Clinical trial NCT00303394: Treatment of Patients With Type 2 Diabetes With an Interleukin-1 Antagonist
Official title: Phase 2 Study of IL-1Ra in Patients With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes
Keywords: Type 2 Diabetes, IL-1, inflammation, glucotoxicity, insulin
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Steno Diabetes Center Copenhagen
First posted: 2006-03-16
Enrollment: 72
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: Aim: To investigate the therapeutic potential of IL-1Ra in type 2 diabetes.

Rationale: Since the major defect leading to a decrease in b-cell mass in type 2 diabetes is increased apoptosis, therapeutic approaches designed to arrest apoptosis could be a significant new development in its management. This approach might actually reverse the disease to a degree rather than just palliate glycemia. Based on current thinking, treatment with IL-1Ra appears as a promising approach. The prospected effect is blocking of the IL-1b-mediated glucotoxicity and thereby to prevent the decline in b-cell mass, together with a rapid restoration of b-cell function. FDA approval for IL-1Ra in the treatment of rheumatoid arthritis occurred based on a favourable tolerability profile.

Detailed description: Methodology: This will be a two-centre (University Hospital, Zurich, Switzerland and Steno Diabetes Center, Gentofte, Denmark) study. 72 patients will be randomised according to a double-blind, placebo-controlled protocol in which half of the patients are treated with IL-1Ra, the other half with saline. The treatment period will last 13 weeks. This time-period should be sufficient for reversal of functional glucotoxicity and feasible in terms of patient compliance. Whether 13 weeks of treatment will be sufficient to make significant changes in b-cell mass in unpredictable. However, blocking b-cell apoptosis, while new islet formation and b-cell replication are normal, may initiate enlargement of b-cell mass, which may progress beyond the treatment period. Patient evaluation will be performed at start and after 4, 13, 26, 39 and 52 weeks. Following 13 weeks, patients with a fasting plasma glucose levels \> 8 mM or with a glycosylated hemoglobin level (HbA1c) \> 8% will be treated with insulin. Insulin treatment will not be initiated earlier to avoid interference with possible effects of insulin on primary outcome in the period where the largest effect of IL-1Ra are expected. To assess effects of IL-1Ra on insulin sensitivity, a subset of 40 patients (20 IL-1Ra- and 20 placebo-treated) will undergo an euglycemic-hyperinsulinemic clamp as well as a muscle and fat biopsy at start and after the end of treatment (13 weeks). The Ethics Committee of both centres have already approved the procedure.

Eligibility criteria: Inclusion Criteria:

* Age \>20
* Diabetes mellitus Type 2 (American Diabetes Association criteria) of at least 3 months duration
* HbA1c \>7.5%
* Body-mass index (BMI) \> 27

Exclusion Criteria:

* Positive GAD 65 or IA-2 antibodies at inclusion.
* HbA1c \>12%, polyuria and thirst (exclusion of severely decompensated patients)
* C-peptide \< 400pmol/l (basal )
* Established anti-inflammatory therapy (includiung cortisone, NSAID, Cox-2-inhibitor). Low dose aspirin (£ 100mg) will be tolerated.
* CRP \>30 mg/dl, fever, current treatment with antibiotics, or chronic granulomatous infections (e.g. tuberculosis) in the history or on a screening chest X-ray.
* Neutropenia or anemia (leucocyte count \< 2.0x109 /l, hemoglobin \<11g/dl for ma les or \<10g/dl for females)
* Pregnancy or breast-feeding. When appropriate (fertile women),anticonception for at last 3 month prior inclusion will be required.
* Severe liver or renal disease ( AST or ALT\>3 times the upper limit of normal laboratory range, serum creatinine \>130mM)
* Ongoing malignant neoplasm
* Use of any investigational drug within 30 days of enrollment into the study or within 5 half-lives of the investigational drug (whichever is longer)
* Immunosuppressive treatment or immunodeficient diseases.

Primary outcomes:
measure: HbA1c
Secondary outcomes:
measure: Insulin requirement
measure: Stimulated C peptide and insulin
measure: Fasting plasma glucose (FPG)
measure: Serum cytokine levels, CRP
measure: Insulin secretion and Insulin-sensitivity index derived from an OGTT with insulin and glucose measurements.
measure: In a subgroup of patients, insulin-sensitivity assessed by clamp techniques
measure: Insulin signaling- and cytokine- gene expression profiles derived from muscle and fat biopsy samples.
Other outcomes:
Locations:
city: Gentofte
country: Denmark
facility: Steno Diabetes Center
state: Copenhagen
city: Zurich
country: Switzerland
facility: University Hospital of Zurich, Division of Endocrinology and Diabetes
Study officials:
affiliation: University of Zurich
name: Marc Y Donath, MD
role: STUDY_CHAIR
References:
citation: Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007 Apr 12;356(15):1517-26. doi: 10.1056/NEJMoa065213.