Clinical Study to Compare Efficacy and Safety of Casirivimab and Imdevimab Combination, Remdesivir and Favipravir in Hospitalized COVID-19 Patients

Study Overview
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Brief Summary
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Introduction: Corona Virus induced disease - 2019 (COVID-19) pandemic stimulates research works to find a solution to this crisis from starting 2020 year up to now. With ending of 2021 year, various advances in pharmacotherapy against COVID-19 have emerged. Regarding antiviral therapy, Casirivimab and imdevimab antibody combination is a type of new immunotherapy against COVID-19. Standard antiviral therapy against COVID-19 includes Remdesivir and Favipravir. Aim of Study: To compare the efficacy of antibodies cocktail (casirivimab and imdevimab), Remdesivir and Favipravir in reducing 28-day mortality in hospitalized patients with moderate, severe or critical COVID19 To compare safety of antibodies cocktail (casirivimab and imdevimab), Remdesivir and Favipravir by monitoring hypersensitivity and infusion related reactions or other significant adverse effects Patients and Population: 265 COVID-19 Polymerase Chain Reaction (PCR) confirmed patients with indication for antiviral therapy is included in this study and will be divided into 3 groups (1:2:2): Group A: REGN3048-3051(Antibodies cocktail (casirivimab and imdevimab)) group B: Remdesivir group C: Favipravir Methods: Study design is single blind non-Randomized Controlled Trial (non-RCT). The drugs of the study are owned by Mansoura University Hospital (MUH), and prescribed by chest diseases lectures of faculty of medicine-Mansoura University. The duration of study is about 6 months after ethical approval.

Detailed Description
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I. INTRODUCTION 1.1. COVID-19 overview and classification COVID-19 is an infectious viral disease caused by sever acute respiratory syndrome-corona virus 2 (SARS CoV-2) that has affected large number of people all over the world with high mortality rate. COVID-19 infection has been classified as: Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging. Moderate Illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level. Severe Illness: Individuals who have Saturation pressure of oxygen (SpO2) <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%. Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunctions. Covid-19 pandemic stimulates research works to find a solution to this crisis from starting 2020 year up to now. With ending of 2021 year, various advances in pharmacotherapy against COVID-19 have emerged. 1.2. Standard and controversial antivirals used in treatment of COVID-19 (Remdesivir and Favipravir) Regarding antiviral drugs used in treatment of COVID-19, Remdesivir is a standard antiviral against COVID-19 and has been approved by Food and drug administration (FDA) for treatment of mild, moderate, sever and critical hospitalized COVID-19 patients. Other drugs have shown controversial antiviral activity include: favipravir, ivermectin, nitazoxanide, hydroxychloroquine, ribavirin. Favipravir became a standard antiviral which has been used for treatment of mild and moderate COVID-19 outpatients. 1.3. Advances in immunotherapy for treatment of COVID-19 Recently with the end of 2020, immunotherapy to target virus antigen has developed. Figure 1 shows two types of immunotherapy include active and passive immunotherapy. Active immunotherapy is to enhance body to produce antibodies against virus as by vaccination. Passive immunotherapy involves direct administration of prepared antibodies acting specifically against virus or administration of product containing antibodies like plasma. There are three targets for these antibodies to work as antiviral including: antibodies that prevent the virus attachment and entry antibodies that inhibit the virus replication and transcription antibodies that hinder various steps of the immune system response Table 1 includes various types of antibodies under investigation for treatment of COVID-19 and their targets. 1.4. Casirivimab and Imdevimab as antibodies cocktail against COVID-19 In the present study, the point of research is antibodies cocktail including REGN3048-3051(casirivimab and imdevimab).REGN3048 and REGN3051 are human monoclonal antibodies targeting the spike glycoprotein on surface of viral particles thereby preventing viral entry into human cells through the angiotensin-converting enzyme 2(ACE2) receptor, and have shown promising antiviral activity and need for further investigation to prove their benefit in COVID patients. Previous study on REGN3048-3051 has mentioned that both efficacy and safety of this antibodies cocktail are proved in COVID-19 outpatients treatment in both low (2.4 g of REGN-COV2), or high (8.0 g of REGN-COV2) dose when compared to placebo, Efficacy is measured as Virologic Efficacy Time-weighted average change from baseline in viral load through day 7 (log10 scale) in patient. Clinical Efficacy Percentage of patients with one or more medically attended visits and Symptoms offset at day 7 Safety is measured as Percentage of treated patients who experience infusion related and hypersensitivity reactions and incidence of any serious and unexpected adverse effect. This previous study concluded that efficacy is greater and more obvious in seronegative outpatients (whose immune response is not developed yet to produce antibodies against virus) and with high baseline viral load outpatients. Now, data is available for these new antibodies cocktails. The U.S. FDA has allowed an Emergency Use Authorization (EUA) for casirivimab and imdevimab combination in the treatment and post-exposure prophylaxis of mild and moderate COVID-19 in adults and pediatric outpatients (more than12 years of age and not less than 40 kg) with positive PCR results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19 requiring hospitalization or causing death.. In contrast, REGN3048 and REGN3051 are still not authorized for use in patients: who are hospitalized due to COVID-19, OR who require oxygen therapy due to COVID-19, OR who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity(FDA, 2021). Now, casirivimab and imdevimab are approved investigational antibodies, Serious and unexpected adverse effects can occur that not previously reported with their use. Confirmed adverse effects include hypersensitivity and infusion related reactions and the study have showed that there is no difference in safety profile between intravenous (I.V) infusion and subcutaneous (S.C) injection. Data about use during pregnancy and breastfeeding mother is insufficient yet. Also, Data not support any dosage adjustment in hepatic and renal patients. This antibody combination follows linear pharmacokinetics after its single intravenous doses with half-life of about 25 to 37 days for both antibodies. Regarding elimination, this combination is not metabolized by liver cytochrome enzymes ,and not excreted by kidneys. Limitations of the previous study performed on antibody cocktail include: short duration of follow up not used much clinical relevant outcomes like mortality rate Not studied the long term effect of antiviral efficacy in lowering viral load on inflammatory markers. Study performed on non-hospitalized patients only and not included hospitalized patients (trial is done only on outpatients and not inpatients) II. AIM OF THE STUDY: To evaluate the efficacy of antibodies cocktail (casirivimab and imdevimab) compared to standard antiviral therapy in reducing 28-day mortality in hospitalized patients with moderate, severe or critical COVID19 To evaluate safety of antibodies cocktail (casirivimab and imdevimab) compared to standard antiviral therapy by monitoring of hypersensitivity and infusion related reactions or other significant adverse effects III. PATIENTS AND POPULATION 265 COVID-19 PCR confirmed patients with indication for antiviral therapy is included in this study and will be randomized (2:1:1) into 3 groups Group A: REGN3048-3051(Antibodies cocktail (casirivimab and imdevimab) ) group B: Remdesivir group C: Favipravir Population in this study are patients hospitalized in isolation hospital-Mansoura university. A computer file containing a written informed consent from included patients will be provided. Paper will not be a tool for providing agreement by patients or their relatives to avoid transmission of infection. IV. INTERVENTIONS Population included in this study will be assigned into 3 groups with 1:2:2 ratios to receive either antibodies cocktail or standard antiviral therapy (remdesvir, favipravir). Group A patients will receive REGN3048-3051(Antibodies cocktail (casirivimab and imdevimab) ) in low-dose regimen 1.2 gm (1200 mg of combined antibodies) diluted in 250 ml 0.9% sodium chloride solution as single I.V infusion over 30-60 minutes. Group B patients will receive Remdesivir : Day1 (loading dose): 200 mg (two 100mg vials) diluted in 500ml 0.9% sodium chloride solution infused I.V over 60 minutes Day 2-5 or Day 2-10 (maintenance dose): 100 mg (one 100mg vial) in 250 ml 0.9% sodium chloride solution infused I.V over 30 minutes Group C patients will receive Favipravir : Day 1 (loading dose): 1600 mg (8 tablets) or 1800 mg (9 tablets) orally or in Ryle tube / 12 hours Day 2-5 or day 2-10 (maintenance dose): 600 mg (3 tablets) or 800 mg (4 tablets) orally or in Ryle tube / 12 hours Patients will be received standard of care by Physicians, Clinical pharmacist , Nurses and as guided by Egyptian COVID-19 treatment protocol. V. METHOD The type of this study is single blind non-RCT and is considered a Phase IV Clinical trial (post-marketing study) to report efficacy and safety of new medicine. We use PubMed search tool to find clinical studies that performed to test efficacy and safety of developed immunotherapy in treatment of COVID-19 with about 4,000 results with focusing on antibodies developed as antiviral against COVID-19 obtaining only 70 results from which REGN-COV2, a Neutralizing Antibody Cocktail is selected with its only one clinical study up to now (REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19) which is published in New England Journal of Medicine on January 21, 2021. Another resource used to obtain data is Fact Sheet for Health Care Providers- EUA OF casirivimab and imdevimab which provides clinical data about the use of this antibodies cocktail. Endnote citation software is used for citation of references.

Official Title
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Clinical Study to Evaluate the Possible Efficacy and Safety of Antibodies Combination (Casirivimab and Imdevimab) Versus Standard Antiviral Therapy (Remdesivir and Favipravir) as Antiviral Agent Against Corona Virus 2 Infection in Hospitalized COVID-19 Patients

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Casirivimab and Imdevimab Drug Combination
* Drug: Remdesivir
* Drug: Favipiravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age more than 12 years old. weight not less than 40 kg. Moderate, sever or critical COVID-19 disease as defined by WHO. PCR- confirmed patients to be Positive before inclusion. Exclusion Criteria: history of hypersensitivity or infusion related reactions after administration of monoclonal antibodies. prior use of standard antiviral therapy (remedsvir or favipravir). Current use of controversial antiviral therapy (hydroxychloroquine, ivermectin, nitazoxanide, oseltemavir, acyclovir, ribavirine, lopinvir/rotinvir, sofosfbuvir, decltasevir, semipirvir, azithromycin). patients expected to die within 48 hours.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: casirivimab and imdevimab<br>casirivimab and imdevimab, vials 1.2 gm (1200 mg of combined antibodies) diluted in 250 ml 0.9% sodium chloride solution as single I.V infusion over 30-60 minutes. | Drug: Casirivimab and Imdevimab Drug Combination<br>* antiviral Monoclonal Antibodies<br>* Other names: REGN-COV2;|
| Experimental: Remdesivir<br>Remdesivir, vials Day1 (loading dose): 200 mg (two 100mg vials) diluted in 500ml 0.9% sodium chloride solution infused I.V over 60 minutes Day 2-5 or Day 2-10 (maintenance dose): 100 mg (one 100mg vial) in 250 ml 0.9% sodium chloride solution infused I.V over 30 minutes | Drug: Remdesivir<br>* antiviral drug<br>* Other names: Veklury;|
| Experimental: Favipravir<br>Favipravir, tablets Day 1 (loading dose): 1600 mg (8 tablets) or 1800 mg (9 tablets) orally or in Ryle tube / 12 hours Day 2-5 or day 2-10 (maintenance dose): 600 mg (3 tablets) or 800 mg (4 tablets) orally or in Ryle tube / 12 hours | Drug: Favipiravir<br>* antiviral drug<br>* Other names: Avigan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-days Mortality Rate | Dead or alive | 28 days | 
| Number of Participants With Positive or Negative Polymerase Chain Reaction (PCR) Test Results at End of Hospital Visit | positive or negative | up to 60 days | 
| Number of Participants With Infusion Related Reactions, Hypersensitivity Reactions and Any Serious Adverse Events | yes or no | up to 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for Invasive Mechanical Ventilation | yes or no | up to 60 days | 
| Oxygen Support Duration (Days) | in days | up to 60 days | 
| Time to Clinical Improvement (Defined as 2 Points Reduction in the WHO Disease Ordinal Progression Scale or Discharge, Whatever Happens First | in days WHO disease ordinal progression scale 0= Uninfected Ambulatory mild disease Asymptomatic; viral RNA detected Symptomatic; independent. Symptomatic; assistance needed Hospitalized: moderate disease Hospitalized; no oxygen therapy Hospitalized; oxygen by mask or nasal prongs Hospitalized: sever disease Hospitalized; oxygen by NIV or high flow Intubation and mechanical ventilation, pO2 /FIO2 ≥ 150 or Spo2 /FiO2 ≥200 Mechanical ventilation pO2/FiO2 <150 (SpO2 /FiO2 < 200) or vasopressors Mechanical ventilation pO2 / FiO2 < 150 and vasopressors, dialysis or ECMO Dead Dead | up to 60 days | 
| Duration of Hospitalization | in days | up to 60 days | 
| Sequential Organ Function Assessment (SOFA) Score on Day 3 | minimum 0 to maximum 24, higher scores mean worse outcomes Platelets, ×10³/µL ≥150 0 100-149+1 50-99+2 20-49+3 <20+4 Glasgow Coma Scale If on sedatives, estimate assumed GCS off sedatives 15 0 13-14+1 10-12+2 6-9+3 <6+4 Bilirubin, mg/dL (μmol/L) <1.2 (<20) 0 1.2-1.9 (20-32)+1 2.0-5.9 (33-101)+2 6.0-11.9 (102-204)+3 ≥12.0 (>204)+4 Mean arterial pressure OR administration of vasoactive agents required Listed doses are in units of mcg/kg/min No hypotension 0 MAP <70 mmHg+1 DOPamine ≤5 or DOBUTamine (any dose)+2 DOPamine >5, EPINEPHrine ≤0.1, or norEPINEPHrine ≤0.1+3 DOPamine >15, EPINEPHrine >0.1, or norEPINEPHrine >0.1+4 Creatinine, mg/dL (μmol/L) (or urine output) <1.2 (<110) 0 1.2-1.9 (110-170)+1 2.0-3.4 (171-299)+2 3.5-4.9 (300-440) or UOP <500 mL/day+3 ≥5.0 (>440) or UOP <200 mL/day+4 | Day 3 | 
| COVID-19 World Health Organization (WHO) Disease Progression Scale at Day 3 | minimum 0 to maximum 10, higher scores mean worse outcomes | Day 3 | 
| Aspartate Aminotransferase (AST) at Day 3 | continuous level | day 3 | 
| Ferritin at Day 3 | continuous level | day 3 | 
| Lactate Dehydrogenase (LDH) at Day 3 | continuous level | day 3 | 
| D-dimer at Day 3 | continuous level | day 3 | 
| Alanine Aminotransferase (ALT) at Day 3 | continuous level | day 3 | 
| Albumin at Day 3 | continuous level | day 3 | 
| Bilirubin at Day 3 | continuous level | day 3 | 
| C-reactive Protein (CRP) at Day 3 | continuous level | day 3 | 
| Duration of Intensive Care Unit (ICU) Stay | duration of ICU stay | up to 60 days | 
| C-reactive Protein (CRP) at Day 7 | continuous level | day 7 | 
| C-reactive Protein (CRP) at Day 14 | continuous level | day 14 | 
| C-reactive Protein (CRP) at Day 28 | continuous level | day 28 | 
| Sequential Organ Function Assessment (SOFA) Score on Day 7 | minimum 0 to maximum 24, higher scores mean worse outcomes | day 7 | 
| Sequential Organ Function Assessment Score (SOFA) on Day 14 | minimum 0 to maximum 24, higher scores mean worse outcomes | day 14 | 
| Sequential Organ Function Assessment Score (SOFA) on Day 28 | minimum 0 to maximum 24, higher scores mean worse outcomes | day 28 | 
| COVID-19 World Health Organization (WHO) Disease Progression Scale at Day 7 | minimum 0 to maximum 10, higher scores mean worse outcomes | day 7 | 
| COVID-19 World Health Organization (WHO) Disease Progression Scale at Day 14 | minimum 0 to maximum 10, higher scores mean worse outcomes | day 14 | 
| COVID-19 World Health Organization (WHO) Disease Progression Scale at Day 28 | minimum 0 to maximum 10, higher scores mean worse outcomes | day 28 | 
| Aspartate Aminotransferase (AST) at Day 7 | continuous level | day 7 | 
| Aspartate Aminotransferase (AST) at Day 14 | continuous level | day 14 | 
| Aspartate Aminotransferase (AST) at Day 28 | continuous level | day 28 | 
| Alanine Aminotransferase (ALT) at Day 7 | Continuous level | day 7 | 
| Alanine Aminotransferase (ALT) at Day 14 | Continuous level | day 14 | 
| Alanine Aminotransferase (ALT) at Day 28 | Continuous level | day 28 | 
| Bilirubin at Day 7 | Continuous level | day 7 | 
| Bilirubin at Day 14 | Continuous level | day 14 | 
| Bilirubin at Day 28 | continuous level | day 28 | 
| Albumin at Day 7 | continuous level | day 7 | 
| Albumin at Day 14 | continuous level | day 14 | 
| Albumin at Day 28 | continuous level | day 28 | 
| Platelets at Day 3 | continuous level | day 3 | 
| Platelets at Day 7 | continuous level | day 7 | 
| Platelets at Day 14 | continuous level | day 14 | 
| Platelets at Day 28 | continuous level | day 28 | 
| Serum Creatinine (S.Cr) at Day 3 | continuous level | day 3 | 
| Serum Creatinine (S.Cr) at Day 7 | continuous level | day 7 | 
| Serum Creatinine (S.Cr) at Day 14 | continuous level | day 14 | 
| Serum Creatinine (S.Cr) at Day 28 | continuous level | day 28 | 
| D-dimer at Day 7 | continuous level | day 7 | 
| D-dimer at Day 14 | continuous level | day 14 | 
| D-dimer at Day 28 | continuous level | day 28 | 
| Creatine Kinase (Ck) at Day 3 | continuous level | day 3 | 
| Creatine Kinase (Ck) at Day 7 | continuous level | day 7 | 
| Creatine Kinase (Ck) at Day 14 | continuous level | day 14 | 
| Creatine Kinase (Ck) at Day 28 | continuous level | day 28 | 
| Lactate Dehydrogenase (LDH) at Day 7 | continuous level | day 7 | 
| Lactate Dehydrogenase (LDH) at Day 14 | continuous level | day 14 | 
| Lactate Dehydrogenase (LDH) at Day 28 | continuous level | day 28 | 
| Ferritin at Day 7 | continuous level | day 7 | 
| Ferritin at Day 14 | continuous level | day 14 | 
| Ferritin at Day 28 | continuous level | day 28 | 
| Incidence of Acute Kidney Injury (AKI) | Incidence of acute kidney injury (AKI) | up to 60 days | 
| Incidence of Acute Liver Damage (ALD) | Incidence of acute liver damage (ALD) | up to 60 days | 
| Day of Death | day of death | up to 60 days | 
| Mortality at Discharge | mortality at discharge | up to 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Casirivimab & Imdevimab, Remdesivir, Favipravir