Nebulized recombinant tissue plasminogen activator (rt-PA) for acute COVID-19-induced severe respiratory failure: an exploratory proof of concept trial (preprint)

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeding events (one severe and three mild) in three patients were considered treatment-related. No significant fibrinogen reductions were reported. Greater improvement in mean P/F ratio from baseline to end of study was observed in C1 compared with MHC [C1; 154 to 299 vs MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in P/F ratio was observed in NIRS patients [NIRS; 126 to 240 vs IMV; 120 to 188) and they required fewer treatment days (NIRS; 7.86 vs IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, showing a trend of improved oxygenation and faster recovery in patients with acute COVID-19-induced respiratory failure requiring respiratory support; this effect was more pronounced in the NIRS group. Further investigation is required to study the potential of this novel treatment approach.

Statistical and Health Economic Analysis Plan Including COVID-19 Mitigation Strategy for the Physio4FMD Trial (preprint)

Background: Functional motor disorder (FMD) is a common cause of disabling neurological symptoms such as weakness and tremor. We are carrying out a pragmatic, multicentre single blind randomised controlled trial to evaluate effectiveness and cost effectiveness of specialist physiotherapy versus treatment as usual to improve physical functioning at 12 months. Like many other studies, this trial was affected by the COVID-19 pandemic, which interrupted the trial towards the end of planned recruitment. In this paper, we discuss (i) the impact of COVID-19 on the trial; (ii) the impact mitigation strategies implemented; and (iii) the planned statistical and health economic analysis methods and sensitivity analyses aimed at assessing the disrupting influence of COVID-19 on the trial. Methods The planned statistical and health economics analyses for this trial are described, as well as the sensitivity analyses designed to assess the disruption caused by COVID-19. The trial treatment of at least 89 participants (33%) was disrupted due to the pandemic response. To account for this, we have extended the trial to increase the sample size. We have identified four groups based on how participants’ involvement in Physio4FMD was affected; A: 24 were unaffected; B: 131 received their trial-treatment before the start of the COVID-19 pandemic and were followed up during the pandemic; C: 89 were recruited in early 2020 and had not received any randomised treatment before clinical services closed because of COVID-19; D: participants recruited after the trial was restarted in July 2021 (target 90 to 120). The primary analysis will involve groups A, B and D. Regression analysis will be used to assess treatment effectiveness. We will conduct descriptive statistics for each of the groups identified and sensitivity regression analyses with participants from all groups, including group C, separately. Discussion The COVID-19 mitigation strategy and analysis plans are designed to maintain the integrity of the trial while providing meaningful results. By publishing our analysis plans ahead of database lock, analysis and unblinding, we aim to avoid bias due to data-driven analysis. Trial registration : The trial was registered with the ISRCTN register on 27/03/2018, number ISRCTN56136713.