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Canakinumab in Patients with COVID-19 and Type 2 Diabetes: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Triall

English title Canakinumab in Patients with COVID-19 and Type 2 Diabetes: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial
Applicant Donath Marc Yves
Number 198415
Funding scheme NRP 78 Covid-19
Research institution Abteilung Endokrinologie, Diabetologie und Metabolismus Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Internal Medicine
Start/End 01.09.2020 - 31.08.2021
Approved amount 433'415.00
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Keywords (3)

Diabetes; Covid-19; Übergewicht

Lay Summary (German)

Lead
Canakinumab zur Behandlung von Patienten mit COVID-19 und Typ 2-Diabetes
Lay summary

Patienten mit ein Typ 2-Diabetes zählen mit zuden besonderen Risikopersonen für schwerere Verläufe nach Infektion mit dem Sars-CoV2-Virus.Dies kann durch eine Überaktivierung des Immunsystems durch den BotenstoffIL-1beta erklärt werden. In der Tat ist die Produktion von IL-1beta bei übergewichtigePatienten mit ein Typ 2-Diabetes stimuliert. SARS-CoV2 stimuliert ebenfalls dasIL-1beta-System. Beide Mechanismen potenzieren sich und könnten die tödliche Hyperinflammationerklären.

In der Vergangenheit konnte gezeigt werden,dass sich eine Blockade von IL-1beta auf die Blutzuckereinstellung und diekardiovaskulären Krankheiten günstig auswirkt. Auch weisen einzelne Berichteauf einen schützenden Effekt durch Blockade von IL-1beta bei Patienten mitSars-CoV-2-Infektion (COVID-19) hin.

Entsprechend werden wir in dieser besondersvulnerablen Patientengruppe ein IL-1beta blockierendes Medikament, Canakinumab,einsetzen. Um es zu testen, ist eine schweizweit klinische Studie beihospitalisierten Patienten mit Typ 2-Diabetikern und neu diagnostizierterSars-CoV-2-Infektion vorgesehen.

Direct link to Lay Summary Last update: 31.07.2020

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Abstract

Rationale:Patients with a metabolic syndrome (overweight, diabetes, hypertension) have a particularly bad outcome if infected with covid-19. This may be explained by an over-activation of the IL-1beta System. Indeed, metabolic stress (increased glucose and lipid levels) induces NLRP3-mediated IL-1beta secretion. Covid-19 also activates NLRP3. Therefore we hypothesize that metabolic stress in patients with overweight and diabetes potentiates covid-19 induced hyper-inflammatory syndrome leading to excess mortality in these vulnerable patients.Backrgoung:Activation of the innate immune system by IL-1 is apparent at all stages of the development of obesity associated type 2 diabetes and its complications. This includes impaired insulin secretion and sensitivity, cardiovascular diseases and heart failure. Accordingly, IL-1 antagonism has been shown to improve glycaemia, cardiovascular complications, and to reduce hospitalization for heart failure and heart failure-related mortality. The latter is of particular importance in the context of Covid-19, because patients with type 2 diabetes per se are at high risk to develop heart failure with a high mortality rate. Several studies have shown that the corona virus stimulates the NLRP3 inflammasome leading to a severe inflammatory response by the IL-1beta pathway, as reflected by CRP and IL-6 increase. In obese diabetic individuals, metabolic stress also promotes the IL-1ß pathway. Thus we hypothesize that both mechanisms will synergize leading to a deleterious hyper-inflammation as often observed in obese diabetic patients affected by Covid-19.Our hypothesis is supported by several recent studies. Indeed, in a cohort of >7’000 Covid-19 patients, type 2 diabetes was associated with a higher death rate. Supporting our hypothesis that glucose-induced IL-1ß will amplify Covid-19 hyper-inflammation, hyperglycemia correlated with a worse outcome. Most importantly, in a retrospective cohort study of patients with Covid-19, treatment with the IL-1 receptor antagonist IL-1Ra was safe and associated with clinical improvement in 72% of patients.Method:This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in hospitalized patients with COVID-19 infection and type 2 diabetes.A total of 116 patients will be randomized using a 1:1 allocation ratio of which 58 subjects will receive a single intravenous canakinumab infusion and 58 patients will receive a single placebo infusion.
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