Bioequivalence Study of Combination Tablets of Saxagliptin / Dapagliflozin / Metformin XR (Extended-release) and Dapagliflozin / Metformin XR Relative to Individual Components in Healthy Subjects

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT03138356
• Date of registration: 21/04/2017
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca
• Public title: Bioequivalence Study of Combination Tablets of Saxagliptin / Dapagliflozin / Metformin XR (Extended-release) and Dapagliflozin / Metformin XR Relative to Individual Components in Healthy Subjects
• Scientific title: A Randomized, Single-dose, Open-label, Single-center, Crossover Study to Assess the Fed- and Fasted State Bioequivalence of Fixed-Dose Combination Tablets of Saxagliptin / Dapagliflozin / Metformin XR and Dapagliflozin / Metformin XR Relative to Individual Components in Healthy Subjects
• Date of first enrolment: May 25, 2017
• Target sample size: 126
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03138356
• 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 Kingdom

Contacts

• Name: Pablo ForteSoto, MD, MSc, PhD
• Affiliation: PAREXEL Early Phase Clinical Unit London

Key inclusion & exclusion criteria

Inclusion Criteria:

- For inclusion in the study subjects should fulfill the following 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 either:

3.1. Be of non-childbearing potential:

- 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 first IMP administration.

- Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation. 3.2. Or, if of
childbearing potential:

- Must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent
units of human chorionic gonadotropin) at Screening and within 24 hours prior to first
IMP administration.

- Must not be nursing (breastfeeding).

- If heterosexually active, agree to consistently use a highly effective 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:

- Subjects will not enter the study if any of the following exclusion criteria are
fulfilled:

1. History of any clinically significant disease or disorder which, in the opinion
of the 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 disease
that may impact drug absorption and affect the PK of the study drugs.
Additionally, any gastrointestinal 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 caffeinecontaining
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.

12. History of heart failure.

13. History of chronic or recurrent urinary tract infection (defined as 3 occurrences
per year)

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. Note: subjects consented
and screened, but not randomized in this study or a previous Phase1 study, are
not excluded.

19. History of 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.

20. Positive screen for drugs of abuse or cotinine at Screening or on first admission
to the study center or positive screen for alcohol on first admission to the
study center

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

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

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

24. 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.

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

26. 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 dapagliflozin / 1000 mg metformin XR FDC

Drug: 5 mg dapagliflozin / 850 mg metformin XR FDC

Drug: 2.5 mg ONGLYZA® (saxagliptin) tablet

Drug: 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tablet

Drug: 500 mg Glucophage XR®

Drug: 2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tablet

Drug: 5 mg Forxiga® (dapagliflozin) tablet

Primary Outcome(s)

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

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

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

Secondary Outcome(s)

Physical examination [Time Frame: At Screening, Day -1 (brief) , Day 4, 72 hours (brief) post-dose (Days 1 to 4), 5 to 7 days post-final dose ]]

Body weight [Time Frame: At Screening, Day -1, 5 to 7 days post-final dose ]]

Secondary PK parameter: ?z (Terminal elimination rate constant) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Twelve-lead electrocardiograms (ECGs) [Time Frame: At Screening, 5 to 7 days post-final dose ]]

Secondary PK parameter: CL/F (Apparent total body clearance of drug from plasma after extravascular administration (parent drug only)) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Laboratory assessments (hematology, clinical chemistry and urinalysis) [Time Frame: At Screening, Day -1, Day 4 (72 hours post-dose), Post-study 5 to 7 days post-final dose]

Secondary PK parameter: AUC0-t/D (Dose normalized AUC0-t (metformin only)) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Secondary PK parameter: t½,?z (Terminal elimination half-life) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Secondary PK parameter: tlast (Time of last quantifiable plasma concentration) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Secondary PK parameter: Vz/F (Apparent volume of distribution during terminal phase after extravascular administration (parent drug only)) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Number of patients with Adverse Events (AEs) [Time Frame: At Day -1, Spontaneous plus Pre-dose, 3, 12, 24, and 48 hours post-dose (Days 1 to 4), 5 to 7 days post-final dose]

Secondary PK parameter: Cmax/D (Dose normalized Cmax (metformin only)) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

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

Secondary PK parameter: MRT (Mean residence time from zero to infinity (parent drug only)) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Secondary PK parameters: AUC/D (Dose normalized AUC (metformin only)) [Time Frame: At Pre-dose, 0.25, 0.5, 1, 1.5, 2,3,4,6,8,12, 18, 24,36, 48, 60 and 72 hours (Days 1 to 4)]

Vital signs (pulse rate) [Time Frame: At Screening, Day -1, Pre-dose and 48 hours (Days 1 to 4), 5 to 7 days post-final dose]]

Vital signs (systolic and diastolic blood pressure [BP]) [Time Frame: At Screening, Day -1, Pre-dose and 48 hours (Days 1 to 4), 5 to 7 days post-final dose]]

Secondary ID(s)

D168AC00002

Source(s) of Monetary Support

Please refer to primary and secondary sponsors