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

Phase 2

Terminated

• Conditions: SARS-CoV-2
• Interventions: Biological: Anakinra; Biological: Emapalumab

• Registration Number: NCT04324021
• Lead Sponsor: Swedish Orphan Biovitrum

Brief 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.

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 Timeline

• Study First Submitted: 2020-03-25
• Study First Submitted QC: 2020-03-25
• Study First Posted: 2020-03-27
• Study Start: 2020-04-02
• Primary Completion: 2020-11-13
• Study Completion: 2020-11-13
• Results First Submitted: 2021-11-29
• Status Verified: 2022-03
• Results First Submitted QC: 2022-03-03
• Last Update Submitted: 2022-03-03
• Results First Posted: 2022-03-10
• Last Update Posted: 2022-03-10

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 16

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Anakinra	Anakinra	Anakinra i.v. infusion four times daily for 15 days. 400 mg/day in total, divided into 4 doses given every 6 hours
Emapalumab	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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (12)

Temple University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Regions hospital; 🇺🇸 Saint Paul, Minnesota, United States

The Valley hospital; 🇺🇸 Ridgewood, New Jersey, United States

NewYork-Presbyterian Queens; 🇺🇸 Flushing, New York, United States

University of Utah Health; 🇺🇸 Salt Lake City, Utah, United States

S.C. Malattie Infettive, Ospedale Galliera; 🇮🇹 Genova, Italy

Dipartimento di Medicina - DIMED, Azienda Ospedale - Università Padova; 🇮🇹 Padova, Italy

ASST Spedali Civili di Brescia Dipartimento di Reumatologia e Immunologia Clinica; 🇮🇹 Brescia, Italy

Ospedale Maggiore Policlinico, Dipartimento di Anestesia-Rianimazione e Medicina di Urgenza; 🇮🇹 Milano, Italy

Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Malattie infettive ed epatologia; 🇮🇹 Parma, Italy

ASL Città di Torino, Unit of Infectious Diseases, Medicine, Rheumatology; 🇮🇹 Torino, Italy

Ospedale Lazzaro Spallanzani, Dipartimento di Malattie Infettive ad alta Intensità di cura ed altamente contagiose,Ospedale Lazzaro Spallanzani; 🇮🇹 Roma, Italy