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

• ClinicalTrials.gov Identifier: NCT00605475
• Recruitment Status: Completed
• First Posted: January 31, 2008
• Results First Posted: February 13, 2012
• Last Update Posted: February 13, 2012
• Sponsor: Novartis
• Information provided by (Responsible Party): Novartis

Study Description

Brief 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).

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes Mellitus	Drug: Canakinumab; Drug: Placebo; Drug: Metformin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 231 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Study Start Date: December 2007
• Actual Primary Completion Date: September 2010
• Actual Study Completion Date: September 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Canakinumab; Eligible participants were assigned to receive canakinumab in one of four cohorts; 1) Single IV infusion of canakinumab 0.3 mg/kg; 2) Singe IV infusion of canakinumab 10 mg/kg; 3) single IV infusion of canakinumab 0.1 mg/kg or 0.3 mg/kg, or 1.5 mg/kg; 4) Single IV injection of canakinumab 0.03 mg/kg. All participants were required to take a concomitant stable daily dose of metformin during the study.	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.; Other Name: ACZ885; Drug: Metformin; Participants continued on their stable daily dose of metformin throughout the study; Other Names: Glucophage; Glumetza
Placebo Comparator: Placebo; Eligible participants were assigned to receive placebo to canakinumab in one of four cohorts; 1) Single IV infusion of placebo to canakinumab 0.3 mg/kg; 2) Singe IV infusion of placebo to canakinumab 10 mg/kg; 3) single IV infusion of placebo to canakinumab 0.1 mg/kg or 0.3 mg/kg, or 1.5 mg/kg; 4) Single IV injection of placebo to canakinumab 0.03 mg/kg. All participants were required to take a concomitant stable daily dose of metformin during the study.	Drug: 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.; Drug: Metformin; Participants continued on their stable daily dose of metformin throughout the study; Other Names: Glucophage; Glumetza

Outcome Measures

Primary Outcome Measures :

1. Mean Change From Baseline in Plasma HbA1c (Glycosylated Hemoglobin / Hemoglobin A1c) [ Time Frame: Baseline, Day 28, Day 84, Day 126, End of Study (168 [+/- 5] days after dosing) ]
   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.
2. Mean Change From Baseline in Plasma Glucose Area Under the Curve (AUC) 0 - 4 Hours Following Oral Glucose Tolerance Test (OGTT ) [ Time Frame: Baseline, Day 28, Day 84 ]
   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.

Secondary Outcome Measures :

1. Mean Change From Baseline in Plasma C-peptide AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test (OGTT) [ Time Frame: Baseline, Day 28, Day 84 ]
   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.
2. Mean Change From Baseline in Plasma Insulin AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test ( OGTT ) [ Time Frame: Baseline, Day 28, Day 84 ]
   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.
3. Mean Change From Baseline in Plasma Proinsulin AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test ( OGTT ) [ Time Frame: Baseline, Day 28, Day 84 ]
   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.
4. Mean Change From Baseline in Plasma Glucagon AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test [ Time Frame: Baseline, Day 28, Day 84 ]
   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.
5. Mean Change From Baseline in Peak Plasma Insulin/Proinsulin Level, Following Oral Glucose Tolerance Test (OGTT) [ Time Frame: Baseline, Day 28, Day 84 ]
   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.
6. Mean Insulin Secretion Rate ( ISR ) Relative to Glucose, 0 - 4 Hours [ Time Frame: Day 28, Day 84 ]

   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.

7. Mean Insulin Secretion Rate ( ISR ), 0 - 4 Hours [ Time Frame: Day 28, Day 84 ]
   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.
8. Insulin Sensitivity Index ( ISI ) at Day 28, Day 48 [ Time Frame: Day 28, Day 84 ]
   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.
9. Insulinogenic Index, 0 - 30 Minutes [ Time Frame: Day 28, Day 84 ]

   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..
10. Mean Change From Baseline in Peak Plasma Glucose Following Oral Glucose Tolerance Test ( OGTT ) [ Time Frame: Baseline, Day 28, Day 84 ]
    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.
11. Mean Change From Baseline in Peak Plasma Fructosamine Level [ Time Frame: Baseline, Day 14, Day 28, Day 56, Day 84, Day 126, End of Study (168 [+/- 5] days after dosing) ]
    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.
12. Insulin Resistance as Measured by the Homeostatic Model Assessment (HOMA-IR) [ Time Frame: Baseline, Day 28, Day 84 ]
    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.
13. β-cell Function as Measured by the Homeostatic Model Assessment (HOMA-β ) [ Time Frame: Baseline, Day 28, Day 84 ]
    β cell function is measured by the Homeostatic Model Assessment(HOMA-β) using a computer to model β cell function and insulin sensitivity . β cell function is related to Insulin Sensitivity (HOMA-%S) and is the reciprocal of insulin resistance (100/S%). HOMA β = [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.
14. Number of Participants Reporting Death, Serious Adverse Events (SAEs), Adverse Events (AE) Above 5% Frequency [ Time Frame: Baseline to End of Study (56[+/-2] and 168 [+/- 5] days after dosing for Cohort 1 and Cohorts 2-4, respectively) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arkansas

Arkansas Research Medical Testing

Little Rock, Arkansas, United States, 72202

United States, Florida

Allied Research International - Cetero Research Miami

Miami, Florida, United States, 33169

Elite Research Institute Miami

Miami, Florida, United States, 33169

United States, Maryland

International Research Center Towson

MD, Maryland, United States, 21286

United States, Oregon

Covance Clinical Research Unit Inc

Portland, Oregon, United States, 97239

United States, Washington

Charles River Clinical Services

NW Tacoma, Washington, United States, 98418

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, Germany

Russian Federation

Novartis Investigative Site

Moscow, Russian Federation

Novartis Investigative Site

St. Petersberg, Russian Federation

Sponsors and Collaborators

Novartis

Investigators

• Principal Investigator: NOVARTIS; Novartis investigator site

More Information

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT00605475
• Other Study ID Numbers: CACZ885A2213
• First Posted: January 31, 2008
• Results First Posted: February 13, 2012
• Last Update Posted: February 13, 2012
• Last Verified: January 2012

Keywords provided by Novartis:

Type 2 Diabetes Mellitus; Canakinumab; ACZ885; IL-1B antagonist; metformin; glycemic control; insulin sensitivity

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs