Safety and Efficacy of Saxagliptin Plus Insulin With or Without Metformin

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00757588
First received: September 22, 2008
Last updated: June 4, 2014
Last verified: June 2014
  Purpose

The purpose of this study is to compare the effects of saxagliptin with those of placebo as add-on therapy to insulin and insulin with metformin in improving glycemic control at 24 and 52 weeks.


Condition Intervention Phase
Type 2 Diabetes
Drug: Saxagliptin, 5 mg + insulin
Drug: Placebo + insulin
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, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin Added to Insulin Monotherapy or to Insulin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Insulin Alone or on Insulin in Combination With Metformin

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Adjusted Mean Change From Baseline in A1C Levels (Last Observation Carried Forward [LOCF]) [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
    Change from baseline: post-pre. Adjusted for baseline (value and metformin use). ANCOVA model: difference between week t and baseline values=baseline values + treatment + metformin use


Secondary Outcome Measures:
  • Change From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Meal Tolerance Test (MTT) [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
    An MTT is a 2-part test that measures glucose and insulin levels after an overnight fast and before ingesting a meal consisting of a nutritional drink and power bar and again at prespecified times (30, 60, 120, and 180 minutes) after the start of ingestion of the meal

  • Change From Baseline in 120-minute PPG Values During an MTT [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
    An MTT is a 2-part test that measures glucose and insulin levels after an overnight fast and before ingesting a meal consisting of a nutritional drink and power bar and again at prespecified times (30, 60, 120, and 180 minutes) after the start of ingestion of the meal.

  • Change From Baseline in Fasting Plasma Glucose Values [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
  • Percentage of Participants Achieving a Therapeutic Glycemic Response [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
    Therapeutic glycemic response is defined as an A1C<7%. Significance was not interpreted with a p value.

  • Change From Baseline in Mean Total Daily Dose of Insulin (MTDDI) (LOCF) [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
    Based on information recorded in the participant's daily diary. The MTDDI was calculated at every visit using the values patients recorded since the last regularly scheduled visit (minimum of 80% of days with a value). At every visit, the MTDDI was compared with the participant's baseline MTDDI (measured during a 4-week lead-in period) to identify any changes in insulin use at that visit compared with insulin use at baseline.


Other Outcome Measures:
  • Number of Participants With Abnormal Changes From Baseline in Electrocardiogram (ECG) Results [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: Yes ]
    ECG abnormalities included those in nonspecific "other" categories (Other nonspecific ST/T, Other intraventricular conduction defect, Other, and Other rhythm abnormalities)and nonspecific findings, such as sinus bradycardia, sinus arrythmia, sinus tachycardia, poor R-wave progression, and ventricular premature contractions.

  • Shift in Absolute Lymphocyte Counts From Baseline to Selected Visits (LOCF) [ Time Frame: Baseline and Weeks 24 and 52 ] [ Designated as safety issue: Yes ]
    Absolute lymphocyte count=value*10^3 c/uL

  • Number of Participants With at Least 1 Adverse Event (AE), at Least 1 Treatment-related AE, Death as Outcome, at Least 1 Serious Adverse Event (SAE), at Least 1 Treatment-related SAE, Discontinuations Due to SAEs, and Discontinuations Due to AEs [ Time Frame: Baseline to Week 52, continuously ] [ Designated as safety issue: Yes ]
    An AE is any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; requires inpatient hospitalization; or prolongs existing hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study treatment.

  • Mean Changes From Baseline in Systolic and Diastolic Blood Pressure Readings [ Time Frame: Baseline to Weeks 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, and 52 ] [ Designated as safety issue: Yes ]
  • Mean Changes From Baseline in Heart Rate [ Time Frame: Baseline to Weeks 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, and 52 ] [ Designated as safety issue: Yes ]
  • Shift in Platelet Counts From Baseline to Selected Visits (LOCF) [ Time Frame: Baseline and Weeks 24 and 52 ] [ Designated as safety issue: Yes ]
    Platelet count=value*10^9 c/L

  • Number of Participants With Marked Laboratory Abnormalities During the 24-Week ST + 52-Week LT Treatment Period [ Time Frame: Baseline and during and up to 14 days after last dose of study drug (in Week 52) ] [ Designated as safety issue: Yes ]

    Marked abnormality=a laboratory value lying outside the predefined criteria and more extreme (farther from the limit)on-treatment than at baseline. ULN=upper limit of normal; LLN=lower limit of normal; prx=pre-RX=pretreatment.

    Criteria 1: if prx=0 use >=2, if prx=0.5 or 1 use >=3, if prx=2 use 4.


  • Percentage of Participants With Reported and Confirmed Hypoglycemia [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: Yes ]
    Confirmed hypoglycemia=fingerstick glucose measurement of ≤50 mg/dL with associated symptoms/


Enrollment: 455
Study Start Date: November 2008
Study Completion Date: April 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Saxagliptin, 5 mg + insulin
Saxagliptin, 5 mg, plus insulin, administered to participants with Type 2 diabetes inadequately controlled with insulin alone or with insulin plus metformin
Drug: Saxagliptin, 5 mg + insulin
Saxagliptin, 5-mg tablets (plus stable insulin dose), given orally once daily (24 weeks short-term, 28 weeks long-term); participants stratified by use of stable metformin dose; flexible insulin dose (as needed for rescue)
Other Name: BMS-477118
Placebo Comparator: Placebo + insulin
Placebo administered to participants with Type 2 diabetes inadequately controlled with insulin alone or with insulin plus metformin
Drug: Placebo + insulin
Placebo tablets given orally once daily for 24 weeks (short-term period)+ insulin with metformin

  Eligibility

Ages Eligible for Study:   18 Years to 78 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes mellitus
  • Must have been taking a stable dose of basal or premixed insulin for 8 weeks or longer prior to screening
  • If taking metformin, must have been taking the same daily dose for 8 weeks or longer prior to screening
  • Insulin type should be intermediate- or long-acting (basal) or premixed (premixed formulation may include short- or rapid-acting insulin as 1 component).
  • Inadequate glycemic control (A1C of 7.5% to 11.0%, inclusive)
  • Body mass index of 45 kg/m² or lower
  • Fasting C-peptide level of 0.8 ng/mL or higher

Exclusion Criteria:

  • Symptoms of poorly controlled diabetes, including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the last 3 months prior to screening or other signs and symptoms
  • History of diabetic ketoacidosis or hyperosmolar nonketotic coma
  • Women of childbearing potential unable or unwilling to use acceptable birth control
  • Women who are pregnant or breastfeeding
  • Active liver disease
  • Anemia
  • Chronic or repeated intermittent corticosteroid treatment (participants receiving stable doses of replacement corticosteroid (except dexamethasone) therapy may be enrolled)
  • Use of short- or rapid-acting insulin
  • Significant cardiovascular history defined as: myocardial infarction, coronary angioplasty or bypass graft, valvular disease or repair, unstable angina pectoris, transient ischemic attack, or cerebrovascular accident
  • Congestive heart failure
  • Unstable or rapidly progressing renal disease
  • History of alcohol or drug abuse within the previous year
  • History of hemoglobinopathies
  • Unstable major psychiatric disorders
  • Immunocompromised status
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00757588

  Show 80 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by AstraZeneca

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT00757588     History of Changes
Other Study ID Numbers: CV181-057, Eudract-2008-001089-10
Study First Received: September 22, 2008
Results First Received: August 10, 2011
Last Updated: June 4, 2014
Health Authority: United States: Food and Drug Administration
Russia: Ethics Committee
India: Central Drugs Standard Control Organization
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
United Kingdom: Medicines and Healthcare Products Regulatory Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Brazil: National Health Surveillance Agency
South Africa: Medicines Control Council
Canada: Canadian Institutes of Health Research

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin, Globin Zinc
Saxagliptin
Metformin
Insulin
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 18, 2014