Clinical Study to Evaluate the Efficacy of Anakinra in Patients With Rheumatoid Arthritis and Diabetes
Status:
Terminated
Trial end date:
2017-12-01
Target enrollment:
Participant gender:
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