Dose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration in Metformin Monotherapy Treated Type 2 Diabetic Patients

Dose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration for the Treatment of Hyperglycemia in Metformin Monotherapy Treated Type 2 Diabetic Patients: a Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study

This was a four month dose ranging study followed by a 24 to 48 month extension at the selected dose to characterize the safety and efficacy of the injectable IL-1B (interleukin 1, beta) antagonist canakinumab in the treatment of patients with Type 2 diabetes mellitus (T2DM) already treated on maximum dose metformin.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Canakinumab; Drug: Metformin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 556
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1704ETD
    • DIM Clinica Privada
  • Buenos Aires, Argentina, C1120AAC
    • Centro Médico Viamonte
  • Buenos Aires, Argentina, C1425AGC
    • Consultorios Asociados de Endocrinologia
  • Corrientes, Argentina, W3410AVV
    • Hospital Juan Ramon Vidal
  • Rosario Santa Fe, Argentina, S2000AII
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000FWO
    • Centro de investigaciones Clinicas del Litoral
  • Santa Fe, Argentina, S3000FNF
    • Instituto de Investigaciones Biomedicas
  • Buenos Aires
    • Mar del Plata, Buenos Aires, Argentina, C1100ABB
      • Clinica de Fracturas y Ortopedia
• Belgium
  • Gozée, Belgium
    • Private Practice - DEMEULEMEESTER
  • Heist-op-den-berg, Belgium
    • Novartis Investigative Site
  • Jette, Belgium
    • UZ Brussel
• China
  • Hong Kong, China
    • Novartis Investigative Site
• Germany
  • Bad Oeynhausen, Germany, 32549
    • Praxis F. Franzmann
  • Berlin, Germany, 10629
    • emovis GmbH
  • Bretten, Germany, 75015
    • Praxis Dr. Stütz
  • Dresden, Germany, 01307
    • GWT-TUB GmbH
  • Düsseldorf, Germany
    • Gemeinschaftspraxis und Dialysezentrum Karlstraße
  • Hamburg, Germany, 20099
    • Asklepios Klinik St. Georg
  • Hannover, Germany, 30167
    • Städt. Kankenhaus Nordstadt
  • Hohenmölsen, Germany, 06679
    • Diabeteszentrum Hohenmölsen
  • Mainz, Germany, 55101
    • Johannes Gutenberg-Universität Mainz
  • Neuwied, Germany, 56564
    • Zentrum für Klinische Forschung Neuwied (ZKSN)
  • Nürnberg, Germany, 90489
    • Praxis Dr. Wunderer
  • Pirna, Germany, 01796
    • Praxis Dr. Kosch
  • Saarlouis, Germany, 66740
    • Praxis Dr. Alawi
  • Schenklengsfeld, Germany, 36277
    • Praxis Dr. Klein
  • Witten, Germany, 58455
    • Forschungszentrum Ruhr, KliFoCenter GmbH
• Hungary
  • Budapest, Hungary
    • Fővárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelőintézet és Baleseti Központ
  • Budapest, Hungary
    • Sandor Karolyi Hospital
  • Budapest, Hungary
    • Semmelweiss Medical University
  • Debrecen, Hungary
    • Kenezy Gyula Korhaz
  • Szeged, Hungary
    • Szegedi Egyetem
  • Zalaegerszeg, Hungary
    • Zala Megyei Kórház
• India
  • Bangalore, India
    • Bangalore Diabetes Hospital
  • Bangalore, India
    • Jnana Sanjeevini Medical Center
  • Bangalore, India
    • SAMATVAM
  • Bangalore-, India
    • Gokula Metropolis Clinical Research Centre
  • Chennai, India
    • Madras Diabetes Reasearch Foundation
  • Cochin, India
    • Amrita Institute of Medical Sciences and Research Center
  • Hyderabaad, India
    • Nizam's Institute of Medical Sciences
  • Indore, India
    • Diabetes Thyroid Hormone Research Institute Pvt. Ltd.
  • Jaipur, India
    • S R Kalla Memorial Gastro & General Hospital
  • Nagpur, India
    • Pitale Diabetes & Hormone Centre
  • Trivandrum, India
    • Health and Research Centre
  • Visakhapatnam, India
    • King George Hospital
• Japan
  • Fukuoka, Japan, 810-0001
    • Saiseikai Fukuoka General Hospital
  • Kitakyusyu, Japan
    • Kokura Medical Center
  • Koriyama, Japan
    • Seino Internal Medicine Clinic
  • Maebashi, Japan
    • Geriatrics Research Institute Hospital
  • Ohkawa, Japan
    • Takagi Hospital
  • Sakai, Japan
    • Sakai hospital Kinki University School of Medicine
  • Aichi
    • Nagoya, Aichi, Japan, 460-0001
      • National Hospital Organization Nagoya Medical Center
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan, 800-0296
      • Kyushu Rosai Hospital
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 245-8575
      • NHO Yokohama Medical Center
  • Tokyo
    • Koganei-city, Tokyo, Japan, 184-0004
      • Musashikoganei Clinic
    • Minato-ku, Tokyo, Japan
      • Novartis Investigative Site
  • Toyama
    • Toyama-city, Toyama, Japan, 930-0964
      • Fujikoshi Hospital
• Korea, Republic of
  • Pusan, Korea, Republic of, 614-735
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 135-710
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 135-720
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 139-872
    • Novartis Investigative Site
  • Suwon, Korea, Republic of, 442-721
    • Novartis Investigative Site
• Peru
  • Arequipa, Peru
    • Instituto Delgado de Investigacion Medica
  • Chiclayo, Peru
    • Clinica Chiclayo
  • San Martin de Porres, Peru
    • Hospital Nacional Cayetano Heredia
  • Trujillo, Peru
    • Centro de Investigacion Clinica Trujillo
• Romania
  • Bucharest, Romania
    • Ambulatory of Institute of Nutrition Diseases and Diabetes
  • Bucuresti, Romania
    • Novartis Investigative Site
  • Bucuresti, Romania
    • Medical Centre "Sanatatea ta"
  • Timisoara, Romania
    • Policlinica Dr. Citu Timisoara
• South Africa
  • Durban, South Africa
    • Parklands Medical Centre
  • Durban, South Africa
    • 203 Maxwell Centre
  • Durban, South Africa
    • St Augustines Medical Centre
  • Durban, South Africa
    • Synapta Clinical Research Centre
  • Johannesburg, South Africa
    • Drs Essack and Mitha
  • Port Elizabeth, South Africa
    • PE Greenacres Hospital
  • Stanger, South Africa
    • 26 Daffodil Street
• Turkey
  • Ankara, Turkey
    • Hacettepe University Medical Faculty
  • Ankara, Turkey
    • Ankara Ataturk Training and Research Hospital
  • Ankara, Turkey
    • Gulhane Askeri Tip Akademisi
  • Ankara, Turkey
    • S.B. Yildirim Beyazit Training and Research Hospital
  • Istanbul, Turkey
    • Istanbul University Cardiology Institute
  • Izmir, Turkey
    • Ege University Medical Faculty
  • Karabuk, Turkey
    • Hayat Tip Merkezi (Hayat Medical Center) Deapartment of Internal Diseases
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Heartlands Hospital
  • Bournemouth, United Kingdom
    • Royal Bournemouth Hospital
  • Wiltshire, United Kingdom
    • Rowden Medical Partnership
  • England
    • Swansea, England, United Kingdom, SA6 6NL
      • Morriston Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States
      • Anasazi Internal Medicine
  • California
    • La Jolla, California, United States
      • Whittier Institute of Diabetes
    • Los Gatos, California, United States
      • Novartis Investigative Site
    • Santa Monica, California, United States, 90404
      • Novartis Investigative Site
    • Tustin, California, United States
      • Orange County Research Center
  • Georgia
    • Atlanta, Georgia, United States
      • Novartis Investigative Site
  • Indiana
    • Evansville, Indiana, United States
      • Deaconess Clinic
  • Mississippi
    • Jackson, Mississippi, United States
      • Novartis Investigative Site
    • Picayune, Mississippi, United States
      • Novartis Investigative Site
  • New Jersey
    • Trenton, New Jersey, United States
      • Novartis Investigative Site
  • Ohio
    • Columbus, Ohio, United States
      • Diabetes Research Center
  • Pennsylvania
    • Beaver, Pennsylvania, United States
      • Tri-State Medical Group
    • Pittsburgh, Pennsylvania, United States
      • Preferred Primary Care Physicians
  • South Carolina
    • Columbia, South Carolina, United States
      • Novartis Investigative Site
  • Texas
    • Lake Jackson, Texas, United States
      • R/D Clinical Research
    • Pasadena, Texas, United States
      • Novartis Investigative Site
    • San Antonio, Texas, United States
      • Novartis Investigative Site
  • Virginia
    • Virginia Beach, Virginia, United States
      • Medical Research Initiatives Inc

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:

1. Patients must have a documented diagnosis of Type 2 diabetes confirmed by World Health Organization (WHO) criteria either a FPG≥ 7.0 mmol/l (126 mg/dl) or an Oral glucose tolerance test (OGTT) test 2-hour PG ≥ 11.1 mmol/l (200 mg/dl).

2. Patients must:

   • be naïve to anti-diabetes drug therapy (except for short term treatment courses with insulin in connection with hospitalization, etc.)
   • meet protocol specified Glycosylated hemoglobin / hemoglobin A1c (HbA1c) criteria
   • be eligible for metformin monotherapy OR
   • be on stable metformin monotherapy treatment for at least three months at Screening
   • meet protocol specified HbA1c criteria
   • take metformin as their first and only treatment with anti-diabetes drug therapy OR
   • be taking an AGI as their first and only anti-diabetes drug therapy (except short term treatment courses with insulin in connection with hospitalizations, etc)
   • meet protocol specified HbA1c criteria
   • be eligible for metformin monotherapy
3. Patients must have a morning fasting plasma glucose result < 180 mg/dl at Visit 3 (Month -1) analyzed by the Central Laboratory.
4. Were on a daily dose of metformin ≥ 1000 mg (or less according to local regulations)

Exclusion Criteria:

1. Type 1 diabetes, diabetes resulting from pancreatic injury or secondary forms of diabetes.

2. Any of the following significant laboratory abnormalities:

   • Serum Glutamic acid decarboxylase (GAD)-antibody positivity
   • Clinically significant Thyroid stimulating hormone (TSH) outside of normal range at Screening
   • Renal function indicating high risk metformin use, including serum creatinine concentrations (≥1.5 mg/dL for males, ≥1.4 mg/dL for females) or other evidence of abnormal creatinine clearance.
   • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN), or total bilirubin > 2 x ULN and/or direct bilirubin > ULN at Screening, confirmed with repeat measure within one week.
3. History or current findings of active pulmonary disease as evidenced by a history of positive purified protein derivative (PPD), QuantiFERON-TB Gold (QFT-G), AFB sputum or positive PPD followed by positive chest x-ray or QFT-G, or ongoing antibiotic treatment for latent TB.
4. Risk factors for TB as defined in protocol
5. Known presence or suspicion of active or recurrent bacterial, fungal or viral infection at the time of enrollment proven or suspected to be related to immunocompromise including HIV or active or recurrent Hepatitis B and Hepatitis C.
6. Systemic or local treatment of any immune modulating agent in doses with systemic effects or live vaccinations within 3 months
7. Stroke, myocardial infarction, acute coronary syndrome, revascularization procedure or recurrent TIA within the last 6 months.
8. Unwillingness to use insulin glargine as the additional medication should glycemic control deteriorate.

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: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Canakinumab 5 mg + Metformin; In 4-Month Dose-finding period, patients visited the clinic monthly and had 5 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose >200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c >7.5% were treated with a daily injection of insulin glargine as add-on therapy.	Drug: Canakinumab; Canakinumab lyophilized cake (25 mg and 150 mg in individual 6 mL glass vials ) was reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.; Drug: Metformin; Before randomization, in drug naïve patients at a dose of 1000 mg with the evening meal or 500 mg b.i.d. (twice daily) with two main meals. At the randomization visit, patients were prescribed with no less than 1,000mg/day.
Experimental: Canakinumab 15 mg + Metformin; In 4-Month Dose-finding period, patients visited the clinic monthly and had 15 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose >200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c >7.5% were treated with a daily injection of insulin glargine as add-on therapy.	Drug: Canakinumab; Canakinumab lyophilized cake (25 mg and 150 mg in individual 6 mL glass vials ) was reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.; Drug: Metformin; Before randomization, in drug naïve patients at a dose of 1000 mg with the evening meal or 500 mg b.i.d. (twice daily) with two main meals. At the randomization visit, patients were prescribed with no less than 1,000mg/day.
Experimental: Canakinumab 50 mg + Metformin; In 4-Month Dose-finding period, patients visited the clinic monthly and had 50 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose >200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c >7.5% were treated with a daily injection of insulin glargine as add-on therapy.	Drug: Canakinumab; Canakinumab lyophilized cake (25 mg and 150 mg in individual 6 mL glass vials ) was reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.; Drug: Metformin; Before randomization, in drug naïve patients at a dose of 1000 mg with the evening meal or 500 mg b.i.d. (twice daily) with two main meals. At the randomization visit, patients were prescribed with no less than 1,000mg/day.
Experimental: Canakinumab 150 mg + Metformin; In 4-Month Dose-finding period, patients visited the clinic monthly and had 150 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose >200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c >7.5% were treated with a daily injection of insulin glargine as add-on therapy.	Drug: Canakinumab; Canakinumab lyophilized cake (25 mg and 150 mg in individual 6 mL glass vials ) was reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.; Drug: Metformin; Before randomization, in drug naïve patients at a dose of 1000 mg with the evening meal or 500 mg b.i.d. (twice daily) with two main meals. At the randomization visit, patients were prescribed with no less than 1,000mg/day.
Placebo Comparator: Placebo + Metformin; In 4 month dose finding period as well as during intermediate period, patients received one injection of canakinumab matching placebo monthly and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations).	Drug: Metformin; Before randomization, in drug naïve patients at a dose of 1000 mg with the evening meal or 500 mg b.i.d. (twice daily) with two main meals. At the randomization visit, patients were prescribed with no less than 1,000mg/day.; Drug: Placebo; Placebo lyophilized cake will be reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II)	Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.	4 months (Period II)
Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II)	HbA1c was measured by National glycohemoglobin standardization program (NGSP) certified methodology. HbA1c is an integrated measure of average glucose concentration in plasma in the last 2-3 months. The analysis of covariance (ANCOVA) included treatment and metformin dose group as main effects and baseline HbA1c as a covariate.	Baseline, Month 4
Change From Baseline in Dynamic Phase Secreted Insulin Per Unit of Glucose Concentration (Φd) Over 4 Months (Period III)	This was planned as interim analysis and was not conducted because the study was terminated in period III.	Baseline, Over Month 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients completed each standard meal challenge with measurement of C-peptide prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to start of meal. C-peptide levels over 4 hrs were shown as Area Under the Curve,(AUC). AUC was calculated as: x=1 AUC ΣAx n Where Ax = AUC for the 240 min.interval, and X = 1 for the 1st interval. The analysis of covariance included baseline C-peptide AUC 0-4 hours as a covariate.	Baseline, Month 4
Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients completed each standard meal challenge with measurement of glucose prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. Glucose levels over 4 hrs were shown as Area Under the Curve,(AUC). AUC was calculated as: x=1 AUC ΣAx n Where Ax = AUC for the 240 min.interval, and X = 1 for the 1st interval. The model of analysis of covariance included baseline plasma glucose AUC 0-4 hours as a covariate.	Baseline, Month 4
Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients completed each standard meal challenge with measurement of insulin prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. Insulin levels over 4 hrs were shown as Area Under the Curve,(AUC). AUC was calculated as: x=1 AUC ΣAx n Where Ax = AUC for the 240 min.interval, and X = 1 for the 1st interval. Model of analysis of covariance included baseline insulin AUC 0-4 hours as covariate.	Baseline, Month 4
Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of glucose prior to and after a liquid mixed meal. The sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline 2-hour glucose level as covariate.	Baseline, Month 4
Change From Baseline in Peak Glucose Level Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of glucose prior to and after a liquid mixed meal. The sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline peak glucose level as covariate.	Baseline, Month 4
Change From Baseline in Peak C-peptide Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on the day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of C-peptide prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline peak C-peptide level as a covariate.	Baseline, Month 4
Change From Baseline in Peak Insulin Level Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of insulin prior to and after a liquid mixed meal. The sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline 2-hour insulin level as covariate.	Baseline, Month 4
Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II)	Change in Insulin Secretion Rate stimulated by Liquid mixed-meal challenge. A standard liquid mixed-meal challenge was done at baseline and Month 4. Blood samples were taken prior to and after meal for glucose and insulin at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes relative to the start of the meal. The model of analysis of covariance included baseline Insulin secretion rate relative to glucose AUC at 0-2 hours as a covariate.	Baseline, Month 4
Change From Baseline in 2 Hour Insulin Secretion Rate Derived Based on Glucose and C-peptide Following at Month 4 Following Meal Test (Period II)	A standard liquid mixed-meal challenge was done at baseline and Month 4. A 2 hour insulin secretion rate using deconvolution was performed. The deconvolution was an algorithm that analyzed the insulin secretion rate relative to glucose and C-peptide combined. Blood samples were taken prior to and after meal at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes relative to the start of the meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline 2 hour Insulin secretion rate as a covariate.	Baseline, Month 4
Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II)	Patients were asked to check their glucose level (7 times) using their glucose meter on one of the seven days prior to the Meal Challenge Visits (Period II: baseline, Month 4. Patient was instructed to test at following timepoints: fasting before breakfast, 2 hours after starting breakfast, before lunch, 2 hours after starting lunch, before dinner, 2 hours after dinner and at bedtime. The patient documented the results in their Study Diary. The analysis of covariance included treatment and metformin dose group as main effects and baseline peak plasma glucose level as a covariate.	Baseline, Month 4
Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II)	Patients were asked to check their glucose level (7 times) using their glucose meter on one of the seven days prior to the Meal Challenge Visits (Period II: Month 0 (Baseline), Month 4. Patient was instructed to test at following timepoints: fasting before breakfast, 2 hours after starting breakfast, before lunch, 2 hours after starting lunch, before dinner, 2 hours after dinner and at bedtime. Patient documented the results in their Study Diary. The analysis of covariance included treatment and metformin dose group as main effects and baseline average plasma glucose level as a covariate.	Baseline, Month 4
Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II)	Change in Fasting Glucose Level measured from plasma taken at Baseline and at Month 4. The analysis of covariance included treatment and metformin dose group as main effects and baseline fasting plasma glucose level as a covariate.	Baseline, Month 4
Change From Baseline in Fasting Insulin at Month 4 (Period II)	Change in fasting insulin Level measured from blood samples taken at Baseline and at Month 4. The analysis of covariance included treatment and metformin dose group as main effects and baseline fasting insulin level as a covariate.	Baseline, Month 4
Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II)	The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state beta cell function (%B) as a percentage of a normal reference population (normal young adults). Time profile of postprandial glucose, insulin and C-peptide were assessed as measures of β-cell response to stimulation. The analysis of covariance included treatment and metformin dose group as main effects and baseline HOMA-B as a covariate.	Baseline, Month 4
Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II)	The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-IR is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin resistance which is the reciprocal of insulin sensitivity (%S)(100/%S)as a percentage of a normal reference population (normal young adults). The analysis of covariance included treatment and metformin dose group as main effects and baseline HOMA2 IR as a covariate.	Baseline, Month 4
Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II)	The Quantitative Insulin Sensitivity Check Index (QUICKI) score, measures insulin sensitivity which is the inverse of insulin resistance. The score is calculated by the equation: 1 /(log(fasting insulin µU/mL) + log(fasting glucose mg/dL)). In normal subjects, the mean score ± SE is 0.366 ± 0.029. The analysis of covariance included treatment and metformin dose group as main effects and baseline QUICKI as a covariate.	Baseline, Month 4
Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II)	The change from baseline in hsCRP (on the logarithmic scale) at Month 4 was measured for this analysis. The analysis of covariance included treatment and metformin dose group as main effects and baseline hsCRP as a covariate.	Baseline, Month 4
Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II)	The fasting lipid profiles included triglycerides, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), calculated very low-density lipoprotein (VLDL), non-HDL cholesterol. Percentage change was measured as [(value at month 4 - baseline value)/baseline value]*100%. The analysis of covariance model included treatment and metformin dose group as main effects and baseline triglycerides, total cholesterol, LDL, HDL, VLDL and non-HDL as covariates.	Baseline, Month 4

Collaborators and Investigators

• Sponsor: Novartis
• Investigators: Study Director: Novartis Pharmaceuticals Corporation, Sponsor GmbH

Publications and helpful links

General Publications

• Noe A, Howard C, Thuren T, Taylor A, Skerjanec A. Pharmacokinetic and pharmacodynamic characteristics of single-dose Canakinumab in patients with type 2 diabetes mellitus. Clin Ther. 2014 Nov 1;36(11):1625-37. doi: 10.1016/j.clinthera.2014.08.004. Epub 2014 Sep 18.
• Hensen J, Howard CP, Walter V, Thuren T. Impact of interleukin-1beta antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab. 2013 Dec;39(6):524-31. doi: 10.1016/j.diabet.2013.07.003. Epub 2013 Sep 25.
• Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T; CANTOS Pilot Investigative Group. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012 Dec 4;126(23):2739-48. doi: 10.1161/CIRCULATIONAHA.112.122556. Epub 2012 Nov 5.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: May 6, 2009
• First Submitted That Met QC Criteria: May 11, 2009
• First Posted (Estimate): May 12, 2009

Study Record Updates

• Last Update Posted (Estimate): February 20, 2012
• Last Update Submitted That Met QC Criteria: January 17, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: type 2 diabetes; canakinumab
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: CACZ885I2202