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

SARS Virus Clinical Trial

— POLYCOR  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04453384
• Other study ID #: RC20_0230
• Status: Completed
• Phase: Phase 2
• Start date: September 1, 2020
• Est. completion date: August 19, 2021

Study information

• Verified date: March 2022
• Source: Nantes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 416
• Est. completion date: August 19, 2021
• Est. primary completion date: May 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Phase 2a:

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

Related Conditions & MeSH terms

• COVID-19
• Pneumonia
• SARS Virus

Intervention

Drug:
• XAV-19
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
• Placebo
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

Locations

Country	Name	City	State
France	CHU Amiens Picardie	Amiens
France	CHU Angers	Angers
France	Hôpital Privé d'Antony	Antony
France	CH Avignon	Avignon
France	CH de la Côte Basque	Bayonne
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 de La Rochelle	La Rochelle
France	CH Le Mans	Le Mans
France	CHRU Lille	Lille
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 Nîmes	Nîmes
France	CHR Orléans La Source	Orléans
France	APHP - Hôpital Tenon	Paris
France	Hôpital Saint Antoine	Paris
France	CH René Dubos	Pontoise
France	CH Cornouaille	Quimper
France	CHU Reims	Reims
France	CHU Saint Etienne	Saint-Priest-en-Jarez
France	CHU Strasbourg	Strasbourg
France	Hôpital FOCH	Suresnes
France	CHRU Nancy	Vandœuvre-lès-Nancy
France	CH Bretagne Atlantique	Vannes
Martinique	CHU Martinique	Fort de France
Réunion	CHU La Réunion	Saint-Pierre

Sponsors (3)

Lead Sponsor	Collaborator
Nantes University Hospital	BPIfrance, Xenothera SAS

Countries where clinical trial is conducted

France,  Martinique,  Réunion, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Phase 2b : Pharmacokinetic Study	Pharmacokinetic analysis correspond to antibody titer measurements at Day 1 (pre-dose, post-dose), Day 3, Day 5, Day 8, Day 15, and Day 29	Day 1, Day 3, Day 5, Day 8, Day 15 and Day 29
Other	Phase 2b : Immunomonitoring Study	The endpoints encompass the following analysis: Spike/ACE2 neutralizing antibody titers: D1 (pre-, post dose), D3, D5, D8, D15 and D29; Lymphocytes sub-population: D1, D3, D5, D8 and D15; Transcriptomic analyses: D1, D3, D5, D8 and D15; Cytokines: D1, D3, D5, D8 and D15	Day 1, Day 3, Day 5, Day 8, Day 15 and Day 29
Other	Phase 2b : Terminal ancillary Study (20 additional patients receiving a fixed dose of 150mg of XAV-19 :	to compare pharmacokinetic parameters in patients receiving a fixed dose of 150mg with patients receiving 2mg/Kg of XAV-19 (master phase 2b), in order to confirm that the exposure and variability are similar; to compare the effects of neutralizing antibodies use on virus-induced immune response on longitudinal follow-up, and targets for "immuno-monitoring"; to investigate the immunogenicity of COVID-19 during treatment with XAV19 in patients receiving a fixed dose of 150mg with patients receiving 2mg/Kg of XAV-19	Day 1, Day 3, Day 5, Day 8, Day 15 and Day 29
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	Phase 2a: Supplemental oxygen	Duration of supplemental oxygen	Day 1 to Day 29
Secondary	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
Secondary	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
Secondary	Phase 2a: Biomarkers	Biomarkers : CRP, Ferritin	Day 1 to Day 29
Secondary	Phase 2a: Hospital length of stay	Evaluation of Hospital length of stay	Day 1 to Day 29
Secondary	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
Secondary	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
Secondary	Phase 2b: Clinical severity	b) Clinical status using the 8-point ordinal scale assessed daily until Day 29	Day 29
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 2b: Clinical severity : Transfer in ICU by Day 29	g) Transfer in ICU	29 Days
Secondary	Phase 2b: Clinical severity : Hospitalization	h) Hospital length of stay (in days)	60 Days
Secondary	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
Secondary	Phase 2b: Clinical severity : Thrombotic events	j) Thrombotic events (peripheral venous, pulmonary, arterial)	60 Days
Secondary	Phase 2b: mortality	k) All cause mortality	29 Days
Secondary	Phase 2b: safety	Occurrence of all suspected XAV-19 related adverse effects or Incidence of serious adverse events	29 days and 60 days
Secondary	Phase 2b: safety of Study drug infusion	Study drug discontinuation or temporary suspension of infusion	29 days and 60 days
Secondary	Phase 2b: safety : study drug discontinuation	Proportion of participants with treatment emergent adverse events leading to study drug discontinuation	29 days and 60 days
Secondary	Phase 2b: safety : major or opportunistic bacterial or fungal infections	Incidence of major or opportunistic bacterial or fungal infections	29 days and 60 days
Secondary	Phase 2b: safety : hypersensitivity reactions and infusion reactions	Incidence of hypersensitivity reactions and infusion reactions	29 days and 60 days
Secondary	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
Secondary	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
Secondary	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