Canakinumab Anti-Inflammatory Thrombosis Outcomes Study - CANTOS Pilot

Description:

The goal of the trial was to evaluate canakinumab, a human monoclonal antibody, against interleukin-1 β compared with placebo among diabetic patients.

Hypothesis:

Canakinumab will reduce inflammatory markers associated with atherosclerosis.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Patients 18-74 years of age with type 2 diabetes and one of the following criteria:
    1) Not taking oral diabetes medications, HbA1c 7.5-11%, and eligible for metformin therapy
    2) On stable metformin monotherapy for at least 3 months, and HbA1c 7-9%
    3) Were taking an alpha-glucosidase inhibitor that had been washed out for 1 week, HbA1c 7-9%, and eligible for metformin therapy

    Number of enrollees: 551
    Duration of follow-up: 4 months
    Mean patient age: 54 years
    Percentage female: 44%

Exclusions:

  • Type 1 diabetes
  • Contraindication for interleukin-1 inhibition (tuberculosis, hepatitis B/C, chronic infection associated with an immunocompromised condition, or use of an immune-modulating medication)
  • Cancer
  • Stroke
  • Requirement for live vaccinations
  • Pregnancy

Primary Endpoints:

  • Change in markers of inflammation: fibrinogen, interleukin-6, and C-reactive protein

Drug/Procedures Used:

In this phase IIb dose-ranging trial and after an 8-week run-in period with placebo, diabetic patients were randomized to monthly subcutaneous canakinumab: 5 mg (n = 93), 15 mg (n = 95), 50 mg (n = 92), and 150 mg (n = 92) versus placebo (n = 179).

Principal Findings:

Overall, 551 patients were randomized. The mean age was 54 years, 44% were women, mean body mass index was 30 kg/m2, 16% were current smokers, mean blood pressure was 128/78 mm Hg, mean duration of diabetes was 3.7 years, and mean glycated hemoglobin (HbA1c) was 7.4%.

There was no significant change in HbA1c after 4 months of treatment with canakinumab 5 mg: -0.2% (p = 0.9), 15 mg: -0.25% (p = 0.2), 50 mg: -0.2% (p = 0.1), and 150 mg: -0.3% (p = 0.5).

There was no significant change in glucose after 4 months of treatment with canakinumab 5 mg: 1.6% (p = 0.2), 15 mg: -1.3% (p = 0.3), 50 mg: -2.7% (p = 0.1), and 150 mg: -1.4% (p = 0.4).

There was no significant change in insulin after 4 months of treatment with canakinumab 5 mg: -2.8% (p = 0.4), 15 mg: 0.4% (p = 0.2), 50 mg: 6.7% (p = 0.2), and 150 mg: 1.9% (p = 0.4).

There was no significant change in low-density lipoprotein (LDL) cholesterol after 4 months of treatment with canakinumab 5 mg: 1.4% (p = 0.4), 15 mg: 2.4% (p = 0.9), 50 mg: 2.1% (p = 0.4), and 150 mg: 4.4% (p = 0.8).

There was a significant change in C-reactive protein after 4 months of treatment with canakinumab 5 mg: -36.4% (p = 0.02), 15 mg: -53.0% (p < 0.0001), 50 mg: -64.6% (p < 0.0001), and 150 mg: -58.7% (p < 0.0001).

There was a significant change in interleukin-6 after 4 months of treatment with canakinumab 5 mg: -23.9% (p = 0.008), 15 mg: -32.5% (p < 0.0001), 50 mg: -47.9% (p < 0.0001), and 150 mg: -44.5% (p < 0.0001).

There was a significant change in fibrinogen after 4 months of treatment with canakinumab 5 mg: -4.9% (p < 0.0001), 15 mg: -11.7% (p < 0.0001), 50 mg: -18.5% (p < 0.0001), and 150 mg: -14.8% (p < 0.0001).

Adverse events with canakinumab 5 mg: 35.5%, 15 mg: 45.3%, 50 mg: 48.9%, 150 mg: 46.7%, and placebo: 42.5%.

Interpretation:

Among well-controlled diabetic patients with elevated cardiovascular risk, the use of canakinumab, a human monoclonal antibody, against interleukin-1 β was effective at reducing markers of inflammation (fibrinogen, interleukin-6, and C-reactive protein) in a dose-dependent fashion. The effect of canakinumab did not reduce glucose or lipid levels. Adverse events were similar across the treatment groups. Phase 3 trials are needed to determine the effect of this medication on adverse cardiovascular events.

References:

Ridker PM, Howard CP, Walter V, et al. Effects of Interleukin-1β Inhibition With Canakinumab on Hemoglobin A1c, Lipids, C-Reactive Protein, Interleukin-6, and Fibrinogen: A Phase IIb Randomized Placebo Controlled Trial. Circulation 2012;Nov 5:[Epub ahead of print].

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Inflammation, Insulin, Atherosclerosis, Interleukin-6, Diabetes Mellitus, Type 2, Blood Pressure, Glucose, Hemoglobin A, Glycosylated, Cholesterol, Interleukin-1beta, C-Reactive Protein, Body Mass Index, Metformin, Cardiovascular Diseases, Hypoglycemic Agents, Fibrinogen


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