A Study to Evaluate the Food Effect on Drug Availability, Pharmacokinetic (PK) Properties, Safety and Tolerability of Two Different Dose Combination Therapy of Saxagliptin/Dapagliflozin/Metformin Extended-release (XR) Against Individual Component Co-administration.

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT03169959
• Date of registration: 23/05/2017
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca
• Public title: A Study to Evaluate the Food Effect on Drug Availability, Pharmacokinetic (PK) Properties, Safety and Tolerability of Two Different Dose Combination Therapy of Saxagliptin/Dapagliflozin/Metformin Extended-release (XR) Against Individual Component Co-administration.
• Scientific title: A Randomised, 3-Period, 3-Treatment, Single-dose, Open-label, Single-center, Crossover Study to Assess the Fed-state Bioequivalence of a Triple Fixed-Combination Drug Product of 2.5 mg Saxagliptin / 5 mg Dapagliflozin / 1000 mg Metformin XR and 5 mg Saxagliptin / 10 mg Dapagliflozin / 1000 mg Metformin XR Relative to Individual Components (Onglyza® and XIGDUO® XR) Co-administered to Healthy Subjects
• Date of first enrolment: May 29, 2017
• Target sample size: 85
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03169959
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Crossover Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

United States

Key inclusion & exclusion criteria

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific
procedures.

2. Healthy male and/or female subjects aged 18 to 55 years with suitable veins for
cannulation or repeated venipuncture.

3. Female subject must have a negative serum pregnancy test (minimum sensitivity 25 IU/L
or equivalent units of human chorionic gonadotropin) at Screening and negative urine
pregnancy test within 24 hours prior to investigational medicinal product (IMP)
administration and either: a) Be of non-childbearing potential, confirmed at screening
by fulfilling one of the following criteria: - Postmenopausal defined as amenorrhea
for at least 12 months or more following cessation of all exogenous hormonal
treatments and FSH levels in the postmenopausal range.

- Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation.

b). Or, if of childbearing potential: - Must not be nursing (breastfeeding). -And, if
heterosexually active, agree to consistently use an acceptable method of contraception
to avoid pregnancy, from at least 4 weeks prior to dosing and throughout the study and
for up to 90 days after the last dose of IMP.

4. Sexually active fertile male subjects must use effective birth control for the entire
study and 90 days after the last dose of IMP if their partners are women of
childbearing potential.

5. Have a body mass index (BMI) between 18 and 32 kg/m2 inclusive and weigh at least 50
kg and no more than 100 kg inclusive.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the
principal investigator (PI), may either put the volunteer at risk because of
participation in the study, or influence the results or the volunteer's ability to
participate in the study.

2. Current or recent (within 3 months of first IMP dosing) gastrointestinal (GI) disease
that may impact drug absorption and affect the PK of the study drugs. Additionally,
any GI surgery (e.g., partial gastrectomy, pyloroplasty) including cholecystectomy
that may impact drug absorption.

3. Any major surgery, as determined by the investigator, within 4 weeks of first IMP
dosing.

4. Donation of > 400 mL of blood within 8 weeks or donation of plasma (except at the
Screening Visit) within 4 weeks of first IMP dosing.

5. Blood transfusion within 4 weeks of first IMP dosing.

6. Inability to tolerate oral medication.

7. Inability to tolerate venipuncture or inadequate venous access as determined by the
investigator.

8. Recent (within 6 months of first IMP dosing) drug or alcohol abuse as defined in the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),
Diagnostic Criteria for Drug and Alcohol Abuse.

9. Subjects who drink more than 3 cups of coffee or other caffeine-containing products a
day, or 5 cups of tea a day.

10. Use of tobacco-containing or nicotine-containing products (including but not limited
to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or
nicotine gum) within 6 months prior to first check-in (Day -1, Treatment Period 1), or
a positive nicotine test (i.e., cotinine) at Screening and/or check-in.

11. History of diabetes mellitus, heart failure, chronic or recurrent urinary tract
infection (defined as 3 occurrences per year) and severe allergy/hypersensitivity or
ongoing allergy/hypersensitivity, as judged by the PI or history of hypersensitivity
to drugs with a similar chemical structure or class to saxagliptin, dapagliflozin and
metformin.

14. Recent vulvovaginal mycotic infection (within 2 months prior to first IMP dosing).

15. Any other sound medical, psychiatric and/or social reason as determined by the
investigator.

16. Any clinically significant illness, medical/surgical procedure, or trauma within 4
weeks of Screening.

17. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C
antibody, and human immunodeficiency virus (HIV) antibody.

18. 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 or one month after the last
visit whichever is the longest.

19. Positive screen for drugs of abuse or cotinine at Screening or on each admission to the
clinical unit or positive screen for alcohol on each admission to the clinical unit.

20. Use of saxagliptin, dapagliflozin and/or metformin within 3 months prior to the first
administration of IMP.

21. Use of any prescription drugs or over the counter acid controllers within 4 weeks prior
to the first administration of IMP except medication cleared by the medical monitor.

22. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks
prior to the first administration of IMP.

23. Use of any prescribed or non-prescribed medication including analgesics (other than
paracetamol / acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times
the recommended daily dose) 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 not allowed.

24. Involvement of any AstraZeneca, PAREXEL or study site employee or their close
relatives.

25. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship,
trusteeship, or committed to an institution by governmental or juridical order.



Age minimum: 18 Years
Age maximum: 55 Years
Gender: All

Health Condition(s) or Problem(s) studied

Type 2 Diabetes Mellitus

Intervention(s)

Drug: 5 mg saxagliptin

Drug: Triple FCDP - 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR

Drug: 10 mg dapagliflozin / 1000 mg metformin XR tablet

Drug: 2.5 mg Saxagliptin tablet

Drug: 5 mg dapagliflozin / 1000 mg metformin XR tablet

Drug: Triple FCDP - 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR

Primary Outcome(s)

Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC0-t) [Time Frame: Day 1 to Day 4 (At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours)]

Area under plasma concentration-time curve from time zero to infinity (AUC) [Time Frame: Day 1 to Day 4 (At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours)]

Maximum observed plasma concentration (Cmax) [Time Frame: Day 1 to Day 4 (At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours)]

Secondary Outcome(s)

Ratio of metabolite AUC to parent AUC (MRAUC) [Time Frame: At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours]

Systolic and diastolic blood pressure [BP] [Time Frame: At screening (Day -28), Day -1, pre-dose, 71 hours post-dose and 5 to 7 days post-final dose follow-up]

Terminal elimination rate constant (?z) [Time Frame: At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours]

Laboratory assessments of Clinical chemistry [Time Frame: From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)]

Laboratory assessments of Hematology [Time Frame: From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)]

Pulse rate [Time Frame: From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)]

Twelve-lead electrocardiograms (ECGs) [Time Frame: From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)]

Laboratory assessments of urinalysis [Time Frame: From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)]

Time to reach maximum observed plasma concentration (tmax) [Time Frame: At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours]

Physical examination [Time Frame: From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)]

Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [Time Frame: At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours]

Apparent volume of distribution (V/F) [Time Frame: At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours]

Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (parent drug only) (MRT) [Time Frame: At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours]

Half-life associated with terminal slope (?z) of a semi-logarithmic concentration-time curve (t1/2) [Time Frame: At pre-dose and post-dose at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours]

Number of subjects with Adverse Events (AEs) [Time Frame: A Day -1, spontaneous plus pre-dose, 1, 2, 3, 24, and 48 hours post-dose]

Secondary ID(s)

D168AC00001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Parexel