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

Phase 2

Completed

• Conditions: SARS Virus
• Interventions: Drug: Placebo; Drug: XAV-19

• Registration Number: NCT04453384
• Lead Sponsor: Nantes University Hospital

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-06-22
• Study First Submitted QC: 2020-06-30
• Study First Posted: 2020-07-01
• Study Start: 2020-09-01
• Primary Completion: 2021-05-21
• Study Completion: 2021-08-19
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-24
• Last Update Posted: 2022-03-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 416

Inclusion Criteria

1. Willing and able to provide written informed consent prior to performing study procedures
2. Male or female ≥ 18 years and ≤ 85 years
3. Hospitalized for COVID-19
4. Positive SARS-CoV-2 RT-PCR in any body specimen (nasopharynx, saliva, sputum) ≤ 10 days before enrolment
5. Evidence of pulmonary involvement (on lung examination [rales/crackles] and/or chest-imaging [Chest X-ray or computed tomography])
6. Requiring O2 supplement ≤ 6L/min at screening
7. Requiring O2 supplementation with SpO2 ≥ 94% on O2 therapy at screening
8. First onset of COVID-19 symptoms ≤ 10 days, among fever and/or chills, headache, myalgias, cough, shortness of breath, whichever as occurred fist
9. WOCBP must have a negative urinary pregnancy test the day of inclusion
10. 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
11. Patients with French social security

Exclusion Criteria

1. Evidence of multiorgan failure (severe COVID-19)
2. Mechanically ventilated (including ECMO)
3. Receipt of immunoglobulins or any blood products in the past 30 days
4. Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the investigator, would affect subject safety and/or compliance
5. End-stage renal disease (eGFR < 15 ml/min/1,73 m2)
6. Child-Pugh C stage liver cirrhosis
7. Decompensated cardiac insufficiency
8. History of active drug abuse
9. Known allergy, hypersensitivity, or intolerance to the study drug, or to any of its components
10. Females of childbearing potential without contraceptive method, or with positive pregnancy test, breastfeeding, or planning to become pregnant during the study period
11. Current documented and uncontrolled bacterial infection.
12. Prior severe (grade 3) allergic reactions to plasma transfusion
13. Patient participating in another interventional clinical trial
14. Life expectancy estimated to be less than 6 months
15. Patient under guardianship or trusteeship

Phase 2b:

Inclusion criteria:

1. Willing and able to provide written informed consent prior to performing study procedures

2. Male or female ≥ 18 years

3. Hospitalized for COVID-19

4. 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

5. Evidence of pulmonary involvement (on lung examination [rales/crackles] and/or chestimaging [Chest X-ray or computed tomography])

6. Requiring O2 supplement ≤ 6L/min at screening

7. Requiring O2 supplementation with SpO2 ≥ 92% on O2 therapy at screening (or ≥ 90

   % if chronic obstructive pulmonary disease)

8. 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)

9. WOCBP must have a negative urinary pregnancy test the day of inclusion

10. 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

11. Patients with French social security

Exclusion criteria:

1. Evidence of multiorgan failure (severe COVID-19)
2. Mechanically ventilated (including ECMO)
3. Receipt of immunoglobulins or any blood products in the past 30 days
4. Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the investigator, would affect subject safety and/or compliance
5. End-stage renal disease (eGFR < 15 ml/min/1,73 m2)
6. Child-Pugh C stage liver cirrhosis
7. Decompensated cardiac insufficiency
8. Known allergy, hypersensitivity, or intolerance to the study drug, or to any of its components
9. Females of childbearing potential without contraceptive method, or with positive pregnancy test, breastfeeding, or planning to become pregnant during the study period
10. Current documented and uncontrolled bacterial infection.
11. Prior severe (grade 3) allergic reactions to plasma transfusion
12. Patient participating in another interventional clinical trial
13. Life expectancy estimated to be less than 6 months
14. Patient under guardianship or trusteeship
15. Patient already included
16. Prior hospitalisation in intensive care unit for the current covid-19 episode

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo arm	Placebo	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
Treatment arm	XAV-19	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

Primary Outcome Measures

Name	Time	Method
Phase 2a: XAV-19 antibody titers	Day 8	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
Phase 2a: Adverse events of XAV-19	Day 29	Adverse events of XAV-19 between the two groups of treated patients and vs. placebo over 29 days
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.	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)

Secondary Outcome Measures

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

Trial Locations

Locations (34)

CH de La Rochelle; 🇫🇷 La Rochelle, France

CHRU Lille; 🇫🇷 Lille, France

CHU Reims; 🇫🇷 Reims, France

APHP - Hôpital Tenon; 🇫🇷 Paris, France

Hôpital Saint Antoine; 🇫🇷 Paris, France

CHU Saint Etienne; 🇫🇷 Saint-Priest-en-Jarez, France

CHR Orléans La Source; 🇫🇷 Orléans, France

CH René Dubos; 🇫🇷 Pontoise, France

CH Cornouaille; 🇫🇷 Quimper, France

CHU Strasbourg; 🇫🇷 Strasbourg, France

CHU Nîmes; 🇫🇷 Nîmes, France

Hôpital FOCH; 🇫🇷 Suresnes, France

CHRU Nancy; 🇫🇷 Vandœuvre-lès-Nancy, France

CHU La Réunion; 🇷🇪 Saint-Pierre, Réunion

CH Bretagne Atlantique; 🇫🇷 Vannes, France

CHU Amiens Picardie; 🇫🇷 Amiens, France

Hôpital Privé d'Antony; 🇫🇷 Antony, France

CHU Angers; 🇫🇷 Angers, France

APHP - Hôpital Avicennes; 🇫🇷 Bobigny, France

CHU Caen; 🇫🇷 Caen, France

CH Métropole Savoie; 🇫🇷 Chambéry, France

CH Colmar; 🇫🇷 Colmar, France

CH Sud Francilien; 🇫🇷 Corbeil-Essonnes, France

CHD Vendée; 🇫🇷 La Roche-sur-Yon, France

CH Le Mans; 🇫🇷 Le Mans, France

CHU Limoges; 🇫🇷 Limoges, France

Hospices Civils Lyon; 🇫🇷 Lyon, France

CH de Mont de Marzan; 🇫🇷 Mont-de-Marsan, France

GHR Mulhouse Sud-Alsace; 🇫🇷 Mulhouse, France

CHU Nantes; 🇫🇷 Nantes, France

CHU Nice; 🇫🇷 Nice, France

CHU Martinique; 🇲🇶 Fort de France, Martinique

CH Avignon; 🇫🇷 Avignon, France

CH de la Côte Basque; 🇫🇷 Bayonne, France