IMPORTANCE Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. OBJECTIVE To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. DESIGN, SETTING, AND PARTICIPANTS A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. INTERVENTIONS Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). MAIN OUTCOMES AND MEASURESThe primary outcome was a composite of tracheal intubation or mortality within 30 days. RESULTSThe trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, −8% [95% CI, −15% to −1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, −1% [95% CI, −8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group.CONCLUSIONS AND RELEVANCE Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings.

Background Both continuous positive airway pressure (CPAP) and high-flow nasal oxygenation (HFNO) have been recommended for acute respiratory failure in COVID-19. However, uncertainty exists regarding effectiveness and safety. Methods In the Recovery- Respiratory Support multi-center, three-arm, open-label, adaptive, randomized controlled trial, adult hospitalized patients with acute respiratory failure due to COVID-19, deemed suitable for treatment escalation, were randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Comparisons were made between each intervention and conventional oxygen therapy. The primary outcome was a composite of tracheal intubation or mortality within 30-days. Results Over 13-months, 1272 participants were randomized and included in the analysis (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). The need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). There was no difference between HFNO and conventional oxygen therapy (HFNO 184 of 414 participants (44.4%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85). Conclusions CPAP, compared with conventional oxygen therapy, reduced the composite outcome of intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. There was no effect observed, compared with conventional oxygen therapy, with the use of HFNO. (Funded by the UK National Institute for Health Research; ISRCTN 16912075).

Total word count including appendix: 93,499 ii ABSTRACT BackgroundThere is good evidence that therapist delivered interventions have modest beneficial effects for people with low back pain (LBP). Identification of subgroups of people with LBP who may benefit from these different treatment approaches is an important research priority. Aim and objectivesOverall aim was to improve the clinical and cost-effectiveness of LBP treatment by providing patients, their clinical advisors, and health service purchasers with better information about which participants are most likely to benefit from which treatment To achieve these objectives required substantial methodological work including the development and evaluation of some novel statistical approaches. This programme of work was not designed to analyse main effect of interventions and no such interpretations should be made.iii MethodsFirstly, we reviewed the literature on treatment moderators and subgroups. We initially invited investigators of trials of therapist-delivered interventions for LBP with >179 participants to share their data with us; some further smaller trials offered to us were also included. Using these trials we developed a repository of individual participant data of therapist delivered interventions for LBP. Using this dataset we sought to identify which participant characteristics, if any, predict response to different treatments (moderators) for clinical and cost effectiveness outcomes.We did an ANCOVA to identify potential moderators to apply in our main analyses.Subsequently we developed and applied three methods of subgroup identification; recursive partitioning (interaction trees and subgroup identification based on a differential effect search), adaptive risk group refinement, and an individual participant data indirect network meta-analysis to identify sub-groups defined by multiple parameters. ResultsWe included data from 19 randomised controlled trials with 9,328 participants (mean age 49 years, 57% females). Our prespecified analyses using recursive partitioning and adaptive risk group refinement performed well and allowed us to identify some subgroups. The differences in the effect size in the different subgroups were typically small, and unlikely to be clinically meaningful. Increasing baseline severity on the outcome of interest was the strongest driver of sub-group identification that we identified. Additionally we explored the application of Bayesian indirect network metaanalysis. This method produced varying probabilities that a particular treatment choice would be most likely to be effective for a specific patient profile. ConclusionThese data lack clinical or cost-effectiveness justification for the use of baseline characteristics in the development of subgroups for back pain. The methodological developments from this work have the potential to be applied in other clinical areas.iv The pooled repository database will serve as a valuable resource to the LBP research community. FundingFunding from the NIHR Programme Grants for Ap...

Background The PULSE (PostUraL tachycardia Syndrome Exercise) study is a randomised controlled trial assessing the feasibility of conducting a multicentre RCT testing supervised exercise rehabilitation with behavioural and motivational support, compared to best-practice usual care, for people with Postural Tachycardia Syndrome (PoTS). The original trial protocol was published in BMC Pilot & Feasibility Studies (accessible at 10.1186/s40814-020-00702-1). The PULSE intervention consists of (1) individual assessment; (2) 12-week, twice-weekly, supervised exercise training; (3) behavioural and motivational support; and (4) guided lifestyle physical activity. The control intervention is best-practice usual care with a single 30-min, one-to-one practitioner appointment, and general advice on safe and effective physical activity. Sixty-two people (aged 18–60 years) with a confirmed diagnosis of PoTS will be invited to enrol on a feasibility RCT with an embedded qualitative study. The primary outcome will be feasibility; process-related measures will include eligibility, recruitment, randomisation and withdrawal rates, along with indicators of exercise programme adherence and acceptability. Secondary physiological, clinical and health-related outcomes will be assessed. In response to the COVID-19 pandemic, here we describe amendments to the trial protocol. Methods Restrictions imposed by the COVID-19 pandemic meant it was necessary to change the delivery of the PULSE and control interventions. These changes reflected the need to limit the risk of COVID-19 transmission in a clinical population, some of whom were at increased risk of contracting the virus and suffering serious illness. The major change was that the originally intended centre-based PULSE and control interventions would now be delivered remotely on-line. Subsequently, there were minor changes to the participant eligibility criteria. These decisions followed an on-line co-creation session with people affected by PoTS, and relevant public and professional stakeholders. Conclusions We present an update of the original trial protocol in response to the COVID-19 pandemic. No participants were recruited to the original protocol; thus, results will reflect the on-line delivery of the intervention. PULSE will be the first randomised trial to assess the feasibility of conducting a definitive multi-centre RCT testing supervised on-line exercise rehabilitation with behavioural and motivational support, compared to best-practice usual care, for people with PoTS. Trial registration ISRCTN45323485 registered on 7 April 2020.