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

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.

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.

Study Overview

• Status: Terminated
• Conditions: SARS-CoV-2
• Intervention / Treatment: Biological: Emapalumab; Biological: Anakinra

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: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Italy
  • Brescia, Italy
    • ASST Spedali Civili di Brescia Dipartimento di Reumatologia e Immunologia Clinica
  • Genova, Italy
    • S.C. Malattie Infettive, Ospedale Galliera
  • Milano, Italy
    • Ospedale Maggiore Policlinico, Dipartimento di Anestesia-Rianimazione e Medicina di Urgenza
  • Padova, Italy
    • Dipartimento di Medicina - DIMED, Azienda Ospedale - Università Padova
  • Parma, Italy
    • Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Malattie infettive ed epatologia
  • Roma, Italy
    • Ospedale Lazzaro Spallanzani, Dipartimento di Malattie Infettive ad alta Intensità di cura ed altamente contagiose,Ospedale Lazzaro Spallanzani
  • Torino, Italy
    • ASL Città di Torino, Unit of Infectious Diseases, Medicine, Rheumatology
• United States
  • Minnesota
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital
  • New York
    • Flushing, New York, United States, 11355
      • NewYork-Presbyterian Queens
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Biological: Emapalumab; I.v. infusion every third day; Other Names: Gamifant
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	Biological: Anakinra; Daily i.v. infusion; Other Names: Kineret
No Intervention: Standard of care; Standard of care according to local practice

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Requiring Mechanical Ventilation	Measured in number of participants	Date of randomization to date of mechanical ventilation, up to 15 Days
Change From Baseline in Modified Early Warning System Score	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	Baseline, Day 15
Change From Baseline in Ferritin	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Lactate Dehydrogenase (LDH)	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in D-dimers	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Resting Peripheral Capillary Oxygen Saturation (SpO2)	Measured in percent (%)	Baseline, 3 assessments every Days 4, 7, 10, 13 and 15
Change From Baseline in Oxygen Supplementation	Measured in l/min	Baseline, Days 4, 7, 10, 13 and 15.
Change From Baseline in Partial Pressure of Oxygen/Fraction of Inspired Oxygen (PaO2/FiO2)	Measured in mmHg	Baseline, Day 15
Number of Participants With Changes in High-resolution Computed Tomography (CT) Scan of the Chest	Measured in scan evaluation: Normal, Abnormal but not clinically significant, Abnormal clinical significant, Not Done	Screening, Day 15
Overall Survival	Confirmation of death	Weeks 6 and 10
Number of Patients With Hospital Discharge	Measured in number of patients	Until discharge up to Week 10
Change of Carbon Dioxide Tension (pCO2) in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change of Oxygen Tension (pO2) in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change of Potassium in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change of Sodium in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change of Chloride in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change of Lactic Acid in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change of Hemoglobin in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in White Blood Cells With Differential Counts	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Red Blood Counts	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Hemoglobin	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Platelet Count	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Fibrinogen	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Complement Factors C3/C4	Measured in local units	Day 15
Change From Baseline in Prothrombin Time	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Cardiac Troponin	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Aspartate Aminotransferase (AST)	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Alanine Aminotransferase (ALT)	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Total Bilirubin Levels	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in C-Reactive Protein	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Change From Baseline in Creatinine	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15

Collaborators and Investigators

• Sponsor: Swedish Orphan Biovitrum
• Investigators: Principal Investigator: Emanuele Nicastri, MD, Direttore Dipartimento di Malattie Infettive

Publications and helpful links

General Publications

• Brands X, de Vries FMC, Uhel F, Haak BW, Peters-Sengers H, Schuurman AR, van Engelen TSR, Lutter R, Cremer OL, Bonten MJ, Schultz MJ, Scicluna BP, van der Poll T; MARS Consortium. Plasma Ferritin as Marker of Macrophage Activation-Like Syndrome in Critically Ill Patients With Community-Acquired Pneumonia. Crit Care Med. 2021 Nov 1;49(11):1901-1911. doi: 10.1097/CCM.0000000000005072.

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2020
• Primary Completion (Actual): November 13, 2020
• Study Completion (Actual): November 13, 2020

Study Registration Dates

• First Submitted: March 25, 2020
• First Submitted That Met QC Criteria: March 25, 2020
• First Posted (Actual): March 27, 2020

Study Record Updates

• Last Update Posted (Actual): March 10, 2022
• Last Update Submitted That Met QC Criteria: March 3, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: Sobi.IMMUNO-101; 2020-001167-93 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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