key: cord-0281131-juu0vrnf authors: KR, R.; Rathod, C.; Darnule, R.; Loganathan, S.; Deodhar, S.; A, R.; Marwah, A.; Chaudhari, N. M.; Thakur, B. K.; Vaidyanathan, S.; Athalye, S. N. title: 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 date: 2021-10-26 journal: nan DOI: 10.1101/2021.10.25.21265462 sha: 73da404164af18edd9dd3892e0053aaede4bc32d doc_id: 281131 cord_uid: juu0vrnf Objective: To evaluate safety and efficacy of Itolizumab in hospitalized COVID-19 patients with PaO2/FiO2 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 SpO2 without increasing FiO2. 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 TNF 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. The coronavirus pandemic caused by SARS-CoV-2 (COVID- 19) infection has, as of date, spread across the globe, with ~250 million confirmed cases and ~5 million deaths. 1 Patients with an increasing severity of the disease can develop hypoxaemia/dyspnoea, and can potentially evolve towards an acute respiratory distress syndrome (ARDS) due to an exaggerated immune response. This stage of the disease is characterized by high levels of pro-inflammatory cytokines such as interferon-γ, interleukin-6 (IL-6), IL-1β, IL-17, IL-18, tumour necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor etc., and without a timely and urgent intervention may progress towards death. [2] [3] [4] There is an elevation of other markers of inflammation, coagulation and organ damage such as C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH) and ferritin. 5 Treatment with immunomodulatory drugs aiming to reduce elevated cytokines have shown survival benefits in patients with hyperinflammation, without an increase in adverse events (AEs). [6] [7] [8] [9] Itolizumab is a humanized IgG1 monoclonal antibody that binds to domain-1 of human-CD6 responsible for priming, activation and differentiation of T-cells. 10 By selectively targeting the CD6-ALCAM pathway, Itolizumab results in decreased IFN-γ, IL-6 and TNF-α levels through the Th-1 pathway and IL-17, IL-6 and TNFα levels through the Th-17 pathway. [10] [11] [12] [13] [14] [15] [16] Itolizumab leads to a reduction in T-cell infiltration at the sites of inflammation without any T-cell depletion. 10 Itolizumab was granted a Restricted Emergency Use Authorization (EUA) in India for the treatment of moderate-to-severe ARDS in patients with COVID-19 infection, based on the favourable outcomes from a smaller controlled trial. 9 In the past 1 year, >27,000 hospitalized patients have been treated for COVID-19 with Itolizumab across India. [17] [18] [19] [20] [21] [22] [23] This post-marketing study in 300 patients, hospitalized in COVID-19-designated Indian tertiary care hospitals, was carried out to assess safety and survival and recovery benefits of Itolizumab treatment in COVID-19 patients requiring oxygen therapy and having a PaO 2 /FiO 2 ratio (PFR) analyses of efficacy and safety endpoints for a 30-day post-treatment period with Itolizumab. The study was designed for an extended follow-up period up to 90 days after treatment. This was a multicentre, single-arm, Phase-4 trial where 300 eligible patients in India were dosed with Itolizumab, as per the prescribing information, in addition to receiving the best supportive care (BSC; Suppl. Figure 1) . Patients were observed for 30 days for mortality and were followed up to 90 days post-treatment for long-term survival as well as any benefit of Itolizumab treatment in long-term complications of COVID-19. The study flow chart is summarized in Figure 1 . This publication presents the 30-day safety and efficacy data and the 90-day mortality rate. 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. Patients with known severe allergic reactions to monoclonal antibodies, with active tuberculosis (TB)/inadequately treated TB/latent TB, on oral anti-rejection or any immunesuppressive 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. Patients with a known history of Hepatitis B, C or HIV, absolute neutrophil count <1000/mm 3 , platelet count <50,000/mm 3 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. and absolute lymphocyte count <500/mm 3 were also excluded. Patients on invasive mechanical ventilation (IMV), in whom progression to IMV or with high probability of death in the next 24-hours were also excluded. The study was carried out at 17 COVID-19-specific tertiary hospitals in India between 02 Oct 2020 and 10 Jul 2021. A modified COVID-19, 8-point ordinal scale was used to characterize the severity of the disease in the patients at baseline (Suppl. 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 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The current study was undertaken with the primary objective of evaluating the safety and efficacy of Itolizumab infusion in patients with moderate-to-severe ARDS due to COVID-19. The secondary objectives of the study were to evaluate the additional efficacy and safety of Itolizumab as per the study outcomes detailed for the first 30 days out of the 90 days extended follow-up after the Itolizumab treatment. The study included two primary outcome measures (1) safety-related outcome measure, namely, the incidence of severe, acute infusion-related reactions (IRRs), and higher, occurring on the day of infusion and (2) mortality rate at 1-month. The key secondary outcome measures included measurement of biomarkers (cytokines IL-6 and TNF-α) and inflammatory markers (CRP, serum ferritin, D-dimer and LDH). Other key secondary measures included measurement of lung function (stable/improved SpO 2 without increasing Continuous variables were summarized using descriptive statistics such as mean, standard deviation (SD), median, 95% confidence interval (CI), minimum and maximum. Categorical variables were summarized using proportions (counts and percentages). Data were summarized at screening/baseline, 24-48 hours post-dosing, at Day-7, at the day of discharge and end of study at Day-30. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The primary safety endpoint was incidence of severe acute IRRs and higher as assessed by CTCAE. This primary endpoint was descriptive in nature as no hypothesis was specified. Summary statistics (frequency, percentage, point estimable, 95% CI using Clopper-Pearson exact test) of incidence of nature and severity of AEs that were severe acute IRRs, and higher, was calculated for the safety analysis set. The 1-month mortality rate, which was the primary efficacy endpoint, was descriptive in nature as no hypothesis was specified. Summary statistics (frequency, percentage, point estimable, 95% CI using Clopper-Pearson exact test) was calculated for the full analysis set and efficacy analysis set. The mortality rate at Day-30 and time to death were summarized with descriptive statistics. All safety analyses were conducted using the safety analysis set. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 23.1). The number and percentage of patients with AEs were tabulated by system organ class/preferred term and displayed by intensity and relationship to the study drug. Vital signs and laboratory data were summarized by patient. The Full Analysis Set (FAS) included all patients who were enrolled in the study (ITT population). Efficacy Analysis Set included all patients of the FAS population who received at-least one full infusion of Itolizumab (without any major protocol deviation; decided before the database lock) and was used for efficacy endpoint analysis (modified ITT [mITT] population). The Safety Analysis Set included all patients who received a partial or complete infusion of Itolizumab, and this was used for all safety endpoint analysis (safety population). All statistical tests were performed at the 5% level of significance (two-sided test) and p ≤ 0.05 was considered statistically significant. All statistical analyses were performed using All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. A total of 395 patients were screened, of which 95 were considered screen failures. The ITT population comprised of 300 patients and the mITT population comprised of 287 (95.7%) patients. A total of 44 patients discontinued from the study and the primary reason was death (18, 6.0%), adverse events (11, 3.7%), or withdrawal of consent (15, 5.0%). Additionally, two patients who were discontinued from the treatment due to AEs died later, resulting in a 1month mortality rate of 6.7% (20/300). At the end of the 90-Day follow-up period, a total of 24 deaths (8%; 24/300) were reported. Patients requiring oxygen therapy at enrolment were on non-invasive ventilation (NIV: bilevel positive airway pressure), high flow nasal cannula (HFNC), non-rebreather mask, a face mask or nasal prongs (Suppl. Table 1 ). Of the total 300 enrolled patients, 74.0% (n=222) patients were at score 5 (requiring any supplemental oxygen) and 26.0% (n=78) were on score 6 (requiring NIV or use of HFNC) on the modified ordinal scale (Suppl. Table 2 ). Thirteen patients (4.3%) could not complete the infusion mainly due to IRRs. Overall, 9 patients (3.0%) required a second discretionary dose of Itolizumab infusion upon assessment by the investigator. Suppl. Table 3 mentions the number of Itolizumab doses provided to each patient. The average duration of each Itolizumab infusion was 5-6 hours. All IRRs resolved on the same day, including in patients where the infusions were interrupted. The mean age of patients in the trial was 53.3 years and all patients were of Asian ethnicity, with 74.7% of the patients being male. The disposition, demographics and baseline characteristics of the patients are given in Suppl. Table 4 . One hundred and fifty patients All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The mean duration of COVID-19-related symptoms at enrolment was 8.41 days, and the most frequently reported COVID-19-related symptom was dyspnoea (92.7%), followed by cough (80.7%) and fever (71.3%). i. Severe acute IRRs were reported in 1.3% of the patients; further details are presented under the safety section. A total of 20 deaths were reported in 300 patients (ITT population), resulting in a 1-month mortality rate of 6.7% [95% CI: 4%, 10%]. For the efficacy analysis population (mITT), a total of 18 deaths were reported, resulting in a mortality rate of 6.6% [18/287; 95% CI: 4%, 10%] at 1-month. Of the 222 patients at score-5 of the ordinal scale at baseline, there were 6 deaths (mortality rate 2.7%) and of the 78 patients at score-6 on the ordinal scale, there were 14 deaths (mortality rate 17.9%). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. for the rest of the visits, the same trend was followed ( Table 2) . Mean PFR improved by about 50% by Day-7 (p<0.001). The increasing trend in PFR that was observed post Itolizumab dose was consistent till Day-30. Improvement from baseline was statistically significant at Days 3 and 7 (p<0.05) (Figure 2 ). iii. The summary of hospitalization duration, ICU stay and time to recovery by Day-30 are presented in Table 3 . Overall, the patients took a median of 8 days for recovery and got discharged from the hospital by a median of 9.5 days. Patients who were severe required a median number of 11 days to get discharged from the ICU. By Day-7, all patients started improving in the clinical status by at least 1 or more points on the ordinal scale. Two hundred and sixty (260; 86.7%) patients showed an improvement in All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 26, 2021. Figure 2a&b) . A decreasing trend was observed from baseline to 48-hours post-infusion in mean IL-6 (227.8 ng/L to 161.9 ng/L; 28.9% decrease, p>0.42) and TNF-α levels (26.7 ng/L to 19.2 ng/L; 28.1%; p>0.16) (Figure 3a & b) . A similar decrease was observed from baseline to 48-hours post the second infusion. Itolizumab use was associated with an overall incidence of 21% TEAEs (123 TEAEs in 63 patients) till Day-30 of this study. The most commonly reported TEAEs were IRRs (7.3%) and lymphopenia (7%, including decreased lymphocyte count) ( Table 4) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 26, 2021. The incidence of severe acute IRRs was one of the primary outcome measures. Of the 34 drug-related IRRs, 6 events in 4 patients (1.3%) were of Severity Grade-3 and -4 and 3 IRRs were reported as SAEs. All IRRs were treated as per the institutional IRR treatment protocol and were considered resolved/recovered on the same day. IRRs led to the early discontinuation of 10 patients from the study. Incidence of severe, acute IRRs and higher, causally related to Itolizumab, is presented in Table 5 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The inflammatory pathophysiology of COVID-19 has encouraged research on several immunomodulatory treatments in moderate-to-severe cases of COVID-19, but the results have been inconclusive. A meta-analysis of eight trials on the use of Tocilizumab has shown no significant difference in 28-day mortality barring one trial (REMAP-CAP) in critically ill patients. 25 In the current study, the 1-month mortality rate for patients, who received one full infusion of Itolizumab, was observed to be 6.7%. A meta-analysis done on six concurrently running COVID-19 trials in India with 11,852 hospitalized patients, representing a similar patient population receiving standard of care, showed an average mortality rate of 27% with 95% CI [16% to 42%] in the control-arm (Suppl. Figure 3 , Suppl. control, 24.4%) trials though a higher proportion of patients received steroids in the RECOVERY trial (tocilizumab, 82%; control, 82%) and in the current study (Itolizumab, 85.3%). In the RECOVERY and COVACTA tocilizumab treated arms, patients who required any supplemental oxygen (equivalent to score-5 on the COVID-19 8-point ordinal scale) had mortality rates of 19% and 11.5% and those requiring NIV/HFNC (equivalent to score-6 on the ordinal scale) had mortality rates of 38% and 19.1%, respectively. 24,31 In the current study, mortality was 2.7% for ordinal score-5 and 17.9% for ordinal score-6 patients treated with Itolizumab. In our study, 91.7% of patients got weaned off from any kind of supplemental oxygen within 6 (3-7.5) days. Only 4% of patients progressed to IMV of which 2.6% did not survive till Day-30. At the end of Day-30, majority of the patients (86.7%) showed an improvement on the ordinal scale by 1 or more points from the baseline score of 5/6 and 8.7% patients showed All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. No new safety concerns were observed in this study. The most frequently reported TEAEs, namely, IRRs (7.3%) and lymphopenia (7%; including decreased lymphocyte count), are All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.25.21265462 doi: medRxiv preprint typically characteristic of treatment with monoclonal antibodies. 9, 15, 35 All IRRs resolved on the same day and most of the lymphopenia events were transient and resolved before Day-30, with a median recovery time of 4 days. It has been observed that on increasing the infusion time from 2 hours to 5-6 hours, the incidence of IRRs can be reduced. 9 In the current study, there were 1.3% IRRs reported as Grade 3/4 and 3.3% of patients withdrew from the study due to an IRR. Of the 30 SAEs observed, none of the 20 fatal SAEs were related to the drug. The most common SAEs were septic shock, worsening of ARDS and respiratory failure, which are generally observed in patient populations with co-morbid conditions. 36,37 The three SAEs related to Itolizumab, namely, bradycardia, anaphylactic reaction and decreased oxygen saturation, were considered as IRRs. The incidence of septic shock in this study (2%) is similar to other reports in COVID-19 patients, where it ranges from 2-4%. [36] [37] [38] [39] In this study, there was no increase in incidences of serious infections or septicaemia and no new infections, such as mucormycosis, were observed when compared to previous clinical experiences or concurrent data. Overall, the clinical trial data suggest that Itolizumab is generally safe and well-tolerated. A subcutaneous version of Itolizumab under development has an added advantage to be used as an outpatient intervention and holds a promise to offset the IRRs. 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. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. AM contributed to the statistical analyses, meta-analysis and interpretation of data. RA was All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Tables: All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Note: N = Itolizumab number of patients in the relevant population, n a or n b = Number of patients on NIV or any supplemental oxygen, respectively, % = n a or b /N *100. *In addition, 18 (6%) patients either died while on NIV or discontinued due to an adverse event; so total of 12+18=30 patients. **In addition, 25 (8.3%) patients either died while on O 2 therapy or discontinued due to an adverse event; so total of 275+25=300 patients. SD = standard deviation. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.25.21265462 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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