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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

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ClinicalTrials.gov Identifier: NCT04412291
Recruitment Status : Recruiting
First Posted : June 2, 2020
Last Update Posted : February 18, 2021
Sponsor:
Collaborator:
Karolinska Institutet
Information provided by (Responsible Party):
Jonas Sundén-Cullberg, Karolinska University Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Covid-19 Drug: Anakinra Prefilled Syringe Drug: Tocilizumab Prefilled Syringe Drug: Standard-of-care treatment Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 11, 2020
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Standard-of-care Treatment (SOC)

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

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)

Other Names:
  • Oxygen supplementation
  • Thrombosis prophylaxis
  • Steroids
  • Antibiotics

Active Comparator: Anakinra + SOC

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
A total dose of 400mg per day (divided in 4 doses of 100 mg iv every 6 hours) for 7 days.

Drug: Standard-of-care treatment

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)

Other Names:
  • Oxygen supplementation
  • Thrombosis prophylaxis
  • Steroids
  • Antibiotics

Active Comparator: Tocilizumab + SOC.
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
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).

Drug: Standard-of-care treatment

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)

Other Names:
  • Oxygen supplementation
  • Thrombosis prophylaxis
  • Steroids
  • Antibiotics




Primary Outcome Measures :
  1. Time to recovery [ Time Frame: Day 1 through Day 29 ]

    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



Secondary Outcome Measures :
  1. Mortality [ Time Frame: Up to day 29 ]
  2. Number of Days on mechanical ventilation [ Time Frame: Up to day 29 ]
  3. Number of days of supplemental oxygen use [ Time Frame: Up to day 29 ]
  4. Number of patients requiring initiation of mechanical ventilation [ Time Frame: Up to day 29 ]
  5. Time to improvement in oxygenation for at least 48 hours [ Time Frame: Up to day 29 ]
    Definition of improvement in oxygenation: Increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

  6. Mean change in the 8-point ordinal scale [ Time Frame: Up to day 15 ]

    8-point Ordinal Scale:

    1. Death
    2. Hospitalized, on invasive mechanical ventilation or ECMO;
    3. Hospitalized, on non-invasive ventilation or high flow nasal cannula;
    4. Hospitalized, requiring supplemental oxygen
    5. Hospitalized, not requiring supplemental oxygen
    6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
    7. Not hospitalized, limitation on activities and/or requiring home oxygen;
    8. Not hospitalized

  7. Proportion of patients on level e-h on the 8-point ordinal scale at day 15 [ Time Frame: Day 15 ]

    8-point Ordinal Scale:

    1. Death
    2. Hospitalized, on invasive mechanical ventilation or ECMO;
    3. Hospitalized, on non-invasive ventilation or high flow nasal cannula;
    4. Hospitalized, requiring supplemental oxygen
    5. Hospitalized, not requiring supplemental oxygen
    6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
    7. Not hospitalized, limitation on activities and/or requiring home oxygen;
    8. Not hospitalized

  8. Time to improvement in one category from baseline using the 8-point ordinal scale [ Time Frame: Up to day 29 ]

    8-point Ordinal Scale:

    1. Death
    2. Hospitalized, on invasive mechanical ventilation or ECMO;
    3. Hospitalized, on non-invasive ventilation or high flow nasal cannula;
    4. Hospitalized, requiring supplemental oxygen
    5. Hospitalized, not requiring supplemental oxygen
    6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
    7. Not hospitalized, limitation on activities and/or requiring home oxygen;
    8. Not hospitalized

  9. Mean change in Sequential organ failure assessment score (SOFA) [ Time Frame: Up to day 15 ]
  10. Time to resolution of fever for at least 48 hours by clinical severity [ Time Frame: Up to day 29 ]
    Defined as ≤36.6°C (axilla), ≤37.2°C (oral) or ≤37.8°C (rectal or tympanic)

  11. Time to improvement of three points from baseline in National Early Warning Score 2 (NEWS2) scoring system [ Time Frame: Up to day 29 ]
    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)

  12. Time to score of <2 maintained for 24 hours in NEWS2 scoring system (National Early Warning Score) [ Time Frame: Up to day 29 ]
    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)

  13. Mean change in NEWS2 scoring system (National Early Warning Score) [ Time Frame: Up to day 15 ]
  14. Number of days with fever. [ Time Frame: Up to day 29 ]
    Based on highest measured daily body temperature. Defined as >36.6°C (axilla), >37.2°C (oral) or >37.8°C (rectal or tympanic

  15. Number of days of resting respiratory rate >24 breaths/min [ Time Frame: Up to day 29 ]
    Based on highest respiratory rate measured between 06.00 and 09.00 each day

  16. Time to saturation ≥94% on room air [ Time Frame: Up to day 29 ]
  17. Cumulative dose of steroids; equivalent to betamethasone dosage (mg) [ Time Frame: From start of steroid treatment for Covid-19 up to day 29 ]
  18. Cumulative dose of steroids during the study; equivalent to betamethasone dosage (mg) [ Time Frame: From day 1 up to day 29 ]
  19. Incidence of serious adverse events [ Time Frame: Up to day 60 ]
  20. Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection [ Time Frame: Up to day 29 ]
  21. Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with grade 4 neutropenia [ Time Frame: Up to day 60 ]
  22. Incidence of hypersensitivity reactions [ Time Frame: Up to day 29 ]
  23. Incidence of infusion reactions [ Time Frame: Up to day 29 ]
  24. Number of ventilator free days in the first 28 days [ Time Frame: Baseline to day 29 ]
  25. Number of patients requiring non-invasive ventilation [ Time Frame: Up to day 29 ]
  26. Number of patients requiring the use of high flow nasal cannula [ Time Frame: Up to day 29 ]
  27. Number of patients requiring Extracorporeal membrane oxygenation (ECMO) [ Time Frame: Up to day 29 ]
  28. Number of patients that have been admitted into an intensive care unit (ICU) [ Time Frame: Up to day 29 ]
  29. Number of patients that have been admitted into a High Dependency Unit ("Intermediärvårdsavdelning") [ Time Frame: Up to day 29 ]
  30. Number of days admitted into a High Dependency Unit ("Intermediärvårdsavdelning") or intensive care unit (ICU) [ [ Time Frame: Up to day 29 ]
  31. Number of days of hospitalization in survivors [ Time Frame: Up to day 29 ]
  32. Number of patients discharged to institution other than normal domicile. [ Time Frame: Up to day 60 ]
  33. Number of deaths due to any cause [ Time Frame: Up to day 60 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years
  2. 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
  3. 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)
  4. 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%..
  5. CRP > 70 mg/L with no non-SARS-Cov2 infections. Values measured up to 48 hours before inclusion are accepted.
  6. Ferritin > 500 µg/L Values measured up to 48 hours before inclusion are accepted.
  7. 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.
  8. Ability to provide informed consent signed by study patient
  9. Willingness and ability to comply with study-related procedures/assessments
  10. 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:

  1. Pregnancy or breast feeding.
  2. Ongoing or completed mechanical ventilation.
  3. In the opinion of the investigator, unlikely to survive for >48 hours from screening.
  4. In the opinion of the investigator, expected overall survival due to other comorbidities less than 3 months.
  5. Severe renal dysfunction eGFR < 30 ml/min.
  6. 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.
  7. Uncontrolled hypertension Systolic BP >180 mm Hg, Diastolic BP > 110 mm Hg.
  8. History of hypersensitivity to the study drugs
  9. 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
  10. 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
  11. Current treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs)/immunosuppressive agents
  12. 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
  13. History of, or current autoimmune or inflammatory systemic or localized disease(s) other than rheumatoid arthritis
  14. Acute systemic infection; verified by blood cultures systemic bacterial infection, systemic fungi-infection or prosthesis-related infection
  15. History of stem-cell or solid organ transplantation
  16. Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections
  17. Diagnosis of, or suspicion of HIV infection, acute hepatitis A and/or chronic hepatitis B and/or C
  18. Previous history of gastrointestinal ulceration or diverticulitis.
  19. Patients who have received immunosuppressive antibody therapy within the past 3 months, including intravenous immunoglobulin or plans to receive during the study period
  20. 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.
  21. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04412291


Contacts
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Contact: Investigator Jonas Sundén-Cullberg, MD PhD +46-8-58580000 Jonas.sunden-cullberg@sll.se
Contact: Jon Lampa, MD PhD +46-8-58580000 jon.lampa@sll.se

Locations
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Sweden
Karolinska University Hospital Recruiting
Huddinge, Stockholm, Sweden, 141 86
Contact: Jonas Sundén-Cullberg, MD, PHD       jonas.sunden-cullberg@sll.se   
Sponsors and Collaborators
Karolinska University Hospital
Karolinska Institutet
Investigators
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Principal Investigator: jonas Sundén-Cullberg, MD PhD Karolinska Universitetssjukhuset
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Responsible Party: Jonas Sundén-Cullberg, MD, PhD, Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT04412291    
Other Study ID Numbers: 2020-001748-24
First Posted: June 2, 2020    Key Record Dates
Last Update Posted: February 18, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Jonas Sundén-Cullberg, Karolinska University Hospital:
Coronavirus 2
SARS-CoV-2
Anakinra
Tocilizumab
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Anti-Bacterial Agents
Interleukin 1 Receptor Antagonist Protein
Anti-Infective Agents
Antirheumatic Agents