Canakinumab in Patients With COVID-19 and Type 2 Diabetes

Study Overview
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Brief Summary
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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
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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.

Official Title
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Canakinumab in Patients With COVID-19 and Type 2 Diabetes - CanCovDia Trial

Conditions
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Coronavirus Infection, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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-

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: active treatment arm<br>Treatment with Canakinumab i.v. administered over 2 hours | Drug: Canakinumab<br>* Body weight adjusted dose in 250 ml 5% dextrose solution i.v. over 2 hours<br>* Other names: Ilaris®;|
| Placebo Comparator: placebo treatment arm<br>placebo treatment | Drug: Placebo<br>* Aqua ad injectabilia in 250 ml 5% dextrose solution i.v. over 2 hours<br>* Other names: Aqua ad injectabilia in 250 ml 5% dextrose solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| unmatched win ratio after treatment with canakinumab compared to Placebo (composite endpoint) | 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): longer survival time longer ventilation-free time longer ICU-free time 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. | within 4 weeks after treatment with canakinumab or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to clinical improvement | 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: not hospitalized with resumption of normal activities; not hospitalized, but unable to resume normal activities; hospitalized, not requiring supplemental oxygen; hospitalized, requiring supplemental oxygen; hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; hospitalized, requiring extracorporeal membrane oxygenation (ECMO), invasive mechanical ventilation, or both; and death | From randomization up to 4 weeks | 
| Death rate | Death rate during the 4-week period after study treatment | 4 weeks | 
| Admission to intensive care unit (ICU) | Admission to the intensive care unit from the medical ward during the 4-week period after study treatment | 4 weeks | 
| Secondary worsening of disease | Secondary worsening of disease (i.e., development of Acute respiratory distress Syndrome (ARDS), increase of oxygen demand after 72h of treatment) | 4 weeks | 
| Prolonged hospital stay | Prolonged hospital stay > 3 weeks | >3 weeks | 
| Change in ratio to baseline in the glycated hemoglobin | Ratio to baseline in the glycated hemoglobin | Baseline, Day 29 and Day 90 | 
| Change in ratio to baseline in the fasting glucose | Ratio to baseline in the fasting glucose | Baseline, Day 29 | 
| Change in ratio to baseline in the fasting insulin | Ratio to baseline in the fasting insulin | Baseline, Day 29 | 
| Change in ratio to baseline in the fasting c-peptide | Ratio to baseline in the fasting c-peptide | Baseline, Day 29 | 
| Ratio to baseline in the C-reactive protein (CRP) | Ratio to baseline in the C-reactive protein (CRP) | Baseline, Day 29 and Day 90 | 
| Change in ratio to baseline in the D-dimer | Ratio to baseline in the D-dimer | Baseline, Day 29 | 
| Change in ratio to baseline in the Natriuretic peptide (NTproBNP) | Ratio to baseline in the Natriuretic peptide (NTproBNP) | Baseline, Day 29 and Day 90 | 
| Change in ratio to baseline in the Glomerular Filtration Rate Renal (eGFR) | Ratio to baseline in the Glomerular Filtration Rate Renal (eGFR) | Baseline, Day 29 and Day 90 | 
| Type of antidiabetic treatment at Day 29 | Type of antidiabetic treatment at Day 29 | Day 29 | 
| Number of antidiabetic treatment at Day 29 | Number of antidiabetic treatment at Day 29 | Day 29 | 
| Type of antidiabetic treatment at three months | Type of antidiabetic treatment at three months | Month 3 | 
| Number of antidiabetic treatment at three months | Number of antidiabetic treatment at three months | Month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NLRP3, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Coronavirus Disease 19 (COVID-19), IL-1beta, hyperinflammatory syndrome, obesity