A Study in Patients With COVID-19 and Respiratory Distress Not Requiring Mechanical Ventilation, to Compare Standard-of-care With Anakinra and Tocilizumab Treatment The Immunomodulation-CoV Assessment (ImmCoVA) Study

Study Overview
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Brief Summary
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The study is designed as a randomized, controlled, multi-center open-label trial to compare standard-of-care (SOC) treatment with SOC + anakinra or SOC + tocilizumab treatment in hospitalized adult subjects who are diagnosed with severe COVID 19. Arm A: Standard-of-care Treatment (SOC) Arm B: Anakinra + SOC Arm C: Tocilizumab + SOC. All subjects will be treated with standard-of-care treatment. Arms B and C will also receive broad spectrum antibiotics initiated before or latest 24 hours after initiation of treatment with study drug. The primary follow-up period of the study is 29 days.

Official Title
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A Multi-center, Randomized, Open-label Study in Patients With COVID-19 and Respiratory Distress Not Requiring Mechanical Ventilation, to Compare Standard-of-care With Anakinra and Tocilizumab Treatment The Immunomodulation-CoV Assessment (ImmCoVA) Study

Conditions
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Covid-19

Intervention / Treatment
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* Drug: Anakinra Prefilled Syringe
* Drug: Tocilizumab Prefilled Syringe
* Drug: Standard-of-care treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay < 7 days prior to screening SARS-CoV-2 infection with duration at least 7 days (i e may be included on day 7) as determined by onset of symptoms (defined as day 1) 5 liters/minute of Oxygen for at least 8 hours to maintain SpO2 at ≥93%. A shorter duration is also accepted if presentation is acute, and the patient needs more than 10 liters/minute of Oxygen, or high flow nasal cannula or non-invasive ventilation, to maintain SpO2 at ≥93%.. CRP > 70 mg/L with no non-SARS-Cov2 infections. Values measured up to 48 hours before inclusion are accepted. Ferritin > 500 µg/L Values measured up to 48 hours before inclusion are accepted. At least two points on a scale of 0-3 where 1 point is awarded for each value of; lymphocytes < 1x 10(9)/L; D-dimer ≥ 0.5 mg/L and; Lactate Dehydrogenase ≥ 8 microkatal/L. The values do not have to be concurrently positive and may be up to 3 days old at inclusion. Ability to provide informed consent signed by study patient Willingness and ability to comply with study-related procedures/assessments In fertile females, willing to comply with effective contraceptive methods for up to 3 months after last dose of study drug. These may include surgical sterilization of patient or partner, intrauterine device or condoms. Gestagen-only birth control pills (mini-pills), which do not increase the risk of deep venous thrombosis, may also be used. Non-fertile woman is defined as more than 12 months of amenorrhea without an alternative medical cause or, in case of ambiguities, an FSH level in the postmenopausal range. Exclusion Criteria: Pregnancy or breast feeding. Ongoing or completed mechanical ventilation. In the opinion of the investigator, unlikely to survive for >48 hours from screening. In the opinion of the investigator, expected overall survival due to other comorbidities less than 3 months. Severe renal dysfunction eGFR < 30 ml/min. Medical history including chronic liver disease with inflammation, fibrosis or cirrhosis including underlying diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, chronic viral hepatitis, alcoholic liver disease, autoimmune liver disease, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, cholangitis, or carcinoma. Uncontrolled hypertension Systolic BP >180 mm Hg, Diastolic BP > 110 mm Hg. History of hypersensitivity to the study drugs Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 2 x 109/L, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN), platelets <100 x 109/L Treatment with anakinra, anti-IL 6, anti-IL-6R antagonists, Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period Current treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs)/immunosuppressive agents Use of chronic oral corticosteroids for a non-COVID-19-related condition in a dose higher than prednisone 10 mg or equivalent per day. Ongoing acute treatment for COVID-19 with any peroral or iv steroid is permitted for up to five days before inclusion. Chronic or acute treatment with inhaled steroids is also permitted History of, or current autoimmune or inflammatory systemic or localized disease(s) other than rheumatoid arthritis Acute systemic infection; verified by blood cultures systemic bacterial infection, systemic fungi-infection or prosthesis-related infection History of stem-cell or solid organ transplantation Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections Diagnosis of, or suspicion of HIV infection, acute hepatitis A and/or chronic hepatitis B and/or C Previous history of gastrointestinal ulceration or diverticulitis. Patients who have received immunosuppressive antibody therapy within the past 3 months, including intravenous immunoglobulin or plans to receive during the study period Participation in any clinical research study evaluating an investigational product (IP) or therapy within 3 months and less than 5 half-lives of IP prior to the screening visit. The use of remdesivir is permitted. Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard-of-care Treatment (SOC)<br>SOC according to local recommendations at the Karolinska University Hospital: Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep or Klexane or new oral anticoagulants incl. dabigatran, apixaban or rivaroxaban). Steroids (Betapred) | Drug: Standard-of-care treatment<br>* SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep and Klexane® or new oral anticoagulants including dabigatran, apixaban or rivaroxaban). Steroids (Betapred 6 mg po) Broad spectrum antibiotics (only in arm B and C)<br>* Other names: Antibiotics;|
| Active Comparator: Anakinra + SOC<br>Anakinra: A total dose of 400mg per day (divided in 4 doses of 100 mg iv every 6 hours) for 7 days. SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep) Steroids (Betapred) Prophylactic broad spectrum antibiotics for seven days.. | Drug: Anakinra Prefilled Syringe<br>* A total dose of 400mg per day (divided in 4 doses of 100 mg iv every 6 hours) for 7 days.<br>Drug: Standard-of-care treatment<br>* SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep and Klexane® or new oral anticoagulants including dabigatran, apixaban or rivaroxaban). Steroids (Betapred 6 mg po) Broad spectrum antibiotics (only in arm B and C)<br>* Other names: Antibiotics;|
| Active Comparator: Tocilizumab + SOC.<br>Tocilizumab: 8mg/kg for a single infusion iv up to max 800 mg. If no clinical response is obtained, another dose of 8mg/kg may be administered after earliest 2 days SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep) Steroids (Betapred) Prophylactic broad spectrum antibiotics for seven days. | Drug: Tocilizumab Prefilled Syringe<br>* 8mg/kg for a single infusion iv up to max 800 mg. If no clinical response is obtained, another dose of 8mg/kg may be administered after earliest 2 days after inclusion with the following condition: The clinical symptoms are worsened (as assessed by decreasing PaO2/FiO2 and/or need of increased ventilatory support such as NIV, HFNC or mechanical ventilation).<br>Drug: Standard-of-care treatment<br>* SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep and Klexane® or new oral anticoagulants including dabigatran, apixaban or rivaroxaban). Steroids (Betapred 6 mg po) Broad spectrum antibiotics (only in arm B and C)<br>* Other names: Antibiotics;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to recovery | Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale:1) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 1; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Not hospitalized, no limitations on activities. 1 LMWH-injections (Fragmin, Innohep) do not count as medical care | Day 1 through Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality |  | Up to day 29 | 
| Number of Days on mechanical ventilation |  | Up to day 29 | 
| Number of days of supplemental oxygen use |  | Up to day 29 | 
| Number of patients requiring initiation of mechanical ventilation |  | Up to day 29 | 
| Time to improvement in oxygenation for at least 48 hours | Definition of improvement in oxygenation: Increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2 | Up to day 29 | 
| Mean change in the 8-point ordinal scale | 8-point Ordinal Scale: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow nasal cannula; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized | Up to day 15 | 
| Proportion of patients on level e-h on the 8-point ordinal scale at day 15 | 8-point Ordinal Scale: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow nasal cannula; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized | Day 15 | 
| Time to improvement in one category from baseline using the 8-point ordinal scale | 8-point Ordinal Scale: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow nasal cannula; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized | Up to day 29 | 
| Mean change in Sequential organ failure assessment score (SOFA) |  | Up to day 15 | 
| Time to resolution of fever for at least 48 hours by clinical severity | Defined as ≤36.6°C (axilla), ≤37.2°C (oral) or ≤37.8°C (rectal or tympanic) | Up to day 29 | 
| Time to improvement of three points from baseline in National Early Warning Score 2 (NEWS2) scoring system | NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C) | Up to day 29 | 
| Time to score of <2 maintained for 24 hours in NEWS2 scoring system (National Early Warning Score) | NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of Air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C) | Up to day 29 | 
| Mean change in NEWS2 scoring system (National Early Warning Score) |  | Up to day 15 | 
| Number of days with fever. | Based on highest measured daily body temperature. Defined as >36.6°C (axilla), >37.2°C (oral) or >37.8°C (rectal or tympanic | Up to day 29 | 
| Number of days of resting respiratory rate >24 breaths/min | Based on highest respiratory rate measured between 06.00 and 09.00 each day | Up to day 29 | 
| Time to saturation ≥94% on room air |  | Up to day 29 | 
| Cumulative dose of steroids; equivalent to betamethasone dosage (mg) |  | From start of steroid treatment for Covid-19 up to day 29 | 
| Cumulative dose of steroids during the study; equivalent to betamethasone dosage (mg) |  | From day 1 up to day 29 | 
| Incidence of serious adverse events |  | Up to day 60 | 
| Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection |  | Up to day 29 | 
| Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with grade 4 neutropenia |  | Up to day 60 | 
| Incidence of hypersensitivity reactions |  | Up to day 29 | 
| Incidence of infusion reactions |  | Up to day 29 | 
| Number of ventilator free days in the first 28 days |  | Baseline to day 29 | 
| Number of patients requiring non-invasive ventilation |  | Up to day 29 | 
| Number of patients requiring the use of high flow nasal cannula |  | Up to day 29 | 
| Number of patients requiring Extracorporeal membrane oxygenation (ECMO) |  | Up to day 29 | 
| Number of patients that have been admitted into an intensive care unit (ICU) |  | Up to day 29 | 
| Number of patients that have been admitted into a High Dependency Unit (Intermediärvårdsavdelning) |  | Up to day 29 | 
| Number of days admitted into a High Dependency Unit (Intermediärvårdsavdelning) or intensive care unit (ICU) [ |  | Up to day 29 | 
| Number of days of hospitalization in survivors |  | Up to day 29 | 
| Number of patients discharged to institution other than normal domicile. |  | Up to day 60 | 
| Number of deaths due to any cause |  | Up to day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus 2, SARS-CoV-2, Anakinra, Tocilizumab