| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| COVID-19 infection in patients with respiratory distress. |
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| E.1.1.1 | Medical condition in easily understood language |
| COVID-19 infection in patients with respiratory distress. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to assess the effect of anakinra and tocilizumab on time to recovery in patients with COVID-19 and respiratory distress. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives of the study are to assess the effect of anakinra and tocilizumab on mortality, need and length of intensive care, and also rate, magnitude and speed of clinical improvement including pulmonary function in patients with COVID-19 and respiratory distress.
Exploratory objectives:
The exploratory objective of the study is to assess the effect of anakinra and tocilizumab on selected biomarkers relevant for hyperinflammation and coagulation disturbances.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < 3 days prior to screening
3) SARS-CoV-2 infection with duration at least 7 days (as determined by onset of symptoms)
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 l liters/minute of Oxygen 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 birth control pills, surgical sterilization of patient or partner, intrauterine device or condoms, but not birth control pills which may increase risk of deep venous thrombosis during COVID infections. 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.
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| E.4 | Principal 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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
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 from baseline and nadir at days 8 and 15
7. Proportion of patients on level e-h on the 8-point ordinal scale at day 15
8. Time to improvement in one category from baseline using the 8-point ordinal scale [ Time Frame: Up to day 29 ]
9. Mean change in SOFA score from baseline until days 5, 10 and 15
10. Time to resolution of fever for at least 48 hours [ 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 the 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 [ 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 from baseline until days 5, 10 and 15
14. Number of days with fever from baseline. Based on highest measured daily body temperature [ Time Frame: Up to day 29 ] Defined as >36.6°C (axilla), >37.2°C (oral) or >37.8°C (rectal or tympanic)
15. Number of days from baseline of resting respiratory rate >24 breaths/min. Based on highest respiratory rate measured between 06.00 and 09.00 each day [ Time Frame: Up to day 29 ]
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 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.
33. Number of deaths due to any cause [ Time Frame: Up to day 60 ]
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluations done up to day 29 except for;
- item 6, 7, 9, 13 up to day 15
- item 19, 21, 33 up to day 60 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| SOC, i.e Oxygen suppl. (SpO2 ≥93 %), antipyretic treatment , thrombosis prophylaxis |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
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