Safety and Efficacy of Saxagliptin Plus Insulin With or Without Metformin

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Saxagliptin, 5 mg + insulin; Drug: Placebo + insulin

• Study Type: Interventional
• Enrollment (Actual): 455
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 0M3
      • Local Institution
  • British Columbia
    • Vancouver, British Columbia, Canada, V6E 1M7
      • Local Institution
  • New Brunswick
    • Bathurst, New Brunswick, Canada, E2A 4X7
      • Local Institution
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • Local Institution
  • Prince Edward Island
    • Charlottetown, Prince Edward Island, Canada, C1A 5Y9
      • Local Institution
  • Quebec
    • Gatineau, Quebec, Canada, J8V 2P5
      • Local Institution
    • Laval, Quebec, Canada, H7T 2P5
      • Local Institution
    • Sherbrooke, Quebec, Canada, J1G 5K2
      • Local Institution
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4P 0W5
      • Local Institution
• France
  • Besancon Cedex, France, 25030
    • Local Institution
  • Montpellier Cedex 5, France, 34295
    • Local Institution
  • Nantes, France, 44093
    • Local Institution
  • Valenciennes, France, 59300
    • Local Institution
• Hungary
  • Balatonfured, Hungary, 8230
    • Local Institution
  • Budapest, Hungary, 1083
    • Local Institution
  • Budapest, Hungary, 1212
    • Local Institution
  • Budapest, Hungary, 1041
    • Local Institution
  • Szentes, Hungary, 6600
    • Local Institution
  • Zalaegerszeg-Pozva, Hungary, 8900
    • Local Institution
• India
  • Hariyana, India, 132001
    • Local Institution
  • Mumbai, India, 400007
    • Local Institution
  • Pune, India, 411011
    • Local Institution
  • Pune, India, 411 030
    • Local Institution
  • Pune, India, 411037
    • Local Institution
  • Vellore, India, 632004
    • Local Institution
  • Madhya Pradesh
    • Indore, Madhya Pradesh, India, 452001
      • Local Institution
• Mexico
  • Aguascalientes, Mexico, 20230
    • Local Institution
  • Aguascalientes, Mexico, 20127
    • Local Institution
  • Mexico City, Mexico, 06700
    • Local Institution
  • Veracruz, Mexico, 91700
    • Local Institution
  • Distrito Federal
    • Ciudad De Mexico, Distrito Federal, Mexico, 14000
      • Local Institution
  • Jalisco
    • Zapopan, Jal., Jalisco, Mexico, 45150
      • Local Institution
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64710
      • Local Institution
    • Monterrey, Nuevo Leon, Mexico, 64060
      • Local Institution
    • Monterrey, Nuevo Leon, Mexico, 64240
      • Local Institution
    • Monterrrey, Nuevo Leon, Mexico, 64700
      • Local Institution
• Poland
  • Elblag, Poland, 82-300
    • Local Institution
  • Gdansk, Poland, 80-286
    • Local Institution
  • Krakow, Poland, 30-510
    • Local Institution
  • Lodz, Poland, 90-153
    • Local Institution
  • Lublin, Poland, 20-950
    • Local Institution
  • Sopot, Poland, 81-756
    • Local Institution
  • Szczecin, Poland, 71-455
    • Local Institution
  • Wroclaw, Poland, 50-088
    • Local Institution
  • Zabrze, Poland, 41-800
    • Local Institution
• Russian Federation
  • Kursk, Russian Federation, 305035
    • Local Institution
  • Saint-Petersburg, Russian Federation, 191015
    • Local Institution
  • Saratov, Russian Federation, 410031
    • Local Institution
  • Smolensk, Russian Federation, 214018
    • Local Institution
  • St Petersburg, Russian Federation, 198013
    • Local Institution
  • St. Petersburg, Russian Federation, 195257
    • Local Institution
  • St. Petersburg, Russian Federation, 194156
    • Local Institution
  • St.Petersburg, Russian Federation, 197022
    • Local Institution
  • Yaroslaval, Russian Federation, 150062
    • Local Institution
• South Africa
  • Gauteng
    • Parktown, Gauteng, South Africa, 2193
      • Local Institution
  • Kwa Zulu Natal
    • Durban, Kwa Zulu Natal, South Africa, 4001
      • Local Institution
    • Umhlanga Rocks, Kwa Zulu Natal, South Africa, 4319
      • Local Institution
  • Western Cape
    • Goodwood, Western Cape, South Africa, 7460
      • Local Institution
    • Tygerberg, Western Cape, South Africa, 7505
      • Local Institution
• United Kingdom
  • Cleveland
    • Middlesborough, Cleveland, United Kingdom, TS4 3BW
      • Local Institution
  • Greater Manchester
    • Salford, Greater Manchester, United Kingdom, M6 8HD
      • Local Institution
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE4 6BE
      • Local Institution
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B9 5SS
      • Local Institution
  • Yorkshire
    • Sheffield, Yorkshire, United Kingdom, S5 7AU
      • Local Institution
• United States
  • Arizona
    • Tempe, Arizona, United States, 85282
      • Clinical Research Advantage, Inc
  • California
    • Fresno, California, United States, 93720
      • Valley Research
    • Lomita, California, United States, 90717
      • Torrance-Lomita Medical Center
    • Northridge, California, United States, 91325
      • Diabetes Medical Center of California
    • San Diego, California, United States, 92117
      • Ritchken & First M.D.'S
    • Spring Valley, California, United States, 91978
      • Encompass Clinical Research
  • Florida
    • Altamonte Springs, Florida, United States, 32701
      • Central Florida Clinical Trials, Inc.
    • Chipley, Florida, United States, 32428
      • Family Care Associates Of Nw Florida
    • Marianna, Florida, United States, 32446
      • Panhandle Family Care Assoc. & Coastal Palms Res. Grp Inc.
  • Georgia
    • Roswell, Georgia, United States, 30076
      • Endocrine Research Solutions, Inc.
  • Mississippi
    • Rolling Fork, Mississippi, United States, 39159
      • Danny W. Jackson P.A.
  • New York
    • West Seneca, New York, United States, 14224
      • Southgate Medical Group
  • South Carolina
    • Taylors, South Carolina, United States, 29687
      • Southeastern Research Associates, Inc.
  • Texas
    • Houston, Texas, United States, 77081
      • Texas Center for Drug Development
    • San Antonio, Texas, United States, 78229
      • Dgd Research, Inc.
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53209
      • Aurora Advanced Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Change From Baseline in A1C Levels (Last Observation Carried Forward [LOCF])	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	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Meal Tolerance Test (MTT)	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	Baseline to Week 24
Change From Baseline in 120-minute PPG Values During an MTT	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.	Baseline to Week 24
Change From Baseline in Fasting Plasma Glucose Values		Baseline to Week 24
Percentage of Participants Achieving a Therapeutic Glycemic Response	Therapeutic glycemic response is defined as an A1C<7%. Significance was not interpreted with a p value.	Baseline to Week 24
Change From Baseline in Mean Total Daily Dose of Insulin (MTDDI) (LOCF)	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.	Baseline to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Abnormal Changes From Baseline in Electrocardiogram (ECG) Results	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.	Baseline to Week 52
Shift in Absolute Lymphocyte Counts From Baseline to Selected Visits (LOCF)	Absolute lymphocyte count=value*10^3 c/uL	Baseline and Weeks 24 and 52
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	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.	Baseline to Week 52, continuously
Mean Changes From Baseline in Systolic and Diastolic Blood Pressure Readings		Baseline to Weeks 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, and 52
Mean Changes From Baseline in Heart Rate		Baseline to Weeks 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, and 52
Shift in Platelet Counts From Baseline to Selected Visits (LOCF)	Platelet count=value*10^9 c/L	Baseline and Weeks 24 and 52
Number of Participants With Marked Laboratory Abnormalities During the 24-Week ST + 52-Week LT Treatment Period	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.	Baseline and during and up to 14 days after last dose of study drug (in Week 52)
Percentage of Participants With Reported and Confirmed Hypoglycemia	Confirmed hypoglycemia=fingerstick glucose measurement of ≤50 mg/dL with associated symptoms/	Baseline to Week 52

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• 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.
• Cook W, Minervini G, Bryzinski B, Hirshberg B. Saxagliptin efficacy and safety in patients with type 2 diabetes mellitus stratified by cardiovascular disease history and cardiovascular risk factors: analysis of 3 clinical trials. Postgrad Med. 2014 Oct;126(6):19-32. doi: 10.3810/pgm.2014.10.2818.
• Barnett AH, Charbonnel B, Li J, Donovan M, Fleming D, Iqbal N. Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clin Drug Investig. 2013 Oct;33(10):707-17. doi: 10.1007/s40261-013-0107-8.
• Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012 Apr;28(4):513-23. doi: 10.1185/03007995.2012.665046. Epub 2012 Mar 1.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: September 22, 2008
• First Submitted That Met QC Criteria: September 22, 2008
• First Posted (Estimate): September 23, 2008

Study Record Updates

• Last Update Posted (Estimate): June 1, 2015
• Last Update Submitted That Met QC Criteria: May 8, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Insulin; Insulin, Globin Zinc; Saxagliptin
• Other Study ID Numbers: CV181-057; Eudract-2008-001089-10