Study to Evaluate the Safety and Efficacy of XAV-19 in Patients With COVID-19 Induced Moderate Pneumonia

Study Overview
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Brief Summary
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Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunt an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions1-3. Because a suboptimal endogenous early antibody response with regard to SARS-CoV-2 replication in severe cases is observed, neutralising antibody treatment can be very interesting for patient with COVID-19 induced moderate pneumonia4,5. Convalescent plasma to treat infected patients is therefore an interesting therapeutic option currently under evaluation. However, the difficulties of collecting plasma and its safety aspects are not adapted to many patients. A new polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) is being developed by Xenothera, which can be administered as intravenous treatment. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, inhibiting infection of ACE-2 positive human cells with SARS-CoV-2. Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates and a First In Human study with another fully representative GH-pAb from Xenothera is ongoing in volunteer patients recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objective of this 2-steps phase 2 randomized double-blind, placebo-controlled study is 1) to define the optimal and safety XAV-19 dose to administrate in patients with COVID-19 induced moderate pneumonia ; 2) to show the clinical benefit of selected dose of XAV-19 when administered to patients with COVID-19 induced moderate pneumonia.

Detailed Description
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For the first set of statistical analyses, to allow early reporting of primary and secondary endpoints at D15, the blind will be partially broken once all patients have completed Day 29. Except for statisticians, only the principal investigator and the scientific coordinator will have access to the full data set for the analysis of the primary and secondary endpoints up to day 29. The database will be partially locked (with all data up to day 29) as neither monitors nor investigators will be informed of the unblinding until the final data for day 60 is completed and the final database is locked.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase 2 (2a and 2b) Study to Evaluate the Safety and Efficacy of XAV-19 in Patients With COVID-19 Induced Moderate Pneumonia

Conditions
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SARS Virus

Intervention / Treatment
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* Drug: XAV-19
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Phase 2a: Inclusion Criteria: Willing and able to provide written informed consent prior to performing study procedures Male or female ≥ 18 years and ≤ 85 years Hospitalized for COVID-19 Positive SARS-CoV-2 RT-PCR in any body specimen (nasopharynx, saliva, sputum) ≤ 10 days before enrolment Evidence of pulmonary involvement (on lung examination [rales/crackles] and/or chest-imaging [Chest X-ray or computed tomography]) Requiring O2 supplement ≤ 6L/min at screening Requiring O2 supplementation with SpO2 ≥ 94% on O2 therapy at screening First onset of COVID-19 symptoms ≤ 10 days, among fever and/or chills, headache, myalgias, cough, shortness of breath, whichever as occurred fist WOCBP must have a negative urinary pregnancy test the day of inclusion All sexually active male subjects must agree to use an adequate method of contraception throughout the study period and for 90 days after the last dose of study drug and agree to no sperm donation until the end of the study, or for 90 days after the last dose of XAV-19, whichever is longer Patients with French social security Exclusion Criteria: Evidence of multiorgan failure (severe COVID-19) Mechanically ventilated (including ECMO) Receipt of immunoglobulins or any blood products in the past 30 days Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the investigator, would affect subject safety and/or compliance End-stage renal disease (eGFR < 15 ml/min/1,73 m2) Child-Pugh C stage liver cirrhosis Decompensated cardiac insufficiency History of active drug abuse Known allergy, hypersensitivity, or intolerance to the study drug, or to any of its components Females of childbearing potential without contraceptive method, or with positive pregnancy test, breastfeeding, or planning to become pregnant during the study period Current documented and uncontrolled bacterial infection. Prior severe (grade 3) allergic reactions to plasma transfusion Patient participating in another interventional clinical trial Life expectancy estimated to be less than 6 months Patient under guardianship or trusteeship Phase 2b: Inclusion criteria: Willing and able to provide written informed consent prior to performing study procedures Male or female ≥ 18 years Hospitalized for COVID-19 Documentation of SARS-Cov-2 infection before enrolment, by positive SARS-CoV-2 RT-PCR or antigen in any body specimen (nasopharynx, oropharynx, saliva, sputum, bronchoalveolar lavage …) before enrolment Evidence of pulmonary involvement (on lung examination [rales/crackles] and/or chestimaging [Chest X-ray or computed tomography]) Requiring O2 supplement ≤ 6L/min at screening Requiring O2 supplementation with SpO2 ≥ 92% on O2 therapy at screening (or ≥ 90 % if chronic obstructive pulmonary disease) First onset of COVID-19 symptoms ≤ 14 days, among fever and/or chills, headache, myalgias, cough, shortness of breath, whichever as occurred fist (other symptoms such as asthenia not to be considered in this list) WOCBP must have a negative urinary pregnancy test the day of inclusion All sexually active male subjects must agree to use an adequate method of contraception throughout the study period and for 90 days after the last dose of study drug and agree to no sperm donation until the end of the study, or for 90 days after the last dose of XAV-19, whichever is longer Patients with French social security Exclusion criteria: Evidence of multiorgan failure (severe COVID-19) Mechanically ventilated (including ECMO) Receipt of immunoglobulins or any blood products in the past 30 days Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the investigator, would affect subject safety and/or compliance End-stage renal disease (eGFR < 15 ml/min/1,73 m2) Child-Pugh C stage liver cirrhosis Decompensated cardiac insufficiency Known allergy, hypersensitivity, or intolerance to the study drug, or to any of its components Females of childbearing potential without contraceptive method, or with positive pregnancy test, breastfeeding, or planning to become pregnant during the study period Current documented and uncontrolled bacterial infection. Prior severe (grade 3) allergic reactions to plasma transfusion Patient participating in another interventional clinical trial Life expectancy estimated to be less than 6 months Patient under guardianship or trusteeship Patient already included Prior hospitalisation in intensive care unit for the current covid-19 episode

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Administrations of XAV-19 Phase 2a: XAV-19 at 0.5 mg/kg at D1 and D5(Group 1) or at 2 mg/kg at D1 and D5 (Group 2), or at 2 mg/kg at D1 (groupe 3) Phase 2b: Selected dose from Phase 2a : one administration at 2 mg/kg on day1 | Drug: XAV-19<br>* Phase 2a: Administration on Day 1 and day 5 for Group1 and 2, Administration on Day 1 for Group 3 Phase 2b: Administration on Day 1<br>|
| Placebo Comparator: Placebo arm<br>same administration as treatment arm Phase 2a: two administrations of placebo (day 1 and day 5) for Group 1 and 2, one administration of placebo on day 1 for Group 3 Phase 2b: one administration of placebo on day 1 | Drug: Placebo<br>* Phase 2a: Administration on Day 1 and day 5 for Group1 and 2, Administration on Day 1 for Group 3 Phase 2b: Administration on Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2a: XAV-19 antibody titers | The primary endpoint is measurement of the antibody titer XAV-19 in all treated patients and in all patients in the placebo group at Day 8 | Day 8 | 
| Phase 2a: Adverse events of XAV-19 | Adverse events of XAV-19 between the two groups of treated patients and vs. placebo over 29 days | Day 29 | 
| Phase 2b: To evaluate the efficacy of XAV-19 + standard-of-care (Soc) therapy compared with placebo + Soc therapy for treatment of COVID-19 assessed by the proportion of patients who die or develop respiratory failure between baseline and Day 15. | Efficacy is defined by the proportion of patients who died or develop respiratory failure, as defined by the requirement of noninvasive ventilation, high-flow oxygen devices, invasive mechanical ventilation (corresponding to a score of 5 or more on the WHO 8 point ordinal scale) or by an increase of the required O2 supplement (more or equals to 10 L/minutes with a non-rebreather mask (oxygen mask with reservoir bag) | Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2a: Pharmacokinetic analysis | XAV-19 Antibody titer over the time | Day 1 (pre-dose, post-dose), at Day 5 (pre-dose, post-dose), Day 8, Day 15, and Day 29 | 
| Phase 2a: Antibody titer between the two groups | The antibody titer of XAV-19 measurements in Group 1 treated patients and Group 2 treated patients | day 15 | 
| Phase 2a: Supplemental oxygen | Duration of supplemental oxygen | Day 1 to Day 29 | 
| Phase 2a: Evaluation of Transfer to intensive care | Transfer to intensive care unit with need for invasive mechanical ventilation or high flow oxygen | Day 1 to Day 29 | 
| Phase 2a: Normalization of Fever | Normalization of fever ≥ 24 hours: clinical assessment every day from Day 1 to Day 14. Evaluation to be performed between 8 and 12 am, Day X evaluation will consider the higher value during Day X-1 | Day 1 to Day 29 | 
| Phase 2a: Biomarkers | Biomarkers : CRP, Ferritin | Day 1 to Day 29 | 
| Phase 2a: Hospital length of stay | Evaluation of Hospital length of stay | Day 1 to Day 29 | 
| Phase 2b: Efficacy of XAV-19 | Proportion of patients who die, develop respiratory failure, as defined by the requirement of noninvasive ventilation, high-flow oxygen devices or invasive mechanical ventilation at Day 8 and D29 | Day 8 and Day 29 | 
| Phase 2b: Clinical severity | a) National Early Warning Score (NEWS) assessed while hospitalized and on Day 15 and Day 29 | Day 3, Day 5, Day 8, Day15 and Day 29 | 
| Phase 2b: Clinical severity | b) Clinical status using the 8-point ordinal scale assessed daily until Day 29 | Day 29 | 
| Phase 2b: Clinical severity : Improvement of clinical and biological parameters | c) Temperature and blood analysis between baseline and Day 15, and Day 29 | Day15, and Day 29 | 
| Phase 2b: Clinical severity : Oxygenation | d) Days of oxygen therapy over 29 days PaO2 / FiO2 at baseline, Day 5, Day 8, Day 15, Day 29 if available | 29 Days | 
| Phase 2b: Clinical severity : Non-invasive ventilation, high-flow oxygen | e) e) Days of non-invasive ventilation or high flow oxygen (if applicable) up to Day 29 | 29 Days | 
| Phase 2b: Clinical severity : Invasive mechanical ventilation / Extra Corporeal Membrane Oxygenation (ECMO) | f) Days of invasive mechanical ventilation/ECMO (if applicable) up to Day 29 | 29 Days | 
| Phase 2b: Clinical severity : Transfer in ICU by Day 29 | g) Transfer in ICU | 29 Days | 
| Phase 2b: Clinical severity : Hospitalization | h) Hospital length of stay (in days) | 60 Days | 
| Phase 2b: Clinical severity : Mortality | i) All-cause mortality evaluated between baseline and Day 15 and between baseline and at Day 29 and at Day 60 | 60 Days | 
| Phase 2b: Clinical severity : Thrombotic events | j) Thrombotic events (peripheral venous, pulmonary, arterial) | 60 Days | 
| Phase 2b: mortality | k) All cause mortality | 29 Days | 
| Phase 2b: safety | Occurrence of all suspected XAV-19 related adverse effects or Incidence of serious adverse events | 29 days and 60 days | 
| Phase 2b: safety of Study drug infusion | Study drug discontinuation or temporary suspension of infusion | 29 days and 60 days | 
| Phase 2b: safety : study drug discontinuation | Proportion of participants with treatment emergent adverse events leading to study drug discontinuation | 29 days and 60 days | 
| Phase 2b: safety : major or opportunistic bacterial or fungal infections | Incidence of major or opportunistic bacterial or fungal infections | 29 days and 60 days | 
| Phase 2b: safety : hypersensitivity reactions and infusion reactions | Incidence of hypersensitivity reactions and infusion reactions | 29 days and 60 days | 
| Phase 2b: safety : biological parameters | White cell count, hemoglobin, platelets, creatinine, ALT, AST, on D1, D3, D5, D8, D15 and D29 | 29 days and 60 days | 
| Phase 2b: Exploratory analysis : qualitative and quantitative SARS-CoV-2 status | SARS-CoV-2 status (positive or negative and quantitatively, including variant information by sequencing) over time (D1, D8, D15, and D29) | Day 1, Day 8, Day 15 and Day 29 | 
| Phase 2b: Exploratory analysis : SARS-CoV-2 status viral load | SARS-CoV-2 status viral load over time (D1, D8, D15, and D29) | Day 1, Day 8, Day 15 and Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-Cov-2, COVID-19, Moderate, pneumonia, antibody