REcovery and SURvival of patients with moderate to severe acute REspiratory distress syndrome (ARDS) due to COVID-19: a multicentre, single-arm, Phase IV Itolizumab Trial: RESURRECT

Abstract

Objective

To evaluate safety and efficacy of Itolizumab in hospitalized COVID-19 patients with PaO ₂ /FiO ₂ ratio (PFR) ≤200 requiring oxygen therapy.

Design

A multicentre, single-arm, Phase-4 study with a treatment period of 30-Days and an extended follow-up period of 90-Days.

Methods

Hospitalized adult patients (n=300) with SARS-CoV-2 infection, with PFR ≤200; oxygen saturation ≤94% and ≥1 elevated inflammatory markers were included from 17 COVID-19-specific tertiary hospitals in India. Patients received Itolizumab infusion 1.6 mg/kg and were assessed for 1-month and then followed up to Day-90.

Results

Day-30 post-treatment safety/efficacy results and Day-90 mortality results are presented. Primary outcome measures: incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) was 1.3% and mortality rate at 1-month was 6.7% (n=20/300). Key secondary analyses: Mortality rate at Day-90 was 8.0% (24/300). 91.7% patients came off the oxygen therapy within Day-30 of treatment. By Day-7, most patients had stable/improved SpO ₂ without increasing FiO ₂ . Mean PFR improved by 50% by Day-7 (p<0.001) and the trend remained consistent till Day-30. Median time of recovery was 8 days. Cumulatively, at Day-30, 260(86.7%), 256(85.3%), 132(44.0%), 113(37.6%) and 32(10.7%) patients showed >1-point, >2-point, >3-point, >4-point and 5-point improvement on the modified COVID-19 8-point ordinal scale and worsening of symptoms by >1 point, >2 points and 3-points was seen in 26(8.7%), 20(6.7%) and 6(2.0%) patients, respectively. CRP, D-dimer, LDH, and serum ferritin levels significantly decreased (p≤0.01) compared with baseline. IL-6 and TNFα levels also decreased 48-hours post-infusion. Overall, 123 treatment-emergent adverse events (TEAEs) were reported in 63 patients, most being Grades 1-3. Most common TEAEs were IRRs and lymphopenia; most common serious TEAEs were septic shock, worsening of ARDS, and respiratory failure. No deaths were attributable to Itolizumab.

Conclusion

Itolizumab shows no new safety concerns and suggests a mortality and recovery benefit at 1-month in hospitalized COVID-19 patients requiring oxygen therapy.

Trial registry number

CTRI/2020/09/027941

SciScore for 10.1101/2021.10.25.21265462: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	Field Sample Permit: This study was carried out following the ethical principles described in the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013), the International Council for Harmonization Good Clinical Practice (ICH GCP) E6 (R2), New Drugs and Clinical Trials Rule-2019 issued by the Government of India and ethical guidelines for biomedical research on human subjects issued by the Indian Council of Medical Research. IRB: The study received approvals from the Independent Ethics Committees of all the participating sites. Consent: The patients provided written informed consent before the initiation of study procedures.
Sex as a biological variable	Study participants: The following patients were included in the study: Adult male or female patients with confirmed virologic diagnosis of SARS-CoV-2 infection (reverse transcriptase-polymerase chain reaction/rapid antigen test/equivalent), hospitalized with moderate-to-severe ARDS due to worsening of COVID-19 as defined by PFR ratio of ≤200 with oxygen saturation at ≤94% at rest in ambient air or requiring supplemental oxygen therapy with one or more inflammatory markers (serum ferritin, LDH, D-dimer, CRP or IL-6) raised above the upper limit of normal.
Randomization	not detected.
Blinding	not detected.
Power Analysis	not detected.

Table 2: Resources

Antibodies
Sentences	Resources
Patients with known severe allergic reactions to monoclonal antibodies, with active tuberculosis (TB)/inadequately treated TB/latent TB, on oral anti-rejection or any immune-suppressive drug in the last 6 months and those who had participated in any clinical trial using an anti-IL-6 therapy, were excluded from the study.	anti-rejection suggested: None anti-IL-6 suggested: None
Software and Algorithms
Sentences	Resources
All statistical analyses were performed using SAS® (version 9.4 or higher) system software (SAS Institute Inc.,	SAS® suggested: (SASqPCR, RRID:SCR_003056) SAS Institute suggested: (Statistical Analysis System, RRID:SCR_008567)

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 trial has the limitation of being a single-arm, open-label study. Typically, collection of concurrent data from the same hospitals/centres can be useful for comparison, however, amidst a pandemic setting this was not feasible. The meta-analysis on concurrent control data collected from nearly 12,000 patients during the same period has the limitation of having high heterogenicity, though, enough care was taken to match the populations, disease severity, BSC and treatment with other immunomodulators.

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.
No protocol registration statement was detected.

Results from scite Reference Check: We found no unreliable references.

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