IL-1-receptor Antagonist During Cephalic Phase of Insulin Secretion in Health and Type 2 Diabetes (Cephalira)

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).

Study Overview

• Status: Recruiting
• Conditions: Inflammation; Metabolic Disease; Diabetes Mellitus Type 2 in Obese; Glucose Metabolism Disorders (Including Diabetes Mellitus)
• Intervention / Treatment: Drug: Anakinra Prefilled Syringe

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marc Y Donath, Prof.Dr. MD; Phone Number: +41 061 265 5078; Email: marc.donath@usb.ch
• Study Contact Backup: Name: Justus Fischer, MD; Phone Number: +41 0613284497; Email: justus.fischer@usb.ch

Study Locations

• Switzerland
  • Basel BS
    • Basel, Basel BS, Switzerland, 4031
      • Recruiting
      • University Hospital Basel
      • Contact: Marc Y Donath, Prof. Dr. MD; Phone Number: +41 061 265 5078; Email: marc.donath@usb.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: healthy individuals; 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. Standard dose of Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB), i. e. 100 mg/ 0.67 ml s. c. or 0.67 ml of saline s. c. (placebo)	Drug: Anakinra Prefilled Syringe; Subcutaneous injection of 100 mg/ 0.67 ml of Kineret or placebo; Other Names: Kineret
Experimental: obese patients with type 2 diabetes; Three crossover visits with a washout period of at least 4 days in-between: 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, C) Additionally, 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. Standard dose of Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB), i. e. 100 mg/ 0.67 ml s. c. or 0.67 ml of saline s. c. (placebo)	Drug: Anakinra Prefilled Syringe; Subcutaneous injection of 100 mg/ 0.67 ml of Kineret or placebo; Other Names: Kineret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin concentration in blood during the cephalic phase of insulin secretion in healthy individuals	Insulin concentration in blood at 0, 3,6 and 10 minutes after ingestion of a standardized meal in healthy individuals.	10 minutes
Change in insulin concentration in blood during the cephalic phase of insulin secretion in obese patients with type 2 diabetes	Insulin concentration in blood at 0, 3, 6 and 10 minutes after ingestion of a standardized meal in healthy individuals in obese patients with type 2 diabetes.	10 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of C-peptide	Plasma level of c-peptide before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of insulin	Plasma level of insulin before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of glucose	Plasma level of glucose before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of glucagon	Plasma level of glucagon before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of GLP-1	Plasma level of GLP-1 before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of pancreatic polypeptide	Plasma level of pancreatic polypeptide before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of IL-1β	Plasma level of IL-1β before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of IL-6	Plasma level of IL-6 before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change of IL-1Ra	Plasma level of IL-1Ra before and after a meal through nasogastric tube or with anakinra or placebo after a standardized meal.	6 hours
Change of TNFa	Plasma level of TNFa before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
change in hunger	Visual analogue scale (VAS) for hunger (from minimum value = not hungry at all to maximum value = extremely hungry) before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours
Change in autonomic function	Change in heart-rate variability during a continuous ECG as indirect measure of measure of the autonomic function before and after a standardized meal after acute treatment or repeated treatment with anakinra or placebo. Repeated Treatment applies only to anakinra and to Group 2.	6 hours

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Marc Y Donath, Prof. Dr. MD, University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2020
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 7, 2020
• First Submitted That Met QC Criteria: January 9, 2020
• First Posted (Actual): January 14, 2020

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: anakinra; cephalic phase of insulin secretion
• Additional Relevant MeSH Terms: Pathologic Processes; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Inflammation; Metabolic Diseases; Glucose Metabolism Disorders; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: EKNZ 2019-02307

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No