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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

29 Pages Posted: 1 Feb 2021

See all articles by Gustavo Lopardo

Gustavo Lopardo

Hospital Municipal Dr. Bernardo Houssay

Waldo Horacio Belloso

Hospital Italiano de Buenos Aires

Esteban Nannini

Departamento de Enfermedades Infecciosas, Sanatorio Británico

Mariana Colonna

Inmunova S.A

Santiago Sanguineti

Inmunova S.A

Vanesa Zylberman

Inmunova S.A

Luciana Muñoz

Inmunova S.A

Martín Dobarro

Sanatorio Sagrado Corazón (OSECAC)

Gabriel Lebersztein

Sanatorio Sagrado Corazón (OSECAC)

Javier Farina

Hospital Cuenca Alta - Servicio de Infectología

Gabriela Vidiella

Ciudad Autónoma de Buenos Aires

Anselmo Bertetti

Ciudad Autónoma de Buenos Aires

Favio Crudo

Hospital Municipal Emilio Zerboni

María Fernanda Alzogaray

Instituto Medico Platense

Laura Barcelona

Hospital Municipal Dr. Bernardo Houssay

Ricardo Teijeiro

Hospital General de Agudos Dr. Ignacio Pirovano

Sandra Lambert

Hospital de Alta Complejidad El Cruce Néstor Kirchner

Darío Scublinsky

Clínica Zabala. Av

Marisa Iacono

Hospital Provincial Neuquén Dr. Castro Rendón

Vanina Stanek

Hospital Italiano de Buenos Aires

Rubén Solari

Hospital Francisco J. Muñiz

Marcelo Martín Casas

Clínica Adventista Belgrano

Lorena Abusamra

Hospital Municipal Dr. Diego Thompson

Héctor Lucas Luciardi

Hospital Centro de Salud Zenón J. Santillán

Alberto Cremona

Hospital Italiano La Plata

Diego Caruso

Ciudad Autónoma de Buenos Aires

Bernardo de Miguel

mAbxience

Santiago Perez Lloret

Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)

Susana Millán

mAbxience

Yael Kilstein

Ciudad Autónoma de Buenos Aires

Ana Pereiro

Fundación Mundo Sano

Omar Sued

Fundación Huésped

Pedro Cahn

Fundación Huésped

Linus Spatz

Inmunova S.A

Fernando Goldbaum

Inmunova S.A

INM005 Study Group

Independent

More...

Abstract

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. reactivación de la economía del conocimiento” and Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación del Ministerio de Ciencia, Tecnología e Innovación. 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.

Suggested Citation

Lopardo, Gustavo and Belloso, Waldo Horacio and Nannini, Esteban and Colonna, Mariana and Sanguineti, Santiago and Zylberman, Vanesa and Muñoz, Luciana and Dobarro, Martín and Lebersztein, Gabriel and Farina, Javier and Vidiella, Gabriela and Bertetti, Anselmo and Crudo, Favio and Alzogaray, María Fernanda and Barcelona, Laura and Teijeiro, Ricardo and Lambert, Sandra and Scublinsky, Darío and Iacono, Marisa and Stanek, Vanina and Solari, Rubén and Casas, Marcelo Martín and Abusamra, Lorena and Luciardi, Héctor Lucas and Cremona, Alberto and Caruso, Diego and de Miguel, Bernardo and Perez Lloret, Santiago and Millán, Susana and Kilstein, Yael and Pereiro, Ana and Sued, Omar and Cahn, Pedro and Spatz, Linus and Goldbaum, Fernando and Group, INM005 Study, 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. Available at SSRN: https://ssrn.com/abstract=3768544 or http://dx.doi.org/10.2139/ssrn.3768544

Gustavo Lopardo

Hospital Municipal Dr. Bernardo Houssay ( email )

Waldo Horacio Belloso

Hospital Italiano de Buenos Aires

Argentina

Esteban Nannini

Departamento de Enfermedades Infecciosas, Sanatorio Británico ( email )

Mariana Colonna

Inmunova S.A ( email )

Santiago Sanguineti

Inmunova S.A ( email )

Vanesa Zylberman

Inmunova S.A ( email )

Luciana Muñoz

Inmunova S.A ( email )

Martín Dobarro

Sanatorio Sagrado Corazón (OSECAC) ( email )

Gabriel Lebersztein

Sanatorio Sagrado Corazón (OSECAC) ( email )

Javier Farina

Hospital Cuenca Alta - Servicio de Infectología ( email )

Gabriela Vidiella

Ciudad Autónoma de Buenos Aires ( email )

Anselmo Bertetti

Ciudad Autónoma de Buenos Aires ( email )

Favio Crudo

Hospital Municipal Emilio Zerboni ( email )

María Fernanda Alzogaray

Instituto Medico Platense ( email )

Laura Barcelona

Hospital Municipal Dr. Bernardo Houssay ( email )

Ricardo Teijeiro

Hospital General de Agudos Dr. Ignacio Pirovano ( email )

Sandra Lambert

Hospital de Alta Complejidad El Cruce Néstor Kirchner ( email )

Darío Scublinsky

Clínica Zabala. Av ( email )

Marisa Iacono

Hospital Provincial Neuquén Dr. Castro Rendón ( email )

Vanina Stanek

Hospital Italiano de Buenos Aires

Argentina

Rubén Solari

Hospital Francisco J. Muñiz ( email )

Marcelo Martín Casas

Clínica Adventista Belgrano ( email )

Lorena Abusamra

Hospital Municipal Dr. Diego Thompson ( email )

Héctor Lucas Luciardi

Hospital Centro de Salud Zenón J. Santillán ( email )

Alberto Cremona

Hospital Italiano La Plata ( email )

Diego Caruso

Ciudad Autónoma de Buenos Aires ( email )

Bernardo De Miguel

mAbxience ( email )

Santiago Perez Lloret

Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) ( email )

Susana Millán

mAbxience ( email )

Yael Kilstein

Ciudad Autónoma de Buenos Aires ( email )

Ana Pereiro

Fundación Mundo Sano ( email )

Omar Sued

Fundación Huésped

Buenos Aires
Argentina

Pedro Cahn

Fundación Huésped

Buenos Aires
Argentina

Linus Spatz

Inmunova S.A ( email )

Fernando Goldbaum (Contact Author)

Inmunova S.A ( email )

Buenos Aires
Argentina

INM005 Study Group

Independent