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Efficacy and Safety of Emapalumab and Anakinra in Reducing Hyperinflammation and Respiratory Distress in Patients With COVID-19 Infection.

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ClinicalTrials.gov Identifier: NCT04324021
Recruitment Status : Recruiting
First Posted : March 27, 2020
Last Update Posted : October 22, 2020
Sponsor:
Information provided by (Responsible Party):
Swedish Orphan Biovitrum

Tracking Information
First Submitted Date  ICMJE March 25, 2020
First Posted Date  ICMJE March 27, 2020
Last Update Posted Date October 22, 2020
Actual Study Start Date  ICMJE April 2, 2020
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 25, 2020)
Treatment success [ Time Frame: Up to Day 15 ]
Defined as the proportion of patients not requiring invasive mechanical ventilation or Extracorporeal membrane oxygenation (ECMO)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 25, 2020)
  • Time to mechanical ventilation [ Time Frame: Date of randomization to date of mechanical ventilation ]
    Measured in days
  • Change from baseline in Modified Early Warning system score [ Time Frame: Baseline, Day 15 ]
    Measured in total score
  • Change from baseline in resting peripheral capillary oxygen saturation (SpO2) [ Time Frame: Baseline, 3 assessments every Days 4, 7, 10, 13 and 15 ]
    Measured in percent (%)
  • Change from baseline in partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) [ Time Frame: Baseline, Day 15 ]
    Measured in percent (%)
  • Change of pH in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change of carbon dioxide tension (pCO2) in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change of oxygen tension (pO2) in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change of potassium in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change of sodium in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change of chloride in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change of lactic acid in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change of hemoglobin in hemogasanalysis from baseline [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in oxygen supplementation [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in l/min
  • Change of findings of high-resolution computed tomography (CT) scan of the chest [ Time Frame: Screening, Day 15 ]
    Measured in scan evaluation: Normal, Abnormal but not clinically significant, Abnormal clinical significant, Not Done
  • Change from baseline in Ferritin [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in lactate dehydrogenase (LDH) [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in D-dimers [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in White Blood Cells with differential counts [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Red Blood Counts [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Hemoglobin [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Platelet count [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Fibrinogen [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Complement factors C3/C4 [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Prothrombin time [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Cardiac troponin [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in aspartate aminotransferase (AST) [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in alanine aminotransferase (ALT) [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in total bilirubin levels [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in C-Reactive Protein [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Change from baseline in Creatinine [ Time Frame: Baseline, Days 4, 7, 10, 13 and 15 ]
    Measured in local units
  • Overall survival [ Time Frame: Weeks 6 and 10 ]
    Confirmation of death
  • Time to hospital discharge [ Time Frame: Weeks 6 and 10 ]
    Measured in days
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Emapalumab and Anakinra in Reducing Hyperinflammation and Respiratory Distress in Patients With COVID-19 Infection.
Official Title  ICMJE A Phase 2/3, Randomized, Open-label, Parallel Group, 3-arm, Multicenter Study Investigating the Efficacy and Safety of Intravenous Administrations of Emapalumab, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, and Anakinra, an Interleukin-1(IL-1) Receptor Antagonist, Versus Standard of Care, in Reducing Hyper-inflammation and Respiratory Distress in Patients With SARS-CoV-2 Infection.
Brief Summary As shown by the data available, hyper-inflammation, caused by a cytokine storm resulting from an exaggerated response of the immune system to the presence of the virus, is considered to represent one of the most important negative prognostic factor in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The objective of this study is to investigate new possibilities to reduce the number of patients requiring mechanical ventilation. This is intended to address the most urgent need to preserve the access to intensive care unit support to the lowest possible number of patients and may potentially reduce mortality.
Detailed Description This is an open label, controlled, parallel group, 3-arm, multicenter study to assess the efficacy and safety of Emapalumab or Anakinra, versus standard of care (SoC). Patients between 30 and 80 years will be eligible to participate in the study. The study is planned to consist of three groups, each comprising 18 patients. Treatment will be randomized to either Emapalumab+SoC, Anakinra+SoC or only SoC for two weeks. Follow-up visit or phone calls will be made 4 and 8 weeks after end of treatment period.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE SARS-CoV-2
Intervention  ICMJE
  • Biological: Emapalumab
    I.v infusion every third day
    Other Name: Gamifant
  • Biological: Anakinra
    Daily i.v infusion
    Other Name: Kineret
Study Arms  ICMJE
  • Active Comparator: Emapalumab
    Emapalumab i.v infusion every 3rd day for a total 5 infusions. Day 1: 6mg/kg. Days 4, 7, 10 and 13: 3 mg/kg
    Intervention: Biological: Emapalumab
  • Active Comparator: Anakinra
    Anakinra i.v infusion four times daily for 15 days. 400 mg/day in total, divided into 4 doses given every 6 hours
    Intervention: Biological: Anakinra
  • No Intervention: Standard of care
    Standard of care according to local practice
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: March 25, 2020)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Signed informed consent provided by the patient, or by the patient's legally authorized representative(s), as applicable.
  2. Documented presence of SARS-CoV-2 infection as per hospital routine.
  3. Age > 18 to < 85 years at the time of screening.
  4. Presence of respiratory distress, defined as:

    1. PaO2/FiO2 < 300 mm Hg and >200 mm Hg or
    2. Respiratory Rate (RR) ≥30 breaths/min or
    3. SpO2 < 93 percent in air at rest. Note: Patients given continous positive airway pressure (CPAP) ventilator support are eligible for inclusion.

Presence of hyperinflammation defined as:

  1. Lymphocyte counts:

    • < 1000 cells/µL, in patients who have not received systemic glucocorticoids for at least 2 days prior to the assessment of the lymphocyte count
    • < 1200 cells/µL, in patients who have received systemic glucocorticoids for at least 2 days prior to the assessment of the lymphocyte count

    and

  2. One of the following three criteria:

i. Ferritin > 500ng/mL

ii. LDH > 300 U/L

iii. D-Dimers > 1000 ng/mL

Exclusion Criteria:

  1. Patients in mechanical ventilation or with modified early warning score (MEWS) >4 with evidence of moderate or above ARDS (Berlin definition, namely with PaO2/FiO2 >100, but <200 mm Hg) or severe respiratory insufficiency or evidence of rapid worsening (respiratory distress requiring mechanical ventilation or presence of shock or presence of concomitant organ failure requiring ICU admission). Note: For the evaluation of patient eligibility, temperature will not be considered in the calculation of the total MEWS score since presence of fever is a hallmark of SARS-CoV-s infection
  2. Impairment of cardiac function defined as poorly controlled heart diseases, such as New York heart association (NYHA) class II (mild) and above, cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, supraventricular or ventricular arrhythmia need treatment or intervention.
  3. Severe renal dysfunction (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m2) or receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis.
  4. Uncontrolled hypertension (seated systolic blood pressure >180 mmHg, or diastolic blood pressure >110mmHg) .
  5. Administration of plasma from convalescent patients who recovered from SARS-CoV-2 infection.
  6. Clinical suspicion of latent tuberculosis.
  7. History of hypersensitivity or allergy to any component of the study drug.
  8. Pregnant women.
  9. Existence of any life-threatening co-morbidity or any other medical condition which, in the opinion of the investigator, makes the patient unsuitable for inclusion.
  10. Enrollment in another concurrent clinical interventional study, or intake of an investigational drug within three months or 5 half-lives prior to inclusion in this study, if considered interfering with this study objectives as assessed by the Investigator.
  11. Foreseeable inability to cooperate with given instructions or study procedures.
  12. Clinical suspicion of active mycobacteria, histoplasma capsulatum, herpes zoster, salmonella, and shigella Infections.
  13. Patients with liver dysfunction defined as AST or ALT > 5 × ULN
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: Carl Johan Treutiger, MD, PhD +46 8 697 20 00 sobi.immuno@sobi.com
Contact: Alessandra Blasiotti, PhD sobi.immuno@sobi.com
Listed Location Countries  ICMJE Italy,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04324021
Other Study ID Numbers  ICMJE Sobi.IMMUNO-101
2020-001167-93 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Swedish Orphan Biovitrum
Study Sponsor  ICMJE Swedish Orphan Biovitrum
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Emanuele Nicastri, MD Direttore Dipartimento di Malattie Infettive
PRS Account Swedish Orphan Biovitrum
Verification Date October 2020

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