Bioequivalence Study of Fixed-dose Combinations and Coadministered Individual Tablets of Saxagliptin/Metformin-Brazil

Bioequivalence Study of Fixed Dose Combinations of Saxagliptin/Metformin Extended Release (XR) Relative to Co-administration of the Individual Components in Healthy Subjects in the Fasted and Fed States

To demonstrate the bioequivalence of saxagliptin and metformin in a saxagliptin, 5-mg/metformin extended-release (XR), 500-mg, fixed-dose combination (FDC) tablet with saxagliptin, 5-mg and metformin, 500-mg XR tablets administered together in both the fasted and fed states. In addition, to demonstrate the bioequivalence of saxagliptin and metformin in a saxagliptin, 5-mg/metformin XR, 1000-mg, FDC tablet with saxagliptin, 5-mg and metformin, 1000-mg XR tablets administered together in both the fasted and fed states.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Saxagliptin/metformin fixed-dose combination (FDC); Drug: Saxagliptin; Drug: Metformin extended-release (XR); Drug: Saxagliptin/Metformin FDC; Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 13073
      • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Healthy men and women
• women of childbearing potential who are using acceptable method of contraception
• Women who are not pregnant or nursing
• Body Mass Index (BMI) of 18 to 29.9 kg/m^2, inclusive. BMI=weight(kg)/height(m)^2.

Key Exclusion Criteria:

• Any significant acute or chronic medical illness.
• History of gastrointestinal (GI) disease
• Major surgery within 4 weeks of study drug administration
• Any GI surgery that could impact study drug absorption
• Donation of blood or plasma to a blood bank or in a clinical study (except a screening visit) within the 6 months of study drug administration.
• Blood transfusion within 3 months of study drug administration for women and within 2 months for men
• Inability to be venipunctured and/or tolerate venous access
• Current smoker or recent (within 1 month) history of regular tobacco use
• Recent (within 6 months of study drug administration) drug or alcohol abuse
• Participation in a bioequivalence study within the last 6 months of study drug administration
• Estimated creatinine clearance of <80 mL/min using Cockcroft-Gault formula
• History of allergy to drug class or related compounds
• History of allergy to metformin or other similar acting agents
• History of any significant drug allergy

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Treatments A,B/B,A; Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg, tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fasted state (Treatment A).	Drug: Saxagliptin/metformin fixed-dose combination (FDC); Tablet, oral, 5 mg/500 mg FDC, once on Day 1 only, 1 day; Other Names: Onglyza/Glucophage extended release (XR); Drug: Saxagliptin; Tablet, oral, 5 mg, once on Day 1 only, 1 day; Other Names: Onglyza; Drug: Metformin extended-release (XR); Tablet, oral, 500 mg, once on Day 1 only, 1 day; Other Names: Glifage XR
Experimental: Arm 2: Treatments C,D/D,C; Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metforminXR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fed state (Treatment C).	Drug: Saxagliptin/metformin fixed-dose combination (FDC); Tablet, oral, 5 mg/500 mg FDC, once on Day 1 only, 1 day; Other Names: Onglyza/Glucophage extended release (XR); Drug: Saxagliptin; Tablet, oral, 5 mg, once on Day 1 only, 1 day; Other Names: Onglyza; Drug: Metformin extended-release (XR); Tablet, oral, 500 mg, once on Day 1 only, 1 day; Other Names: Glifage XR
Experimental: Arm 3: Treatments E, F/F,E; Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg fixed-dose combination (FDC), in the fasted state (Treatment E), followed by a washout period of at least 7 days. Participants received single oral doses of saxagliptin, 5-mg and metformin extended-release (XR), 1000-mg tablets together in the fasted state (Treatment F). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5- mg and metformin XR, 1000-mg tablets together in the fasted state (Treatment F), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg FDC, in the fasted state (Treatment E).	Drug: Saxagliptin; Tablet, oral, 5 mg, once on Day 1 only, 1 day; Other Names: Onglyza; Drug: Saxagliptin/Metformin FDC; Tablet, Oral, 5 mg/1000 mg FDC, once on Day 1 only, 1 day; Other Names: Onglyza/Glucophage XR; Drug: Metformin; Tablet, oral, 1000 mg, once on Day 1 only, 1 day; Other Names: Glifage XR
Experimental: Arm 4: Treatments G,H/H,G; Period 1: Participants received a single oral dose of saxagliptin , 5 mg/metformin, 1000 mg fixed-dose combination (FDC), in the fed state (Treatment G), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg and metformin extended-release (XR), 1000-mg tablets together in the fed state (Treatment H). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 1000-mg tablets together in the fed state (Treatment H), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg FDC, in the fed state (Treatment G).	Drug: Saxagliptin; Tablet, oral, 5 mg, once on Day 1 only, 1 day; Other Names: Onglyza; Drug: Saxagliptin/Metformin FDC; Tablet, Oral, 5 mg/1000 mg FDC, once on Day 1 only, 1 day; Other Names: Onglyza/Glucophage XR; Drug: Metformin; Tablet, oral, 1000 mg, once on Day 1 only, 1 day; Other Names: Glifage XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Concentrations (Cmax) of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets		Days 1, 2, and 3 of Periods 1 and 2
AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets	AUC=Area under the concentration-time curve	Days 1, 2, and 3 of Periods 1 and 2
AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) for Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets	AUC=Area Under the Concentration-time Curve	Days 1, 2, and 3 of Periods 1 and 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Death as Outcome and Serious Adverse Events (SAEs)	SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.	Continuously, from screening through Day 1 to within 30 days of drug discontinuation on Day 1

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: May 16, 2011
• First Submitted That Met QC Criteria: June 1, 2011
• First Posted (Estimate): June 3, 2011

Study Record Updates

• Last Update Posted (Estimate): May 8, 2015
• Last Update Submitted That Met QC Criteria: April 21, 2015
• Last Verified: April 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; Metformin; Saxagliptin
• Other Study ID Numbers: CV181-162