To Compare the Effect of a Subcutaneous Canakinumab Administration to Placebo in Patients With Impaired Glucose Tolerance or Patients With Type 2 Diabetes With Differing Baseline Diabetes Therapies

Study Overview
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Brief Summary
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This was a 10-week, placebo-controlled, randomized study to investigate the effect of injectable IL-1B antagonist, Canakinumab , in participants with impaired glucose tolerance or Type 2 Diabetes Mellitus (T2DM) already treated on different background diabetes therapies.

Official Title
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A Multi-center, Double-blind, Placebo-controlled, Randomized Study to Compare the Effect of a Subcutaneous Canakinumab Administration to Placebo in Patients With Impaired Glucose Tolerance or Patients With Type 2 Diabetes Treated With Differing Baseline Diabetes Therapies

Conditions
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Impaired Glucose Tolerance, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Canakinumab 150 mg
* Drug: Placebo to Canakinumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must fulfill all criteria in one of the following groups: Impaired Glucose Tolerance (IGT) as diagnosed per protocol and not on an anti-diabetic medicine during the study Diagnosis of Type 2 diabetes in stable treatment with metformin Diagnosis of Type 2 diabetes in stable treatment with metformin (at least 1000 mg/day) in combination with a sulfonylurea Diagnosis of Type 2 diabetes in stable treatment with metformin (at least 1000 mg/day), sulfonylurea and thiazolidinedione combination therapy Diagnosis of Type 2 diabetes in stable treatment with at least two insulin injections a day with or without metformin HbA1c between 6.5% and 8%, inclusive, at Screening; this criterion does not apply to the IGT group Age from 18-74 years, inclusive, and of either sex Exclusion Criteria: Type 1 diabetes or diabetes that is a result of pancreatic injury or other secondary forms of diabetes History or current findings of active pulmonary disease (e.g. tuberculosis, fungal diseases) as defined in the protocol: Known presence or suspicion of active or recurrent bacterial, fungal or viral infection at the time of enrollment proven.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canakinumab 150 mg + Metformin<br>Eligible participants received a single subcutaneous injection Canakinumab 150 mg.Patients must have had documented diagnosis of Type 2 Diabetes Mellitus and be on a stable dose of Metformin (Met) monotherapy treatment at least 1000 mg/day for 3 months prior to screening | Drug: Canakinumab 150 mg<br>* Single subcutaneous injection of Canakinumab 150 mg.<br>* Other names: NPH Iletin;|
| Placebo Comparator: Placebo + Metformin<br>Eligible participants received a single subcutaneous injection of Placebo to Canakinumab. Patients must have had documented diagnosis of Type 2 Diabetes Mellitus and be on a stable dose of Metformin (Met) monotherapy treatment at least 1000 mg/day for 3 months prior to screening | Drug: Placebo to Canakinumab<br>* Single subcutaneous injection of Placebo to Canakinumab.<br>* Other names: NPH Iletin;|
| Experimental: Canakinumab 150 mg + Metforimin + Sulfonylurea<br>Eligible participants received a single subcutaneous injection of Canakinumab 150 mg.Patients must have had documented diagnosis of Type 2 Diabetes Mellitus and be on a stable dose of Metformin (Met) at least 1000 mg/day , and a Sulfonylurea (Sulfonyl), at least 1/2 the maximally labeled dose combination therapy, for 3 months prior to screening. | Drug: Canakinumab 150 mg<br>* Single subcutaneous injection of Canakinumab 150 mg.<br>* Other names: NPH Iletin;|
| Placebo Comparator: Placebo + Metforimin + Sulfonylurea<br>Eligible participants received a single subcutaneous injection of Placebo to Canakinumab.Patients must have had documented diagnosis of Type 2 Diabetes Mellitus and be on a stable dose of Metformin (Met) at least 1000 mg/day , and a Sulfonylurea (Sulfonyl), at least 1/2 the maximally labeled dose combination therapy, for 3 months prior to screening. | Drug: Placebo to Canakinumab<br>* Single subcutaneous injection of Placebo to Canakinumab.<br>* Other names: NPH Iletin;|
| Experimental: Canakinumab 150 mg + Met + Sulfonyl + Thiazolidinedione<br>Eligible participants received a single subcutaneous injection of Canakinumab 150 mg.Patients must have had documented diagnosis of Type 2 Diabetes Mellitus and be on a stable dose of Metformin (Met) at least 1000 mg/day , and a Sulfonylurea (Sulfonyl), at least 1/2 the maximally labeled dose, and a Thiazolidinedione (Thiaz)at least 1/2 the maximally labeled dose combination therapy, for 3 months prior to screening. | Drug: Canakinumab 150 mg<br>* Single subcutaneous injection of Canakinumab 150 mg.<br>* Other names: NPH Iletin;|
| Placebo Comparator: Placebo + Met + Sulfonyl + Thiazolidinedione<br>Eligible participants received a single subcutaneous injection of Placebo to Canakinumab. Patients must have had documented diagnosis of Type 2 Diabetes Mellitus and be on a stable dose of Metformin (Met) at least 1000 mg/day , and a Sulfonylurea (Sulfonyl), at least 1/2 the maximally labeled dose, and a Thiazolidinedione (Thiaz)at least 1/2 the maximally labeled dose combination therapy, for 3 months prior to screening. | Drug: Placebo to Canakinumab<br>* Single subcutaneous injection of Placebo to Canakinumab.<br>* Other names: NPH Iletin;|
| Experimental: Canakinumab 150 mg + Insulin<br>Eligible participants received a single subcutaneous injection of Canakinumab 150 mg. Patients must have had documented diagnosis of Type 2 Diabetes Mellitus for 3 months prior to screening and be on a stable dose of Insulin, 2 insulin injections per day for a total daily dose of less than 100 U with or without Metformin (Met)for 3 months prior to screening | Drug: Canakinumab 150 mg<br>* Single subcutaneous injection of Canakinumab 150 mg.<br>* Other names: NPH Iletin;|
| Placebo Comparator: Placebo + Insulin<br>Eligible participants received a single subcutaneous injection of Placebo to Canakinumab. Patients must have had documented diagnosis of Type 2 Diabetes Mellitus for 3 months prior to screening and be on a stable dose of Insulin, 2 insulin injections per day for a total daily dose of less than 100 U with or without Metformin (Met)for 3 months prior to screening | Drug: Placebo to Canakinumab<br>* Single subcutaneous injection of Placebo to Canakinumab.<br>* Other names: NPH Iletin;|
| Experimental: Canakinumab 150 mg in patients with IGT<br>Eligible participants received a single subcutaneous injection of Canakinumab 150 mg. Patients must have had Impaired Glucose Tolerance (IGT) as defined by the World Health Organization (WHO) criteria confirmed at screening visit. | Drug: Canakinumab 150 mg<br>* Single subcutaneous injection of Canakinumab 150 mg.<br>* Other names: NPH Iletin;|
| Placebo Comparator: Placebo in patients with IGT<br>Eligible participants received a single subcutaneous injection of Placebo to Canakinumab. Patients must have had Impaired Glucose Tolerance (IGT) as defined by the World Health Organization (WHO) criteria confirmed at screening visit. | Drug: Placebo to Canakinumab<br>* Single subcutaneous injection of Placebo to Canakinumab.<br>* Other names: NPH Iletin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Meal Stimulated Insulin Secretion Rate (ISR) Relative to Glucose 0-2 Hours, From Baseline to 4 Weeks. | Change in Insulin Secretion Rate stimulated by Liquid mixed-meal challenge. 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.A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include patients from the IGT population | Baseline, 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Meal Stimulated Insulin Secretion Rate (ISR) Relative to Glucose 2-4 Hours, From Baseline to 4 Weeks | Change in Insulin Secretion Rate stimulated by Liquid mixed-meal challenge 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. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population | Baseline, 4 weeks | 
| Mean Change in Meal Stimulated Insulin Secretion Rate (ISR) Relative to Glucose 0-4 Hours, From Baseline to 4 Weeks. | Change in Insulin Secretion Rate stimulated by Liquid mixed-meal challenge. Blood samples were taken prior to and after meal for glucose, insulin and C-peptide at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes relative to the start of the meal. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population. | Baseline, 4 weeks | 
| Mean Change in Fasting Plasma Glucose, From Baseline to 4 Weeks | Change in Fasting Glucose Level measured from plasma taken at Baseline and after 4 weeks of treatment. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population | Baseline, 4 weeks | 
| Mean Change in Fructosamine, From Baseline to 4 Weeks | Change in Fructosamine Level taken from plasma, measured at Baseline and after 4 weeks of treatment. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population | Baseline, 4 weeks | 
| Mean Change in Fasting Plasma Insulin, From Baseline to 4 Weeks | Change in Fasting Insulin level taken from plasma, measured at Baseline and after 4 weeks of treatment. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population | Baseline, 4 weeks | 
| Mean Change in Quantitative Insulin Sensitivity Check Index (QUICKI) Score, From Baseline to 4 Weeks | 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. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population. | Baseline, 4 weeks | 
| Mean Change in Fasting Glucose Disposition Index(GDI)1 and Index 2, From Baseline to 4 Weeks | GDI 1 is the product of insulin sensitivity index (Si)during the 1st phase of insulin secretion and β-cell function as measured by the acute insulin response (AIR).GDI 2 is the product of (Si)during the 2nd phase of insulin secretion and β-cell function as measured by the acute insulin response (AIR). A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT group. | Baseline, 4 weeks | 
| Mean Change in Absolute Glucose Level at 2 Hours, From Baseline to 4 Weeks | Change in glucose level measured after 2 hours of fasting. Blood sample was drawn at 0 minutes and at 240 minutes. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population. | Baseline, 4 weeks | 
| Mean Change in Insulin Area Under the Curve (AUC) 0-4 Hours, From Baseline to 4 Weeks | Blood samples were drawn after a test meal at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. 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. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab vs placebo within each T2DM group. The mixed model didn't include the IGT group. | Baseline, 4 weeks | 
| Mean Change in C-peptide Area Under the Curve (AUC), 0-4 Hours, From Baseline to 4 Weeks | Blood samples were drawn after a test meal at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. 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. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab vs placebo within each T2DM group. The mixed model didn't include the IGT group. | Baseline, 4 weeks | 
| Mean Change in Post-prandial Glucose Area Under the Curve (AUC)0-4 Hours, From Baseline to 4 Weeks | Blood samples were drawn after a test meal at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. 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. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab vs placebo within each T2DM group. The mixed model didn't include the IGT group. | Baseline, 4 weeks | 
| Mean Change in Peak Plasma Glucose, From Baseline to 4 Weeks | Change in peak plasma glucose level as measured from Baseline to 4 weeks of treatment. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population. | Baseline, 4 weeks | 
| Mean Change in Peak Plasma Insulin, From Baseline to 4 Weeks | Change in mean peak plasma Insulin level as measured from Baseline to 4 weeks of treatment. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population. | Baseline, 4 weeks | 
| Mean Change in Peak Plasma C-peptide Level, From Baseline to 4 Weeks | Change in mean peak plasma C-peptide level measured from Baseline to 4 weeks of treatment. A mixed model with treatment fitted as fixed effect, and population and the interaction of population and treatment fitted as random effects were used for the comparison of Canakinumab versus placebo within each T2DM population. The mixed model did not include participants from the IGT population. | Baseline, 4 weeks | 
| Number of Participants Reporting Death, Serious Adverse Events (SAEs) and Adverse Events (AEs) Above 5% Frequency, From Baseline to 4 Weeks | An adverse event is any unwanted event, whether related to study drug or not occuring during the study period. A Serious Adverse Event (SAE) is an event resulting in death, requiring or prolonging hospitalization, a congenital anomaly or other important medical event. AEs and SAEs were recorded at each visit. | Baseline, 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, canakinumab, Pre diabetic, glucose intolerant, oral anti diabetic medication, insulin treatment, metabolic syndrome