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

ABSTRACT

Background

Itolizumab, an anti-CD6 monoclonal antibody, down-regulates COVID-19-mediated inflammation and the acute effects of cytokine release syndrome. This study aimed to evaluate the safety and efficacy of itolizumab in hospitalized COVID-19 patients with PaO₂/FiO₂ ratio (PFR) ≤200 requiring oxygen therapy.

Research design and methods

This multicenter, single-arm, Phase 4 study enrolled 300 hospitalized adults with SARS-CoV-2 infection, PFR ≤200, oxygen saturation ≤94%, and ≥1 elevated inflammatory markers from 17 COVID-19 specific tertiary Indian hospitals. Patients received 1.6 mg/kg of itolizumab infusion, were assessed for 1 month, and followed-up to Day 90. Primary outcome measures included incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) and mortality rate at 1 month.

Results

Incidence of severe acute IRRs was 1.3% and mortality rate at 1 month was 6.7% (n = 20/300). Mortality rate at Day 90 was 8.0% (n = 24/300). By Day 7, most patients had stable/improved SpO₂ without increasing FiO₂ and by Day 30, 91.7% patients were off oxygen therapy. Overall, 63 and 10 patients, respectively, reported 123 and 11 treatment-emergent adverse events up to Days 30 and 90. No deaths were attributable to itolizumab. Patient-reported outcomes showed gradual and significant improvement for all five dimensions on EQ-5D-5L.

Conclusion

Itolizumab demonstrated acceptable safety with a favorable prognosis in hospitalized COVID-19 patients.

Clinical trial registration

CTRI/2020/09/027941 (Clinical Trials Registry of India).

KEYWORDS:

• Acute respiratory distress syndrome
• anti-CD6
• COVID-19
• immune hyperactivation
• immunotherapy
• itolizumab

Supplementary Material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2023.2204186.

Acknowledgments

Medical writing support was provided by Shivani Mittra, PhD (Biocon Biologics Limited). Dev B Baruah (M. Pharm), Vathsala Jayanth (M.D.), and Geetanjali Tonpe (MSc) provided editorial support (all from Biocon Biologics Limited). Statistical programming support was provided by Bhatu K Patil and Avinash Sevankar, M.Sc. (no longer employed by Biocon Biologics Limited). The manuscript was previously published as a preprint on medRxiv: https://www.medrxiv.org/content/10.1101/2021.10.25.21265462v2.

Declaration of interest

R KR, C Rathod, and R Darnule received funding for the study and professional fees as Principal Investigators from Biocon Biologics Limited. S Loganathan, S Deodhar, A Marwah, NM Chaudhari, BK Thakur, and SN Athalye are employees of Biocon Biologics Limited and may be eligible for stock and stock options. R A and S Vaidyanathan were employed by Biocon Biologics Limited at the time of conceptualization and conduct of this study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethics statement

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. The study received approvals from the Independent Ethics Committees of all the participating sites. The patients provided written informed consent before the initiation of study procedures.

Author contributions

R Darnule, S Loganathan, S Deodhar, R A, A Marwah, S Vaidyanathan, and SN Athalye contributed to the conception and design of the work. R KR, C Rathod, R Darnule, BK Thakur, S Deodhar, and R A contributed substantially to the conduct of this study, acquisition of the data, and interpretation of the results. SN Athalye is the guarantor of the study. A Marwah contributed to the statistical analyses, meta-analysis, and interpretation of data. R A was responsible for medical monitoring, and NM Chaudhari was responsible for the supervision and acquisition of safety data and review and analysis of the SAE/AEs. All authors have critically reviewed the manuscript for important intellectual content and approved the same for publication.

Data availability statement

The data that support the findings of this study are available in Zenodo at https://doi.org/10.5281/zenodo.7559578, reference number 7,559,578.

This project contains the following underlying data:

Data file 1. ITOLI-C19-04-I-01 ADRG

Data file 2. ITOLI-C19-04-I-01 cSDRG

Data file 3. Itolizumab_AdaM_Combined

Data file 4. Itolizumab_SDTM_Combined

Additional information

Funding

This paper was funded by Biocon Biologics Limited. The sponsors did not have any role in patient recruitment and management