Clinical trial NCT00711503: Anti-Interleukin-1 in Diabetes Action
Official title: A Randomised Clinical Trial of the Effect of Interleukin-1 Receptor Antagonism on the Insulin Production in Patients With New Onset Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Type 1 Diabetes
Keywords: endogenous insulin production
C-peptide level
insulin requirement
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
name: Oeresund Diabetes Academy
First posted: 2008-07-09
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A draw trial of the effect of Interleukin-1 Receptor Antagonist (anakinra, Kineret®) on the insulin production in patients with new onset Type 1 diabetes.

Kineret® is already being used in the treatment of patients suffering from rheumatoid arthritis and preclinical studies are now suggesting that it may also be useful for patients with Type 1 diabetes. The active substance in Kineret is interleukin-1 receptor antagonist, a blocker of an immune-signal molecule named interleukin-1.

The trial is a blinded randomised trial, in which the patient is allocated to receive the active drug (Kineret®) or placebo (saline). The hypothesis is that anti-IL-1 treatment as add-on therapy to conventional insulin therapy will preserve or enhance beta-cell function.

Detailed description: Objectives:

The aim of the Anti-Interleukin-1 in Diabetes Action trial (AIDA) study is to test the feasibility, safety/tolerability and potential efficacy of anti-IL-1 therapy in maintaining or enhancing beta-cell function in people with new onset Type 1 diabetes.

Trial Design:

A randomized, placebo controlled, double masked, parallel group, multicentre trial of IL-1 antagonism in subjects with newly-diagnosed Type 1 diabetes. Patients are instructed to inject 100 mg human recombinant interleukin-1 receptor antagonist (anakinra, Kineret®, Amgen, CA) or placebo s.c. once daily for 2 years. Endpoints will be evaluated every three months, with an interim analysis after 6 months.

Trial population:

The design will be a two-stage phase 2a study to address feasibility, safety/tolerability and potential efficacy. In the first phase 80 patients between 18 and 35 years of age with new on-set Type 1 diabetes will be randomized to anakinra or placebo, and endpoints will be analyzed as an interim analysis after 6 months by an independent data and safety monitoring board (DSMB). A futility analysis will be performed at this time point to prevent continuation of the trial if it shows no likelihood of demonstrating efficacy. In the event the trial does show promise of efficacy considering the power of the first phase based on a conditional analysis the DSMB can recommend prolongation of the study with recruitment to ensure adequate power, and that additional funding is provided.

Methods and interventions:

The patients are instructed to administer anti-IL-1 therapy in the form of recombinant human non-glycosylated interleukin-1 receptor antagonist (anakinra) at a dose of 100 mg once daily or placebo by subcutaneous injection at the same time-point in the morning. Primary and secondary endpoints and safety parameters are investigated after 1 month and then every 3 months.

Safety:

Anakinra is FDA approved for the indication rheumatoid arthritis and has an acceptable risk / benefit profile in this indication, with more than 100.000 patients treated. Most common ad-verse events include mild and transient local injection reactions in 20-50% of subjects treated with Anakinra. Consistent with its mechanism of action, anakinra reduces WBC/ANC in 2.4% of patients and this may increase the risk of infection. Accordingly, treatment with anakinra will not be initiated in patients with active infections. Safety will be monitored by physical exams and blood and urine tests.

Eligibility criteria: Inclusion Criteria:

* Type 1 diabetes diagnosed according to WHO 1999 criteria
* Positive GAD auto-antibodies
* Age 18-35 yrs at onset of diabetes
* Time from first symptoms of diabetes \< 12 weeks
* Peak C-peptide more than or equal to 200 pM after a standardized mixed meal test (Boost) at a test carried out when the subject is metabolically stable, i.e. after resolution of any polyuria, polydypsia or ketoacidosis.

Exclusion Criteria:

* Severe liver or renal disease (creatinine \> 100 μmol/L, ASAT/ALAT \> 2\* ULN, alkaline phosphatase \> 2 \* ULN)
* History of heart disease, signs of cardiac failure or abnormal ECG
* Present or previous malignancy
* Pregnancy or failure of fertile female to comply with contraceptional planning, or breast-feeding. (Safe contraceptive methods include birth control pills, IUD, and gestagen implants) . Plans of pregnancy within 2 years.
* Participation in other clinical intervention studies
* Anti-inflammatory therapy (except aspirin £ 100 mg/d)
* Active infections (CRP\>30), history of recurrent infection or predisposition to infections
* Neutropenia: ANC \< 1.5\*109/L, or anaemia: Haemoglobin \< 8.0 g/dL
* Immune-suppressive treatment or immune-deficiency
* Presence at diagnosis of late diabetic complications
* Concurrent vaccination with live vaccine. Known need for live vaccinations within 2 years.
* Use of Etanercept within 6 months before screening or during the double-blinded study period
* Hypersensitivity to E. coli-derived proteins, anakinra or any components of the product.

Primary outcomes:
measure: Δ 2-h AUC C-peptide response
timeFrame: 1 month, 3 months, 6 months, 9 months
Secondary outcomes:
measure: Incremental and/or peak C-peptide response, Time to peak C-peptide, insulin requirement per kg body weight per day,frequency of insulin free state with maintenance of HbA1c <7.5%, HbA1c, Means of fasting glucose values, circulating IL-6 and CRP
timeFrame: 1 month, 3 months, 6 months, 9 months
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg Hospital
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital
city: Copenhagen
country: Denmark
facility: Bispebjerg Universitetshospital
city: Gentofte
country: Denmark
facility: Steno Diabetes Center
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital, Hillerød
city: Ulm
country: Germany
facility: Ulm University, Dept. of Internal Medicine
state: Donau
city: Duesseldorf
country: Germany
facility: Leibniz Center for Diabetes research, Heinrich-Heine University
city: Frankfurt am Main
country: Germany
facility: University of Frankfurt am Main
city: Munich
country: Germany
facility: Institut für Diabetesforschung, Munich University of Technology
city: Rome
country: Italy
facility: University Campus Bio-Medico
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Bialystok
country: Poland
facility: Medical University of Bialystok
city: Barakaldo
country: Spain
facility: Hospital de Cruces, Diabetes Research Group
state: Bizkaia
city: Las Palmas
country: Spain
facility: Hospital Unversitario Insular de Gran Canaria
state: Gran Canaria
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: Lleida
country: Spain
facility: Hospital Arnua de Vilanova
city: Zürich
country: Switzerland
facility: University Hospital Zürich
Study officials:
affiliation: Steno Diabetes Center Copenhagen
name: Thomas R Mandrup-Poulsen, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Universtity of Zürich
name: Marc Donath
role: STUDY_DIRECTOR
affiliation: Steno Diabetes Center Copenhagen
name: Flemming Pociot, DMSc
role: STUDY_DIRECTOR
affiliation: University of Colorado Health Science Center
name: Charles Dinarello
role: STUDY_DIRECTOR
affiliation: Bristol University, UK
name: Edwin Gale, Professor
role: STUDY_CHAIR
References:
citation: Pickersgill LM, Mandrup-Poulsen TR. The anti-interleukin-1 in type 1 diabetes action trial--background and rationale. Diabetes Metab Res Rev. 2009 May;25(4):321-4. doi: 10.1002/dmrr.960.
citation: Moran A, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Greenbaum CJ, Herold KC, Marks JB, Raskin P, Sanda S, Schatz D, Wherrett DK, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Canakinumab Study Group; Pickersgill L, de Koning E, Ziegler AG, Boehm B, Badenhoop K, Schloot N, Bak JF, Pozzilli P, Mauricio D, Donath MY, Castano L, Wagner A, Lervang HH, Perrild H, Mandrup-Poulsen T; AIDA Study Group. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013 Jun 1;381(9881):1905-15. doi: 10.1016/S0140-6736(13)60023-9. Epub 2013 Apr 5.