Bioequivalence Study of the Fixed Dose Combination of 5 mg Saxagliptin and 500 mg Metformin XR Tablet (Manufactured in Mt Vernon, IN) Relative to 5 mg Saxagliptin Tablet and 500 mg Metformin XR Tablet (Manufactured in Evansville, IN)

• ClinicalTrials.gov Identifier: NCT01192139
• Recruitment Status: Completed
• First Posted: August 31, 2010
• Results First Posted: May 17, 2011
• Last Update Posted: May 21, 2015
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

The purpose of this study is to demonstrate bioequivalence (BE) of a 5 mg saxagliptin/500 mg metformin extended release (XR) fixed-dose combination (FDC) tablet (manufactured in Mt Vernon, Indiana [IN]) to coadministered 5 mg saxagliptin and 500 mg metformin XR tablet (manufactured in Evansville, IN) in fed healthy subjects.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus	Drug: saxagliptin; Drug: metformin XR; Drug: saxagliptin + metformin XR (FDC tablet)	Phase 1

Detailed Description:

This study is designed to evaluate if the FDC tablet of 5 mg saxagliptin/500 mg metformin extended release (manufactured in Mt Vernon, Indiana) is bioequivalent to the coadministered 5 mg saxagliptin and 500 mg metformin XR tablet (manufactured in Evansville, Indiana)

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: Bioequivalence Study of the Fixed Dose Combination of 5 mg Saxagliptin and 500 mg Metformin XR Tablet (Manufactured in Mt Vernon, IN) Relative to 5 mg Saxagliptin Tablet and 500 mg Metformin XR Tablet (Manufactured in Evansville, IN) Coadministered to Healthy Subjects in a Fed Condition
• Study Start Date: November 2009
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: December 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: 5 mg saxagliptin + a single 500 mg metformin XR tablet	Drug: saxagliptin; Tablets, Oral, 5 mg, once daily, Single dose; Other Name: Onglyza; Drug: metformin XR; Tablets, Oral, 500 mg. once daily, Single dose; Other Name: Glucophage XR
Experimental: FDC tablet (5 mg saxagliptin + 500 mg metformin XR) (Fed); under fed state	Drug: saxagliptin + metformin XR (FDC tablet); Tablet, Oral, (saxagliptin 5 mg)(metformin XR 500 mg), once daily, Single dose
Experimental: FDC tablet (5 mg saxagliptin + 500 mg metformin XR) (Fasting); under fasted state	Drug: saxagliptin + metformin XR (FDC tablet); Tablet, Oral, (saxagliptin 5 mg)(metformin XR 500 mg), once daily, Single dose

Outcome Measures

Primary Outcome Measures :

1. Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
   Area under the plasma concentration versus time curve from time 0 extrapolated to infinity; calculated as AUC0-t [calculated using the linear trapezoidal rule] + Ct/Kel, where Ct was the last measurable concentration and Kel was the terminal rate constant
2. Saxagliptin Observed Maximum Plasma Concentration (Cmax) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
3. Metformin AUC(0-inf) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
   Area under the plasma concentration versus time curve from time 0 extrapolated to infinity; calculated as AUC0-t [calculated using the linear trapezoidal rule] + Ct/Kel, where Ct was the last measurable concentration and Kel was the terminal rate constant
4. Metformin Cmax [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Secondary Outcome Measures :

1. Saxagliptin Terminal Half-life (T1/2) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
   terminal half life; calculated as ln(2)/Kel
2. Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
   Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (Ct), calculated using the linear trapezoidal rule.
3. Time to Achieve the Observed Maximum Saxagliptin Plasma Concentration (Tmax) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
4. Saxagliptin Fraction of AUC(0-inf) Contributed by AUC(0-t) (AUC[0-t]/AUC[0-inf]) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
5. Active Metabolite BMS-510849 AUC(0-inf) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
   Area under the plasma concentration versus time curve from time 0 extrapolated to infinity; calculated as AUC0-t [calculated using the linear trapezoidal rule] + Ct/Kel, where Ct was the last measurable concentration and Kel was the terminal rate constant
6. Active Metabolite BMS-510849 AUC(0-t) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
   Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (Ct), calculated using the linear trapezoidal rule.
7. Active Metabolite BMS-510849 Cmax [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
8. Active Metabolite BMS-510849 T1/2 [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
   terminal half life; calculated as ln(2)/Kel
9. Active Metabolite BMS-510849 Tmax [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
10. Active Metabolite BMS-510849 AUC(0-t)/AUC(0-inf) [ Time Frame: Period 1 (samples taken before dosing, and at 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]
11. Metformin AUC(0-t) [ Time Frame: Period 1 (samples taken before dosing, and at 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]
    Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (Ct), calculated using the linear trapezoidal rule.
12. Metformin T1/2 [ Time Frame: Period 1 (before dosing, 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]
    terminal half life; calculated as ln(2)/Kel
13. Metformin Tmax [ Time Frame: Periods 1, 2, and 3 (before dosing, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]
14. Metformin Fraction of AUC(0-inf) Contributed by AUC(0-t)(AUC[0-t]/AUC[0-inf]) [ Time Frame: Period 1 (before dosing, 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]
15. Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) [ Time Frame: AEs: from initiation of study drug administration on Day 1/Period 1 through study discharge Day 3/Period 3. SAEs: from date of written consent until 30 days after discontinuation of dosing or participation in study if last scheduled visit occurred later. ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.
16. Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and Electrocardiogram (ECG) Abnormalities [ Time Frame: From Day 1 of Period 1 through Day 3 of Period 3 (study discharge) ]
    Abnormalities considered by the investigator to be clinically significant and/or reported as an AE.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy male and female subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiogram (ECG), and clinical laboratory determinations
• Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive
• Ages 18 to 45, inclusive

Exclusion Criteria:

• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations beyond what is consistent with the target population
• Major surgical procedure within 4 weeks prior to randomization
• Positive serology test for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
• Clinically significant history or presence of any of the following conditions: heart, liver, or kidney disease, neurologic or psychiatric disease
• History of gastrointestinal disease within the past 3 months
• Any clinically significant medical condition that could potentially affect your participation in the study and/or personal well-being, as judged by the investigator
• Donated blood or blood products to a blood bank, blood transfusion or participated in a clinical study (except a screening visit) requiring withdrawal of blood within 4 weeks prior to randomization
• Unable to tolerate oral and/or intravenous (IV) medications
• Unable to tolerate the puncturing of veins for drawing of blood
• Known allergy or hypersensitivity to any component of the study medication
• History of any significant drug allergies (such as anaphylaxis or hepatotoxicity)
• Used any prescription drugs or over the counter products to control acid (for example, Prevacid, Mylanta or Rolaids) within 4 weeks prior to randomization
• Used any other drugs including over the counter medications and herbal preparations within 1 week prior to randomization
• Taken any investigational drug or placebo (inactive drug) within 4 weeks prior to randomization

Contacts and Locations

Locations

United States, Texas

Ppd Development, Lp

Austin, Texas, United States, 78744

Sponsors and Collaborators

AstraZeneca

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

More Information

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

Boulton DW, Smith CH, Li L, Huang J, Tang A, LaCreta FP. Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects. Clin Drug Investig. 2011;31(9):619-30. doi: 10.2165/11590290-000000000-00000.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01192139
• Other Study ID Numbers: CV181-111
• First Posted: August 31, 2010
• Results First Posted: May 17, 2011
• Last Update Posted: May 21, 2015
• Last Verified: May 2015

Additional relevant MeSH terms:

Metformin; Saxagliptin; 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