RESULTS
A Unified Toolbox for Adaptive Platform Trials Across Therapeutic Areas
The Adaptive Platform Trial toolbox aims at collecting the accumulated knowledge, experience, and resources (collectively names as “tools”) from multiple projects and trials in a disease-agnostic manner into a practical and guided toolbox to facilitate the design and conduct of adaptive platform trials. The toolbox is a practical selection of tools deemed to be reflective of the requirements and challenges within the current clinical research environment. This toolbox will help clinical researchers develop new adaptive platform trials in any therapeutic area and train clinical research personnel.
Link to the toolbox:
JAK Inhibitors for COVID-19: New Insights from an Individual Participant Data Meta-Analysis
Clinical guidelines have varied in interpreting evidence on JAK inhibitors for adults hospitalized due to COVID-19. Previous systematic reviews pooled six randomized trials, showing clinical benefits, but emphasized the need for more high-quality data especially regarding safety and certain subgroups.
This study, published in The Lancet Respiratory Medicine and initiated by EU-RESPONSE, analyzed data from 12 trials, revealing significant survival benefits, faster hospital discharge, and reduced need for respiratory support. No credible effect modifications were found across key subgroups, except for age, whereby younger patients experienced larger relative benefits. Concerns about safety in vaccinated individuals were also refuted.
With over 96% of global trial data on this topic included, this study provides the most comprehensive evidence. It also highlights the need for timely data sharing to influence clinical guidelines in real-time – as emphasized by the accompanying editorial.
Link to the article published in The Lancet Respiratory Medicine :
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(25)00055-4/fulltext
sST2 is a Key outcome Biomarker in COVID-19: Insights from Discovery Randomized Trial
We investigated whether baseline levels of biomarkers related to endotheliopathy, thromboinflammation, and fibrosis were associated with clinical outcomes in hospitalized COVID-19 patients. We analyzed the associations between baseline levels of 21 biomarkers and time to hospital discharge and change in NEWS-2 score in patients from DisCoVeRy trial. We fitted multivariate models adjusted for baseline ISARIC 4C score, disease severity, D-dimer values, and treatment regimen. Between March 22 and June 29, 2020, 603 participants were randomized; 454 had a sample collected at baseline and analyzed. The backward selection of multivariate models showed that higher baseline levels of soluble suppressor of tumorigenicity 2 (sST2) and nucleosomes were statistically associated with a lower chance of hospital discharge before day 29 (sST2: aHR 0.24, 95% CI [0.15-0.38], p < 10-9; nucleosomes: aHR 0.62, 95% CI [0.48-0.81], p < 10-3). Likewise, higher levels of baseline sST2 were statistically associated with lower changes in the NEWS-2 score between baseline and day 15 (adjusted beta 4.47, 95% CI [2.65-6.28], p < 10-5). Moreover, we evaluated sST2 involvement in a confirmation cohort (SARCODO study, 103 patients) and found that elevated baseline sST2 levels were significantly associated with lower rates of hospital discharge before day 29 and a higher model performance (AUC at day 29 of 92%) compared to models without sST2. sST2 emerged as an independent predictor of clinical outcomes in two large cohort of hospitalized COVID-19 patients, warranting further investigation to elucidate its role in disease progression and potential as a therapeutic target.
Link to the article published in Scientific Reports :
Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial
There is ongoing need to urgently address the mAb treatment gap, particularly for immunocompromised patients. The unmet need is further highlighted by the DisCoVeRy Phase 3, adaptive, multicenter European, randomized, double-blind, superiority trial that evaluated the efficacy and safety of intravenous T-C in SARS-CoV-2 antigenic positive patients (i.e. those with a high SARS- CoV-2 viral load) hospitalized with COVID-19 and followed-up to day 90.
Link to the article:
Cardiac Adverse Events and Remdesivir in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19): A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial
The study aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) receiving remdesivir plus standard of care (SoC) compared to SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases.
Link to the article:
Association between SARS-CoV-2 viral kinetics and clinical score evolution in hospitalized patients
The role of antiviral treatment in COVID-19 hospitalized patients remains controversial. In this study, we analyzed nasopharyngeal viral load and the clinical score of patients (as measured by the National Early Warning Score 2 (NEWS-2)) in the DisCoVeRy trial, where 664 patients were randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to model the evolution of viral dynamics and its potential impact on clinical evolution, and to model the impact of effective antiviral treatment on clinical evolution.
Simulations predicted that antiviral activity greater than 99% could reduce the time to clinical improvement by 2 days in patients with high viral loads, regardless of the NEWS2 score on admission. While no clinically substantial effect was predicted in patients with low viral loads, these results suggest that highly potent antivirals could accelerate clinical improvement in hospitalized patients with high viral loads.
This study provides new insights into the potential role of antiviral treatment in hospitalized COVID-19 patients.
Link to the article:
Ensuring quality control in a COVID-19 clinical trial during the pandemic: The experience of the Inserm C20–15 DisCoVeRy study
The study Sponsor is responsible for ensuring participants’ safety and reliability of the data collected, in particular through the monitoring carried out in the investigating centers. This article presents the experience of quality control assurance in the context of the SARS-Cov2 pandemic and its multiple associated constraints.
Link to the article:
Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial
During a pandemic crisis, sponsors should educate and train investigators about the importance of the pharmacovigilance issues.
•The assessment of the safety profile of the investigational medicinal drug is crucial in a clinical trial related to a health crisis, but needs to be adapted.
•In a pandemic crisis: the right balance must be found between collecting a lot of data and taking into account the investigators’ lack of time to provide these data.
•The added value of this work is that the management of safety during a clinical trial in the event of a pandemic needs to be simplified, pragmatic and prioritized to avoid increasing the workload of study staff and site investigators
Link to the article:
https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.1072
Results of the EU-SolidAct Adaptive Platform Trial of Baricitinib as a Treatment for Hospitalized COVID-19 Patients Published in Critical Care Journal
EU-SolidAct is an Adaptive Platform Trial developed to evaluate drug interventions in hospitalized patients with COVID-19 and to facilitate a joint European response to future pandemics, as part of EU-RESPONSE. The first drug tested on this platform is baricitinib, a tablet approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. Results of the Bari-SolidAct clinical trial, conducted in 14 European countries, have been published in Critical Care on January 10th 2023. While this trial was stopped early due to external evidence and is therefore underpowered to assess survival benefit, we observed a possible safety signal in vaccinated participants, who were older with more comorbidities.
Link to the article published in Critical CARE Journal :
https://pubmed.ncbi.nlm.nih.gov/36627655/
The EMA application for baricitinib was recently withdrawn.
https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/olumiant
Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial
The use of remdesivir has been associated to contradictory virological and clinical results in the past months. Here, we analyzed its effect on viral dynamics in the DisCoVeRy trial, where 665 patients were randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct virological profiles and to estimate the antiviral efficacy of remdesivir in reducing viral production.
Using this model, we showed that remdesivir has a significant antiviral activity, reducing the amount of viral particles released by infected cells by a 2-fold factor on average. Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average.
In conclusion our results reconciliate the contradictory findings of the literature, demonstrating that remdesivir has an antiviral activity, albeit too limited to generate, as a monotherapy, a clinical effect.
Link to the article published in the Journal of Antimicrobial Chemotherapy :
https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac048/6540540?searchresult=1
Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial
Data from 832 patients hospitalized between March 2020 and January 2021, recruited in 5 European countries (418 patients receiving standard of care and 414 additionally receiving remdesivir), were analyzed. The analysis has shown no difference between the two groups in patient clinical status 15 and 29 days after receipt of the first remdesivir dose, in time to discharge from hospital, and in death rate on Day 28. There was also no demonstrated difference between the groups in terms of speed of elimination of the virus at nasopharyngeal level. Severe side effects were distributed similarly between the two groups. These data support those of the Solidarity trial conducted by the WHO, in particular by providing results on a larger number of endpoints.
Link to the article published in the The Lancet Infectious Diseases :
Remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1 have finally little or no effect on hospitalized patients with Covid-19 and are not recommended in severe forms of the disease.
They don’t decrease the risk of mortality, the need of ventilation, and the duration of hospital stay. Those conclusions are issued after data analysis of 11,330 adults included in the Solidarity trial (including Discovery trial). They were hospitalized in 405 different hospitals in 30 countries.
In total, 1253 deaths were reported between 4 to 14 days after randomisation with a 11,8% rate of mortality at 28 days. This risk depended on several factors, particularly age (20.4% if ≥70 years and 6.2% if <50 years) and ventilation status (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise).
Compared with the group with no trial drugs, the ones receiving remdesivir, hydroxychloroquine, lopinavir or interferon didn’t show any improvement regarding mortality or initiation of ventilation. They neither reduced the duration of hospital stay, which suggests that none of the four treatments has a pharmacologic effect to substantially reduce time to recovery. Those results were consistent overall or in any particular subgroup of age, sex, or health condition.
This trial proves the lack of efficacy for those four repurposed antivirals in reducing COVID-19 mortality, refuting early hopes for those treatments, initially based on smaller or nonrandomized studies.
Articles:
Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results
NEJM DOI: 10.1056/NEJMoa2023184
Antiviral drugs in hospitalized patients with COVID-19 – the DisCoVeRy trial
doi: https://doi.org/10.1101/2021.01.08.20248149