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Bioequivalence Study of Saxagliptin and Glucophage Combination Formulations in Healthy Subjects (B)

This study has been completed.
Sponsor:
Collaborator:
AstraZeneca
Information provided by:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00897390
First received: May 8, 2009
Last updated: February 22, 2011
Last verified: December 2010
History of Changes
  Purpose

To demonstrate bioequivalence of a 2.5 mg saxagliptin/1000 mg metformin (glucophage) immediate release (IR) fixed dose combination (FDC) tablet to the 2.5 mg saxagliptin tablet and 1000 mg metformin IR tablet co-administered to healthy subjects in a fasted and in a fed state.


Condition Intervention Phase
Type 2 Diabetes Mellitus
 Drug: Saxagliptin
Drug: Metformin IR (glucophage)
Drug: Saxagliptin + Metformin IR (FDC)
 Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: Bioequivalence Study of the Fixed Dose Combination of 2.5 mg Saxagliptin and 1000 mg Metformin Immediate Release (IR) Tablet Relative to 2.5 mg Saxagliptin Tablet and 1000 mg Metformin IR Tablet Co-administered to Healthy Subjects in a Fasted and in a Fed State

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.

  • Saxagliptin PK Parameter Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUC[0-T]) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.

  • Saxagliptin PK Parameter Maximum Observed Plasma Concentration (Cmax) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.

  • Saxagliptin PK Parameter Plasma Terminal Half-life (T-HALF) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.

  • Saxagliptin PK Parameter Time of Maximum Observed Plasma Concentration (Tmax) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.

  • Metformin PK Parameter AUC(INF) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of metformin were derived from plasma concentration versus time data.

  • Metformin PK Parameter AUC(0-T) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of metformin were derived from plasma concentration versus time data.

  • Metformin PK Parameter Cmax [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of metformin were derived from plasma concentration versus time data.

  • Metformin PK Parameter T-HALF [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of metformin were derived from plasma concentration versus time data.

  • Metformin PK Parameter Tmax [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of metformin were derived from plasma concentration versus time data.


Secondary Outcome Measures:
  • BMS-510849 PK Parameter AUC(INF) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.

  • BMS-510849 PK Parameter AUC(0-T) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.

  • BMS-510849 PK Parameter Cmax [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.

  • BMS-510849 PK Parameter T-Half [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from their respective plasma concentration versus time data.

  • BMS-510849 PK Parameter T-Max [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
    Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.

  • Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuations Due to AEs [ Time Frame: AEs collected from Day 1/Period 1 through study discharge (study duration: approximately 45 days). SAEs collected from date of written consent until 30 days post discontinuation of dosing or subject's participation in the study. ] [ Designated as safety issue: Yes ]
    An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient or clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An SAE is 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, or is an important medical event.

  • AEs of Special Interest [ Time Frame: AEs collected from Day 1/Period 1 through study discharge (study duration: approximately 45 days). ] [ Designated as safety issue: Yes ]
    See Outcome Measure 16 for a definition of AEs. AEs of clinical interest for saxagliptin were defined as those relating to the following:skin disorders, infection-related AEs (system organ class [SOC]: Infections and Infestations), thrombocytopenia, lymphopenia, hypoglycemia, cardiovascular AEs indicative of acute cardiovascular events, localized edema, fractures, pancreatitis, and AEs of hypersensitivity.

  • Number of Participants With Marked Laboratory Abnormalities (MA) [ Time Frame: Within 21 days of study Day 1, Days 1-3 of Periods 1, 2, 3, and 4. ] [ Designated as safety issue: Yes ]
    Laboratory abnormalities=any result that is clinically significant, met the definition of an SAE, required discontinuation or interruption of study drug, or required specific corrective therapy. Upper normal (UN)/lower normal (LN) values: leukocytes UN, 11.40x10^3 c/uL; absolute neutrophils/bands LN, 1.500x10^3 c/uL; aspartate aminotransferase UN, 48 U/L; alanine aminotransferase UN, 67 U/L; blood urea nitrogen UN, 20.0 mg/dL; creatine kinase UN, 350 U/L; lactate dehydrogenase UN, 249 U/L.

  • Number of Participants With Marked Urinalysis Abnormalities [ Time Frame: Within 21 days of study Day 1, Days 1-3 of Periods 1, 2, 3, and 4. ] [ Designated as safety issue: Yes ]
    Protein, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). Glucose, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). Blood, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). White Blood Cell (WBC), Urine Abnormality: if value >= 2+ (or if pretreatment value >= 2+, then >= 4+). Red Blood Cell (RBC), Urine Abnormality: if value >= 2+ (or if pretreatment value >= 2+, then >= 4+). (The '+' is a normal lab result and refers to the magnitude of the finding.)

  • Electrocardiogram (ECG), Vital Sign, and Physical Finding Abnormalities [ Time Frame: At Screening (within 21 days of Study Day 1), Day -1 of Period 1 (ECG and Physical only), Day 1 of Periods 1-4 (Vitals only), at Study Discharge (Day 3 of Period 4) or Discontinuation ] [ Designated as safety issue: Yes ]
    12-lead Electrocardiogram (ECG), Vital Sign (body temperature, respiratory rate, seated blood pressure and heart rate), and Physical Finding Abnormalities reported by investigator as AEs.


Enrollment: 24
Study Start Date: June 2009
Study Completion Date: July 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Arm A
Co-administration of single oral doses of a 2.5 mg tablet of saxagliptin and a 1000 mg tablet of metformin IR under fasted conditions
 Drug: Saxagliptin
Tablet, Oral, 2.5 mg, Once Daily, 1 week
Other Name: Onglyza
Drug: Metformin IR (glucophage)
Tablets, Oral, 1000 mg, Once Daily, 1 week
Other Name: Glucophage
Arm B
Single oral dose of a FDC tablet consisting of 2.5 mg saxagliptin/ 1000 mg metformin IR under fasted conditions
 Drug: Saxagliptin + Metformin IR (FDC)
Tablet, Oral, Saxagliptin 2.5 mg + metformin IR 1000 mg, Once Daily, 1 Week
Other Names:
  • Onglyza
  • Glucophage
Arm C
Co-administration of single oral doses of a 2.5 mg tablet of saxagliptin and a 1000 mg tablet of metformin IR under fed conditions with a standard meal
 Drug: Saxagliptin
Tablet, Oral, 2.5 mg, Once Daily, 1 week
Other Name: Onglyza
Drug: Metformin IR (glucophage)
Tablets, Oral, 1000 mg, Once Daily, 1 week
Other Name: Glucophage
Arm D
Single oral dose of a FDC tablet consisting of 2.5 mg saxagliptin/ 1000 mg metformin IR under fed conditions with a standard meal
 Drug: Saxagliptin + Metformin IR (FDC)
Tablet, Oral, Saxagliptin 2.5 mg + metformin IR 1000 mg, Once Daily, 1 Week
Other Names:
  • Onglyza
  • Glucophage

  Eligibility

Ages Eligible for Study:   19 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Men and women ages 19 to 45 inclusive
  • Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations
  • Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive. BMI = weight (kg)/ [height (m)]2

Exclusion Criteria:

  • Women of child-bearing potential (WOCBP) who are unwilling or unable to use acceptable barrier methods (condoms and spermicides) to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of investigational product
  • Any significant acute or chronic medical illness
  • Current or recent (within 3 months) gastrointestinal disease
  • Any major surgery within 4 weeks of study drug administration
  • History of allergy to Dipeptidyl peptidase 4 (DPP4) inhibitor or related compounds
  • History of allergy or intolerance to metformin or other similar acting agents
  • Prior exposure to saxagliptin
  • Prior exposure to metformin within 3 months of study drug administration
  • Estimated creatinine clearance (Clcr) of < 80ml/min using the Cockcroft Gault formula
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00897390

Locations
United States, Nebraska
Mds Pharma Services
Lincoln, Nebraska, United States, 68502
Sponsors and Collaborators
Bristol-Myers Squibb
AstraZeneca
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
BMS Clinical Trials Disclosure  This link exits the ClinicalTrials.gov site
Investigator Inquiry form  This link exits the ClinicalTrials.gov site
For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm  This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party: Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00897390     History of Changes
Other Study ID Numbers: CV181-092
Study First Received: May 8, 2009
Results First Received: August 26, 2010
Last Updated: February 22, 2011
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
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 19, 2013