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

Phase 3TerminatedNCT04324021

Swedish Orphan Biovitrum16 enrolled

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

SARS-CoV-2

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Number of Participants With Treatment Success

Defined as the number of patients not requiring invasive mechanical ventilation or Extracorporeal membrane oxygenation (ECMO)

Time frame: Up to Day 15

Secondary Outcomes

Number of Participants Requiring Mechanical Ventilation

Measured in number of participants

Time frame: 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

Time frame: Baseline, Day 15

Change From Baseline in Ferritin

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Lactate Dehydrogenase (LDH)

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in D-dimers

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Resting Peripheral Capillary Oxygen Saturation (SpO2)

Measured in percent (%)

Time frame: Baseline, 3 assessments every Days 4, 7, 10, 13 and 15

Change From Baseline in Oxygen Supplementation

Measured in l/min

Time frame: 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

Time frame: 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

Time frame: Screening, Day 15

Overall Survival

Confirmation of death

Time frame: Weeks 6 and 10

Number of Patients With Hospital Discharge

Measured in number of patients

Time frame: Until discharge up to Week 10

Change of Carbon Dioxide Tension (pCO2) in Hemogasanalysis From Baseline

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change of Oxygen Tension (pO2) in Hemogasanalysis From Baseline

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change of Potassium in Hemogasanalysis From Baseline

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change of Sodium in Hemogasanalysis From Baseline

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change of Chloride in Hemogasanalysis From Baseline

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change of Lactic Acid in Hemogasanalysis From Baseline

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change of Hemoglobin in Hemogasanalysis From Baseline

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in White Blood Cells With Differential Counts

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Red Blood Counts

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Hemoglobin

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Platelet Count

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Fibrinogen

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Complement Factors C3/C4

Measured in local units

Time frame: Day 15

Change From Baseline in Prothrombin Time

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Cardiac Troponin

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Aspartate Aminotransferase (AST)

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Alanine Aminotransferase (ALT)

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Total Bilirubin Levels

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in C-Reactive Protein

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

Change From Baseline in Creatinine

Measured in local units

Time frame: Baseline, Days 4, 7, 10, 13 and 15

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

Overview

Conditions

Interventions

Eligibility

Locations (12)

Outcomes

Primary Outcomes

Secondary Outcomes