Bioequivalence Study Coadministered to Healthy Subjects in the Fasted State

A Bioequivalence Study of Fixed-dose Combination Tablet of 5 Milligrams Saxagliptin/10 Milligrams Dapagliflozin Relative to Their Respective Individual Components Coadministered to Healthy Subjects in the Fasted State

The purpose of this study is to demonstrate bioequivalence of coadministered drugs on healthy subjects.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Saxagliptin

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed Informed Consent Form

   • Signed written informed consent must be obtained from the subjects in accordance with requirements of the study center's IRB or IEC before the initiation of any protocol-required procedures.

2. Target Population

   • Healthy subjects as determined by no clinically significant deviation from normal in medical history, psychiatric history, physical examination findings, vital sign measurements, 12-lead ECG measurements, physical measurements, and clinical laboratory test results.

3. Age and Reproductive Status

   • Males and females, ages 19 to 55 years, inclusive. To extent possible, the distribution of men and women between the sequences will be balanced
   • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.

   • Women must not be breastfeeding. d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs saxagliptin and dapagliflozin plus 5 half lives of study drug dapagliflozin (the longer half life between the 2 drugs; 3 days) for a total of 3 days following treatment completion.

     e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs saxagliptin and dapagliflozin plus 5 half lives of dapagliflozin (the longer half life between the 2 drugs; 3 days) for a total of 3 days following treatment completion.

     f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section

   Exclusion Criteria:

   • Any significant acute or chronic medical illness.
   • Current or recent (within 3 months of study drug administration) gastrointestinal disease that could impact upon the absorption of study drug
   • Any other sound medical, psychiatric, and/or social reason as determined by the investigator
   • Any major surgery within 4 weeks of study drug administration.
   • Any prior GI surgery including cholecystectomy (remote history of appendectomy will not be exclusionary).
   • Current, recent (within 3 months of study drug administration), or remote history of pancreatitis.
   • Donation of blood or plasma to a blood bank or in a clinical study (except at screening visit) within 4 weeks before study drug administration.
   • Blood transfusion within 4 weeks of study drug administration. h) Inability to tolerate oral medication.
   • Inability to be venipunctured performed and/or tolerate venous access.
   • Use of tobacco- or nicotine-containing products (including, but not limited to, cigarettes, pipes, e-cigarettes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months before check-in.
   • Drug or alcohol abuse (within 2 years of study drug administration) as defined in the Diagnostic and Statistical Manual of Mental Disorders - 4th Edition, Diagnostic Criteria for Drug and Alcohol Abuse History of glucose intolerance or diabetes mellitus.
   • For females, history of chronic or recurrent urinary tract infection (UTI) (defined as 3 occurrences per year) or UTI in the past 3 months. For males, any UTI within the previous 5 years that has not been thoroughly evaluated and for which an explanation is not clear.
   • History of recurrent (defined as 3 occurrences per year) or recent vulvovaginal mycotic infections.
   • Any other sound medical, psychiatric, and/or social reason as determined by the investigator.

   Physical and Laboratory Test Findings

   1. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECGs, or clinical laboratory determinations beyond what is consistent with the target population.
   2. Abnormal urinalysis at screening (may repeat once). If the urinalysis is abnormal on Day -1 of Period 1, continuation in the study is up to the investigator's discretion. The CRO medical monitor should be consulted.
   3. Glucosuria or hematoria at screening or Day -1 of Period 1, repeat is not permitted. d) A positive nicotine test (ie, cotinine).

   e) Abnormal liver function tests (alanine or aspartate aminotransferase [ALT or AST, respectively], or total bilirubin).

   f) Any of the following on 12-lead ECG prior to study drug administration, confirmed by repeat.

   i) PR ≥ 210 ms ii) QRS ≥ 120 ms iii) QT ≥ 500 ms iv) QTcF ≥ 450 ms g) Positive urine screen for drugs of abuse. h) Positive urine alcohol test. i) Positive blood screen for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV)-1 or HIV-2 antibodies at screening.

4. Allergies and Adverse Drug Reaction

   1. History of allergy or adverse reactions to DPP4 or SGLT inhibitors or related compounds.
   2. History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).

5. Other Exclusion Criteria

   1. Prisoners or subjects who are involuntarily incarcerated.
   2. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
   3. Inability to comply with restrictions and prohibited activities/treatments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment A; Single oral dose of saxagliptin tablet coadministered with dapagliflozin tablet	Drug: Dapagliflozin; Other Names: Farxiga in the United States; Forxiga in other countries; Drug: Saxagliptin; Other Names: Onglyza
Experimental: Treatment B; Single oral dose of FDC (fixed-dose combination) tablet	Drug: Dapagliflozin; Other Names: Farxiga in the United States; Forxiga in other countries; Drug: Saxagliptin; Other Names: Onglyza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Saxagliptin Maximum Observed Concentrations (Cmax)	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state	Day 1-3 (Period 1) and Day 8-10 (Period 2)
Dapagliflozin Maximum Observed Concentrations (Cmax)	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state	Day 1 to 3 (Period 1) and Day 8 to 10 (Period 2)
Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state	Day 1-3 (Period 1) and Day 8-10 (Period 2)
Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state	Day 1-3 (Period 1) and Day 8-10 (Period 2)
Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state	Day 1-3 (Period 1) and Day 8-10 (Period 2)
Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state	Day 1-3 (Period 1) and Day 8-10 (Period 2)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Michael Gartner, MD, Celerion

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: August 19, 2014
• First Submitted That Met QC Criteria: August 21, 2014
• First Posted (Estimate): August 22, 2014

Study Record Updates

• Last Update Posted (Estimate): April 27, 2016
• Last Update Submitted That Met QC Criteria: March 25, 2016
• Last Verified: March 1, 2016

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; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Dapagliflozin; Saxagliptin
• Other Study ID Numbers: CV181-364