Too low recruitment in group with patients with diabetes.

A prospective, randomized, mixed double- and single-blinded, placebo-controlled, cross-over clinical trial to test whether acute treatment with an IL-1 receptor antagonist impacts insulin secretion over time during the cephalic phase, defined as the first 10 minutes after the first sensorial contact to food, in healthy individuals in healthy humans (Group 1) and in obese patients with type 2 diabetes (Group 2).

The role of the immune system in metabolism has been extensively investigated in pancreatic islets and insulin sensitive tissues. However little attention has been given to a potential role of the innate immune system in the cephalic phase of insulin secretion. In humans, the cephalic phase of insulin secretion appear reduced in obesity and in patients with type 2 diabetes.

In this prospective, randomized, mixed double- and single-blinded, placebo-controlled, cross-over clinical trial we aim to test whether acute treatment with an IL-1 receptor antagonist impacts insulin secretion over time during the cephalic phase, defined as the first 10 minutes after the first sensorial contact to food, in healthy individuals in healthy humans (Group 1) and in obese patients with type 2 diabetes (Group 2).

Group 1: After screening, subjects will be randomized to two crossover visits with a washout period of at least 4 days in-between visits and at most two weeks: A) subcutaneous saline injection 3h before an oral standardized meal, B) subcutaneous injection of 100 mg of the IL-1 receptor antagonist anakinra 3h before an oral standardized meal. Treatments will be placebo controlled, crossover, double blinded. The study will be performed in a population of healthy individuals.

Group 2: Same as for Group 1 with the following addition: after the second study day, participant in group 2 will be trained to self-inject the medication for 6 days. On the 7th day, an oral standardized meal test will be performed.

Healthy subjects from group 1 will be matched for sex and age to the diabetic cohort from group 2.

Inclusion criteria:

Main inclusion criteria:

• Age ≥ 18 years and ≤ 70 years at screening
• Male or female of non-child-bearing potential (meaning for women: not currently pregnant, post-menopausal female or using condoms and either intrauterine devices or 3-monthly contraceptive injection or birth-control pill.)

Healthy subjects:

• No apparent disease requiring medication
• BMI < 25 kg/ m2
• C-reactive protein ≤ 2 mg/L

Obese diabetic type 2 subjects:

• Type 2 diabetes
• HbA1c 7.0 -10.0%
• BMI ≥ 30.0 kg/m2
• C-reactive protein ≥ 2 mg/L

Exclusion criteria:

Subjects will be excluded from the study if they meet any of the following criteria:

• Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation
• Aversion or allergy to paracetamol or any component of the meal.
• Known history of allergy or hypersensitivity to any component of the investigational product formulations
• Concomitant treatment with GLP-1 agonists, DPP-4 inhibitors, insulin or insulin derivative
• Change in diabetes medication within the last 30 days
• Any biologic drugs targeting the immune system
• Fever, or other signs of infection requiring antibiotics within 3 weeks prior to screening, history of recurrent infection, immunodeficiency, known HIV or tuberculosis infection, active foot ulcer
• Participation in another study with investigational drug within 30 days prior to Screening and during the present study
• eGFR < 30 mL/min/1.73m2 per MDRD formula or kidney transplant (regardless of renal function)
• Known active or recurrent hepatic disorder (including cirrhosis, hepatitis B and hepatitis C, or confirmed ALAT/ASAT levels > 3 times ULN or total bilirubin > 2 times ULN),
• Haemoglobin <10.0 g/dL, white blood cell <3.0 x 103/mm3, platelet count <125 x 103/mm3
• Atrial fibrillation and/or a pacemaker

Randomized, double-blinded and open-label, placebo-controlled, partly cross-over clinical trial