Study Assessing Saxagliptin Treatment In Type 2 Diabetic Subjects Who Are Not Controlled With Metformin Alone

Study Description

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Brief Summary:

The purpose of this clinical research study is to learn whether Saxagliptin added to Metformin therapy is more effective than Metformin alone as a treatment for type 2 diabetic subjects who are not sufficiently controlled with Metformin alone

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: Saxagliptin + Metformin; Drug: Placebo + Metformin; Drug: Pioglitazone	Phase 3

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 pioglitizone added onto their blinded study medication

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1462 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	"A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial to Evaluate the Efficacy and Safety of BMS-477118 in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Alone"
Study Start Date :	August 2005
Actual Primary Completion Date :	October 2006
Actual Study Completion Date :	February 2010

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Saxagliptin + Metformin (A); Pioglitazone 15-45 mg (as needed for rescue)	Drug: Saxagliptin + Metformin; Tablets, Oral, 2.5 mg Saxagliptin (plus flexible metformin dose), Once daily (24 weeks ST, 42 months LT); Other Name: BMS-477118 Drug: Pioglitazone; Tablets, Oral, 15 - 45 mg (as needed for rescue)
Experimental: Saxagliptin + Metformin (B); Pioglitazone 15-45 mg (as needed for rescue)	Drug: Saxagliptin + Metformin; Tablets, Oral, 5 mg Saxagliptin (plus flexible metformin dose), Once daily (24 weeks ST, 42 months LT); Other Name: BMS-477118 Drug: Pioglitazone; Tablets, Oral, 15 - 45 mg (as needed for rescue)
Experimental: Saxagliptin + Metformin (C); Pioglitazone 15-45 mg (as needed for rescue)	Drug: Saxagliptin + Metformin; Tablets, Oral, 10 mg Saxagliptin (plus flexible metformin dose), Once daily (24 weeks ST, 42 months LT); Other Name: BMS-477118 Drug: Pioglitazone; Tablets, Oral, 15 - 45 mg (as needed for rescue)
Placebo Comparator: Placebo+ Metformin (D); Pioglitazone 15-45 mg (as needed for rescue)	Drug: Placebo + Metformin; Tablets, Oral, 0 mg, Once daily (24 weeks ST, 42 months LT) Drug: Pioglitazone; Tablets, Oral, 15 - 45 mg (as needed for rescue)

Outcome Measures

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Primary Outcome Measures :

1. Baseline and Change From Baseline in Hemoglobin A1c (A1C) at Week 24 [ Time Frame: Baseline, Week 24 ]
   Mean change from baseline is adjusted for baseline value.

Secondary Outcome Measures :

1. Baseline and Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [ Time Frame: Baseline, Week 24 ]
   Mean change from baseline is adjusted for baseline value.
2. Percentage of Participants Achieving Therapeutic Glycemic Response (A1C < 7.0%) at Week 24 [ Time Frame: Week 24 ]
3. Baseline and Change From Baseline at Week 24 in Postprandial Glucose (PPG) Area Under the Curve (AUC) [ Time Frame: Baseline, Week 24 ]
   Mean change from baseline is adjusted for baseline value.

Other Outcome Measures:

1. Overall Summary of Adverse Events During ST+LT Treatment Period [ Time Frame: AEs: up to last treatment day + 1 day or last visit day in the ST+LT period; SAEs: up to last treatment day + 30 days or last visit day + 30 days in the LT+ST period. Mean duration of exposure: 124, 118, 130, 95 wks respectively for 2.5mg, 5mg, 10 mg, pla ]
   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.
2. 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: 124, 118, 130, 95 weeks, respectively, for 2.5mg, 5mg, 10 mg, placebo. ]
   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.
3. 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 ]
4. 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 ]
5. 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 ]
6. 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 ]
7. 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 ]
8. 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 ]
9. 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 ]
10. 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 ]
11. 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 ]
12. 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 ]
13. Changes From Baseline in Systolic Blood Pressure During the ST + LT Period [ Time Frame: 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 ]
14. Changes From Baseline in Diastolic Blood Pressure During the ST + LT Period [ Time Frame: 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 ]
15. Changes From Baseline in Heart Rate During the ST + LT Period [ Time Frame: 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 ]
16. 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.
17. All Reported Hypoglycemic Adverse Events During the ST + LT Treatment Period [ Time Frame: AEs: up to last treatment day + 1 day or last visit day in the ST+LT period; SAEs: up to last treatment day + 30 days or last visit day + 30 days in the LT+ST period. Mean duration of exposure: 124, 118, 130, 95 wks respectively for 2.5mg, 5mg, 10 mg, pla ]
    Hypoglycemic Events are based upon the Saxagliptin Predefined List of Events, which are hypoglycemia, blood glucose decreased, and hypoglycemic unconsciousness.
18. Confirmed Hypoglycemia During the ST + LT Treatment Period [ Time Frame: AEs: up to last treatment day + 1 day or last visit day in the ST+LT period; SAEs: up to last treatment day + 30 days or last visit day + 30 days in the LT+ST period. Mean duration of exposure: 124, 118, 130, 95 wks respectively for 2.5mg, 5mg, 10 mg, pla ]
    'Confirmed' = recorded on the hypoglycemia AE case report form with a fingerstick glucose <= 50 mg/dL and associated symptoms.

Eligibility Criteria

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years to 77 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Type 2 diabetes mellitus requiring treatment with at least 1500 mg but not greater than 2550 mg of a maximum tolerated dose of Metformin therapy for at least 8 weeks prior to screening.
• HbA1c >= 7.0% and <= 10.0 %
• Body mass index <= 40 kg/m2
• Fasting C-peptide >= 1 ng/dL

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 females

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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Sponsors and Collaborators

AstraZeneca

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

BMS Clinical Trials Disclosure 

For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm 

Publications:

DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, Chen RS; Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984. Epub 2009 May 28.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Karyekar CS, Frederich R, Ravichandran S. Clinically relevant reductions in HbA1c without hypoglycaemia: results across four studies of saxagliptin. Int J Clin Pract. 2013 Aug;67(8):759-67. doi: 10.1111/ijcp.12212. Epub 2013 Jun 24.

Karyekar C, Donovan M, Allen E, Fleming D, Ravichandran S, Chen R. Efficacy and safety of saxagliptin combination therapy in US patients with type 2 diabetes. Postgrad Med. 2011 Jul;123(4):63-70. doi: 10.3810/pgm.2011.07.2305.

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT00121667 History of Changes
Other Study ID Numbers:	CV181-014
First Posted:	July 21, 2005
Results First Posted:	April 8, 2011
Last Update Posted:	April 29, 2015
Last Verified:	March 2015

Additional relevant MeSH terms:

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