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

SARS-CoV-2 Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04324021
• Other study ID #: Sobi.IMMUNO-101
• Secondary ID: 2020-001167-93
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: April 2, 2020
• Est. completion date: November 13, 2020

Study information

• Verified date: March 2022
• Source: Swedish Orphan Biovitrum
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: November 13, 2020
• Est. primary completion date: November 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• SARS-CoV-2

Intervention

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Swedish Orphan Biovitrum

Countries where clinical trial is conducted

United States,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of Participants Requiring Mechanical Ventilation	Measured in number of participants	Date of randomization to date of mechanical ventilation, up to 15 Days
Secondary	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
Secondary	Change From Baseline in Ferritin	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Lactate Dehydrogenase (LDH)	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in D-dimers	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Resting Peripheral Capillary Oxygen Saturation (SpO2)	Measured in percent (%)	Baseline, 3 assessments every Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Oxygen Supplementation	Measured in l/min	Baseline, Days 4, 7, 10, 13 and 15.
Secondary	Change From Baseline in Partial Pressure of Oxygen/Fraction of Inspired Oxygen (PaO2/FiO2)	Measured in mmHg	Baseline, Day 15
Secondary	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
Secondary	Overall Survival	Confirmation of death	Weeks 6 and 10
Secondary	Number of Patients With Hospital Discharge	Measured in number of patients	Until discharge up to Week 10
Secondary	Change of Carbon Dioxide Tension (pCO2) in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change of Oxygen Tension (pO2) in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change of Potassium in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change of Sodium in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change of Chloride in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change of Lactic Acid in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change of Hemoglobin in Hemogasanalysis From Baseline	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in White Blood Cells With Differential Counts	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Red Blood Counts	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Hemoglobin	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Platelet Count	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Fibrinogen	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Complement Factors C3/C4	Measured in local units	Day 15
Secondary	Change From Baseline in Prothrombin Time	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Cardiac Troponin	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Aspartate Aminotransferase (AST)	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Alanine Aminotransferase (ALT)	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Total Bilirubin Levels	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in C-Reactive Protein	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15
Secondary	Change From Baseline in Creatinine	Measured in local units	Baseline, Days 4, 7, 10, 13 and 15