Infliximab in the Treatment of Patients With Severe COVID-19 Disease

Study Overview
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Brief Summary
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In this trial, patients that are severely affected by the disease COVID-19 will either receive infliximab, an anti-inflammatory drug, or standard therapy. Infliximab is a drug that inhibits inflammation by blocking a molecule called TNFα. The patients receive the drug via an infusion into a vein. The primary goal of this trial is to see whether the drug infliximab affects how many people died from COVID-19 after 28 days by comparing patients receiving the drug in addition to standard therapy with patients only receiving standard therapy. Furthermore, this trial will look at whether the drug is safe to use in these patients, whether it has an effect on the inflammation and whether it can affect how ill patients are after surviving the disease. The trial is conducted in more than one hospital. As COVID-19 is responsible for a global pandemic, positive results of this trial could affect patients, healthcare and economic systems worldwide.

Detailed Description
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The long-term goal of this research project is to develop a new pharmacological treatment strategy for patients with COVID-19. Its primary aim is the assessment of efficacy and safety of the TNFα antibody infliximab in the treatment of patients with severe COVID-19 in a phase-2 trial. Infliximab is expected to attenuate the inflammatory reaction in patients and thereby positively influence the course of the disease. The primary endpoint is the difference in 28-day-mortality of patients with severe COVID-19 receiving one dose of 5mg per kg body weight infliximab intravenously in addition to the standard of care (intervention group) compared with patients receiving standard of care (control group). Secondary aims of this trial include the assessment of the safety of the TNFα antibody infliximab in the treatment of patients with severe COVID-19, of its effect on an excessive immune response and of its effect on the morbidity and prognosis as well as the characterization of the analytical cohorts. The multi-centre design facilitates the transferability of study results to hospitals of similar healthcare level. Should infliximab prove to be superior to standard therapy, this could be reflected in a reduced disease severity and mortality. The results of this study could influence the therapy of patients with COVID-19 worldwide and affect the course of the disease worldwide, as infliximab is approved by several international drug agencies and globally available. Due to the high incidence of COVID-19 worldwide and the immense effects of the pandemic on societies, health care and economic systems, any progress in the treatment of this new disease would constitute a great success. This would not only impact individual patients but also have positive economic effects.

Official Title
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A Randomized, Controlled, Multicenter, Open Label Phase II Clinical Study to Evaluate Infliximab in the Treatment of Patients With Severe COVID-19 Disease

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Infliximab
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Infection with SARS-CoV-2 (virus detection by means of a PCR test not older than 72 hours) Bipulmonary infiltrates (detection by means of X-rays or computed tomography) COVID inflammation score ≥ 10 Ferritin concentration (serum or plasma) ≥ 500 ng / ml Arterial oxygen saturation ≤ 93% when breathing room air written informed consent from the patient Potentially childbearing women: negative pregnancy test Exclusion Criteria (in medical history): Contraindications study medication: Hypersensitivity to the active substance infliximab (or any of the other ingredients of the medicine) or to other murine proteins active or latent tuberculosis acute or chronic hepatitis B severe infections such as invasive fungal infections, bacterial sepsis, or abscesses opportunistic infections (e.g. pneumocystosis, listeriosis) moderate or severe heart failure (NYHA class III / IV) Immunosuppression (e.g. organ transplantation, AIDS, leukopenia) Malignancies or lymphoproliferative diseases or chemotherapy within the last 4 weeks Multiple sclerosis or peripheral demyelinating diseases, including the Guillain-Barré syndrome Treatment with other biologics for therapy for approved indications of infliximab (e.g. for rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, psoriasis) Further exclusion criteria: Autoimmune disease with biologics therapy Current treatment with TNF antibodies, convalescent plasma, bamlanivimab, or other experimental treatments for COVID-19 High-flow oxygen therapy, non-invasive / invasive ventilation (WHO-COVID-19 PROGRESSION Scale > 5) pre-existing long-term ventilation or home oxygen therapy Child-Pugh C liver cirrhosis Pregnancy or breastfeeding Patients with a life expectancy < 90 days due to other medical conditions Limitation or discontinuation of therapy (e.g. refusal of artificial ventilation) Participation in another interventional study Previous participation in this study Interdependence between the patient and the coordinating investigator or other members of the study team

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infliximab + Standard of Care<br> | Drug: Infliximab<br>* single intravenous administration of 5 milligrams/kilogram<br>Other: Standard of Care<br>* Standard of Care<br>|
| Active Comparator: Standard of Care<br> | Other: Standard of Care<br>* Standard of Care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality | differences in mortality-rates between both study arms (Infliximab + Standard of Care vs. Standard of Care) 28 days after randomisation | 28 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety of Infliximab administration | frequencies of adverse events (AEs) and serious adverse events (SAEs) | up to 90 days after randomization | 
| assessment of the effect of infliximab on an excessive immune response in patients with COVID-19: Interleukin 6 | change in the interleukin-6 (IL-6) concentration in the blood from randomization to day 7 and day 14 after randomization | day 7 and day 14 after randomization | 
| assessment of the effect of infliximab on an excessive immune response in patients with COVID-19: ferritin | change in the ferritin concentration in the blood from randomization to day 7 and day 14 after randomization | day 7 and day 14 after randomization | 
| assessment of the effect of infliximab on an excessive immune response in patients with COVID-19: lymphocyte count | change in the lymphocyte count from randomization to day 7 and day 14 after randomization | day 7 and day 14 after randomization | 
| assessment of the severity and frequency of organ failure: ventilation-free days | ventilation-free days until 28 days after randomization | day 28 after randomization | 
| assessment of the severity and frequency of organ failure: renal replacement therapy-free days | renal replacement therapy-free days until 28 days after randomization | day 28 after randomization | 
| assessment of the severity and frequency of organ failure: vasopressor-free days | vasopressor-free days until 28 days after randomization | day 28 after randomization | 
| occurence of Acute Respiratory Distress Syndrome (ARDS) | rate of occurrence of ARDS until 28 days after randomization | day 28 after randomization | 
| WHO-COVID-19-Progression Scale | WHO-COVID-19-Progression Scale on day 7, 14 and 28 after randomization | day 7, 14 and 28 after randomization | 
| rate of admission to the intensive care unit | rate of admission to the intensive care unit after randomization up to day 28 | day 28 after randomization | 
| length of stay: hospital | length of hospital stay up to day 28 after randomization | day 28 after randomization | 
| length of stay: intensive care unit | length of intensive care unit stay up to day 28 after randomization | day 28 after randomization | 
| mortality | mortality rates 14 and 90 days after randomization | day 14 and 90 after randomization | 
| health related quality of life: visual analogue scale | EQ5D-3L: visual analog scale value 90 days after randomization | day 90 after randomization | 
| health related quality of life: index | EQ5D-3L: index value 90 days after randomization | day 90 after randomization | 
| incidence of cardiomyopathy | incidence of cardiomyopathy 3 and/or 7 days after randomization | day 3 and 7 after randomization |