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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00899470
First received: May 8, 2009
Last updated: June 4, 2014
Last verified: June 2014
  Purpose

To demonstrate bioequivalence of a 2.5 mg saxagliptin/500 mg metformin (glucophage) immediate release (IR) fixed dose combination (FDC) tablet to the 2.5 mg saxagliptin tablet and 500 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: Co-administration of Saxagliptin and Metformin IR, Fasted
Drug: Saxagliptin/Metformin, Fasting
Drug: Co-administration of Saxagliptin and Metformin IR, Fed
Drug: Saxagliptin/Metformin, Fed
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 500 mg Metformin Immediate Release (IR) Tablet Relative to 2.5 mg Saxagliptin Tablet and 500 mg Metformin IR Tablet Co-administered to Healthy Subjects in a Fasted and in a Fed State

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Saxagliptin Mean Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    Cmax of single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg), or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.

  • Saxagliptin Mean Area Under the Plasma Concentration Time Curve From Time Zero To Time of Last Quantifiable Concentration (AUC [0-T]} [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    AUC (0-T) for single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg), or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.

  • Saxagliptin Mean Area Under the Plasma Concentration Time Curve From Time Zero To Infinity (AUC [0-INF]) [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    AUC (0-T) for single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg), or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.

  • Saxagliptin Mean Plasma Half-life (T-half) and Mean Time of Maximum Observed Plasma Concentration (T-max) [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    T-half and T-max for single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg) or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.

  • Metformin Mean Cmax [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    Cmax of single-dose metformin IR (500 mg), either coadministered with saxagliptin (2.5 mg) or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.

  • Metformin Mean AUC (0-T) [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    AUC (0-T for single-dose metformin (500 mg), either coadministered with saxagliptin (2.5 mg) or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.

  • Metformin Mean AUC(0-INF) [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    AUC (0-INF) for single-dose metformin IR (500 mg), either coadministered with saxagliptin (2.5 mg) or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.

  • Metformin T-half and T-max [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    T-half and T-max for single-dose metformin IR (500 mg), either coadministered with saxagliptin (2.5 mg), or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions.


Secondary Outcome Measures:
  • BMS-510849 Mean Cmax [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    Cmax of the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administered as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions.

  • BMS-510849 Mean AUC (0-T) [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    AUC (0-T) for the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administration as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions.

  • BMS-510849 Mean AUC (0-INF) [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    AUC (0-T)= for the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administered as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions.

  • BMS-510849 Mean T-half and T-max [ Time Frame: Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr ] [ Designated as safety issue: No ]
    T-half and Tmax of the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administerd as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions.

  • Number of Participants With at Least 1 Adverse Event (AE), Death, Serious AE (SAE), or AEs Leading to Discontinuation [ Time Frame: From Day 1 through Day 45, including up to 56 days after last dose of study medication ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Laboratory Marked Abnormalities [ Time Frame: From Day 1 through Day 45, including up to 56 days after last dose of study medication ] [ Designated as safety issue: Yes ]
    High=greater than Upper Normal Limit (ULN), Low=lower than Lower Normal Limit (LLN). LLN/ULN= Leukocytes: <0.9 x LLN/ >1.2 x ULN; blood urea nitrogen (BUN): >1.1 x ULN; creatinine: >1.33 x BL; phosphorous (P): <0.75 x LLN/ >1.2 5 x ULN; creatinine kinase (CK): >1.5 x ULN; urine blood=use ≥2 x BL if value ≥2+ or BL1+

  • Number of Participants With Clinically Relevant Electrocardiogram (ECG) Abnormalities [ Time Frame: Period 1 Day 1, Period 2 Day 1, Period 3 Day 1, Period 4 Day 1, Period 4 Day 3 ] [ Designated as safety issue: Yes ]
    PR interval, QRS complex, width of QRS, QT interval, and QT corrected for heart rate adjusting for heart rate using either Bazett formula or Fridericia formula were measured. ECG abnormalities were judged to be of medical importance by the Investigator.

  • Number of Participants With Clinically Relevant Vital Sign Abnormalities [ Time Frame: Period 1 Day 1, Period 2 Day 1, Period 3 Day 1, Period 4 Day 1, Period 4 Day 3 ] [ Designated as safety issue: Yes ]
    Mean systolic and diastolic blood pressure, heart rate, respiration, and temperature were assessed.Vital sign abnormalities abnormalities were judged to be of medical importance by the Investigator.

  • Number of Participant With Clinically Relevant Physical Examination Abnormalities [ Time Frame: Screen, Period 1 Day -1, prior to discharge ] [ Designated as safety issue: Yes ]
    A physical examination was conducted which included height and weight measurements, from which the Body Mass Index was determined. Physical examination abnormalities were judged to be of medical importance by the Investigator.


Enrollment: 24
Study Start Date: June 2009
Study Completion Date: August 2009
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: S+ M, (fasted)> S/M (fed)> S/M (fasted)>S+M (fed)
Participants were randomized to receive oral co-administration of a 2.5 mg tablet of saxagliptin plus a 500 mg tablet of metformin immediate release (IR) under fasted conditions (S + M [fasted]) followed by a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions (S/M [fed]) followed by S/M under fasting conditions (S/M [fasted]) followed by S + M under fed conditions (S + M [fed])
Drug: Co-administration of Saxagliptin and Metformin IR, Fasted
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions
Other Name: Onglyza
Drug: Saxagliptin/Metformin, Fasting
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions
Other Names:
  • Onglyza
  • Glucophage
Drug: Co-administration of Saxagliptin and Metformin IR, Fed
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions
Drug: Saxagliptin/Metformin, Fed
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions
Experimental: S/M (fasted)> S+M (fasted)> S+M (fed)> S/M (fed)
Participants were randomized to receive S/M (fasted) followed by S + M (fasted) followed by S + M (fed) followed by S/M (fed)
Drug: Co-administration of Saxagliptin and Metformin IR, Fasted
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions
Other Name: Onglyza
Drug: Saxagliptin/Metformin, Fasting
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions
Other Names:
  • Onglyza
  • Glucophage
Drug: Co-administration of Saxagliptin and Metformin IR, Fed
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions
Drug: Saxagliptin/Metformin, Fed
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions
Experimental: S+M (fed)> S/M (fasted) >S/M (fed)> S+M (fasted)
Participants were randomized to receive S + M (fed) followed by S/M (fasted) followed by S/M (fed) followed by S+M (fasted)
Drug: Co-administration of Saxagliptin and Metformin IR, Fasted
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions
Other Name: Onglyza
Drug: Saxagliptin/Metformin, Fasting
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions
Other Names:
  • Onglyza
  • Glucophage
Drug: Co-administration of Saxagliptin and Metformin IR, Fed
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions
Drug: Saxagliptin/Metformin, Fed
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions
Experimental: S/M (fed)> S+M (fed)> S+M (fasted)> S/M (fasted)
Participants were randomized to receive S/M (fed) followed by S+M (fed) followed by S+M (fasted) followed by S/M (fasted)
Drug: Co-administration of Saxagliptin and Metformin IR, Fasted
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions
Other Name: Onglyza
Drug: Saxagliptin/Metformin, Fasting
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions
Other Names:
  • Onglyza
  • Glucophage
Drug: Co-administration of Saxagliptin and Metformin IR, Fed
Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions
Drug: Saxagliptin/Metformin, Fed
Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions

  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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00899470

Locations
United States, Nebraska
Mds Pharma Services
Lincoln, Nebraska, United States, 68502
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: NCT00899470     History of Changes
Other Study ID Numbers: CV181-081
Study First Received: May 8, 2009
Results First Received: December 21, 2010
Last Updated: June 4, 2014
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 July 22, 2014