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.
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: 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 Name: Array
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
Karolinska University Hospital
Huddinge, Stockholm, Sweden
Investigator: Jonas Sundén-Cullberg, MD, PHD
jonas.sunden-cullberg@sll.se
Investigator Jonas Sundén-Cullberg, MD PhD
+46-8-58580000
Jonas.sunden-cullberg@sll.se
Jon Lampa, MD PhD
+46-8-58580000
jon.lampa@sll.se
jonas Sundén-Cullberg, MD PhD, Principal Investigator
Karolinska Universitetssjukhuset