Safety and Effectiveness of an Immunobiological Drug in CoViD-19

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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COVID-19 Pneumonia, COVID-19 Respiratory Infection, Covid19

Intervention / Treatment
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* Drug: Anti-SARS-CoV-2
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects over 18 years old and under 80 years old. Positive results by RT-PCR for SARS CoV-2 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. Patient with good disposition towards the study and that signs the informed consent. Exclusion Criteria: 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%) Patients with clinical disease corresponding to severe forms (Severe pneumonia: presence of severity criteria (ATS / IDSA), one of two major or three minor criteria.) 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. Pregnant or lactating women. Women of childbearing potential not using an effective contraceptive method (withdrawal, intrauterine device, or oral contraceptives). History of severe anaphylactic reaction with the administration of equine plasma. Patients with comorbidities that justify a risk of high mortality from causes independent of SARS-CoV-2 infection (eg, stage IV cancer) Patient who does not consent to participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an adaptive phase 2/3, randomized, blinded, placebo-controlled study. 200 total patients (ratio 1:1) will be included with intermediate evaluations when reaching the initial 20 patients (initial analysis of safety and pharmacokinetics), 100 (analysis of safety and efficacy) and 200 (final analysis).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Anti-SARS-CoV-2<br>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<br>* Purified F(ab')2 Fragments of Equine hyperimmune Serum with anti-SARS-CoV-2 neutralizing activity (titer 1/5120 or higher)<br>* Other names: Treatment Group;|
| Placebo Comparator: Placebo<br>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<br>* 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-).<br>* Other names: Control Group;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-SARS-CoV-2, Purified F(ab')2 Fragments, Passive immunotherapy, Equine Serum