Clinical trial NCT04324021: Efficacy and Safety of Emapalumab and Anakinra in Reducing Hyperinflammation and Respiratory Distress in Patients With COVID-19 Infection.
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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: SARS-CoV-2
Lead sponsor: Swedish Orphan Biovitrum
Sponsor class: INDUSTRY
First posted: 2020-03-27
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Treatment Success
timeFrame: Up to Day 15
Secondary outcomes:
measure: Number of Participants Requiring Mechanical Ventilation
timeFrame: Date of randomization to date of mechanical ventilation, up to 15 Days
measure: Change From Baseline in Modified Early Warning System Score
timeFrame: Baseline, Day 15
measure: Change From Baseline in Ferritin
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Lactate Dehydrogenase (LDH)
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in D-dimers
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Resting Peripheral Capillary Oxygen Saturation (SpO2)
timeFrame: Baseline, 3 assessments every Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Oxygen Supplementation
timeFrame: Baseline, Days 4, 7, 10, 13 and 15.
measure: Change From Baseline in Partial Pressure of Oxygen/Fraction of Inspired Oxygen (PaO2/FiO2)
timeFrame: Baseline, Day 15
measure: Number of Participants With Changes in High-resolution Computed Tomography (CT) Scan of the Chest
timeFrame: Screening, Day 15
measure: Overall Survival
timeFrame: Weeks 6 and 10
measure: Number of Patients With Hospital Discharge
timeFrame: Until discharge up to Week 10
measure: Change of Carbon Dioxide Tension (pCO2) in Hemogasanalysis From Baseline
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change of Oxygen Tension (pO2) in Hemogasanalysis From Baseline
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change of Potassium in Hemogasanalysis From Baseline
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change of Sodium in Hemogasanalysis From Baseline
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change of Chloride in Hemogasanalysis From Baseline
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change of Lactic Acid in Hemogasanalysis From Baseline
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change of Hemoglobin in Hemogasanalysis From Baseline
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in White Blood Cells With Differential Counts
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Red Blood Counts
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Hemoglobin
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Platelet Count
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Fibrinogen
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Complement Factors C3/C4
timeFrame: Day 15
measure: Change From Baseline in Prothrombin Time
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Cardiac Troponin
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Aspartate Aminotransferase (AST)
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Alanine Aminotransferase (ALT)
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Total Bilirubin Levels
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in C-Reactive Protein
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
measure: Change From Baseline in Creatinine
timeFrame: Baseline, Days 4, 7, 10, 13 and 15
Other outcomes:
Locations:
city: Saint Paul
country: United States
facility: Regions hospital
state: Minnesota
city: Ridgewood
country: United States
facility: The Valley hospital
state: New Jersey
city: Flushing
country: United States
facility: NewYork-Presbyterian Queens
state: New York
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah Health
state: Utah
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia Dipartimento di Reumatologia e Immunologia Clinica
city: Genova
country: Italy
facility: S.C. Malattie Infettive, Ospedale Galliera
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico, Dipartimento di Anestesia-Rianimazione e Medicina di Urgenza
city: Padova
country: Italy
facility: Dipartimento di Medicina - DIMED, Azienda Ospedale - Università Padova
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Malattie infettive ed epatologia
city: Roma
country: Italy
facility: Ospedale Lazzaro Spallanzani, Dipartimento di Malattie Infettive ad alta Intensità di cura ed altamente contagiose,Ospedale Lazzaro Spallanzani
city: Torino
country: Italy
facility: ASL Città di Torino, Unit of Infectious Diseases, Medicine, Rheumatology
Study officials:
affiliation: Direttore Dipartimento di Malattie Infettive
name: Emanuele Nicastri, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.