Diabetes Mellitus, Type 2
Conditions
Keywords
type 2 diabetes, canakinumab
Brief summary
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.
Interventions
DRUGCanakinumab
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.
DRUGMetformin
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.
DRUGPlacebo
Placebo lyophilized cake will be reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | 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. |
| Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Dynamic Phase Secreted Insulin Per Unit of Glucose Concentration (Φd) Over 4 Months (Period III) | Baseline, Over Month 4 | This was planned as interim analysis and was not conducted because the study was terminated in period III. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Peak Glucose Level Following Meal Test (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Peak C-peptide Following Meal Test (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Peak Insulin Level Following Meal Test (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II) | Baseline, Month 4 | 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. |
| 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) | Baseline, Month 4 | 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. |
| Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Fasting Insulin at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II) | Baseline, Month 4 | 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. |
| Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | Baseline, Month 4 | 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. |
Countries
Argentina, Belgium, China, Germany, Hungary, India, Japan, Peru, Romania, South Africa, South Korea, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Study consisted of four periods: screening (Period I), dose-finding (Period II), intermediate (Period III),and long-term continuation (Period IV). Eligible patients were randomized for 4-month treatment of Period II. Intermediate period continued until primary analysis was completed and optimal dose was selected. Study got terminated in Period III.
Pre-assignment details
A total of 556 patients were randomized in Period II. 5 patients one in each 5, 15, 50mg Canakinumab arms and 2 in Placebo were randomized in error, but never received study treatment. All tables reflect the 551 treated patients.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 93 |
| 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. | 95 |
| 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. | 92 |
| 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. | 92 |
| 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). | 179 |
| Total | 551 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Dose Finding: Period II (4 Months) | Administrative problems | 1 | 0 | 0 | 0 | 0 |
| Dose Finding: Period II (4 Months) | Lost to Follow-up | 2 | 0 | 0 | 1 | 3 |
| Dose Finding: Period II (4 Months) | Withdrawal by Subject | 2 | 2 | 5 | 1 | 9 |
| Intermediate: Period III | Administrative problems | 85 | 92 | 84 | 90 | 163 |
| Intermediate: Period III | Lost to Follow-up | 2 | 0 | 0 | 0 | 1 |
| Intermediate: Period III | Withdrawal by Subject | 0 | 1 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Canakinumab 5 mg + Metformin | Canakinumab 15 mg + Metformin | Canakinumab 50 mg + Metformin | Canakinumab 150 mg + Metformin | Placebo + Metformin | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 53.5 years STANDARD_DEVIATION 10.27 | 55.5 years STANDARD_DEVIATION 9.7 | 53.0 years STANDARD_DEVIATION 9.29 | 53.7 years STANDARD_DEVIATION 10.36 | 54.3 years STANDARD_DEVIATION 10.15 | 54.1 years STANDARD_DEVIATION 9.99 |
| Sex: Female, Male Female | 38 Participants | 46 Participants | 47 Participants | 35 Participants | 74 Participants | 240 Participants |
| Sex: Female, Male Male | 55 Participants | 49 Participants | 45 Participants | 57 Participants | 105 Participants | 311 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 93 | 9 / 95 | 15 / 92 | 8 / 92 | 26 / 179 |
| serious Total, serious adverse events | 3 / 93 | 1 / 95 | 5 / 92 | 7 / 92 | 8 / 179 |
Outcome results
Primary
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
Population: The benefit of canakinumab for the treatment of patients with type 2 diabetes mellitus in combination with metformin was inadequate to continue patients into Period IV in the present study, and therefore decided to terminate the study during Period III.
Primary
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
Population: The full analysis set (included all randomized patients except for mis-randomized patients who randomized in error but did not receive study drug. Last observation carried forward (LOCF) method was used for patients without Month 4 HbA1c data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II) | -0.19 percentage of hemoglobin A1c | Standard Error 0.072 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II) | -0.29 percentage of hemoglobin A1c | Standard Error 0.071 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II) | -0.31 percentage of hemoglobin A1c | Standard Error 0.073 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II) | -0.25 percentage of hemoglobin A1c | Standard Error 0.071 |
| Placebo + Metformin | Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II) | -0.13 percentage of hemoglobin A1c | Standard Error 0.053 |
Primary
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)
Population: The safety set (SAF) included all patients who received at least one dose of study medication during Period II.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Any Adverse Events | 33 Participants |
| Canakinumab 5 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Serious Adverse Events | 2 Participants |
| Canakinumab 5 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Death | 0 Participants |
| Canakinumab 15 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Death | 0 Participants |
| Canakinumab 15 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Any Adverse Events | 43 Participants |
| Canakinumab 15 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Serious Adverse Events | 1 Participants |
| Canakinumab 50 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Death | 0 Participants |
| Canakinumab 50 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Any Adverse Events | 45 Participants |
| Canakinumab 50 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Serious Adverse Events | 2 Participants |
| Canakinumab 150 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Any Adverse Events | 43 Participants |
| Canakinumab 150 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Serious Adverse Events | 5 Participants |
| Canakinumab 150 mg + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Death | 0 Participants |
| Placebo + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Death | 0 Participants |
| Placebo + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Any Adverse Events | 76 Participants |
| Placebo + Metformin | Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) | Serious Adverse Events | 6 Participants |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II) | -0.427 mmol/L | Standard Error 0.2537 |
| Canakinumab 15 mg + Metformin | Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II) | -0.239 mmol/L | Standard Error 0.2457 |
| Canakinumab 50 mg + Metformin | Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II) | -0.777 mmol/L | Standard Error 0.2471 |
| Canakinumab 150 mg + Metformin | Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II) | 0.262 mmol/L | Standard Error 0.2445 |
| Placebo + Metformin | Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II) | -0.347 mmol/L | Standard Error 0.1873 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | 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) | -17.022 pmol/min/m² | Standard Error 10.4317 |
| Canakinumab 15 mg + Metformin | 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) | -9.607 pmol/min/m² | Standard Error 9.9815 |
| Canakinumab 50 mg + Metformin | 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) | -31.296 pmol/min/m² | Standard Error 10.2302 |
| Canakinumab 150 mg + Metformin | 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) | -38.515 pmol/min/m² | Standard Error 10.0176 |
| Placebo + Metformin | 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) | -24.812 pmol/min/m² | Standard Error 7.698 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II) | -0.357 mmol/L | Standard Error 0.1626 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II) | -0.218 mmol/L | Standard Error 0.1589 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II) | -0.275 mmol/L | Standard Error 0.1614 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II) | -0.040 mmol/L | Standard Error 0.1569 |
| Placebo + Metformin | Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II) | -0.091 mmol/L | Standard Error 0.1203 |
Secondary
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.
Time frame: Baseline, Month 4
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | -0.399 nmol*hour/L | Standard Error 0.1444 |
| Canakinumab 15 mg + Metformin | Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | -0.388 nmol*hour/L | Standard Error 0.1394 |
| Canakinumab 50 mg + Metformin | Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | -0.834 nmol*hour/L | Standard Error 0.1425 |
| Canakinumab 150 mg + Metformin | Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | -0.610 nmol*hour/L | Standard Error 0.1396 |
| Placebo + Metformin | Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | -0.588 nmol*hour/L | Standard Error 0.107 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Fasting Insulin at Month 4 (Period II) | 4.3 pmol/L | Standard Error 4.74 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Fasting Insulin at Month 4 (Period II) | 7.2 pmol/L | Standard Error 4.57 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Fasting Insulin at Month 4 (Period II) | 7.0 pmol/L | Standard Error 4.67 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Fasting Insulin at Month 4 (Period II) | 4.4 pmol/L | Standard Error 4.47 |
| Placebo + Metformin | Change From Baseline in Fasting Insulin at Month 4 (Period II) | -0.4 pmol/L | Standard Error 3.5 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II) | 0.25 mmol/L | Standard Error 0.162 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II) | -0.19 mmol/L | Standard Error 0.159 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II) | -0.29 mmol/L | Standard Error 0.162 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II) | 0.19 mmol/L | Standard Error 0.16 |
| Placebo + Metformin | Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II) | 0.01 mmol/L | Standard Error 0.118 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II) | -0.19 log (mg/L) | Standard Error 0.037 |
| Canakinumab 15 mg + Metformin | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II) | -0.32 log (mg/L) | Standard Error 0.036 |
| Canakinumab 50 mg + Metformin | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II) | -0.44 log (mg/L) | Standard Error 0.037 |
| Canakinumab 150 mg + Metformin | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II) | -0.40 log (mg/L) | Standard Error 0.036 |
| Placebo + Metformin | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II) | -0.08 log (mg/L) | Standard Error 0.027 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II) | -1.067 percentage of beta cell function | Standard Error 6.0549 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II) | 2.259 percentage of beta cell function | Standard Error 5.9304 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II) | 8.215 percentage of beta cell function | Standard Error 5.9727 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II) | 6.217 percentage of beta cell function | Standard Error 5.7307 |
| Placebo + Metformin | Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II) | -2.182 percentage of beta cell function | Standard Error 4.4846 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II) | 0.245 percentage of insulin resistance | Standard Error 0.3107 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II) | 0.517 percentage of insulin resistance | Standard Error 0.299 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II) | 0.255 percentage of insulin resistance | Standard Error 0.3054 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II) | 0.252 percentage of insulin resistance | Standard Error 0.2925 |
| Placebo + Metformin | Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II) | 0.013 percentage of insulin resistance | Standard Error 0.2286 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | 18.623 pmol*hour/L | Standard Error 28.5445 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | 66.237 pmol*hour/L | Standard Error 27.4053 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | -14.016 pmol*hour/L | Standard Error 27.9738 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | -20.583 pmol*hour/L | Standard Error 26.5602 |
| Placebo + Metformin | Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) | 0.121 pmol*hour/L | Standard Error 20.7195 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II) | -0.369 pmol/min/m²/mmol *hour/L | Standard Error 0.6922 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II) | -0.331 pmol/min/m²/mmol *hour/L | Standard Error 0.6705 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II) | -1.761 pmol/min/m²/mmol *hour/L | Standard Error 0.6744 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II) | -2.428 pmol/min/m²/mmol *hour/L | Standard Error 0.6681 |
| Placebo + Metformin | Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II) | -1.635 pmol/min/m²/mmol *hour/L | Standard Error 0.5084 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Peak C-peptide Following Meal Test (Period II) | -0.075 nmol/L | Standard Error 0.0524 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Peak C-peptide Following Meal Test (Period II) | -0.115 nmol/L | Standard Error 0.0509 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Peak C-peptide Following Meal Test (Period II) | -0.227 nmol/L | Standard Error 0.0523 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Peak C-peptide Following Meal Test (Period II) | -0.207 nmol/L | Standard Error 0.0506 |
| Placebo + Metformin | Change From Baseline in Peak C-peptide Following Meal Test (Period II) | -0.212 nmol/L | Standard Error 0.0394 |
Secondary
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.
Time frame: Baseline, Month 4
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Peak Glucose Level Following Meal Test (Period II) | -0.386 mmol/L | Standard Error 0.2302 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Peak Glucose Level Following Meal Test (Period II) | -0.380 mmol/L | Standard Error 0.2257 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Peak Glucose Level Following Meal Test (Period II) | -0.565 mmol/L | Standard Error 0.227 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Peak Glucose Level Following Meal Test (Period II) | 0.381 mmol/L | Standard Error 0.2208 |
| Placebo + Metformin | Change From Baseline in Peak Glucose Level Following Meal Test (Period II) | -0.339 mmol/L | Standard Error 0.1711 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Peak Insulin Level Following Meal Test (Period II) | 13.1 pmol/L | Standard Error 14.4 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Peak Insulin Level Following Meal Test (Period II) | 26.0 pmol/L | Standard Error 14 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Peak Insulin Level Following Meal Test (Period II) | 2.0 pmol/L | Standard Error 13.88 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Peak Insulin Level Following Meal Test (Period II) | -7.0 pmol/L | Standard Error 13.61 |
| Placebo + Metformin | Change From Baseline in Peak Insulin Level Following Meal Test (Period II) | 1.7 pmol/L | Standard Error 10.59 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II) | -0.549 mmol/L | Standard Error 0.2669 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II) | -0.129 mmol/L | Standard Error 0.261 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II) | -0.421 mmol/L | Standard Error 0.2653 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II) | -0.333 mmol/L | Standard Error 0.2578 |
| Placebo + Metformin | Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II) | -0.212 mmol/L | Standard Error 0.1975 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II) | -0.999 mmol*hour/L | Standard Error 0.8094 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II) | -1.012 mmol*hour/L | Standard Error 0.7917 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II) | -2.103 mmol*hour/L | Standard Error 0.7928 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II) | 1.618 mmol*hour/L | Standard Error 0.7791 |
| Placebo + Metformin | Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II) | -0.851 mmol*hour/L | Standard Error 0.6053 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who inadvertently randomized into study and did not receive study drug. Last observation carried forward method was used for patients without Month 4 data for any reason and who used rescue medication or any other glucose lowering agents other than metformin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab 5 mg + Metformin | Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II) | -0.001 units on a scale | Standard Error 0.0017 |
| Canakinumab 15 mg + Metformin | Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II) | 0.000 units on a scale | Standard Error 0.0016 |
| Canakinumab 50 mg + Metformin | Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II) | -0.003 units on a scale | Standard Error 0.0017 |
| Canakinumab 150 mg + Metformin | Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II) | -0.001 units on a scale | Standard Error 0.0016 |
| Placebo + Metformin | Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II) | 0.000 units on a scale | Standard Error 0.0013 |
Secondary
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
Population: The full analysis set included all randomized patients except for mis-randomized patients who randomized in error, did not receive study drug. LOCF method was used for patients without Month 4 data for any reason and who used rescue drug or any other glucose lowering agents other than metformin. 'n' = patients with baseline and endpoints data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Canakinumab 5 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Total cholesterol (n = 91, 93, 88, 91, 172) | 3.163 percent change | Standard Error 1.5364 |
| Canakinumab 5 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Triglycerides (n = 91, 93, 88, 91, 172) | 16.127 percent change | Standard Error 4.313 |
| Canakinumab 5 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | LDL (n = 90, 90, 85, 87, 165) | 2.624 percent change | Standard Error 2.4606 |
| Canakinumab 5 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | HDL (n = 91, 93, 88, 91, 172) | 1.438 percent change | Standard Error 1.6619 |
| Canakinumab 5 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | VLDL (n= 90, 90, 85, 87, 165) | 15.646 percent change | Standard Error 3.9196 |
| Canakinumab 5 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Non-HDL (n = 91, 93, 88, 91, 172) | 4.25 percent change | Standard Error 2.022 |
| Canakinumab 15 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | VLDL (n= 90, 90, 85, 87, 165) | 6.711 percent change | Standard Error 3.9118 |
| Canakinumab 15 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Non-HDL (n = 91, 93, 88, 91, 172) | 4.40 percent change | Standard Error 1.999 |
| Canakinumab 15 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Total cholesterol (n = 91, 93, 88, 91, 172) | 3.922 percent change | Standard Error 1.5188 |
| Canakinumab 15 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | LDL (n = 90, 90, 85, 87, 165) | 4.741 percent change | Standard Error 2.4582 |
| Canakinumab 15 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | HDL (n = 91, 93, 88, 91, 172) | 5.346 percent change | Standard Error 1.6441 |
| Canakinumab 15 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Triglycerides (n = 91, 93, 88, 91, 172) | 7.903 percent change | Standard Error 4.2688 |
| Canakinumab 50 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | HDL (n = 91, 93, 88, 91, 172) | 8.074 percent change | Standard Error 1.6853 |
| Canakinumab 50 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | VLDL (n= 90, 90, 85, 87, 165) | 16.533 percent change | Standard Error 3.9986 |
| Canakinumab 50 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Total cholesterol (n = 91, 93, 88, 91, 172) | 5.334 percent change | Standard Error 1.5542 |
| Canakinumab 50 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | LDL (n = 90, 90, 85, 87, 165) | 2.705 percent change | Standard Error 2.5137 |
| Canakinumab 50 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Triglycerides (n = 91, 93, 88, 91, 172) | 19.937 percent change | Standard Error 4.3684 |
| Canakinumab 50 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Non-HDL (n = 91, 93, 88, 91, 172) | 5.17 percent change | Standard Error 2.046 |
| Canakinumab 150 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | HDL (n = 91, 93, 88, 91, 172) | 6.780 percent change | Standard Error 1.6494 |
| Canakinumab 150 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Triglycerides (n = 91, 93, 88, 91, 172) | 18.795 percent change | Standard Error 4.2786 |
| Canakinumab 150 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | LDL (n = 90, 90, 85, 87, 165) | 5.938 percent change | Standard Error 2.4752 |
| Canakinumab 150 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Non-HDL (n = 91, 93, 88, 91, 172) | 7.25 percent change | Standard Error 2.005 |
| Canakinumab 150 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | VLDL (n= 90, 90, 85, 87, 165) | 16.618 percent change | Standard Error 3.9373 |
| Canakinumab 150 mg + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Total cholesterol (n = 91, 93, 88, 91, 172) | 6.265 percent change | Standard Error 1.5234 |
| Placebo + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | VLDL (n= 90, 90, 85, 87, 165) | 7.370 percent change | Standard Error 2.9203 |
| Placebo + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | LDL (n = 90, 90, 85, 87, 165) | 5.129 percent change | Standard Error 1.8351 |
| Placebo + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Triglycerides (n = 91, 93, 88, 91, 172) | 7.009 percent change | Standard Error 3.1813 |
| Placebo + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Non-HDL (n = 91, 93, 88, 91, 172) | 3.04 percent change | Standard Error 1.491 |
| Placebo + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | HDL (n = 91, 93, 88, 91, 172) | 3.963 percent change | Standard Error 1.2303 |
| Placebo + Metformin | Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) | Total cholesterol (n = 91, 93, 88, 91, 172) | 2.697 percent change | Standard Error 1.1334 |