Clinical trial NCT04453384: Study to Evaluate the Safety and Efficacy of XAV-19 in Patients With COVID-19 Induced Moderate Pneumonia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: SARS Virus
Keywords: SARS-Cov-2
COVID-19
Moderate
pneumonia
antibody
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
Collaborators: name: BPIfrance
name: Xenothera SAS
First posted: 2020-07-01
Enrollment: 416
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 2a: XAV-19 antibody titers
timeFrame: Day 8
measure: Phase 2a: Adverse events of XAV-19
timeFrame: Day 29
measure: 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.
timeFrame: Day 15
Secondary outcomes:
measure: Phase 2a: Pharmacokinetic analysis
timeFrame: Day 1 (pre-dose, post-dose), at Day 5 (pre-dose, post-dose), Day 8, Day 15, and Day 29
measure: Phase 2a: Antibody titer between the two groups
timeFrame: day 15
measure: Phase 2a: Supplemental oxygen
timeFrame: Day 1 to Day 29
measure: Phase 2a: Evaluation of Transfer to intensive care
timeFrame: Day 1 to Day 29
measure: Phase 2a: Normalization of Fever
timeFrame: Day 1 to Day 29
measure: Phase 2a: Biomarkers
timeFrame: Day 1 to Day 29
measure: Phase 2a: Hospital length of stay
timeFrame: Day 1 to Day 29
measure: Phase 2b: Efficacy of XAV-19
timeFrame: Day 8 and Day 29
measure: Phase 2b: Clinical severity
timeFrame: Day 3, Day 5, Day 8, Day15 and Day 29
measure: Phase 2b: Clinical severity
timeFrame: Day 29
measure: Phase 2b: Clinical severity : Improvement of clinical and biological parameters
timeFrame: Day15, and Day 29
measure: Phase 2b: Clinical severity : Oxygenation
timeFrame: 29 Days
measure: Phase 2b: Clinical severity : Non-invasive ventilation, high-flow oxygen
timeFrame: 29 Days
measure: Phase 2b: Clinical severity : Invasive mechanical ventilation / Extra Corporeal Membrane Oxygenation (ECMO)
timeFrame: 29 Days
measure: Phase 2b: Clinical severity : Transfer in ICU by Day 29
timeFrame: 29 Days
measure: Phase 2b: Clinical severity : Hospitalization
timeFrame: 60 Days
measure: Phase 2b: Clinical severity : Mortality
timeFrame: 60 Days
measure: Phase 2b: Clinical severity : Thrombotic events
timeFrame: 60 Days
measure: Phase 2b: mortality
timeFrame: 29 Days
measure: Phase 2b: safety
timeFrame: 29 days and 60 days
measure: Phase 2b: safety of Study drug infusion
timeFrame: 29 days and 60 days
measure: Phase 2b: safety : study drug discontinuation
timeFrame: 29 days and 60 days
measure: Phase 2b: safety : major or opportunistic bacterial or fungal infections
timeFrame: 29 days and 60 days
measure: Phase 2b: safety : hypersensitivity reactions and infusion reactions
timeFrame: 29 days and 60 days
measure: Phase 2b: safety : biological parameters
timeFrame: 29 days and 60 days
measure: Phase 2b: Exploratory analysis : qualitative and quantitative SARS-CoV-2 status
timeFrame: Day 1, Day 8, Day 15 and Day 29
measure: Phase 2b: Exploratory analysis : SARS-CoV-2 status viral load
timeFrame: Day 1, Day 8, Day 15 and Day 29
Other outcomes:
measure: Phase 2b : Pharmacokinetic Study
timeFrame: Day 1, Day 3, Day 5, Day 8, Day 15 and Day 29
measure: Phase 2b : Immunomonitoring Study
timeFrame: Day 1, Day 3, Day 5, Day 8, Day 15 and Day 29
measure: Phase 2b : Terminal ancillary Study (20 additional patients receiving a fixed dose of 150mg of XAV-19 :
timeFrame: Day 1, Day 3, Day 5, Day 8, Day 15 and Day 29
Locations:
city: Amiens
country: France
facility: CHU Amiens Picardie
city: Angers
country: France
facility: CHU Angers
city: Antony
country: France
facility: Hôpital Privé d'Antony
city: Avignon
country: France
facility: CH Avignon
city: Bayonne
country: France
facility: CH de la Côte Basque
city: Bobigny
country: France
facility: APHP - Hôpital Avicennes
city: Caen
country: France
facility: CHU Caen
city: Chambéry
country: France
facility: CH Métropole Savoie
city: Colmar
country: France
facility: CH Colmar
city: Corbeil-Essonnes
country: France
facility: CH Sud Francilien
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: La Rochelle
country: France
facility: CH de La Rochelle
city: Le Mans
country: France
facility: CH Le Mans
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: Hospices Civils Lyon
city: Mont-de-Marsan
country: France
facility: CH de Mont de Marzan
city: Mulhouse
country: France
facility: GHR Mulhouse Sud-Alsace
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Nîmes
country: France
facility: CHU Nîmes
city: Orléans
country: France
facility: CHR Orléans La Source
city: Paris
country: France
facility: APHP - Hôpital Tenon
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Pontoise
country: France
facility: CH René Dubos
city: Quimper
country: France
facility: CH Cornouaille
city: Reims
country: France
facility: CHU Reims
city: Saint-Priest-en-Jarez
country: France
facility: CHU Saint Etienne
city: Strasbourg
country: France
facility: CHU Strasbourg
city: Suresnes
country: France
facility: Hôpital FOCH
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU Nancy
city: Vannes
country: France
facility: CH Bretagne Atlantique
city: Fort de France
country: Martinique
facility: CHU Martinique
city: Saint-Pierre
country: Réunion
facility: CHU La Réunion
Study officials:
affiliation: Nantes University Hospital
name: Benjamin Gaborit
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
citation: Gaborit B, Dailly E, Vanhove B, Josien R, Lacombe K, Dubee V, Ferre V, Brouard S, Ader F, Vibet MA, Le Thuaut A, Danger R, Flet L, Omnes A, Berly L, Chiffoleau A, Jobert A, Duvaux O, Raffi F; POLYCOR Trial Group. Pharmacokinetics and Safety of XAV-19, a Swine Glyco-humanized Polyclonal Anti-SARS-CoV-2 Antibody, for COVID-19-Related Moderate Pneumonia: a Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study. Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0123721. doi: 10.1128/AAC.01237-21. Epub 2021 Aug 17.
citation: Gaborit B, Vanhove B, Vibet MA, Le Thuaut A, Lacombe K, Dubee V, Ader F, Ferre V, Vicaut E, Orain J, Le Bras M, Omnes A, Berly L, Jobert A, Morineau-Le Houssine P, Botturi K, Josien R, Flet L, Degauque N, Brouard S, Duvaux O, Poinas A, Raffi F; POLYCOR study group. Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial. Trials. 2021 Mar 9;22(1):199. doi: 10.1186/s13063-021-05132-9.