Coronavirus Infection, Diabetes Mellitus, Type 2
Conditions
Keywords
NLRP3, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Coronavirus Disease 19 (COVID-19), IL-1beta, hyperinflammatory syndrome, obesity
Brief summary
The purpose of this study is to evaluate whether Canakinumab has beneficial effects on patients with Type 2 diabetes mellitus and coronavirus disease 19 (COVID19).
Detailed description
Patients with a metabolic syndrome (overweight, diabetes, hypertension) have a particularly bad outcome if infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). This may be explained by an over-activation of the Interleukin-1 (IL-1) beta system. Metabolic stress (increased glucose and lipid levels) induces NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) -mediated IL-1beta secretion. SARS-CoV2 also activates NLRP3. Therefore, the study proposes that metabolic stress in patients with overweight and diabetes potentiates COVID-19 induced hyperinflammatory syndrome leading to excess mortality in these vulnerable patients. Canakinumab (Ilaris®) is a recombinant, human monoclonal antibody antagonizing IL-1beta by blocking IL-1beta activity. The aim of the study is to investigate the effect of canakinumab in type 2 diabetic patients with COVID-19.
Interventions
DRUGPlacebo
Aqua ad injectabilia in 250 ml 5% dextrose solution i.v. over 2 hours
DRUGCanakinumab
Body weight adjusted dose in 250 ml 5% dextrose solution i.v. over 2 hours
Sponsors
Novartis
Swiss National Science Foundation
University Hospital, Basel, Switzerland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of type 2 diabetes mellitus * Body mass index \> 25 kg/m² (overweight) * Hospitalized with COVID-19
Exclusion criteria
* Suspected or known untreated active bacterial, fungal, viral, or parasitic infection with the exception of COVID-19 * Treatment with immunomodulators or immunosuppressant drugs, including but not limited to tocilizumab, tumor necrosis factor (TNF) inhibitors and anti-IL-17 agents within 5 half-lives or 30 days (whichever is longer) prior to randomization with the exception of anakinra which is excluded within 5 half-lives only. Note: Immunomodulators (topical or inhaled) for asthma and atopic dermatitis, and corticosteroids (any route of administration) such as dexamethasone are permitted. * History of hypersensitivity to canakinumab or to biologic drugs * Neutrophil count \<1000/mm3 * Pregnant or nursing (lactating) women * Participation in another study with investigational drug within the 30 days preceding and during the present study-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| unmatched win ratio after treatment with canakinumab compared to Placebo (composite endpoint) | within 4 weeks after treatment with canakinumab or placebo | Treatment and placebo will be compared on the basis of the unmatched win-ratio approach of Pocock. When comparing two patients, the winner will be determined by the first component in which the two patients differ (4 weeks after randomization): 1. longer survival time 2. longer ventilation-free time 3. longer ICU-free time 4. shorter hospitalization time If there is no difference between treatment and Placebo: the win ratio is 1. If there is a difference between treatment and Placebo: the win ratio is not 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Death rate | 4 weeks | Death rate during the 4-week period after study treatment |
| Admission to intensive care unit (ICU) | 4 weeks | Admission to the intensive care unit from the medical ward during the 4-week period after study treatment |
| Secondary worsening of disease | 4 weeks | Secondary worsening of disease (i.e., development of Acute respiratory distress Syndrome (ARDS), increase of oxygen demand after 72h of treatment) |
| Prolonged hospital stay | >3 weeks | Prolonged hospital stay \> 3 weeks |
| Change in ratio to baseline in the glycated hemoglobin | Baseline, Day 29 and Day 90 | Ratio to baseline in the glycated hemoglobin |
| Change in ratio to baseline in the fasting glucose | Baseline, Day 29 | Ratio to baseline in the fasting glucose |
| Change in ratio to baseline in the fasting insulin | Baseline, Day 29 | Ratio to baseline in the fasting insulin |
| Change in ratio to baseline in the fasting c-peptide | Baseline, Day 29 | Ratio to baseline in the fasting c-peptide |
| Time to clinical improvement | From randomization up to 4 weeks | Time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever comes first. The seven-category ordinal scale consists of the following categories: 1. not hospitalized with resumption of normal activities; 2. not hospitalized, but unable to resume normal activities; 3. hospitalized, not requiring supplemental oxygen; 4. hospitalized, requiring supplemental oxygen; 5. hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6. hospitalized, requiring extracorporeal membrane oxygenation (ECMO), invasive mechanical ventilation, or both; and 7. death |
| Change in ratio to baseline in the D-dimer | Baseline, Day 29 | Ratio to baseline in the D-dimer |
| Change in ratio to baseline in the Natriuretic peptide (NTproBNP) | Baseline, Day 29 and Day 90 | Ratio to baseline in the Natriuretic peptide (NTproBNP) |
| Change in ratio to baseline in the Glomerular Filtration Rate Renal (eGFR) | Baseline, Day 29 and Day 90 | Ratio to baseline in the Glomerular Filtration Rate Renal (eGFR) |
| Type of antidiabetic treatment at Day 29 | Day 29 | Type of antidiabetic treatment at Day 29 |
| Number of antidiabetic treatment at Day 29 | Day 29 | Number of antidiabetic treatment at Day 29 |
| Type of antidiabetic treatment at three months | Month 3 | Type of antidiabetic treatment at three months |
| Number of antidiabetic treatment at three months | Month 3 | Number of antidiabetic treatment at three months |
| Ratio to baseline in the C-reactive protein (CRP) | Baseline, Day 29 and Day 90 | Ratio to baseline in the C-reactive protein (CRP) |
Countries
Switzerland
Outcome results
None listed