Blockade of Interleukin Seventeen (IL-17A) with Secukinumab in Hospitalized COVID-19 patients – the BISHOP study
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
Background
Patients with severe COVID-19 seem to have a compromised antiviral response and hyperinflammation. Neutrophils are critical players in COVID-19 pathogenesis. IL-17A plays a major role in protection against extracellular pathogens and neutrophil attraction and activation. We hypothesized that secukinumab, an anti-IL17A monoclonal antibody, could mitigate the deleterious hyperinflammation in COVID-19.
Methods
BISHOP was an open-label, single-center, phase-II controlled trial. Fifty adults hospitalized Covid-19 patients, confirmed by a positive SARS-CoV-2 RT-PCR, were randomized 1:1 to receive 300mg of secukinumab subcutaneously at day-0 (group A) plus standard of care (SoC: antiviral drugs, antimicrobials, corticosteroids, and/or anticoagulants) or SoC alone (group B). A second dose of 300mg of secukinumab could be administered on day-7, according to staff judgment. The primary endpoint was ventilator-free days at day-28 (VFD-28). Secondary efficacy and safety outcomes were also explored.
Findings
An intention-to-treat analysis showed no difference in VFD-28: 23.7 (95%CI 19.6-27.8) in group A vs. 23.8 (19.9-27.6) in group B, p=0.62; There was also no difference in hospitalization time, intensive care unit demand, the incidence of circulatory shock, acute kidney injury, fungal or bacterial co-infections, and severe adverse events. Pulmonary thromboembolism was less frequent in group A (4.2% vs. 26.2% p=0.04). There was one death in each group. Viral clearance, defined by the viral load fold change (2-ΔΔCT) in upper airways, between day-0 and day-7, was also similar: 0.17 (0.05-0.56) in group A vs. 0.24 (0.10-0.57) in group B.
Interpretation
The efficacy of secukinumab in the treatment of Covid19 was not demonstrated. No difference between groups in adverse events and no unexpected events were observed.
Funding
Novartis Brazil supported this research providing expert input in the development of the project, drug supply, data management, and monitoring.
Article activity feed
-
SciScore for 10.1101/2021.07.21.21260963: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by the National Research Ethics Commission – CONEP (approval number 4.100.115, on June 20th, 2020) and was registered at the Brazilian Registry of Clinical Trials – ReBEC (RBR-5vpyh4, on June 6th, 2020).
Consent: The informed consent form (ICF) was applied to all patients or their legal guardians for patients unable due to their medical condition.Sex as a biological variable not detected. Randomization Randomization and procedures: Enrolled patients were sequentially subjected to block randomization to receive 300 mg of secukinumab subcutaneously at day-0 plus standard of care (SoC) Blinding not detected. Power Analysis The minimum sample size to achieve 80% power to … SciScore for 10.1101/2021.07.21.21260963: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by the National Research Ethics Commission – CONEP (approval number 4.100.115, on June 20th, 2020) and was registered at the Brazilian Registry of Clinical Trials – ReBEC (RBR-5vpyh4, on June 6th, 2020).
Consent: The informed consent form (ICF) was applied to all patients or their legal guardians for patients unable due to their medical condition.Sex as a biological variable not detected. Randomization Randomization and procedures: Enrolled patients were sequentially subjected to block randomization to receive 300 mg of secukinumab subcutaneously at day-0 plus standard of care (SoC) Blinding not detected. Power Analysis The minimum sample size to achieve 80% power to detect an increase of 5.5 days in the VFD-28 was 25 patients per group. Table 2: Resources
Software and Algorithms Sentences Resources Data were collected using the Research Electronic Data Capture (REDCap) database (https://www.project-redcap.org). REDCapsuggested: (REDCap, RRID:SCR_003445)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This study had some limitations. It was open-label with a small sample size. The sample size was calculated based on the risk of intubation and death observed at the beginning of the epidemic in Brazil. When inclusions started in September 2020, all patients were already taking corticosteroids because of its benefits in oxygen-dependent COVID-19 patients (36). Possibly, this issue improved the challenge to show the significant effects of an anti-inflammatory intervention on top of steroid use. In fact, smaller studies with another anti-cytokine therapy (anti-IL-6R) have also reported no improvement in COVID-19 patients, while two larger trials clearly showed a benefit (37). Furthermore, the optimal dose, route of administration, and timing of secukinumab to ensure therapeutic tissue concentrations in COVID-19 are unknown. The dose regimen chosen in this study was the maximum weekly dose, currently approved for other indications. In conclusion, secukinumab exhibited a satisfactory safety profile in severe COVID-19 patients. Although the blockade of anti-IL-17A with secukinumab appears not to show a clear benefit, compared to the standard of care, in the context of COVID-19 pulmonary failure, there was a significant reduction of pulmonary thromboembolism. Larger clinical trials of secukinumab in COVID-19 may be warranted.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
-
