key: cord-0937021-k04ml7p1 authors: Patel, J.; Beishuizen, A.; Bocca Ruiz, X.; Boughanmi, H.; Cahn, A.; Criner, G. J.; Davy, K.; de-Miguel-Diez, J.; Fernandes, S.; Francois, B.; Gupta, A.; Hanrott, K.; Hatlen, T.; Inman, D.; Isaacs, J. D.; Jarvis, E.; Kostina, N.; Lacherade, J.-C.; Martinez-Ayala, P.; McEvoy, C.; Munoz-Bermudez, R.; Neisen, J.; Plantefeve, G.; Schifano, L.; Schwab, L.; Shahid, Z.; Shirano, M.; Smith, J. E.; Sprinz, E.; Summers, C.; Terzi, N.; Tidswell, M. A.; Williamson, R.; Wyncoll, D.; Layton, M. title: A Randomized Trial of Otilimab in Severe COVID-19 Pneumonia (OSCAR) date: 2021-04-17 journal: nan DOI: 10.1101/2021.04.14.21255475 sha: 9e2d6f802ecd8346275ba18345dd643d46a3fb47 doc_id: 937021 cord_uid: k04ml7p1 BACKGROUND Increasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19. METHODS We conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60. RESULTS Overall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI 0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined [≥]70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19. CONCLUSIONS Although not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged [≥]70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged [≥]70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684). Reports of severe pneumonia associated with a novel 2019 coronavirus (SARS-CoV-2) began to emerge from Wuhan, China in January 2020. Cases often required intensive care and were associated with significant mortality, with some hospitalized patients having elevated inflammatory cytokines, including granulocyte-monocyte colonystimulating factor (GM-CSF) and interleukin 6 (IL-6), compared with healthy controls. 1, 2 The severity and spectrum of the disease (COVID-19) resulting from this infection and associated immunopathology has been the subject of intense clinical research spanning trials of a wide range of potential therapeutic agents. [3] [4] [5] [6] [7] [8] [9] [10] [11] Severe disease is characterized by systemic inflammation, dysregulated myeloid cell responses, and respiratory and/or cardiovascular failure. [12] [13] [14] [15] [16] Older age and chronic health conditions, such as obesity, diabetes and cardiovascular disease, are risk factors for severe disease. 17, 18 In particular, increasing age is strongly associated with worsened disease severity, intensive care unit (ICU) admission, and increased mortality. [19] [20] [21] GM-CSF has been implicated as a key cytokine in driving and perpetuating the hyperinflammation observed in severe COVID-19. [22] [23] [24] [25] Otilimab is a well-tolerated and effective, high-affinity, anti-GM-CSF monoclonal antibody that has been shown to reduce inflammatory disease activity in rheumatoid arthritis (RA). 26 We designed a double-blind, placebo-controlled, randomized clinical trial (OSCAR [Otilimab in Severe COVID-19 Related Disease]; ClinicalTrials.gov identifier NCT04376684) to investigate whether otilimab was able to improve clinical outcomes in patients hospitalized with respiratory failure and systemic inflammation secondary to severe COVID-19. During the study design, we aimed to address the multiple challenges of conducting a high-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 7 quality clinical trial within the context of a pandemic. We were conscious of the large number of uncontrolled, cohort, open-label, and small therapeutic trials that had been initiated, and the frequent changes in new treatments introduced into clinical practice, often with minimal data to support their emergency use. We designed our protocol to minimize the burden on researchers where possible, to reflect ethnic diversity, and adapted it as necessary to evolving standards of care. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 17, 2021. ; https://doi.org/10.1101/2021.04.14.21255475 doi: medRxiv preprint planned to be in clinical status Category 5 or 6 according to the GSK-modified WHO ordinal scale 27 where: 1 = not hospitalized, no limitation of activity; 2 = not hospitalized, limitation of activity; 3 = hospitalized, no oxygen therapy; 4 = hospitalized, low-flow oxygen by mask or nasal prongs; 5 = hospitalized, high-flow oxygen (≥15 L/min), continuous positive airway pressure, bilevel positive airway pressure non-invasive ventilation; 6 = hospitalized, intubation and MV; 7 = hospitalized, MV plus additional organ support; 8 = death. Additional details are provided in the protocol. As a precaution, a safety cohort was planned, whereby initial dosing for the first four Category 5 patients was staggered and safety data were independently reviewed prior to enrollment of an initial safety cohort of 16 additional Category 5 patients, before the study progressed to the main cohort of patients. Patients were centrally randomized 1:1 by interactive response technology in a blinded manner to either a single one-hour intravenous (IV) infusion of otilimab 90 mg (aiming to achieve serum otilimab concentrations through to Day 7 similar to steady-state trough in patients with RA) or placebo (saline). In the safety cohort a randomization block size of two was used for the first and second sentinel pairs, and four for the remaining 16 patients. In the main cohort, patients were stratified by clinical status (Category 5 or 6) and age group (<60, 60 to 69, and 9 institutional protocols. Medications not permitted prior to enrollment or during the study included monoclonal antibodies (e.g. tocilizumab, sarilumab), immunosuppressants, and chronic oral corticosteroid use >10 mg/day prednisone equivalent for a non-COVID-19-related condition. Additional or prior medications for COVID-19-related disease were permitted if part of local institutional policies and not part of a clinical trial. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 17, 2021. ; endpoints are listed in the protocol. Occurrence of adverse events (AEs) and serious adverse events (SAEs) was reported up to Day 60 and recorded according to the system organ class and preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA), v23.1. The study used a group sequential design, using a Lan-DeMets alpha-spending function to control the type I error with four interim analyses planned for futility using Pocock analogue rules, and two interim analyses planned for efficacy using the O'Brien-Fleming analogue rules. 28 The final interim analysis was not performed as the study completed recruitment prior to the data-cut being reached. Full details of the design parameters and decision criteria are included in the statistical analysis plan. A sample size of 800 patients provided approximately 90% power to detect a difference of 12% in the proportion of patients alive and free of respiratory failure at a one-sided 2.5% significance level and an assumed placebo response rate of 45%. The primary endpoint was analyzed using logistic regression adjusting for treatment, age group and clinical status (Category 5 and Category 6) at baseline. Missing data in the overall primary analysis were imputed using multiple imputation, assuming data are missing at random, and adjusting for analysis covariates. The primary endpoint was also analyzed by pre-defined subgroups of clinical status (Categories 5 and 6) and age group (<60, 60 to 69, and ≥ 70 years), as detailed in the statistical analysis plan. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 17, 2021. ; The primary population for analysis included all patients who were randomized and received study drug (modified intent-to-treat [mITT]). Results are presented with twosided p-values. Additional details are provided in the statistical analysis plan. The study was conducted in accordance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, International Conference on Harmonization, Good Clinical Practice, and applicable country-specific regulatory requirements. The protocol was approved by relevant institutional review boards (IRB/IEC). Before patient enrollment, informed consent was obtained written/orally from the patient or written/orally from the patient's legally authorized representative. An Independent Data Monitoring Committee (IDMC) monitored in-stream unblinded safety and efficacy data throughout the study and at predefined interim analyses. A total of 851 patients were screened, 806 were randomized, and 793 included in the mITT population (395 in the otilimab group and 398 in the placebo group) (Figure 1 ). Within the pre-defined stratification groups, 630 (78%) were in clinical status Category 5 and 176 (22%) in Category 6; with 363 (45%), 262 (33%), and 181 (22%) in the <60, 60 to 69, and ≥ 70-year age groups, respectively. The safety population included 397 treated with otilimab and 396 in the placebo group, because two patients randomized to placebo were incorrectly dosed with otilimab. By Day 60, 379/403 (94%) patients in the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 17, 2021. ; otilimab group and 388/403 (96%) on placebo either completed the study or had died. None of the patients discontinued participation because of safety reasons. Baseline demographic and disease characteristics were generally well balanced between the two study groups and were reflective of severe COVID-19 with elevated levels of markers of systemic inflammation and GM-CSF (Table 1 ) compared with healthy controls (data not shown). The mean (± standard deviation) age was 59.8 (±11.7) years in the otilimab group and 59.4 (±11.9) years in the placebo group. Most patients were pre-treated with COVID-19 medications; specifically, 83% received corticosteroids (including dexamethasone), 34% received remdesivir, and 6% received convalescent plasma prior to randomization. Two patients (<1%) in the otilimab group and 7 (2%) in the placebo group received tocilizumab post-study treatment, and none received sarilumab. Although 71% of patients in the otilimab group were alive and free of respiratory failure at Day 28 compared with 67% on placebo ( Figure 2 ), the model-adjusted difference of 5.3% did not reach statistical significance (95% CI -0.8, 11.4; p=0.09). Similar modeladjusted treatment differences of 5.9% (95% CI -0.8, 12.7) and 4.6% (95% CI -9.6, 18.8) were observed for patients in Categories 5 and 6 ( Figure 2 ). However, although the pre-defined subgroup analysis by age revealed little benefit in patients aged <60 or 60 to 69 years, there was a nominally significant model-adjusted difference of 19.1% (95% CI 5.2, 33.1; p=0.009) in patients ≥ 70 years (Figure 2 ). . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; Although post-hoc analyses suggested a greater benefit with otilimab in females and patients with comorbidities (particularly hypertension), there was little impact of geographic region or pre-treatment (and mostly continued) use of dexamethasone ( Figure S1A ; appendix 2). However, the response in patients aged ≥ 70 years was consistent regardless of disease severity (Figure 2 ), dexamethasone use, or comorbidities ( Figure S1B ; appendix 2). In the mITT population, all-cause mortality at Day 60 was 23% in the otilimab group . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; https://doi.org/10.1101/2021.04.14.21255475 doi: medRxiv preprint A single dose of otilimab resulted in mean C max of 20.2 μ g/mL after dosing on Day 1 and 1.9 μ g/mL on Day 7, with coefficient of variation of 43% and 69% respectively; similar levels were achieved in the ≥ 70 age group (Supplementary Figure S2 ). In the otilimab arm, GM-CSF levels at Day 2, proximal to C max , were reduced by 95% to a mean of 0.037 ng/L with 255/381 (67%) samples falling below the assay lower limit of quantification (0.036 ng/L); levels in the placebo arm remained unchanged (data not shown). Overall, safety findings, including the scope of AEs and SAEs, were reflective of the severe COVID-19 population. Of note, an overall pattern of increasing frequency of AEs and SAEs was observed with advancing age irrespective of treatment assignment. The most common AEs and SAEs in the safety population and each age subgroup (defined post hoc) are listed in Table 2 . No safety signals related to treatment with otilimab were identified. In patients ≥ 70 years who received otilimab, there were reduced frequencies of investigator-reported hypoxemia and pulmonary embolism compared with placebo. This observation may be linked to the greater recovery from respiratory failure with otilimab seen in this ≥ 70-year subgroup of patients compared with the total safety population. This double-blind, placebo-controlled, randomized clinical trial in hospitalized adults with severe COVID-19 pneumonia (clinical status Categories 5 and 6) showed that otilimab was associated with a model-adjusted increase of 5.3% in the proportion of patients . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; alive and free of respiratory failure (clinical status Categories 1, 2, 3, or 4) at Day 28. Although this result did not reach statistical significance in the overall population, in the pre-defined subgroup of patients aged 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 April 17, 2021. ; 60. The observed trends in improved oxygenation response to otilimab may be reflective of an early mechanistic response. Assumptions made about placebo group responses during the design of the study in March 2020 proved to significantly underestimate the observed response (67% cf. 45%). This difference likely reflects the substantial improvements in the standard of care of COVID-19 during our study timeframe, including ventilation practices and corticosteroid use, amongst many other changes to patient management and healthcare resourcing. At the time of writing, severe COVID-19 is still prevalent in older adults (with additional waves in many countries), and the high mortality in this age group supports the urgent need for additional treatment options for these most at-risk patients. We have therefore expedited enrollment of an additional cohort of patients ≥ 70 years with severe COVID-19 to urgently confirm these findings in an extension of the OSCAR study. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; 18. Mani VR, Kalabin A, Valdivieso SC, Murray-Ramcharan M, Donaldson B. New York Inner City Hospital COVID-19 Experience and Current Data: Retrospective . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021 . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021 . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021 . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; https://doi.org/10.1101/2021.04.14.21255475 doi: medRxiv preprint 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 April 17, 2021. ; https://doi.org/10.1101/2021.04.14.21255475 doi: medRxiv preprint ≥ 70 year group (N) 1 Analyzed using the trimmed means approach 37 where the proportion of data to be trimmed was determined by the amount of missing data due to intercurrent events. Results presented until >50% of population experience the intercurrent event. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; https://doi.org/10.1101/2021.04.14.21255475 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 17, 2021. ; https://doi.org/10.1101/2021.04.14.21255475 doi: medRxiv preprint 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 April 17, 2021. A d v e r s e e v e n t S a f e t y p o p u l a t i o n A g e < 6 0 y e a r s A g e 6 0 t o 6 9 y e a r s A g e ≥ 7 0 y e a 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 April 17, 2021. ; https://doi.org/10.1101/2021.04.14.21255475 doi: medRxiv preprint Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Pathogenic T cells and inflammatory monocytes 10 Tocilizumab in Hospitalized Patients with GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Cohort Study Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study Two distinct immunopathological profiles in autopsy lungs of COVID-19 Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study Neutrophil-to-lymphocyte ratio on admission is an independent risk factor for the severity and mortality in patients with coronavirus disease 2019 Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region The authors thank the patients and their families who participated in this clinical study, as well as the doctors, nurses, pharmacists, and other allied health