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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT00605475
First received: January 18, 2008
Last updated: January 10, 2012
Last verified: January 2012
  Purpose

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 Intervention Phase
Type 2 Diabetes Mellitus
Drug: Canakinumab
Drug: Placebo
Drug: Metformin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Baseline in Peak Plasma Insulin/Proinsulin Level, Following Oral Glucose Tolerance Test (OGTT) [ Time Frame: Baseline, Day 28, Day 84 ] [ Designated as safety issue: No ]
    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.

  • Mean Insulin Secretion Rate ( ISR ) Relative to Glucose, 0 - 4 Hours [ Time Frame: Day 28, Day 84 ] [ Designated as safety issue: No ]

    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.


  • Mean Insulin Secretion Rate ( ISR ), 0 - 4 Hours [ Time Frame: Day 28, Day 84 ] [ Designated as safety issue: No ]
    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.

  • Insulin Sensitivity Index ( ISI ) at Day 28, Day 48 [ Time Frame: Day 28, Day 84 ] [ Designated as safety issue: No ]
    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.

  • Insulinogenic Index, 0 - 30 Minutes [ Time Frame: Day 28, Day 84 ] [ Designated as safety issue: No ]

    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..

  • Mean Change From Baseline in Peak Plasma Glucose Following Oral Glucose Tolerance Test ( OGTT ) [ Time Frame: Baseline, Day 28, Day 84 ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • Insulin Resistance as Measured by the Homeostatic Model Assessment (HOMA-IR) [ Time Frame: Baseline, Day 28, Day 84 ] [ Designated as safety issue: No ]
    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.

  • β-cell Function as Measured by the Homeostatic Model Assessment (HOMA-β ) [ Time Frame: Baseline, Day 28, Day 84 ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 231
Study Start Date: December 2007
Study Completion Date: September 2010
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Other Name: Placebo
Drug: Metformin
Participants continued on their stable daily dose of metformin throughout the study
Other Names:
  • Glucophage
  • Glumetza

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00605475

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

No publications provided

Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT00605475     History of Changes
Other Study ID Numbers: CACZ885A2213
Study First Received: January 18, 2008
Results First Received: September 1, 2011
Last Updated: January 10, 2012
Health Authority: United States: Food and Drug Administration

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
Antibodies, Monoclonal
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Immunologic Factors

ClinicalTrials.gov processed this record on July 31, 2014