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

• ClinicalTrials.gov Identifier: NCT00121641
• Recruitment Status: Completed
• First Posted: July 21, 2005
• Results First Posted: May 11, 2011
• Last Update Posted: April 3, 2015
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: July 15, 2005
• First Posted Date: July 21, 2005
• Results First Submitted Date: April 12, 2011
• Results First Posted Date: May 11, 2011
• Last Update Posted Date: April 3, 2015
• Study Start Date: July 2005
• Actual Primary Completion Date: August 2006 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 15, 2011)

• Hemoglobin A1c (A1C) Changes From Baseline at Week 24 [ Time Frame: Baseline, Week 24 ]
  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 ]
  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%.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: April 12, 2011)

• Baseline and Change From Baseline at Week 24 in Fasting Plasma Glucose (FPG) [ Time Frame: Baseline, Week 24 ]
• Percentage of Participants Achieving Therapeutic Glycemic Response (A1C < 7.0%) at Week 24 [ Time Frame: Week 24 ]
• Baseline and Change From Baseline at Week 24 in Postprandial Glucose (PPG) Area Under the Curve (AUC) [ Time Frame: Baseline, Week 24 ]
• Baseline and Change From Baseline at Week 24 in Fasting Plasma Glucose (FPG) - Open Label Cohort [ Time Frame: Baseline, Week 24 ]
• Percentage of Participants Achieving Therapeutic Glycemic Response (A1C < 7.0%) at Week 24 - Open Label Cohort [ Time Frame: Week 24 ]
• 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 ]

• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: August 5, 2011)

• Baseline Demographic Characteristic (Age, Continuous) - Summary for ST + LT Treatment Period - Open-Label Cohort [ Time Frame: Baseline ]
  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 ]
  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 ]
  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 ]
  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. ]
  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. ]
  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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
  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. ]
  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. ]
  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. ]
  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. ]
  '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. ]
  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. ]
  '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 ]
  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 ]
• 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 ]
• 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 ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Saxagliptin Treatment in Subjects With Type 2 Diabetes Who Are Not Controlled With Diet and Exercise
• 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
• Brief Summary: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Diabetes Mellitus, Type 2

Intervention

• Drug: Saxagliptin
  Tablets, Oral, 2.5 mg, Once daily (24 weeks short term [ST], 42 months long term [LT])
  Other Name: BMS-477118
• Drug: Saxagliptin
  Tablets, Oral, 5 mg, Once daily (24 weeks ST, 42 months LT)
  Other Name: BMS-477118
• Drug: Saxagliptin
  Tablets, Oral, 10 mg, Once daily (24 weeks ST, 42 months LT)
  Other Name: BMS-477118
• 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: Placebo matching Metformin
  Tablets, Oral, 0 mg, daily (42 months LT)
• 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)

Study Arms

• Experimental: Saxagliptin 2.5 mg (A)
  Metformin 500-2000 mg (as needed for rescue)
  Interventions:

  • Drug: Saxagliptin
  • Drug: Placebo matching Metformin
  • Drug: Metformin
• Experimental: Saxagliptin 5 mg (B)
  Metformin 500-2000 mg (as needed for rescue)
  Interventions:

  • Drug: Saxagliptin
  • Drug: Placebo matching Metformin
  • Drug: Metformin
• Experimental: Saxagliptin 10 mg (C)
  Metformin 500-2000 mg (as needed for rescue)
  Interventions:

  • Drug: Saxagliptin
  • Drug: Placebo matching Metformin
  • Drug: Metformin
• Placebo Comparator: Placebo (D)
  Metformin 500-2000 mg (as needed for rescue)
  Interventions:

  • Drug: Placebo matching Saxagliptin
  • Drug: Metformin
  • Drug: Metformin
• Experimental: Open-Label Treatment Cohort (Direct Enrollees) (E)

  Saxagliptin 10 mg

  Metformin 500-2000 mg (as needed for rescue)

  Interventions:

  • Drug: Saxagliptin
  • Drug: Metformin

Publications *

• Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R; CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009 Oct;25(10):2401-11. doi: 10.1185/03007990903178735.
• Esu E, Berens-Riha N, Pritsch M, Nwachuku N, Loescher T, Meremikwu M. Intermittent screening and treatment with artemether-lumefantrine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in pregnancy: a facility-based, open-label, non-inferiority trial in Nigeria. Malar J. 2018 Jul 6;17(1):251. doi: 10.1186/s12936-018-2394-2.
• Perl S, Cook W, Wei C, Iqbal N, Hirshberg B. Saxagliptin Efficacy and Safety in Patients With Type 2 Diabetes and Moderate Renal Impairment. Diabetes Ther. 2016 Sep;7(3):527-35. doi: 10.1007/s13300-016-0184-9. Epub 2016 Jul 11.
• Bonora E, Bryzinski B, Hirshberg B, Cook W. A post hoc analysis of saxagliptin efficacy and safety in patients with type 2 diabetes stratified by UKPDS 10-year cardiovascular risk score. Nutr Metab Cardiovasc Dis. 2016 May;26(5):374-9. doi: 10.1016/j.numecd.2015.11.004. Epub 2015 Dec 1.
• Rosenstock J, Gross JL, Aguilar-Salinas C, Hissa M, Berglind N, Ravichandran S, Fleming D. Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes. Diabet Med. 2013 Dec;30(12):1472-6. doi: 10.1111/dme.12267. Epub 2013 Jul 19.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 12, 2011): 1035
• Original Enrollment: Not Provided
• Actual Study Completion Date: February 2010
• Actual Primary Completion Date: August 2006 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 77 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Mexico, Puerto Rico, Taiwan, United States

Administrative Information

• NCT Number: NCT00121641
• Other Study ID Numbers: CV181-011
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Not Provided
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Bristol-Myers Squibb
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: March 2015