RBD-Specific Polyclonal F(ab´) 2 Fragments of Equine Antibodies in Patients with Moderate to Severe COVID-19 Disease: A Randomized, Double-Blind, Placebo-Controlled, Adaptive Phase 2/3 Clinical Trial

Background: Passive immunotherapy is a therapeutic alternative for patients with COVID-19. Equine polyclonal antibodies (EpAbs) could represent a source of easily scaled up neutralizing antibodies against SARS-CoV-2. Methods: We conducted a double-blind, randomized, placebo-controlled trial of EpAbs (INM005) in hospitalized adult patients with moderate and severe COVID-19 pneumonia in 19 hospitals of Argentina. Primary endpoint was improvement in at least two categories in WHO ordinal clinical scale at day 28 (ClinicalTrials.gov number NCT04494984). Findings: Enrolled patients were assigned to receive two doses of INM005 (n=118) or placebo (n=123). Median age was 54 years old, 65·1% were male and 61% had moderate disease at baseline. The median time from the onset of COVID-19 symptoms to the administration of the first dose of intervention was 6 days (interquartile range 5 to 8 days). At day 28 no significant difference was noted between study groups on primary endpoint (odds ratio, 1·61%, 95% confidence interval [95%CI] 0·71 to 3·63 p=0·34); however, overall variation in ordinal clinical status during the 28 days follow up period favored INM005. Improvement in at least two categories was significantly higher in INM005 at days 7, 14 and 21 of follow up. A significant difference was noted in time to improvement in at least two ordinal categories or hospital discharge: 14·2 (± 0·7) days in the INM005 group and 16·3 (± 0·7) days in the placebo group. Pre-specified subgroup analyses showed a more pronounced effect of the intervention over severe patients and with no antibody response at baseline. Overall mortality was 6·8% the INM005 group and 11·4% in the placebo group. Interpretation: Albeit not having reached the primary endpoint, we found clinical improvement of hospitalized patients with SARS-CoV-2 pneumonia, particularly those with severe disease.  Funding: Funded by Inmunova and grants from the Ministries of Science and Production of Argentina. Trial Registration: ClinicalTrials.gov number NCT04494984 Declaration of Interests: MC, SS, VZ, LM, LS, FG received grants from Ministerio de Desarrollo Productivo “Programa soluciona. reactivacion de la economia del conocimiento” and Agencia Nacional de Promocion de la Investigacion, el Desarrollo Tecnologico y la Innovacion del Ministerio de Ciencia, Tecnologia e Innovacion. MD, JF, GV, AB, FC, MFA, LB, RT, SL, DS, MI, VS, RS, PC, MMC, LA, HLL, AC, DC declare reimbursement for conduction of clinical trial as investigator of the study. PC, OS, YK report other funds from Inmunova. EN, GL, WHB, SPLL report personal fees from Inmunova. AP, B de M, SM, Gabriel L declare no competing interests. SPLL declare personal fees from Movement Disorders Society, Laboratorio Elea and Merck pharmaceuticals. Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards of all participant clinical sites as well as regional or jurisdictional Ethics Committees as applicable. The Argentinean National Administration of Medicines, Food and Medical Technology (ANMAT) also approved the study protocol.