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
Overview
- Phase
- Phase 2
- Intervention
- Standard-of-care treatment
- Conditions
- Covid-19
- Sponsor
- Karolinska University Hospital
- Enrollment
- 120
- Locations
- 1
- Primary Endpoint
- Time to recovery
- Last Updated
- 5 years ago
Overview
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.
Investigators
Jonas Sundén-Cullberg
MD, PhD
Karolinska University Hospital
Eligibility Criteria
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
Arms & Interventions
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)
Intervention: Standard-of-care treatment
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..
Intervention: Anakinra Prefilled Syringe
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..
Intervention: Standard-of-care treatment
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.
Intervention: Tocilizumab Prefilled Syringe
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.
Intervention: Standard-of-care treatment
Outcomes
Primary Outcomes
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 Outcomes
- Incidence of serious adverse events(Up to day 60)
- Incidence of hypersensitivity reactions(Up to day 29)
- Mortality(Up to day 29)
- Cumulative dose of steroids during the study; equivalent to betamethasone dosage (mg)(From day 1 up to day 29)
- Number of ventilator free days in the first 28 days(Baseline to day 29)
- Number of Days on mechanical ventilation(Up to day 29)
- Time to resolution of fever for at least 48 hours by clinical severity(Up to day 29)
- Mean change in NEWS2 scoring system (National Early Warning Score)(Up to day 15)
- Number of days of resting respiratory rate >24 breaths/min(Up to day 29)
- Time to improvement in oxygenation for at least 48 hours(Up to day 29)
- Mean change in the 8-point ordinal scale(Up to day 15)
- Cumulative dose of steroids; equivalent to betamethasone dosage (mg)(From start of steroid treatment for Covid-19 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)
- Mean change in Sequential organ failure assessment score (SOFA)(Up to day 15)
- Time to improvement of three points from baseline in National Early Warning Score 2 (NEWS2) scoring system(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 days of supplemental oxygen use(Up to day 29)
- Number of patients requiring initiation of mechanical ventilation(Up to day 29)
- Proportion of patients on level e-h on the 8-point ordinal scale at day 15(Day 15)
- Number of days with fever.(Up to day 29)
- Time to saturation ≥94% on room air(Up to day 29)
- Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection(Up to day 29)
- Number of patients requiring non-invasive ventilation(Up to day 29)
- Number of days of hospitalization in survivors(Up to day 29)
- Number of deaths due to any cause(Up to day 60)
- Time to improvement in one category from baseline using the 8-point ordinal scale(Up to day 29)
- Time to score of <2 maintained for 24 hours in NEWS2 scoring system (National Early Warning Score)(Up to day 29)
- Incidence of infusion reactions(Up to day 29)
- Number of patients discharged to institution other than normal domicile.(Up to day 60)
- 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)