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

Phase 3TerminatedNCT00900146

Novartis556 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

556

Conditions

Diabetes Mellitus, Type 2

Interventions

CanakinumabDRUG

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.

MetforminDRUG

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.

PlaceboDRUG

Placebo lyophilized cake will be reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 74 Years

Medical Language ↔ Plain English

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

Locations (106)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Over Month 4

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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Anasazi Internal Medicine

Phoenix, Arizona, United States

Whittier Institute of Diabetes

La Jolla, California, United States

Novartis Investigative Site

Los Gatos, California, United States

Novartis Investigative Site

Santa Monica, California, United States

Orange County Research Center

Tustin, California, United States

Novartis Investigative Site

Atlanta, Georgia, United States

Deaconess Clinic

Evansville, Indiana, United States

Novartis Investigative Site

Jackson, Mississippi, United States

Novartis Investigative Site

Picayune, Mississippi, United States

Novartis Investigative Site

Trenton, New Jersey, United States

...and 96 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Month 4

Change From Baseline in Peak Glucose Level Following Meal Test (Period II)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Month 4