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

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ClinicalTrials.gov Identifier: NCT04453384
Recruitment Status : Recruiting
First Posted : July 1, 2020
Last Update Posted : December 7, 2020
Sponsor:
Collaborators:
BPIfrance
Xenothera SAS
Information provided by (Responsible Party):
Nantes University Hospital

Tracking Information
First Submitted Date  ICMJE June 22, 2020
First Posted Date  ICMJE July 1, 2020
Last Update Posted Date December 7, 2020
Actual Study Start Date  ICMJE September 1, 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 3, 2020)
  • Phase 2a: XAV-19 antibody titers [ Time Frame: 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 [ Time Frame: Day 29 ]
    Adverse events of XAV-19 between the two groups of treated patients and vs. placebo over 29 days
  • Phase 2b: Time to weaning of supplemental oxygen. [ Time Frame: Day 15 ]
    Efficacy is defined by the proportion of patients who die or develop respiratory failure in the two groups of treatment between baseline and Day 15. Patient with respiratory failure will be patient requiring noninvasive ventilation, high-flow oxygen devices or invasive mechanical ventilation (corresponding to 8-point ordinal scale ≥ 6).
Original Primary Outcome Measures  ICMJE
 (submitted: June 30, 2020)
  • Phase 2a: XAV-19 antibody titers [ Time Frame: 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 [ Time Frame: Day 29 ]
    Adverse events of XAV-19 between the two groups of treated patients and vs. placebo over 29 days
  • Phase 2b: Time to weaning of supplemental oxygen. [ Time Frame: Day 15 ]
    If patient is still on oxygen at Day 15 or if the patient is weaned but put back on oxygen then the delay will be censored at 15 days.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2020)
  • Phase 2a: Pharmacokinetic analysis [ Time Frame: 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 2a: Antibody titer between the two groups [ Time Frame: day 15 ]
    The antibody titer of XAV-19 measurements in Group 1 treated patients and Group 2 treated patients
  • Phase 2a: Supplemental oxygen [ Time Frame: Day 1 to Day 29 ]
    Duration of supplemental oxygen
  • Phase 2a: Evaluation of Transfer to intensive care [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Day 1 to Day 29 ]
    Biomarkers : CRP, Ferritin
  • Phase 2a: Hospital length of stay [ Time Frame: Day 1 to Day 29 ]
    Evaluation of Hospital length of stay
  • Phase 2b: Efficacy of XAV-19 [ Time Frame: Day 8 and Day 29 ]
    a) Proportion of patients who die, develop respiratory failure (requiring noninvasive ventilation, high-flow oxygen devices or invasive mechanical ventilation) between baseline and Day 8, then between baseline and D29
  • Phase 2b: National Early Warning Score (NEWS) [ Time Frame: Day 8, Day 15 and Day 29 ]
    b) National Early Warning Score (NEWS) at Day 15 and difference in NEWS between baseline and D8 / D15 / D29
  • Phase 2b: clinical status [ Time Frame: Day 3, Day 5, Day 8, Day15, and Day 29 ]
    c) Clinical status using the 8-point ordinal scale assessed and difference between baseline and D3, D5, D8, D15, and D29
  • Phase 2b: Time to improvement [ Time Frame: 29 Days ]
    d) Time to improvement of one category from admission using the 8-point ordinal scale. This scale is rated 0 to 8 with score 0 being the better score (no clinical impact) and 8 being the worst score (death)
  • Phase 2b: fever normalization [ Time Frame: 29 Days ]
    e) Time to first fever normalization (criteria for normalization: temperature < 36.6°C armpit, < 37.2°C oral, < 37.8°C rectal or tympanic)
  • Phase 2b: Oxygen therapy [ Time Frame: 29 Days ]
    f) Duration of oxygen therapy
  • Phase 2b: oxygen requirement [ Time Frame: 29 Days ]
    g) Comparison of oxygen requirement between the two groups
  • Phase 2b: Time to weaning [ Time Frame: Day8, Day 15 and Day 29 ]
    h) Time to weaning in supplemental oxygen and proportion without O2 requirement at Day 8, D15 and Day 29, according to baseline (D1) oxygen requirement (≤ 4 L/min or 4 L/min)
  • Phase 2b: Ventilation [ Time Frame: 29 Days ]
    i) Incidence and duration of non-invasive ventilation or high flow oxygen devices, of invasive mechanical ventilation during the study
  • Phase 2b: Hospital length of stay [ Time Frame: 29 Days ]
    j) Evaluation of hospital length of stay
  • Phase 2b: mortality [ Time Frame: 29 Days ]
    k) All cause mortality
  • Phase 2b: safety [ Time Frame: 29 Days ]
    l) Occurrence of all suspected XAV-19 related adverse effects or Incidence of serious adverse events
    • Proportion of participants with treatment emergent adverse events leading to study drug discontinuation
    • Incidence of major or opportunistic bacterial or fungal infections
    • Incidence of hypersensitivity reactions and infusion reactions
    • White cell count, hemoglobin, platelets, creatinine, ALT, AST, on D1, D3, D5, D8, D11, D15 and D29
    • SARS-CoV-2 viral load over time (D1-D29), as collected by nasopharyngeal swab samples
    • Time to RT-PCR virus negativity in nasopharyngeal swab samples
Original Secondary Outcome Measures  ICMJE
 (submitted: June 30, 2020)
  • Phase 2a: Pharmacokinetic analysis [ Time Frame: 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 2a: Antibody titer between the two groups [ Time Frame: day 15 ]
    b) The antibody titer of XAV-19 measurements in Group 1 treated patients and Group 2 treated patients
  • Phase 2a: Supplemental oxygen [ Time Frame: Day 1 to Day 29 ]
    Duration of supplemental oxygen
  • Phase 2a: Evaluation of Transfer to intensive care [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Day 1 to Day 29 ]
    Biomarkers : CRP, Ferritin
  • Phase 2a: Hospital length of stay [ Time Frame: Day 1 to Day 29 ]
    Evaluation of Hospital length of stay
  • Phase 2b: National Early Warning Score (NEWS) [ Time Frame: Day 1 and Day 15 ]
    Evaluation of the National Early Warning Score at Day 15 and difference in NEWS between Day1 and Day15. The NEWS is graded from to 23 with an aggregated score between 0-4 being a low clinical risk and an aggregated score >7 being a hich clinical risk
  • Phase 2b: clinical status [ Time Frame: Day 3, Day 5, Day 8, Day 11, Day15, and Day 29 ]
    Clinical status using the 7-point ordinal scale assessed
  • Phase 2b: Time to improvement [ Time Frame: 29 Days ]
    Time to improvement of one category from admission using the 7-point ordinal scale. This scale is rated 0 to 7 with score 0 being the better score (no clinical impact) and 7 being the worst score (death)
  • Phase 2b: fever normalization [ Time Frame: 29 Days ]
    d) Time to first fever normalization (criteria for normalization: temperature < 36.6°C armpit, < 37.2°C oral, < 37.8°C rectal or tympanic)
  • Phase 2b: Oxygen therapy [ Time Frame: 29 Days ]
    Duration of oxygen therapy
  • Phase 2b: oxygen requirement [ Time Frame: 29 Days ]
    Comparison of oxygen requirement between the two groups
  • Phase 2b: Time to weaning [ Time Frame: Day 15 ]
    g) Time to weaning in supplemental oxygen and proportion without O2 requirement at D15, according to baseline (D1) oxygen requirement (≤ 4 L/min or 4 L/min)
  • Phase 2b: Ventilation [ Time Frame: 29 Days ]
    h) Incidence and duration of non-invasive ventilation or high flow oxygen devices, of invasive mechanical ventilation during the study
  • Phase 2b: Hospital length of stay [ Time Frame: 29 Days ]
    Evaluation of hospital length of stay
  • Phase 2b: mortality [ Time Frame: 29 Days ]
    All cause mortality
  • Phase 2b: safety [ Time Frame: 29 Days ]
    • Occurrence of all suspected XAV-19 related adverse effects or Incidence of serious adverse events
    • Proportion of participants with treatment emergent adverse events leading to study drug discontinuation
    • Incidence of major or opportunistic bacterial or fungal infections
    • Incidence of hypersensitivity reactions and infusion reactions
    • White cell count, hemoglobin, platelets, creatinine, ALT, AST, on D1, D3, D5, D8, D11, D15 and D29
    • SARS-CoV-2 viral load over time (D1-D29), as collected by nasopharyngeal swab samples
    • Time to RT-PCR virus negativity in nasopharyngeal swab samples
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate the Safety and Efficacy of XAV-19 in Patients With COVID-19 Induced Moderate Pneumonia
Official Title  ICMJE 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
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 Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE SARS Virus
Intervention  ICMJE
  • Drug: XAV-19
    Phase 2a: Administration on Day 1 and day 5 Phase 2b: Administration on Day 1
  • Drug: Placebo
    Phase 2a: Administration on Day 1 and day 5 Phase 2b: Administration on Day 1
Study Arms  ICMJE
  • Experimental: Treatment arm

    Administrations of XAV-19

    • Phase 2a: XAV-19 at 0.5 mg/kg (Group 1) or at 2 mg/kg (Group 2), two administrations (day 1 and day 5)
    • Phase 2b: Selected dose from Phase 2a, one administration on day1
    Intervention: Drug: XAV-19
  • Placebo Comparator: Placebo arm

    same administration as treatment arm

    • Phase 2a: two administrations of placebo (day 1 and day 5)
    • Phase 2b: one administration of placebo on day 1
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 3, 2020)
414
Original Estimated Enrollment  ICMJE
 (submitted: June 30, 2020)
368
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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 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 ≤ 10 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. 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Benjamin GABORIT +33 (0)2 44 76 82 92 benjamin.GABORIT@chu-nantes.fr
Contact: François RAFFI francois.raffi@chu-nantes.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04453384
Other Study ID Numbers  ICMJE RC20_0230
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Nantes University Hospital
Study Sponsor  ICMJE Nantes University Hospital
Collaborators  ICMJE
  • BPIfrance
  • Xenothera SAS
Investigators  ICMJE
Principal Investigator: Benjamin Gaborit CHU Nantes
PRS Account Nantes University Hospital
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP