Clinical trial NCT04412291: 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
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Covid-19
Keywords: Coronavirus 2
SARS-CoV-2
Anakinra
Tocilizumab
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
Collaborators: name: Karolinska Institutet
First posted: 2020-06-02
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Time to recovery
timeFrame: Day 1 through Day 29
Secondary outcomes:
measure: Mortality
timeFrame: Up to day 29
measure: Number of Days on mechanical ventilation
timeFrame: Up to day 29
measure: Number of days of supplemental oxygen use
timeFrame: Up to day 29
measure: Number of patients requiring initiation of mechanical ventilation
timeFrame: Up to day 29
measure: Time to improvement in oxygenation for at least 48 hours
timeFrame: Up to day 29
measure: Mean change in the 8-point ordinal scale
timeFrame: Up to day 15
measure: Proportion of patients on level e-h on the 8-point ordinal scale at day 15
timeFrame: Day 15
measure: Time to improvement in one category from baseline using the 8-point ordinal scale
timeFrame: Up to day 29
measure: Mean change in Sequential organ failure assessment score (SOFA)
timeFrame: Up to day 15
measure: Time to resolution of fever for at least 48 hours by clinical severity
timeFrame: Up to day 29
measure: Time to improvement of three points from baseline in National Early Warning Score 2 (NEWS2) scoring system
timeFrame: Up to day 29
measure: Time to score of <2 maintained for 24 hours in NEWS2 scoring system (National Early Warning Score)
timeFrame: Up to day 29
measure: Mean change in NEWS2 scoring system (National Early Warning Score)
timeFrame: Up to day 15
measure: Number of days with fever.
timeFrame: Up to day 29
measure: Number of days of resting respiratory rate >24 breaths/min
timeFrame: Up to day 29
measure: Time to saturation ≥94% on room air
timeFrame: Up to day 29
measure: Cumulative dose of steroids; equivalent to betamethasone dosage (mg)
timeFrame: From start of steroid treatment for Covid-19 up to day 29
measure: Cumulative dose of steroids during the study; equivalent to betamethasone dosage (mg)
timeFrame: From day 1 up to day 29
measure: Incidence of serious adverse events
timeFrame: Up to day 60
measure: Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection
timeFrame: Up to day 29
measure: Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with grade 4 neutropenia
timeFrame: Up to day 60
measure: Incidence of hypersensitivity reactions
timeFrame: Up to day 29
measure: Incidence of infusion reactions
timeFrame: Up to day 29
measure: Number of ventilator free days in the first 28 days
timeFrame: Baseline to day 29
measure: Number of patients requiring non-invasive ventilation
timeFrame: Up to day 29
measure: Number of patients requiring the use of high flow nasal cannula
timeFrame: Up to day 29
measure: Number of patients requiring Extracorporeal membrane oxygenation (ECMO)
timeFrame: Up to day 29
measure: Number of patients that have been admitted into an intensive care unit (ICU)
timeFrame: Up to day 29
measure: Number of patients that have been admitted into a High Dependency Unit ("Intermediärvårdsavdelning")
timeFrame: Up to day 29
measure: Number of days admitted into a High Dependency Unit ("Intermediärvårdsavdelning") or intensive care unit (ICU) [
timeFrame: Up to day 29
measure: Number of days of hospitalization in survivors
timeFrame: Up to day 29
measure: Number of patients discharged to institution other than normal domicile.
timeFrame: Up to day 60
measure: Number of deaths due to any cause
timeFrame: Up to day 60
Other outcomes:
Locations:
city: Huddinge
country: Sweden
facility: Karolinska University Hospital
state: Stockholm
Study officials:
affiliation: Karolinska Universitetssjukhuset
name: jonas Sundén-Cullberg, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: