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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
416
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
...and 24 more locations
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
Time frame: 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
Time frame: 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)
Time frame: Day 15
Phase 2a: Pharmacokinetic analysis
XAV-19 Antibody titer over the time
Time frame: 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
Time frame: day 15
Phase 2a: Supplemental oxygen
Duration of supplemental oxygen
Time frame: 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
Time frame: 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
Time frame: Day 1 to Day 29
Phase 2a: Biomarkers
Biomarkers : CRP, Ferritin
Time frame: Day 1 to Day 29
Phase 2a: Hospital length of stay
Evaluation of Hospital length of stay
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 29 Days
Phase 2b: Clinical severity : Transfer in ICU by Day 29
g) Transfer in ICU
Time frame: 29 Days
Phase 2b: Clinical severity : Hospitalization
h) Hospital length of stay (in days)
Time frame: 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
Time frame: 60 Days
Phase 2b: Clinical severity : Thrombotic events
j) Thrombotic events (peripheral venous, pulmonary, arterial)
Time frame: 60 Days
Phase 2b: mortality
k) All cause mortality
Time frame: 29 Days
Phase 2b: safety
Occurrence of all suspected XAV-19 related adverse effects or Incidence of serious adverse events
Time frame: 29 days and 60 days
Phase 2b: safety of Study drug infusion
Study drug discontinuation or temporary suspension of infusion
Time frame: 29 days and 60 days
Phase 2b: safety : study drug discontinuation
Proportion of participants with treatment emergent adverse events leading to study drug discontinuation
Time frame: 29 days and 60 days
Phase 2b: safety : major or opportunistic bacterial or fungal infections
Incidence of major or opportunistic bacterial or fungal infections
Time frame: 29 days and 60 days
Phase 2b: safety : hypersensitivity reactions and infusion reactions
Incidence of hypersensitivity reactions and infusion reactions
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: Day 1, Day 8, Day 15 and Day 29
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