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

Overview

Hyper-inflammation, caused by a cytokine storm resulting from an exaggerated response of the immune system in the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered to represent one of the most important negative prognostic factors in patients infected with sSARS-CoV-2. The objective of this study is to investigate new treatment options 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.

Full Title of Study: “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.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 13, 2020

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.

Interventions

  • Biological: Emapalumab
    • I.v. infusion every third day
  • Biological: Anakinra
    • Daily i.v. infusion

Arms, Groups and Cohorts

  • 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
  • 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
  • No Intervention: Standard of care
    • Standard of care according to local practice

Clinical Trial Outcome Measures

Primary Measures

  • Number of Participants With Treatment Success
    • Time Frame: Up to Day 15
    • Defined as the number of patients not requiring invasive mechanical ventilation or Extracorporeal membrane oxygenation (ECMO)

Secondary Measures

  • Number of Participants Requiring Mechanical Ventilation
    • Time Frame: Date of randomization to date of mechanical ventilation, up to 15 Days
    • Measured in number of participants
  • Change From Baseline in Modified Early Warning System Score
    • Time Frame: Baseline, Day 15
    • The full (unabbreviated) scale name is Modified Early Warning system score (MEWS score) Measured in total score Total score is the sum of 5 categorized components (blood pressure, heart rate, respiratory rate, temperature and alert/voice/pain/unresponsive score) that are assigned a score between 0 and 2 or 0 and 3. MEWS total score range is 0 to 14. Higher score= worse outcome
  • 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 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 Oxygen Supplementation
    • Time Frame: Baseline, Days 4, 7, 10, 13 and 15.
    • Measured in l/min
  • Change From Baseline in Partial Pressure of Oxygen/Fraction of Inspired Oxygen (PaO2/FiO2)
    • Time Frame: Baseline, Day 15
    • Measured in mmHg
  • Number of Participants With Changes in 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
  • Overall Survival
    • Time Frame: Weeks 6 and 10
    • Confirmation of death
  • Number of Patients With Hospital Discharge
    • Time Frame: Until discharge up to Week 10
    • Measured in number of patients
  • 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 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: Day 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

Participating in This Clinical Trial

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-2 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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 85 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Swedish Orphan Biovitrum
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Emanuele Nicastri, MD, Principal Investigator, Direttore Dipartimento di Malattie Infettive

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