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

Primary Purpose

Diabetes Mellitus Type 2 in Obese, Inflammation, Metabolic Disease

Status

Recruiting

Phase

Phase 2

Locations

Switzerland

Study Type

Interventional

Intervention

Anakinra Prefilled Syringe

About this trial

This is an interventional basic science trial for Diabetes Mellitus Type 2 in Obese focused on measuring anakinra, cephalic phase of insulin secretion

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

University Hospital BaselRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

healthy individuals

obese patients with type 2 diabetes

Arm Description

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)

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)

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT04227769

First Posted

January 7, 2020

Last Updated

November 30, 2022

Sponsor

University Hospital, Basel, Switzerland

1. Study Identification

Unique Protocol Identification Number

NCT04227769

Brief Title

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

Acronym

Cephalira

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Recruiting

Study Start Date

January 13, 2020 (Actual)

Primary Completion Date

June 30, 2023 (Anticipated)

Study Completion Date

December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Basel, Switzerland

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus Type 2 in Obese, Inflammation, Metabolic Disease, Glucose Metabolism Disorders (Including Diabetes Mellitus)

Keywords

anakinra, cephalic phase of insulin secretion

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Masking Description

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

Allocation

Randomized

Enrollment

24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

healthy individuals

Arm Type

Experimental

Arm Description

Arm Title

obese patients with type 2 diabetes

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Anakinra Prefilled Syringe

Other Intervention Name(s)

Kineret

Intervention Description

Subcutaneous injection of 100 mg/ 0.67 ml of Kineret or placebo

Primary Outcome Measure Information:

Title

Change in insulin concentration in blood during the cephalic phase of insulin secretion in healthy individuals

Description

Insulin concentration in blood at 0, 3,6 and 10 minutes after ingestion of a standardized meal in healthy individuals.

Time Frame

10 minutes

Title

Change in insulin concentration in blood during the cephalic phase of insulin secretion in obese patients with type 2 diabetes

Description

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.

Time Frame

10 minutes

Secondary Outcome Measure Information:

Title

Change of C-peptide

Description

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.

Time Frame

6 hours

Title

Change of insulin

Description

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.

Time Frame

6 hours

Title

Change of glucose

Description

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.

Time Frame

6 hours

Title

Change of glucagon

Description

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.

Time Frame

6 hours

Title

Change of GLP-1

Description

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.

Time Frame

6 hours

Title

Change of pancreatic polypeptide

Description

Time Frame

6 hours

Title

Change of IL-1β

Description

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.

Time Frame

6 hours

Title

Change of IL-6

Description

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.

Time Frame

6 hours

Title

Change of IL-1Ra

Description

Plasma level of IL-1Ra before and after a meal through nasogastric tube or with anakinra or placebo after a standardized meal.

Time Frame

6 hours

Title

Change of TNFa

Description

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.

Time Frame

6 hours

Title

change in hunger

Description

Time Frame

6 hours

Title

Change in autonomic function

Description

Time Frame

6 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Marc Y Donath, Prof.Dr. MD

Phone

061 265 5078

Ext

+41

marc.donath@usb.ch

First Name & Middle Initial & Last Name or Official Title & Degree

Jonathan M Mudry, Dr. MD

Phone

0612652525

Ext

+41

jonathan.mudry@usb.ch

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Marc Y Donath, Prof. Dr. MD

Organizational Affiliation

University Hospital, Basel, Switzerland

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Hospital Basel

City

Basel

State/Province

Basel BS

ZIP/Postal Code

4031

Country

Switzerland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marc Y Donath, Prof. Dr. MD

Phone

+41 061 265 5078

marc.donath@usb.ch

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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