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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01068860

Enrollment

246

Registered

2010-02-15

Start date

2010-02-28

Completion date

2010-08-31

Last updated

2011-09-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Impaired Glucose Tolerance, Type 2 Diabetes Mellitus

Keywords

Type 2 Diabetes Mellitus, canakinumab, Pre diabetic, glucose intolerant, oral anti diabetic medication, insulin treatment, metabolic syndrome

Brief summary

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.

Interventions

DRUGCanakinumab 150 mg

Single subcutaneous injection of Canakinumab 150 mg.

DRUGPlacebo to Canakinumab

Single subcutaneous injection of Placebo to Canakinumab.

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

Inclusion criteria

1. 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 2. HbA1c between 6.5% and 8%, inclusive, at Screening; this criterion does not apply to the IGT group 3. Age from 18-74 years, inclusive, and of either sex

Exclusion criteria

1. Type 1 diabetes or diabetes that is a result of pancreatic injury or other secondary forms of diabetes 2. History or current findings of active pulmonary disease (e.g. tuberculosis, fungal diseases) as defined in the protocol: 3. Known presence or suspicion of active or recurrent bacterial, fungal or viral infection at the time of enrollment proven.

Design outcomes

Primary

Measure	Time frame	Description
Mean Change in Meal Stimulated Insulin Secretion Rate (ISR) Relative to Glucose 0-2 Hours, From Baseline to 4 Weeks.	Baseline, 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

Secondary

Measure	Time frame	Description
Mean Change in Meal Stimulated Insulin Secretion Rate (ISR) Relative to Glucose 0-4 Hours, From Baseline to 4 Weeks.	Baseline, 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.
Mean Change in Fasting Plasma Glucose, From Baseline to 4 Weeks	Baseline, 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
Mean Change in Fructosamine, From Baseline to 4 Weeks	Baseline, 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
Mean Change in Fasting Plasma Insulin, From Baseline to 4 Weeks	Baseline, 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
Mean Change in Quantitative Insulin Sensitivity Check Index (QUICKI) Score, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Fasting Glucose Disposition Index(GDI)1 and Index 2, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Absolute Glucose Level at 2 Hours, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Meal Stimulated Insulin Secretion Rate (ISR) Relative to Glucose 2-4 Hours, From Baseline to 4 Weeks	Baseline, 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
Mean Change in C-peptide Area Under the Curve (AUC), 0-4 Hours, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Post-prandial Glucose Area Under the Curve (AUC)0-4 Hours, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Peak Plasma Glucose, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Peak Plasma Insulin, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Peak Plasma C-peptide Level, From Baseline to 4 Weeks	Baseline, 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.
Number of Participants Reporting Death, Serious Adverse Events (SAEs) and Adverse Events (AEs) Above 5% Frequency, From Baseline to 4 Weeks	Baseline, 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.
Mean Change in Insulin Area Under the Curve (AUC) 0-4 Hours, From Baseline to 4 Weeks	Baseline, 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.

Countries

Australia, Canada, Finland, Germany, India, Italy, United States

Participant flow

Pre-assignment details

Qualified patients entered a 4-week run-in period while taking current therapy thru the study. After the run-in, patients had the baseline meal challenge. Then patients were randomized. A 2nd meal challenge was performed after 4 wks. This ended the study except for a follow up phone call after approx.90 days to record serious adverse events (SAEs)

Participants by arm

Arm	Count
Canakinumab 150 mg + Metformin 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	33
Placebo + Metformin 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	17
Canakinumab 150 mg + Metformin + Sulfonylurea 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.	33
Placebo + Metformin + Sulfonylurea 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.	17
Canakinumab 150 mg Canakinumab 150 mg + Met + Sulfonyl + Thia 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.	32
Placebo + Met + Sulfonyl + Thiaz 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.	16
Canakinumab 150 mg + Insulin 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	28
Placebo + Insulin 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	15
Canakinumab 150 mg in Participants With IGT 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.	28
Placebo in Participants With IGT 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.	27
Total	246

Withdrawals & dropouts

Period	Reason	FG001	FG003	FG005	FG009
Overall Study	Administrative problems; misrandomized	0	1	0	1
Overall Study	Lost to Follow-up	1	0	0	0
Overall Study	Withdrawal by Subject	0	0	2	3

Baseline characteristics

Characteristic	Canakinumab 150 mg + Metformin	Placebo + Metformin	Canakinumab 150 mg + Metformin + Sulfonylurea	Placebo + Metformin + Sulfonylurea	Canakinumab 150 mg Canakinumab 150 mg + Met + Sulfonyl + Thia	Placebo + Met + Sulfonyl + Thiaz	Canakinumab 150 mg + Insulin	Placebo + Insulin	Canakinumab 150 mg in Participants With IGT	Placebo in Participants With IGT	Total
Age, Customized	55.9 years STANDARD_DEVIATION 10.5	56.5 years STANDARD_DEVIATION 9.3	60.0 years STANDARD_DEVIATION 8.17	59.4 years STANDARD_DEVIATION 8.02	59.1 years STANDARD_DEVIATION 10.63	57.2 years STANDARD_DEVIATION 9.39	58.6 years STANDARD_DEVIATION 10.11	57.0 years STANDARD_DEVIATION 13.86	52.8 years STANDARD_DEVIATION 10.9	57.6 years STANDARD_DEVIATION 10.07	57.4 years STANDARD_DEVIATION 10.16
Sex: Female, Male Female	19 Participants	3 Participants	14 Participants	10 Participants	11 Participants	5 Participants	13 Participants	10 Participants	12 Participants	16 Participants	113 Participants
Sex: Female, Male Male	14 Participants	14 Participants	19 Participants	7 Participants	21 Participants	11 Participants	15 Participants	5 Participants	16 Participants	11 Participants	133 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	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	0 / 33	4 / 17	6 / 32	3 / 17	4 / 32	3 / 16	6 / 28	3 / 15	0 / 28	0 / 26
serious Total, serious adverse events	0 / 33	0 / 17	0 / 32	0 / 17	0 / 32	0 / 16	0 / 28	0 / 15	0 / 28	0 / 26

Outcome results

Primary

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

Time frame: Baseline, 4 weeks