classify and estimate how study results are overinterpreted and misreported in prognostic factor studies in oncology. METHODS: This systematic review focused on 17 oncology journals with an impact factor above 7. PubMed was searched for primary clinical studies published in 2015, evaluating prognostic factors. We developed a classification system, focusing on three domains: misleading reporting (selective, incomplete reporting, misreporting), misleading interpretation (unreliable statistical analysis, spin) and misleading extrapolation of the results (claiming irrelevant clinical applicability, ignoring uncertainty). RESULTS: Our search identified 10,844 articles. The 98 studies included investigated a median of two prognostic factors (Q1-Q3, 1-7). The prognostic factors' effects were selectively and incompletely reported in 35/98 and 24/98 full texts, respectively. Twenty-nine articles used linguistic spin in the form of strong statements. Linguistic spin rejecting non-significant results was found in 34 full-text results and 15 abstract results sections. One in five articles had discussion and/or abstract conclusions that were inconsistent with the study findings. Sixteen reports had discrepancies between their full-text and abstract conclusions. CONCLUSIONS: Our study provides evidence of frequent overinterpretation of findings of prognostic factor assessment in high-impact medical oncology journals.

Adaptive designs in clinical trials: why use them, and how to run and report them.

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial's course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

Neurodevelopmental outcome of nutritional intervention in newborn infants at risk of neurodevelopmental impairment: the Dolphin neonatal double-blind randomized controlled trial.

AIM: To investigate whether neonates at risk for neurodevelopmental impairment have improved neurodevelopment after docosahexaenoic acid, choline, and uridine-5-monophosphate supplementation versus controls. METHOD: Recruitment was from UK neonatal units. Eligible for inclusion were infants born at less than 31 weeks' gestation with a weight less than the ninth centile; infants born at less than 31 weeks' gestation with a grade II or higher intraventricular haemorrhage/preterm white matter injury; infants born between 31 weeks' and 40 weeks' gestation plus 28 days with a grade II or higher intraventricular haemorrhage/preterm white matter injury, moderate or severe hypoxic-ischaemic encephalopathy, or defined neuroimaging abnormalities. Treatment/control supplementation was for 2 years (double-blind, randomized, controlled design). Infants were stratified according to sex, gestation, and brain injury severity. Primary outcome was cognitive composite score (CCS) of the Bayley Scales of Infant Development, Third Edition (Bayley-III at 24mo). Secondary outcomes were language composite score (LCS) of the Bayley-III, motor composite score (MCS) of the Bayley-III, and Vineland Adaptive Behaviour Scales, Second Edition (VABS-II) score. RESULTS: Sixty-two neonates were recruited, 59 were randomized (34 males, 25 females). Fifty-three started supplementation. Most families found supplementation acceptable. The treatment group CCS-Bayley-III scores were non-significantly higher than controls (mean score difference at 24mo: 9.0; 95% confidence interval -0.2 to 18.2). Language and VABS-II scores, but not motor score, were non-significantly higher in the treatment group. INTERPRETATION: Most families found supplementation feasible. Improved neurodevelopmental outcomes in the treatment group were not statistically significant. A larger multicentre trial exploration is warranted. WHAT THIS PAPER ADDS: Dietary supplementation of neonates at risk of neurodevelopmental impairment is feasible. No statistically significant neurodevelopmental advantages were identified for the treatment group compared to controls. Treatment group cognitive and language advantage are of a clinically meaningful magnitude.

Efficacy of ß blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis.

BACKGROUND: Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. ß blockers are indicated in patients with symptomatic heart failure with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of ß blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation. METHODS: We extracted individual-patient data from ten randomised controlled trials of the comparison of ß blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov, number NCT0083244, and PROSPERO, number CRD42014010012. FINDINGS: 18,254 patients were assessed, and of these 13,946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13,945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. ß-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67-0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83-1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy. INTERPRETATION: Based on our findings, ß blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. FUNDING: Menarini Farmaceutica Internazionale (administrative support grant).

Interventions to reduce waiting times for elective procedures.

BACKGROUND: Long waiting times for elective healthcare procedures may cause distress among patients, may have adverse health consequences and may be perceived as inappropriate delivery and planning of health care. OBJECTIVES: To assess the effectiveness of interventions aimed at reducing waiting times for elective care, both diagnostic and therapeutic. SEARCH METHODS: We searched the following electronic databases: Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946-), EMBASE (1947-), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), ABI Inform, the Canadian Research Index, the Science, Social Sciences and Humanities Citation Indexes, a series of databases via Proquest: Dissertations & Theses (including UK & Ireland), EconLit, PAIS (Public Affairs International), Political Science Collection, Nursing Collection, Sociological Abstracts, Social Services Abstracts and Worldwide Political Science Abstracts. We sought related reviews by searching the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effectiveness (DARE). We searched trial registries, as well as grey literature sites and reference lists of relevant articles. SELECTION CRITERIA: We considered randomised controlled trials (RCTs), controlled before-after studies (CBAs) and interrupted time series (ITS) designs that met EPOC minimum criteria and evaluated the effectiveness of any intervention aimed at reducing waiting times for any type of elective procedure. We considered studies reporting one or more of the following outcomes: number or proportion of participants whose waiting times were above or below a specific time threshold, or participants' mean or median waiting times. Comparators could include any type of active intervention or standard practice. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from, and assessed risk of bias of, each included study, using a standardised form and the EPOC 'Risk of bias' tool. They classified interventions as follows: interventions aimed at (1) rationing and/or prioritising demand, (2) expanding capacity, or (3) restructuring the intake assessment/referral process.For RCTs when available, we reported preintervention and postintervention values of outcome for intervention and control groups, and we calculated the absolute change from baseline or the effect size with 95% confidence interval (CI). We reanalysed ITS studies that had been inappropriately analysed using segmented time-series regression, and obtained estimates for regression coefficients corresponding to two standardised effect sizes: change in level and change in slope. MAIN RESULTS: Eight studies met our inclusion criteria: three RCTs and five ITS studies involving a total of 135 general practices/primary care clinics, seven hospitals and one outpatient clinic. The studies were heterogeneous in terms of types of interventions, elective procedures and clinical conditions; this made meta-analysis unfeasible.One ITS study evaluating prioritisation of demand through a system for streamlining elective surgery services reduced the number of semi-urgent participants waiting longer than the recommended time (< 90 days) by 28 participants/mo, while no effects were found for urgent (< 30 days) versus non-urgent participants (< 365 days).Interventions aimed at restructuring the intake assessment/referral process were evaluated in seven studies. Four studies (two RCTs and two ITSs) evaluated open access, or direct booking/referral: One RCT, which showed that open access to laparoscopic sterilisation reduced waiting times, had very high attrition (87%); the other RCT showed that open access to investigative services reduced waiting times (30%) for participants with lower urinary tract syndrome (LUTS) but had no effect on waiting times for participants with microscopic haematuria. In one ITS study, same-day scheduling for paediatric health clinic appointments reduced waiting times (direct reduction of 25.2 days, and thereafter a decrease of 3.03 days per month), while another ITS study showed no effect of a direct booking system on proportions of participants receiving a colposcopy appointment within the recommended time. One RCT and one ITS showed no effect of distant consultancy (instant photography for dermatological conditions and telemedicine for ear nose throat (ENT) conditions) on waiting times; another ITS study showed no effect of a pooled waiting list on the number of participants waiting for uncomplicated spinal surgery.Overall quality of the evidence for all outcomes, assessed using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) tool, ranged from low to very low.We found no studies evaluating interventions to increase capacity or to ration demand. AUTHORS' CONCLUSIONS: As only a handful of low-quality studies are presently available, we cannot draw any firm conclusions about the effectiveness of the evaluated interventions in reducing waiting times. However, interventions involving the provision of more accessible services (open access or direct booking/referral) show some promise.

Self-harm in people with epilepsy: a retrospective cohort study.

OBJECTIVES: Little is known about self-harm in people with epilepsy, despite suicide being recognized as a leading cause of mortality in this population. This study aimed to investigate the characteristics of self-harm in people with epilepsy, and associated demographic and psychosocial factors. METHODS: Patients presenting to hospital following self-harm between 1994 and 2008 were identified from the Oxford Monitoring System for Self-Harm. Epilepsy diagnosis was confirmed through review of medical records. Demographic features, patient, and self-harm characteristics of 132 people with epilepsy and 9,778 self-harm patients without epilepsy were compared using a regression model, adjusting for age, sex, and repetition. Patients presenting between 1998 and 2008 were followed up for all-cause mortality to the end of 2011. RESULTS: The rate of self-harm per individual with epilepsy was 2.04 (95% confidence interval [CI] 1.85-2.25) times that of the comparison group, and time between first and second self-harm events was shorter (hazard ratio 1.86; 1.46-2.38). People with epilepsy were significantly more likely to use antiepileptic medication in overdose, although overall methods of self-harm were similar in the two groups. No significant differences in suicide intent scores or the proportion of patients who died by suicide were found. Previous outpatient psychiatric treatment, longer duration of unemployment, experience of violence, and housing problems were associated with self-harm in people with epilepsy. SIGNIFICANCE: People with epilepsy who self-harm do so more frequently than other self-harm patients. Clinicians should be aware of this and pay attention to contributory factors as these may enhance risk in this population. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Statistical analysis plan for the TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation of potentially clinically significant prostate cancer) multicentre randomised controlled trial.

BACKGROUND: The TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation) trial assesses the clinical and cost-effectiveness of two biopsy procedures in terms of detection of clinically significant prostate cancer (PCa). This article describes the statistical analysis plan (SAP) for the TRANSLATE randomised controlled trial (RCT). METHODS/DESIGN: TRANSLATE is a parallel, superiority, multicentre RCT. Biopsy-naïve men aged ≥ 18 years requiring a prostate biopsy for suspicion of possible PCa are randomised (computer-generated 1:1 allocation ratio) to one of two biopsy procedures: transrectal (TRUS) or local anaesthetic transperineal (LATP) biopsy. The primary outcome is the difference in detection rates of clinically significant PCa (defined as Gleason Grade Group ≥ 2, i.e. any Gleason pattern ≥ 4 disease) between the two biopsy procedures. Secondary outcome measures are th eProBE questionnaire (Perception Part and General Symptoms) and International Index of Erectile Function (IIEF, Domain A) scores, International Prostate Symptom Score (IPSS) values, EQ-5D-5L scores, resource use, infection rates, complications, and serious adverse events. We describe in detail the sample size calculation, statistical models used for the analysis, handling of missing data, and planned sensitivity and subgroup analyses. This SAP was pre-specified, written and submitted without prior knowledge of the trial results. DISCUSSION: Publication of the TRANSLATE trial SAP aims to increase the transparency of the data analysis and reduce the risk of outcome reporting bias. Any deviations from the current SAP will be described and justified in the final study report and results publication. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN98159689, registered on 28 January 2021 and registered on the ClinicalTrials.gov (NCT05179694) trials registry.

Cost-utility analysis of molnupiravir plus usual care versus usual care alone as early treatment for community-based adults with COVID-19 and increased risk of adverse outcomes in the UK PANORAMIC trial.

BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over six months. DESIGN AND SETTING: Economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK National Health Service and personal social services perspective and a six-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] 445 to 453) and higher mean QALYs of 0.0055 (95% CI 0.004 to 0.007) than usual care (mean incremental cost per QALY of £81190). Sensitivity and subgroup analyses showed similar results, except those aged ≥75 years with a 55% probability of being cost-effective at a £30000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15000 per QALY threshold. CONCLUSION: Molnupiravir at the current cost of £513 per course is unlikely to be cost-effective relative to usual care over a six-month time horizon among mainly vaccinated COVID-19 patients at increased risk of adverse outcomes, except those aged ≥75 years.

Time trends in biological fertility in Western Europe.

We investigated trends in biological fertility in a comprehensive analysis of 5 major European data sets with data on time to pregnancy (TTP) and proportion of contraceptive failures. In particular, we distinguished a period effect from a birth cohort effect (lifelong tendency) in both sexes. Attempts at conception not resulting in birth were excluded. We analyzed data on pregnancies occurring in 9,247 couples between 1953 and 1993 and performed sensitivity analyses to check the robustness of findings. Separate analyses of each time effect showed an increasing fertility trend. Mutually adjusted analyses demonstrated that this rise was visible as a male cohort effect for both TTP and contraceptive failure. On the other hand, the female birth cohort effect showed a slight fall in the first half of the study period for both TTP and contraceptive failure. As a period effect, fertility remained generally stable, the slight trends in TTP and contraceptive failure being in opposite directions, likely indicating an artifact. The rising trend accords with most previous evidence. The increasing trend in male fertility does not contradict the previously reported semen quality deterioration, the effects of which are calculated to be small. The declining female fertility accords with a falling dizygotic twinning rate during the same period.

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease.

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.

Visualising harms in publications of randomised controlled trials: consensus and recommendations.

OBJECTIVE: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes. DESIGN: Consensus study. SETTING: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ. PARTICIPANTS: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians. MAIN OUTCOME: measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached. RESULTS: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. CONCLUSIONS: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles.

Effect of moderate to high intensity aerobic exercise on blood pressure in young adults: The TEPHRA open, two-arm, parallel superiority randomized clinical trial.

Background: Exercise is advised for young adults with elevated blood pressure, but no trials have investigated efficacy at this age. We aimed to determine whether aerobic exercise, self-monitoring and motivational coaching lowers blood pressure in this group. Methods: The study was a single-centre, open, two-arm, parallel superiority randomized clinical trial with open community-based recruitment of physically-inactive 18-35 year old adults with awake 24 h blood pressure 115/75mmHg-159/99 mmHg and BMI<35 kg/m2. The study took place in the Cardiovascular Clinical Research Facility, John Radcliffe Hospital, Oxford, UK. Participants were randomized (1:1) with minimisation factors sex, age (<24, 24-29, 30-35 years) and gestational age at birth (<32, 32-37, >37 weeks) to the intervention group, who received 16-weeks aerobic exercise training (three aerobic training sessions per week of 60 min per session at 60-80% peak heart rate, physical activity self-monitoring with encouragement to do 10,000 steps per day and motivational coaching to maintain physical activity upon completion of the intervention. The control group were sign-posted to educational materials on hypertension and recommended lifestyle behaviours. Investigators performing statistical analyses were blinded to group allocation. The primary outcome was 24 h awake ambulatory blood pressure (systolic and diastolic) change from baseline to 16-weeks on an intention-to-treat basis. Clinicaltrials.gov registered on March 30, 2016 (NCT02723552). Findings: Enrolment occurred between 30/06/2016-26/10/2018. Amongst the 203 randomized young adults (n = 102 in the intervention group; n = 101 in the control group), 178 (88%; n = 76 intervention group, n = 84 control group) completed 16-week follow-up and 160 (79%; n = 68 intervention group, n = 69 control group) completed 52-weeks follow-up. There were no group differences in awake systolic (0·0 mmHg [95%CI, -2·9 to 2·8]; P = 0·98) or awake diastolic ambulatory blood pressure (0·6 mmHg [95%CI, -1·4. to 2·6]; P = 0·58). Aerobic training increased peak oxygen uptake (2·8 ml/kg/min [95%CI, 1·6 to 4·0]) and peak wattage (14·2watts [95%CI, 7·6 to 20·9]) at 16-weeks. There were no intervention effects at 52-weeks follow-up. Intepretation: These results do not support the exclusive use of moderate to high intensity aerobic exercise training for blood pressure control in young adults. Funding: Wellcome Trust, British Heart Foundation, National Institute for Health Research, Oxford Biomedical Research Centre.

Randomised phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer (OCTOVA): a study protocol.

INTRODUCTION: Patients relapsing within 12 months of platinum-based chemotherapy usually have a poorer response to subsequent treatments. To date, extensive research into the mechanism of resistance to platinum agents in the treatment of ovarian cancer has not resulted in improved responses or longer survival. Further experimental work and clinical trials with novel agents are therefore justified to address this unmet need.Patients with ovarian, fallopian tube or primary peritoneal cancer that has relapsed within 12 months of platinum-based chemotherapy will be randomised with stratification for BReast CAncer gene (BRCA) status, prior poly (ADP-ribose) polymerase (PARP) exposure and prior antiangiogenic therapy into weekly paclitaxel (chemotherapy), olaparib or the combination of cediranib and olaparib. They will be followed until disease progression or unacceptable toxicity develops. Our trial design permits two investigations. We will compare the efficacy and tolerability of single-agent olaparib with weekly paclitaxel. We will also compare the efficacy and tolerability of olaparib with the combination of olaparib and cediranib. The required sample size of 138 participants (46 per arm) was calculated using a 20% one-sided type I error, 80% power and 15% dropout rate. Recruitment will last 34 months with a follow-up of 18 months. METHODS AND ANALYSIS: ETHICS AND DISSEMINATION: This study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency Clinical Trials Authorisation. Approval to conduct the study was obtained from the responsible authority before beginning the study. The sponsor will retain ownership of all data arising from the trial. We aim to publish this research in a specialist peer-reviewed scientific journal on study completion. EudraCT number: 2016-000559-28, ethics reference number: 16/LO/2150. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN14784018, clinicaltrials.gov: NCT03117933; Pre-results.

A multicentre retrospective review of SABR reirradiation in rectal cancer recurrence.

BACKGROUND AND PURPOSE: Locally recurrent rectal cancer (LRRC) is associated with considerable morbidity, poor quality of life and an overall survival of 9 months. The non-operative treatment of LRRC is an understudied area, there is no consensus on management in this setting. We aim to perform a retrospective, multicentre analysis of patients treated with SABR reirradiation. MATERIALS AND METHODS: All patients were identified who received SABR re-irradiation for LRRC, at 3 UK centres, between August 2015 and September 2020. Eligible patients had pelvic recurrence and were either not suitable/opted not for surgery, or margin positive after exenturative surgery. Patients were treated with 30 Gy in 5 fractions and followed up with clinical review and CT scan at 3, 6, 12, 18 and 24 months. RESULTS: 69 patients with 81 lesions were identified and median follow up was 28 months. Median progression free survival (PFS) and overall survival (OS) were 12.1 months (10.4, 17.7) and 38.7 months (28.9,-) respectively. 2-year OS was 0.77 (0.66, 0.89). 58.3% of deaths were as a result of consequences of local relapse. 42.6% of patients had local relapse at death or last follow up. CONCLUSION: Our outcomes are encouraging for a population who had R1 resections, refused or were refused surgery; as they are similar to those in surgical series. Prospective data including details of survival, local relapse and QOL; with an optimised SABR technique, is required to establish SABR as an alternative to surgery.