Clinical trial NCT03216278: The Purpose of the Study is to Compare Two Fixed Dose Combination Tablets of Dapagliflozin/Metformin XR in Healthy Subjects Under Fasting and Fed Conditions
Official title: A Two Part Bioequivalence Study to Compare Two Fixed Dose Combination (FDC) Tablets of Dapagliflozin/Metformin XR 5/500 mg (Part 1) and 10/1000 mg (Part 2) Manufactured at Two Different Plants (Humacao, Puerto Rico and Mount Vernon, US) in Healthy Subjects Under Fasting and Fed Conditions
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects in Fasted and Fed State
Keywords: healthy,
fasted,
fed
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-07-13
Enrollment: 284
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This is a bioequivalence study of two doses of the dapagliflozin/metformin XR tablet manufactured at two different plants.

Detailed description: This is a two part, open-label, randomized, 4-period, 4-treatment (per study part) crossover study in healthy subjects (males and females of non-childbearing potential), performed at a single study center, conducted to establish the bioequivalence of 2 strengths of dapagliflozin/metformin XR tablets manufactured at two different plants.

Eligibility criteria: Inclusion criteria

1. Provision of signed and dated, written informed consent prior to any study-specific procedures
2. Healthy male and female subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture
3. Females must have a negative serum pregnancy test at screening and negative urine pregnancy test on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria:

   * Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post menopausal range
   * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation
4. Have a body mass index (BMI) between 18.50 and 24.90 kg/m2 inclusive \[15% variance on the upper limit is permitted (i.e., up to 28.63 kg/m2)\] and weigh between 50 and 100 kg inclusive at screening

Exclusion Criteria

1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study
2. History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs
3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP
4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator
5. Any clinically significant abnormal findings in vital signs, as judged by the investigator
6. Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) as judged by the investigator
7. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody
8. Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) \>3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) \>3x ULN
9. Total bilirubin \>2.0 mg/dL (34.2 µmol/L)
10. Known or suspected history of drug abuse, as judged by the investigator
11. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose.

    Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.
12. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening
13. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to dapagliflozin/metformin XR.
14. Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
15. Positive screen for drugs of abuse or alcohol at screening or on each admission to the study center
16. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP
17. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, vitamins and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life Note: Hormonal replacement therapy is allowed for females.
18. Known or suspected history of alcohol abuse or excessive intake of alcohol, as judged by the investigator
19. Inclusion of any AstraZeneca or study site employee or their close relatives
20. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements
21. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order

Primary outcomes:
measure: Part 1 - Area under the plasma concentration versus time curve (AUC) for each analyte and each state
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Part 2 - Area under the plasma concentration versus time curve (AUC) for each analyte and each state
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Part 1 - Peak Plasma Concentration (Cmax) for each analyte and each state
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Part 2 - Peak Plasma Concentration (Cmax) for each analyte and each state
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
Secondary outcomes:
measure: Area under plasma concentration - time curve from time zero to infinity (AUC)
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Adverse events
timeFrame: 10,5 weeks
measure: Blood pressure
timeFrame: 10,5 weeks
measure: Electrocardiogram (ECG)
timeFrame: 10,5 weeks
measure: Time to reach maximum plasma concentration (tmax)
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Terminal elimination rate constant (λz)
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Apparent total body clearance after extravascular administration (CL/F)
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
timeFrame: Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times
measure: Laboratory assessments - hematology
timeFrame: 10,5 weeks
measure: Heart rate
timeFrame: 10,5 weeks
measure: Laboratory assessments - clinical chemistry
timeFrame: 10,5 weeks
measure: Laboratory assessments - urinalysis
timeFrame: 10,5 weeks
Other outcomes:
Locations:
city: Aparecida de Goiania
country: Brazil
facility: Research Site
Study officials:
References: