Saxagliptin Treatment in Subjects With Type 2 Diabetes Who Are Not Controlled With Diet and Exercise

This study has been completed.
Sponsor:
Information provided by:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00121641
First received: July 15, 2005
Last updated: June 4, 2014
Last verified: June 2014
  Purpose

The purpose of this clinical research study is to learn whether saxagliptin (BMS-477118) is more effective than placebo as a treatment for type 2 diabetic subjects who are not sufficiently controlled with diet and exercise


Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: Saxagliptin
Drug: Placebo matching Saxagliptin
Drug: Metformin
Drug: Placebo matching Metformin
Phase 3

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 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin (BMS-477118) as Monotherapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control With Diet and Exercise

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Hemoglobin A1c (A1C) Changes From Baseline at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    To compare the change from baseline in HbA1c achieved with each dose of saxagliptin versus placebo in treatment naive subjects with type 2 diabetes who have inadequate glycemic control defined as A1C ≥7.0% and ≤10.0%.

  • A1C Changes From Baseline at Week 24 - Open Label Cohort [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    To compare the change from baseline in HbA1c achieved with each dose of saxagliptin versus placebo in treatment naive subjects with type 2 diabetes who have inadequate glycemic control defined as A1C ≥7.0% and ≤10.0%.


Secondary Outcome Measures:
  • Baseline and Change From Baseline at Week 24 in Fasting Plasma Glucose (FPG) [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  • Percentage of Participants Achieving Therapeutic Glycemic Response (A1C < 7.0%) at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Baseline and Change From Baseline at Week 24 in Postprandial Glucose (PPG) Area Under the Curve (AUC) [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  • Baseline and Change From Baseline at Week 24 in Fasting Plasma Glucose (FPG) - Open Label Cohort [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  • Percentage of Participants Achieving Therapeutic Glycemic Response (A1C < 7.0%) at Week 24 - Open Label Cohort [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Baseline and Change From Baseline at Week 24 in Postprandial Glucose (PPG) Area Under the Curve (AUC) - Open Label Cohort [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Baseline Demographic Characteristic (Age, Continuous) - Summary for ST + LT Treatment Period - Open-Label Cohort [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    This cohort represents a different population (screening A1C > 10.0% and ≤ 12.0%) than the double-blind cohort, and was presented separately in the study report.

  • Baseline Demographic Characteristics - Summary for ST + LT Treatment Period - Open-Label Cohort [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    This cohort represents a different population (screening A1C > 10.0% and ≤ 12.0%) than the double-blind cohort, and was presented separately in the study report.

  • Baseline Demographic Characteristic (Weight) - Summary for ST + LT Treatment Period - Open-Label Cohort [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    This cohort represents a different population (screening A1C > 10.0% and ≤ 12.0%) than the double-blind cohort, and was presented separately in the study report.

  • Baseline Demographic Characteristic (Body Mass Index) - Summary for ST + LT Treatment Period - Open-Label Cohort [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    This cohort represents a different population (screening A1C > 10.0% and ≤ 12.0%) than the double-blind cohort, and was presented separately in the study report.

  • Overall Summary of Adverse Events During ST+LT Treatment Period [ Time Frame: AEs: up to last treatment day + 1 day or last visit; SAEs: up to last treatment day + 30 days or last visit + 30 days. Mean duration of exposure was 109 weeks in 10 mg arm, 94.7 weeks in 2.5 mg arm, 103 weeks in 5 mg arm, and 98.4 weeks in placebo arm. ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Related events=relationship of certain, probable, possible, or missing.

  • Marked Laboratory Abnormalities - During ST + LT Treatment Period [ Time Frame: Lab assessments taken during and up to 14 days after the last dose of study drug during the ST + LT Treatment Period. Mean duration of exposure was 109 weeks in 10 mg arm, 94.7 weeks in 2.5 mg arm, 103 weeks in 5 mg arm, and 98.4 weeks in placebo arm. ] [ Designated as safety issue: Yes ]
    A laboratory value was considered a marked abnormality if it is outside the pre-defined criteria for marked abnormality and the on-treatment value was more extreme (farther from the limit) than the baseline value. Pre-Rx=pretreatment; ULN=upper limit of normal; ALP=alkaline phosphatase; AST=aspartate aminotransferase; ALT=alanine aminotransferase; unspec=unspecified; sodium serum low: <0.9 x Pre-Rx & <=130mEq/L / high: >1.1 x Pre-Rx & >=150mEq/L; potassium, serum low: <=0.8 x Pre-Rx & >=6.0mEq/L / high: 1.2 x Pre-Rx & >=6.0mEq/L; LLN=lower limit of normal.

  • Baseline and Changes From Baseline in Hemoglobin During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Hematocrit During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Red Blood Cell Counts (x 10^6 c/µL) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Platelet Counts (x 10^9 c/L) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in White Blood Cell Counts (x 10^3 c/µL) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Absolute Neutrophil Counts (x 10^3 c/µL) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Absolute Lymphocyte Counts (x 10^3 c/µL) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Absolute Monocyte Counts (x 10^3 c/µL) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Absolute Basophil Counts (x 10^3 c/µL) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Baseline and Changes From Baseline in Absolute Eosinophil Counts (x 10^3 c/µL) During the ST + LT Period [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Changes From Baseline in Systolic Blood Pressure During the ST + LT Period [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Changes From Baseline in Diastolic Blood Pressure During the ST + LT Period [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Changes From Baseline in Heart Rate During the ST + LT Period [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206 ] [ Designated as safety issue: Yes ]
  • Electrocardiogram (ECG) Tracings - Shift Table From Baseline (BL) to Selected Visits During ST + LT Treatment Period [ Time Frame: Baseline, Weeks 12, 24, 76, 102, 154, 206 ] [ Designated as safety issue: Yes ]
    The normality/abnormality of the ECG tracing was determined by the investigator.

  • Overall Summary of Adverse Events During ST+LT Treatment Period - Open-Label Cohort [ Time Frame: AEs: up to last treatment day + 1 day or last visit; SAEs: up to last treatment day + 30 days or last visit + 30 days. Mean duration of exposure was 34 weeks. ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Related events=relationship of certain, probable, possible, or missing.

  • Marked Laboratory Abnormalities During ST + LT Treatment Period - Open-Label Cohort [ Time Frame: Lab assessments taken during and up to 14 days after the last dose of study drug during the ST + LT Treatment Period. Mean duration of exposure was 34 weeks. ] [ Designated as safety issue: Yes ]
    A laboratory value was considered a marked abnormality if it is outside the pre-defined criteria for marked abnormality and the on-treatment value was more extreme (farther from the limit) than the baseline value. Pre-Rx=pretreatment; ULN=upper limit of normal; ALP=alkaline phosphatase; AST=aspartate aminotransferase; ALT=alanine aminotransferase; unspec=unspecified; sodium serum low: <0.9 x Pre-Rx & <=130mEq/L / high: >1.1 x Pre-Rx & >=150mEq/L; potassium, serum low: <=0.8 x Pre-Rx & >=6.0mEq/L / high: 1.2 x Pre-Rx & >=6.0mEq/L; LLN=lower limit of normal.

  • All Reported Hypoglycemic Adverse Events During ST + LT Treatment Period [ Time Frame: AEs: up to last treatment day + 1 day or last visit; SAEs: up to last treatment day + 30 days or last visit + 30 days. Mean duration of exposure was 109 weeks in 10 mg arm, 94.7 weeks in 2.5 mg arm, 103 weeks in 5 mg arm, and 98.4 weeks in placebo arm. ] [ Designated as safety issue: Yes ]
    Hypoglycemic Events are based upon the Saxagliptin Predefined List of Events, which included hypoglycemia, blood glucose decreased, and hypoglycemic unconsciousness.

  • Confirmed Hypoglycemia During ST + LT Treatment Period [ Time Frame: AEs: up to last treatment day + 1 day or last visit; SAEs: up to last treatment day + 30 days or last visit + 30 days. Mean duration of exposure was 109 weeks in 10 mg arm, 94.7 weeks in 2.5 mg arm, 103 weeks in 5 mg arm, and 98.4 weeks in placebo arm. ] [ Designated as safety issue: Yes ]
    'Confirmed' = recorded on the hypoglycemia AE case report form page with a fingerstick glucose <= 50 mg/dL and associated symptoms

  • All Reported Hypoglycemic Adverse Events During ST + LT Treatment Period - Open-Label Cohort [ Time Frame: AEs: up to last treatment day + 1 day or last visit; SAEs: up to last treatment day + 30 days or last visit + 30 days. Mean duration of exposure was 34 weeks. ] [ Designated as safety issue: Yes ]
    Hypoglycemic Events are based upon the Saxagliptin Predefined List of Events, which included hypoglycemia, blood glucose decreased, and hypoglycemic unconsciousness.

  • Confirmed Hypoglycemia During ST + LT Treatment Period - Open-Label Cohort [ Time Frame: AEs: up to last treatment day + 1 day or last visit; SAEs: up to last treatment day + 30 days or last visit + 30 days. Mean duration of exposure was 34 weeks. ] [ Designated as safety issue: Yes ]
    'Confirmed' = recorded on the hypoglycemia AE case report form page with a fingerstick glucose <= 50 mg/dL and associated symptoms

  • Electrocardiogram (ECG) Tracings - Shift Table From Baseline (BL) to Selected Visits During ST + LT Treatment Period - Open Label Cohort [ Time Frame: Baseline, Weeks 12, 24, 76, 102, 154, 206 ] [ Designated as safety issue: Yes ]
    The normality/abnormality of the ECG tracing was determined by the investigator.

  • Changes From Baseline in Systolic Blood Pressure During the ST + LT Period - Open Label Cohort [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167 ] [ Designated as safety issue: Yes ]
  • Changes From Baseline in Diastolic Blood Pressure During the ST + LT Period - Open Label Cohort [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167 ] [ Designated as safety issue: Yes ]
  • Changes From Baseline in Heart Rate During the ST + LT Period - Open Label Cohort [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 37, 50, 63, 76, 89, 102, 115, 128, 141, 154, 167 ] [ Designated as safety issue: Yes ]

Enrollment: 1035
Study Start Date: July 2005
Study Completion Date: February 2010
Primary Completion Date: August 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Saxagliptin 2.5 mg (A)
Metformin 500-2000 mg (as needed for rescue)
Drug: Saxagliptin
Tablets, Oral, 2.5 mg, Once daily (24 weeks short term [ST], 42 months long term [LT])
Other Name: BMS-477118
Drug: Placebo matching Metformin
Tablets, Oral, 0 mg, daily (42 months LT)
Drug: Metformin
Tablets, Oral, 500-2000 mg (as needed for rescue)
Experimental: Saxagliptin 5 mg (B)
Metformin 500-2000 mg (as needed for rescue)
Drug: Saxagliptin
Tablets, Oral, 5 mg, Once daily (24 weeks ST, 42 months LT)
Other Name: BMS-477118
Drug: Placebo matching Metformin
Tablets, Oral, 0 mg, daily (42 months LT)
Drug: Metformin
Tablets, Oral, 500-2000 mg (as needed for rescue)
Experimental: Saxagliptin 10 mg (C)
Metformin 500-2000 mg (as needed for rescue)
Drug: Saxagliptin
Tablets, Oral, 10 mg, Once daily (24 weeks ST, 42 months LT)
Other Name: BMS-477118
Drug: Placebo matching Metformin
Tablets, Oral, 0 mg, daily (42 months LT)
Drug: Metformin
Tablets, Oral, 500-2000 mg (as needed for rescue)
Placebo Comparator: Placebo (D)
Metformin 500-2000 mg (as needed for rescue)
Drug: Placebo matching Saxagliptin
Tablets, Oral, 0mg, Once daily (24 weeks ST, 42 months LT)
Drug: Metformin
Tablets, Oral, 500 mg, daily (42 months LT)
Drug: Metformin
Tablets, Oral, 500-2000 mg (as needed for rescue)
Experimental: Open-Label Treatment Cohort (Direct Enrollees) (E)

Saxagliptin 10 mg

Metformin 500-2000 mg (as needed for rescue)

Drug: Saxagliptin
Tablets, Oral, 10 mg, Once daily (24 weeks ST, 42 months LT) Open Label
Other Name: BMS-477118
Drug: Metformin
Tablets, Oral, 500-2000 mg (as needed for rescue)

Detailed Description:

All subjects will participate in a lead-in period, and qualifying subjects will continue into a short-term randomized treatment period. Subjects who complete the short-term period will be eligible to enter the long term extension period. Also, subjects in the short-term period who have an elevated blood sugar that requires additional medication for blood sugar control will be eligible to enter the long-term treatment extension period where they will receive metformin added onto their blinded study medication. Subjects with screening hemoglobin A1c (A1C) > 10.0% and ≤ 12.0%, who otherwise meet all inclusion/exclusion criteria, were eligible to enroll directly into Open-Label Treatment Cohort (Direct Enrollees) and receive open-label saxagliptin 10 mg. Those who completed the short-term period were eligible to enter into the long-term treatment extension period.Saxagliptin dose titration was not permitted.

  Eligibility

Ages Eligible for Study:   18 Years to 77 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes mellitus
  • Drug naive
  • Hemoglobin (Hb) A1c >= 7.0% and <= 10.0% (>10% and <= 12% for open label arm)
  • Fasting C-peptide >= 1 ng/mL
  • Body mass index <= 40 kg/m2

Exclusion Criteria:

  • Symptomatic poorly controlled diabetes
  • Recent cardiac or cerebrovascular event
  • Serum creatinine >= 1.5 mg/dL for males and >= 1.4 mg/dL for Women of Child Bearing Potential
  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: NCT00121641

  Show 135 Study Locations
Sponsors and Collaborators
AstraZeneca
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00121641     History of Changes
Other Study ID Numbers: CV181-011
Study First Received: July 15, 2005
Results First Received: April 12, 2011
Last Updated: June 4, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Saxagliptin
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014