Clinical Study to Evaluate the Efficacy of Anakinra in Patients With Rheumatoid Arthritis and Diabetes

Summary

The TRACK \[Treatment of Rheumatoid Arthritis and Comorbidities with Kineret (anakinra)\]-study: a randomized, open-label multicenter study assessing the efficacy of anakinra in lowering HbA1c (glycated hemoglobin) as well as changes in DAS28 in Rheumatoid Arthritis (R.A.) patients with type 2 diabetes (T2D) Authors: R. Giacomelli,(A,B) P. Cipriani (A) and P. Ruscitti (A) on behalf of the TRACK study-group; (A) University of L'Aquila, L'Aquila, Italy; Background: Interleukin-1 (IL-1) plays a pivotal role in R.A., joint erosion and cartilage destruction.(1) Anakinra (a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), which blocks the activity of both IL-1α and IL-1β) has shown in a number of RCTs (2-6) to be effective in the treatment of R.A., in monotherapy,(2,4) as well as associated to methotrexate (MTX).(3,5,6) IL-1β plays also an important role in the pathogenesis of T2D: Glucose has been shown to induce IL-1β hypersecretion through inflammasome activation, while IL-1β induces impairment of β-cell secretory function and β-cell apoptosis.(7) In prediabetic subjects, the expression of IL-1Ra is induced by IL-1β and reflects the body's response to counterbalance increased IL-1β activity.(7) Levels of IL-1Ra tend to rise up to 6 years before the diagnosis of T2D.(8,9) IL-1Ra has been successfully used as a marker for the risk of developing T2D in subjects with metabolic syndrome.(10) As a clinical proof of concept, IL-1 inhibition with anakinra in patients with T2D has shown to improve the secretorial function of beta-cells as well as to lower the ratio of proinsulin/insulin and glycated hemoglobin/hemoglobin significantly, favoring glycemic control and possibly reducing the severity and prevalence of the associated complications of this disease.(11) Summarizing, IL-1 inhibition with anakinra has a clinical impact on R.A. as well as T2D. As from 6-10% of Italian R.A. patients have also T2D, this trial aims at investigating the impact of IL-1 inhibition on both diseases. Very recent data also show that T2D is a predictor of response to anakinra-treatment in R.A. patients,(12) which furthermore justifies the use of anakinra in this subset of R.A. patients. Objectives: \[Primary\] To evaluate the change in HbA1c between baseline, 3 months, 6 months, 1 year and at last follow up of 2 years from the beginning; \[Secondary\] To evaluate the efficacy on controlling signs \& symptoms of R.A., assessing the remission rate at 3 months, 6 months, 1 year and at follow up (2 years), using the evaluation scale of disease activity on 28 joints, DAS28 and SDAI improvements from baseline conditions over time points, according to EULAR response criteria. Methods: 200 patients in 28 Italian centers with active R.A. refractory to treatment with methotrexate and T2D will be enrolled and randomized to receive either 100mg of anakinra once daily by subcutaneous injection or any anti-TNF-alfa drug treatment. \[84 subjects will be required in each treatment arm to reach 90% power with an alpha error of 0.05 to detect a mean difference between the study arms of 0.25 percentage points of HbA1c . The assumed difference of HbA1c is rather conservative when compared to previously published changes in T2D patients (11).\] Anti-diabetic treatment is required to be unchanged for at least one month prior to enrolment. Patients will be invited to maintain dietary habits and lifestyle during the study period. Further details can be viewed on the trials website after subscription.(13) References: (1) Arend \& Dayer, Adv. Imm. 1993; 54: 167-227. (2) Bresnihan, Arthritis Rheum. 1998; 41: 2196-2204. (3) Cohen, Arthritis Rheum. 2002; 46: 614-624. (4) Nuki, Arthritis. Rheum. 2002; 46: 2838-2846. (5) Cohen, ARD 2004; 63: 1062-1068. (6) Cohen, Rheumatology 2004; 43: 704-711. (7) Donath, Nat. Rev. Immunol. 2011; 11: 98-107. (8) Herder, Diabetes Care 2009; 32: 421-423. (9) Carstensen, Diabetes 2010; 59: 1222-1227. (10) Luotola, J. Intern. Med. 2011; 269: 322-332. (11) Larsen, NEJM 2007; 356: 1517-1526. (12) Missler-Karger, EULAR 2013, Abs. FRI0219. (13) http://www.anakinra-ra-diabetes.org/ Disclosure: This trial is receiving support from Swedish Orphan Biovitrum AB according to the Italian law decree 17 December 2004. (B) speaker fees

Conditions

• Diabetes Mellitus, Type 2
• Arthritis, Rheumatoid

Interventions

DRUG

Anakinra

DRUG

TNF alpha inhibitors

Sponsors & Collaborators

• Prof. Roberto Giacomelli

  lead OTHER

Principal Investigators

• Roberto Giacomelli, Professor · University of L'Aquila

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2013-07-31

Primary Completion

2017-12-31

Completion

2017-12-31

Countries

• Italy

Study Locations