Safety & Effectiveness on Vascular Structure and Function of ACZ885 in Atherosclerosis and Either T2DM or IGT Patients

A Multi-center, Randomized , Double Blind, Placebo-controlled, Study of the Safety, Tolerability, and Effects on Arterial Structure and Function of ACZ885 in Patients With Clinically Evident Atherosclerosis and Either T2DM or IGT

This study will evaluate the effect of ACZ885 on vascular function in patients with documented atherosclerotic disease and T2DM or IGT.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Atherosclerosis; Prediabetic State
• Intervention / Treatment: Drug: Placebo; Drug: ACZ885

• Study Type: Interventional
• Enrollment (Actual): 189
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Novartis Investigative Site
• Germany
  • Mainz, Germany, 55116
    • Novartis Investigative Site
  • Neuss, Germany, 41460
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 91120
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, EC1M 6BQ
    • Novartis Investigative Site
  • UK
    • Oxford, UK, United Kingdom, OX2 6HE
      • Novartis Investigative Site
• United States
  • New York
    • New York, New York, United States, 10029
      • Novartis Investigative Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with known atherosclerotic disease and documented diagnosis of T2DM for ≤ 14 years OR IGT
• HbA1c between 6.0% and 10.0%
• On stable statin therapy or statin intolerant
• Patients who are eligible and able to participate in the study

Exclusion Criteria:

• Contraindications to MRI
• NYHA class IV Heart Failure
• NYHA class I - III heart failure with acute exacerbation in 3 months prior to screening
• Patients with type 1 diabetes
• Acute infections
• HsCRP > 30 mg/dL
• Aortic aneurysm ≥5cm

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; subcutaneous (SQ) monthly	Drug: Placebo; Matching placebo to ACZ885 was administered subcutaneously once a month for 12 months.
Experimental: ACZ885; 150 mg SQ monthly	Drug: ACZ885; ACZ885 150 mg was administered subcutaneously once a month for 12 months.; Other Names: Canakinumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events, Serious Adverse Events and Death	Participants were monitored for adverse events, serious adverse events and death throughout the study.	12 months
Change From Baseline in Aortic Distensibility	Two axial, ECG-gated, steady state free precession (SSFP) 'cine' images were acquired during breath-hold to determine aortic distensibility. The first image was obtained at the level of the right pulmonary artery through the ascending and proximal descending aorta and the second through the distal aorta below the diaphragm. Imaging of the aorta also enabled evaluation of the plaque burden and additional vascular function measures.	baseline, 3 months, 12 months
Change From Baseline in Plaque Burden (Aortic Vessel Wall Area and Carotid Vessel Wall Area)	For assessment of atherosclerotic plaque burden of the aorta, vessel wall images of the aorta were acquired with an ECG gated double-inversion recovery (black blood) fast spin echo sequence applied breath-holding. Using an oblique sagittal image of the aorta as a pilot, serial axial images were acquired to cover a section of the descending thoracic aorta. The midpoint of the right pulmonary artery in cross section was used as the anatomical reference for the first slice in baseline and follow-up scans. For assessment of the atherosclerotic plaque burden in the carotids, vessel wall images were acquired with an axial ECG gated PD (proton density) weighted black blood sequence. The carotid bifurcation was used as the anatomical reference for all three imaging time points (baseline, 12 weeks, 48 weeks) with axial slice planes acquired below the bifurcation region. The mean values reported here for the carotid are reported for the proximal common carotid region.	baseline, 3 months, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pulse Wave Velocity and Pulse Wave Velocity Error	Utilizing the SphygmoCor Device, ECG leads placed at the carotid and femoral arteries provided the measure of the pulse wave at that particular arterial location. The distance between the two vascular beds divided by the pulse wave time shift provided a measure of the pulse wave velocity.	baseline, 3 months, 12 months
Change From Baseline in Plaque Composition	During the carotid MRI acquisition, in addition to the PD weighted ECG gated double inversion fast spin echo sequences T1 and T2 weighted sequences were acquired. In combination with the PD weighted images, the multi-contrast images were analyzed to determine regions of interest with contrast patterns consistent with the presence of necrotic lipid core, calcification and fibrous tissue in participants who had complex carotid plaque present in the bifurcation region.	baseline, 3 months, 12 months
Change From Baseline in Aortic Strain	Arterial strain was computed directly from the cine SSFP images and the change in lumen diameters over the cardiac cycle. The value was independent of pulse pressure and is unitless ratio derived from the maximum to minimum lumen diameters diastole and systole, respectively..	baseline, 3 months, 12 months
Change From Baseline in High Sensitivity C-reactive Protein (hsCRP)	Blood samples were collected to analyze hsCRP.	baseline, 3 months, 12 months
Change From Baseline in Fasting Plasma Glucose	Blood samples were collected to analyze fasting plasma glucose.	baseline, 3 months, 12 months
Change From Baseline in Hemoglobin A1c (HbA1c)	Blood samples were collected to analyze HbA1c.	baseline, 3 months, 12 months
Change From Baseline in 2 Hour Glucose Post Oral Glucose Tolerance Test (OGTT)	Blood samples were collected to analyze the 2 hour glucose post OGTT.	baseline, 3 months, 12 months
Change From Baseline in Beta Cell Function (HOMA-B)	Blood samples were collected to analyze beta cell function. Beta cell function was calculated by the Homeostasis Model Assessments (of beta cell function (HOMA-B) as follows: HOMA-B: The product of 20 and basal insulin (µU/mL) levels divided by the value of basal glucose (mmol/L) concentrations minus 3.5 [i.e., HOMA-B = 20*basal insulin/(basal glucose-3.5)].	baseline, 3 months, 12 months
Change From Baseline Insulin Resistance (HOMA-IR)	Blood samples were collected to analyze insulin resistance. Insulin resistance was calculated by the Homeostasis Model Assessments of insulin resistance (HOMA-IR)) as follows: HOMA-IR: The product of basal glucose (mmol/L) and insulin (µU/mL) levels divided by 22.5 [i.e., HOMA-IR = basal glucose*basal insulin/22.5].	baseline, 3 months, 12 months
Pharmacokinetics: ACZ885 Serum Concentrations	Blood samples were collected to analyze the ACZ885 serum concentrations.	pre-dose, 0.167 day post dose 1, 7 days post dose 1, 14 days post dose 1, every 30 days post each dose from doses 1 through 12, 60 days post dose 12, 90 days post dose 12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Choudhury RP, Birks JS, Mani V, Biasiolli L, Robson MD, L'Allier PL, Gingras MA, Alie N, McLaughlin MA, Basson CT, Schecter AD, Svensson EC, Zhang Y, Yates D, Tardif JC, Fayad ZA. Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance. J Am Coll Cardiol. 2016 Oct 18;68(16):1769-1780. doi: 10.1016/j.jacc.2016.07.768.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: October 15, 2009
• First Submitted That Met QC Criteria: October 15, 2009
• First Posted (Estimate): October 16, 2009

Study Record Updates

• Last Update Posted (Estimate): June 29, 2015
• Last Update Submitted That Met QC Criteria: June 1, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Atherosclerosis,; Type 2 Diabetes Mellitus, T2DM,; Cardiovascular Diseases, ACZ885, impaired glucose tolerance, IGT, Canakinumab
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Prediabetic State; Atherosclerosis
• Other Study ID Numbers: CACZ885I2206; 2009-014618-80