Safety and Effectiveness of an Immunobiological Drug in CoViD-19 (INPB001)

Study to Evaluate the Safety and Effectiveness of an Immunobiological Drug (Anti SARS-CoV-2) in the Treatment of Coronavirus Disease 2019 (CoViD-19)

The aims of this study is to analyze the efficacy and safety of a passive immunotherapy strategy using hyperimmune equine serum known as Anti-SARS-CoV-2 elaborated by the National Institute for the Production of Biologicals (ANLIS-Malbrán) as an addition to the standard therapeutic approach for hospitalized patients with COVID-19, in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection aged 18 to 80 years.

Study Overview

• Status: Recruiting
• Conditions: Covid19; COVID-19 Pneumonia; COVID-19 Respiratory Infection
• Intervention / Treatment: Drug: Anti-SARS-CoV-2; Drug: Placebo

Detailed Description

This is an adaptive phase II/III study that aims to analyze the efficacy and safety of a immunobiological drug (Anti SARS-CoV-2) in the treatment of CoViD-19. This treatment is a passive immunotherapy strategy developed as a purified F(ab')2 fraction of equine hyperimmune serum (Anti-SARS-CoV-2). The equine serum was generated from antigenic stimulation with the SARS-CoV-2 receptor binding domain (RBD) purified protein.

This type of product (equine hyperimmune serum F(ab')2) has been widely used in our country in the last 100 years with satisfactory results and an acceptable safety profile in the treatment of accidents with poisonous animals such as anti-loxosceles, anti -latrodectus, anti-scorpionic, and anti-phoneutria, anti-bothropic, anti-micrurus, and anti-crotalic sera, all developed by the National Institute of Biological Production (ANLIS-Malbrán) and distributed free of charge in public hospitals in the country .

In the present study, evaluates the effect and safety of this immunobiological treatment in patients with COVID-19 that require hospitalization.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Guillermo A Keller, MD PhD; Phone Number: 011-4961-0943; Email: gkeller@anlis.gob.ar
• Study Contact Backup: Name: Claudio Bonel, PhD; Phone Number: 011-4303-1801; Email: cbonel@anlis.gob.ar

Study Locations

• Argentina
  • Ciudad Autónoma De Buenos Aires, Argentina, 1408
    • Recruiting
    • Hospital General de Agudos Donación Francisco J. Santojanni
    • Contact: Guillermo A Keller, MD PhD; Phone Number: 01149610943; Email: gkeller@anlis.gob.ar
    • Contact: Claudio Bonel, PhD; Phone Number: 011-4303-2492; Email: cbonel@anlis.gob.ar
    • Principal Investigator: Guillermo A Keller, MD PhD
    • Sub-Investigator: Guillermo Di Girolamo, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects over 18 years old and under 80 years old.
2. Positive results by RT-PCR for SARS CoV-2
3. Clinical picture compatible with respiratory compromise in the form of pneumonia attributed to COVID-19 (Stage 3, 4 or 5 according to the WHO scale), lasting up to 72 hours from the onset of symptoms to their evaluation to be incorporated into the study.
4. Patient with good disposition towards the study and that signs the informed consent.

Exclusion Criteria:

1. Patients with clinical disease corresponding to mild / asymptomatic forms (Absence of radiological infiltrate and risk factors, with normal auscultation and arterial saturation of oxygen (SatO2) greater than 95%)
2. Patients with clinical disease corresponding to severe forms (Severe pneumonia: presence of severity criteria (ATS / IDSA), one of two major or three minor criteria.)
3. Patients who have received other therapeutic strategies in the framework of an experimental study that make it difficult to evaluate the results obtained, including (but not limited to): convalescent plasma, lopinavir / ritonavir, hydroxychloroquine, and azithromycin.
4. Pregnant or lactating women.
5. Women of childbearing potential not using an effective contraceptive method (withdrawal, intrauterine device, or oral contraceptives).
6. History of severe anaphylactic reaction with the administration of equine plasma.
7. Patients with comorbidities that justify a risk of high mortality from causes independent of SARS-CoV-2 infection (eg, stage IV cancer)
8. Patient who does not consent to participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Anti-SARS-CoV-2; Administration of 10 ml of a concentrated equine hyperimmune serum solution with neutralizing activity of SARS-CoV-2 not less than1/5120, administered in slow intravenous infusion (10 ml diluted in100 ml of physiological solution, administered over 50 to 60 minutes in slow drip), produced by ANLIS-Malbrán, administered twice (time 0 when incorporated into the study -initial dose- and at 48 hours -second dose-).	Drug: Anti-SARS-CoV-2; Purified F(ab')2 Fragments of Equine hyperimmune Serum with anti-SARS-CoV-2 neutralizing activity (titer 1/5120 or higher); Other Names: Treatment Group; Purified F(ab')2 Fragments of Equine hyperimmune Serum; F(ab')2 Fragments; Passive Immunotherapy; Equine F(ab')2 Fragments; Hyperimmune Equine Serum
Placebo Comparator: Placebo; Administration of 10 ml of a control-solution with no-neutralizing activity of SARS-CoV-2, administered in slow intravenous infusion (10ml diluted in 100 ml of physiological solution, administered over 50 to60 minutes in slow drip), produced by ANLIS-Malbrán, administered twice (time 0when incorporated into the study -initial dose- and at 48 hours -second dose-).	Drug: Placebo; Administration of 10 ml of a control-solution without neutralizing activity against SARS-CoV-2, administered in slow intravenous infusion (10 ml diluted in 100 ml of saline solution, administered over 50 to 60 minutes in slow drip), produced by ANLIS-Malbrán, administered twice (time 0 when incorporated into the study -initial dose- and at 48 hours -second dose-).; Other Names: Control Group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in time needed to clinical improvement	In subjects admitted to the general ward for active infection by SARS-CoV-2 and a clinical picture of pneumonia who receive supportive treatment recommended by the guidelines of the Ministry of Health of the Argentine Nation (Population), if slow intravenous administration of Anti SARS-CoV-2 in two doses 48 hours apart (Intervention) added to supportive treatment, compared to supportive treatment alone (patients will receive slow intravenous administration of a placebo solution in two doses 48 hours apart to maintain the "blind" as Comparator), changes the time needed to clinical improvement (Outcome), during 28 days after the assignment (Time).	Reached each day between day 1 and 28 post-inclusion in the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the number of patients in each World Health Organization (WHO) Ordinal Scale Category (0 to 8 being 0 better and 8 worse)	(a) Change in the number of patients in each World Health Organization Ordinal Scale Category (0 to 8 being 0 better and 8 worse), expecting a lower proportion of patients in categories 4, 5, 6, and 7 (OUTCOME - Efficacy);	days 7, 14 and 21 post-inclusion
Change in Mortality rate	(b) Change of all-cause mortality at day 28 (OUTCOME - Efficacy);	28 days post-inclusion
Change in Mechanical Ventilation Requirement rate	(c) Determination of the frequency of invasive mechanical ventilation in the total analysis period (OUTCOME - Efficacy);	28 days post-inclusion
Change in duration of oxygen treatment requirement	(d) Change of the duration of oxygen therapy quantified in days of oxygen therapy (OUTCOME - Efficacy);	28 days post-inclusion
Change in Length of Hospitalization	(e) Change of hospital length of hospitalization, quantified in days from study inclusion until hospital discharge (OUTCOME - Efficacy);	28 days post-inclusion
Change in frequency of nosocomial infection	(F) Change in the frequency of patients with nosocomial infection (OUTCOME - Efficacy);	28 days post-inclusion
Change in Lymphocyte cell count	(g) Change of absolute lymphocyte count (OUTCOME - Efficacy);	28 days post-inclusion
Change in viral RNA Negativization rate on nasopharyngeal swab test	(h) change in the proportion of patients with detected viral RNA and the viral RNA load, measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), on day 7, 14, 21, and 28 (OUTCOME - Efficacy);	7, 14, 21, and 28 days post-inclusion
Description of adverse events type and frequency	(i) description of reported adverse events, discriminated by their severity, and classified according to MedDRA (OUTCOME - Safety).	28 days post-inclusion
Requirement of additional treatments for Adverse Drug reactions	(j) The number of subjects who required additional treatment as a consequence of reported adverse events in each therapeutic branch (OUTCOME - Safety)	28 days post-inclusion
Describe the AUC of purified F(ab')2 Anti-SARS-CoV-2	(k1) Describe area under the curve (AUC) of the active drug, based on concentrations determined in plasma samples obtained from the first 20 patients	Time 0 (Basal, prior to drug administration), hours 1, 3, 6, 24, 48, 49 and 96, days 7, 14, 21 and 28 days
Describe the Cmax of purified F(ab')2 Anti-SARS-CoV-2	(k2) Describe maximum plasma concentration (Cmax) of the active drug, based on concentrations determined in plasma samples obtained from the first 20 patients (at time Minute 0 min, hours 1, 3, 6, 24, 48, 49 and 96, day 7, 14, 21 and 28 days).	Time 0 (Basal, prior to drug administration), hours 1, 3, 6, 24, 48, 49 and 96, days 7, 14, 21 and 28 days
Describe the t1/2 of purified F(ab')2 Anti-SARS-CoV-2	(k3) Describe plasma half life (t1/2) of the active drug, based on concentrations determined in plasma samples obtained from the first 20 patients (at time Minute 0 min, hours 1, 3, 6, 24, 48, 49 and 96, day 7, 14, 21 and 28 days).	Time 0 (Basal, prior to drug administration), hours 1, 3, 6, 24, 48, 49 and 96, days 7, 14, 21 and 28 days
Describe the Ke of purified F(ab')2 Anti-SARS-CoV-2	(k4) Describe elimination constant (Ke) of the active drug, based on concentrations determined in plasma samples obtained from the first 20 patients (at time Minute 0 min, hours 1, 3, 6, 24, 48, 49 and 96, day 7, 14, 21 and 28 days).	Time 0 (Basal, prior to drug administration), hours 1, 3, 6, 24, 48, 49 and 96, days 7, 14, 21 and 28 days

Collaborators and Investigators

• Sponsor: Administracion Nacional de Laboratorios e Institutos de Salud Dr. Carlos G. Malbran
• Investigators: Principal Investigator: Guillermo A Keller, PhD, INPB - ANLIS Malbrán

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Anticipated): November 30, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: June 1, 2021
• First Submitted That Met QC Criteria: June 2, 2021
• First Posted (Actual): June 4, 2021

Study Record Updates

• Last Update Posted (Actual): September 17, 2021
• Last Update Submitted That Met QC Criteria: September 11, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Anti-SARS-CoV-2; Purified F(ab')2 Fragments; Passive immunotherapy; Equine Serum
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Respiratory Tract Infections
• Other Study ID Numbers: INPB001; PRIISA.BA 2578 (Registry Identifier: PRIISA.BA); RENIS IS003268 (Registry Identifier: RENIS); DI-2021-2196-APN-ANMAT#MS (Other Identifier: Disposición ANMAT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Publication of the results of all data obtained is planned.
• IPD Sharing Time Frame: After completion of the study.
• IPD Sharing Access Criteria: By request to the Principal Investigator
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No