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

• ClinicalTrials.gov Identifier: NCT00897390
• Recruitment Status: Completed
• First Posted: May 12, 2009
• Results First Posted: January 21, 2011
• Last Update Posted: May 21, 2015
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Type 2 Diabetes Mellitus	Drug: Saxagliptin; Drug: Metformin IR (glucophage); Drug: Saxagliptin + Metformin IR (FDC)	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (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
• Study Start Date: June 2009
• Actual Primary Completion Date: July 2009
• Actual Study Completion Date: July 2009

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
2. 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 ]
   Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
3. 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 ]
   Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
4. 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 ]
   Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
5. 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 ]
   Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
6. 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 ]
   Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
7. 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 ]
   Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
8. 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 ]
   Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
9. 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 ]
   Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
10. 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 ]
    Single-dose PK parameters of metformin were derived from plasma concentration versus time data.

Secondary Outcome Measures :

1. 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 ]
   Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
2. 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 ]
   Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
3. 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 ]
   Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
4. 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 ]
   Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from their respective plasma concentration versus time data.
5. 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 ]
   Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
6. 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. ]
   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.
7. AEs of Special Interest [ Time Frame: AEs collected from Day 1/Period 1 through study discharge (study duration: approximately 45 days). ]
   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.
8. 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. ]
   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.
9. 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. ]
   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.)
10. 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 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 19 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• 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

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

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

Upreti VV, Keung CF, Boulton DW, Chang M, Li L, Tang A, Hsiang BC, Quamina-Edghill D, Frevert EU, Lacreta FP. Bioequivalence of saxagliptin/metformin immediate release (IR) fixed-dose combination tablets and single-component saxagliptin and metformin IR tablets in healthy adult subjects. Clin Drug Investig. 2013 May;33(5):365-74. doi: 10.1007/s40261-013-0075-z.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00897390
• Other Study ID Numbers: CV181-092
• First Posted: May 12, 2009
• Results First Posted: January 21, 2011
• Last Update Posted: May 21, 2015
• Last Verified: May 2015

Additional relevant MeSH terms:

Diabetes Mellitus, Type 2; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; 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