Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ACZ885 in Patients With Type 2 Diabetes

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A Multi Center, Randomized, Double Blind, Placebo-controlled, Dose Escalation Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ACZ885 Administered Intravenously to Patients With Type 2 Diabetes Mellitus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00605475
• Other study ID #: CACZ885A2213
• Status: Completed
• Phase: Phase 2
• First received: January 18, 2008
• Last updated: January 10, 2012
• Start date: December 2007
• Est. completion date: September 2010

Study information

• Verified date: January 2012
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to evaluate, in patients with Type 2 Diabetes Mellitus, whether Canakinumab can lower Glycosylated hemoglobin / hemoglobin A1c (HbA1c) and/or peak glucose levels in response to an oral glucose tolerance test (OGTT).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 231
• Est. completion date: September 2010
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Male or female patients aged 18 to 70 years, with type 2 diabetes mellitus (non-insulin dependent diabetes) for at least 6 months prior to study start

• HbA1c between 7.0 and 9.5%

• On stable dose metformin monotherapy

• Stable body weight

Exclusion Criteria:

• Poorly controlled type 2 diabetes (very low or very high blood sugar levels, or other indicators of poor control)

• Acute infections prior to dosing

• Patients with type 1 diabetes (insulin-dependent diabetes)

• Taking diabetes medication (other than metformin)

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Canakinumab
Canakinumab given as single dose IV injection of 0.03 mg/kg, or single dose IV infusion at doses of 0.1 mg/kg 0.3 mg/kg, 1.5 mg/kg or 10 mg/kg.
• Placebo
Placebo to Canakinumab given as single dose IV injection of 0.03 mg/kg, or single dose IV infusion at doses of 0.1 mg/kg 0.3 mg/kg, 1.5 mg/kg or 10 mg/kg.
• Metformin
Participants continued on their stable daily dose of metformin throughout the study

Locations

Country	Name	City	State
Germany	Novartis Investigator Site	Berlin
Germany	Novartis Investigator Site	Kiel
Germany	Novartis Investigator Site	Moenchengladbach
Germany	Novartis Investigator Site	Munich
Germany	Novartis Investigative Site	Neuss
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St. Petersberg
United States	Arkansas Research Medical Testing	Little Rock	Arkansas
United States	International Research Center Towson	MD	Maryland
United States	Allied Research International - Cetero Research Miami	Miami	Florida
United States	Elite Research Institute Miami	Miami	Florida
United States	Charles River Clinical Services	NW Tacoma	Washington
United States	Covance Clinical Research Unit Inc	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Novartis

Countries where clinical trial is conducted

United States,  Germany,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change From Baseline in Plasma HbA1c (Glycosylated Hemoglobin / Hemoglobin A1c)	Blood was drawn after an overnight fast to measure plasma HbA1c levels. End of Study is defined as the last Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84, Day 126, End of Study (168 [+/- 5] days after dosing)	No
Primary	Mean Change From Baseline in Plasma Glucose Area Under the Curve (AUC) 0 - 4 Hours Following Oral Glucose Tolerance Test (OGTT )	Mean Change in Glucose level stimulated by OGTT. Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. Glucose levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84	No
Secondary	Mean Change From Baseline in Plasma C-peptide AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test (OGTT)	Blood samples were drawn after an overnight fast and standard OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. C-peptide levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84	No
Secondary	Mean Change From Baseline in Plasma Insulin AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test ( OGTT )	Blood samples were drawn after an overnight fast and OGTT 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). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84	No
Secondary	Mean Change From Baseline in Plasma Proinsulin AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test ( OGTT )	Blood samples were drawn after an overnight fast and OGTT 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). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84	No
Secondary	Mean Change From Baseline in Plasma Glucagon AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test	Blood samples were drawn after an overnight fast and OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. Glucagon levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84	No
Secondary	Mean Change From Baseline in Peak Plasma Insulin/Proinsulin Level, Following Oral Glucose Tolerance Test (OGTT)	Blood samples were drawn after an overnight fast and OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. Insulin and proinsulin levels were measured. The insulin/proinsulin level was calculated by dividing the insulin level by the proinsulin level. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84	No
Secondary	Mean Insulin Secretion Rate ( ISR ) Relative to Glucose, 0 - 4 Hours	Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. Mean ISR relative to glucose over 0-4 hours was calculated as follows: Mean ISR relative to glucose = mean ISR / (glucose AUC/time interval). The mean ISR was computed as an AUC (area under the curve) using the linear trapezoidal rule divided by the corresponding time interval. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Day 28, Day 84	No
Secondary	Mean Insulin Secretion Rate ( ISR ), 0 - 4 Hours	Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. The mean ISR over 0 - 4 hours was computed as an AUC (area under the curve) using the linear trapezoidal rule divided by the corresponding time interval. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Day 28, Day 84	No
Secondary	Insulin Sensitivity Index ( ISI ) at Day 28, Day 48	Insulin sensitivity index (ISI) = 10000 / [fasting insulin (µIU/mL) x fasting glucose (mg/dL) x mean 2 hour insulin(µIU/mL) x mean 2 hour glucose (mg/dL)]1/2 where mean 2 hour insulin (or glucose) was defined as the insulin (or glucose)AUC(0-2 hr) divided by the time period (2 hr). In normal subjects the mean score ± SE is 0.366 ± 0.029. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data.	Day 28, Day 84	No
Secondary	Insulinogenic Index, 0 - 30 Minutes	Insulinogenic index (0-30 min); [Change in insulin (0-30 min) (µIU/mL)] / [Change in glucose (0-30 min) (mg/dL)]; [insulin (µIU/mL) at 30 min - insulin (µIU/mL) at 0 min] / [glucose (mg/dL) at 30 min - glucose (mg/dL) at 0 min), where insulin (or glucose) at 0 min was defined as the arithmetic mean of the -15, -10 and 0 min pre-glucose load values. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data..	Day 28, Day 84	No
Secondary	Mean Change From Baseline in Peak Plasma Glucose Following Oral Glucose Tolerance Test ( OGTT )	Mean Change in Peak Glucose level stimulated by OGTT. Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. Change from baseline assessed at Day 28 and 84. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 28, Day 84	No
Secondary	Mean Change From Baseline in Peak Plasma Fructosamine Level	Blood was drawn to measure change in plasma Fructosamine Level, from baseline to Day 14, 28, 56, 84, 126 and End of Study ( defined as the final available post-randomization assessment up to the last regularly scheduled visit at Day 168 [+/- 5]). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed.	Baseline, Day 14, Day 28, Day 56, Day 84, Day 126, End of Study (168 [+/- 5] days after dosing)	No
Secondary	Insulin Resistance as Measured by the Homeostatic Model Assessment (HOMA-IR)	Insulin Resistance is measured via the Homeostatic Model Assessment (HOMA-IR) using a computer to model insulin sensitivity. Insulin Sensitivity (HOMA-%S), where 100% is normal, is the reciprocal of insulin resistance (100/S%). HOMA IR = [fasting insulin (µU/mL)] x [fasting plasma glucose (mmol/L)] / 22.5 where fasting insulin (or glucose) was defined as the arithmetic mean of the -15, -10 and 0 min pre-glucose load values. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data.	Baseline, Day 28, Day 84	No
Secondary	ß-cell Function as Measured by the Homeostatic Model Assessment (HOMA-ß )	ß cell function is measured by the Homeostatic Model Assessment(HOMA-ß) using a computer to model ß cell function and insulin sensitivity . ß cell function is related to Insulin Sensitivity (HOMA-%S) and is the reciprocal of insulin resistance (100/S%). HOMA ß = [20 x fasting insulin (µU/mL)] / [fasting plasma glucose (mmol/L) - 3.5] where fasting insulin (or glucose) was defined as the arithmetic mean of the -15, -10 and 0 min pre-glucose load values. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data.	Baseline, Day 28, Day 84	No
Secondary	Number of Participants Reporting Death, Serious Adverse Events (SAEs), Adverse Events (AE) Above 5% Frequency	An adverse event is any unwanted event, whether related to study drug or not occurring 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 to End of Study (56[+/-2] and 168 [+/- 5] days after dosing for Cohort 1 and Cohorts 2-4, respectively)	Yes