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.

Type 2 Diabetes Mellitus Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03169959
• Other study ID #: D168AC00001
• Status: Completed
• Phase: Phase 1
• First received: May 23, 2017
• Last updated: August 11, 2017
• Start date: May 29, 2017
• Est. completion date: August 3, 2017

Study information

• Verified date: August 2017
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A Study to Assess the Fed-state Bioequivalence of a Triple Fixed-Combination Drug Product (FCDP) 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-administration. A randomized, open-label, cross over design has been chosen to minimize the effects of between-subject variability and any period effects on the overall results.

Description:

This study will be randomized, 3-period, 3-treatment, single-dose, open-label, single-center, crossover to assess the fed-state bioequivalence of a two triple Fixed-combination Drug Product (FCDP) of saxagliptin/dapagliflozin/metformin extended-release (XR) relative to individual components co-administered in approximately 84 healthy adult subjects. Eligible subjects will be healthy male and female aged 18 to 55 years, with a body weight of 50 to 100 kg and body mass index (BMI) of 18 to 32 kg/m2. Of the 84 randomized subjects (2 cohorts of 42 subjects each [3 treatments in each cohort]), at least 72 subjects (36 in each cohort) should be evaluable. Each randomized subject will receive 3 single-dose treatments and each treatment will be administered within 1 of the 3 successive treatment periods. Within each cohort subjects will be randomized to 1 to 6 treatment sequences prescribing the ordered sequence of 3 administered treatments with 7 subjects in each treatment sequence. The investigational medicinal product (IMPs) will be administered orally at single-dose to subjects within 5 minutes after standard meal (light-fat, low-calorie) in the morning (fed condition) or following a 10 hour fast (fasted condition). In both cohorts, test product will be compared with treatments of fed and fasted conditions Subjects in Cohort 1 will be randomized to one of the treatment sequences (ABC), (ACB), (BAC), (BCA), (CAB) or (CBA).

Treatment A (Reference Product under fed conditions) - Single-dose of 2.5 mg saxagliptin (ONGLYZA) and 5 mg dapagliflozin / 1000 mg metformin XR (XIGDUO XR) tablets.

Treatment B (Test Product under fed conditions) - Single-dose of triple FCDP consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR.

Treatment C (Test Product fasted conditions) - Single-dose of triple FCDP tablet consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR.

Subjects in Cohort 2 will be randomized to one of the treatment sequences (DEF), (DFE), (EDF), (EFD), (FDE) or (FED).

Treatment D (Reference product under fed conditions) - Single-dose of 5 mg saxagliptin (ONGLYZA) and 10 mg dapagliflozin / 1000 mg metformin XR (XIGDUO XR) tablet.

Treatment E (Test Product under fed conditions) - Single-dose of triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR.

Treatment F (Test Product under fasted conditions) - Single-dose of triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR.

The study will comprise:

• A screening period of maximum 28 days;

• Three resident treatment periods - Day before dosing with the IMP (Day -1) until at least 72 hours after dosing; and will be discharged on the morning of Day 4; and

• A follow-up visit within 5 to 7 days after the last dose of IMP. Treatment periods will be separated by a minimum washout period of 7 to 14 days between each IMP dose. The duration of the study will be approximately 7 to 9 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: August 3, 2017
• Est. primary completion date: August 3, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• 2.5 mg Saxagliptin tablet
A competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, slows the inactivation of the incretin hormones, thereby increases their bloodstream concentrations and reduces fasting and post-prandial glucose concentrations in a glucose-dependent manner in subjects with Type 2 diabetes mellitus (T2DM).
• 5 mg dapagliflozin / 1000 mg metformin XR tablet
Dapagliflozin - An inhibitor of sodium-glucose co-transporter 2 (SGLT-2), reduces re-absorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin - Lowers both basal and post-prandial plasma glucose by decreasing hepatic glucose production and intestinal absorption of glucose; improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
• Triple FCDP - 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR
Saxagliptin - A competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, slows the inactivation of the incretin hormones, thereby increases their bloodstream concentrations and reduces fasting and post-prandial glucose concentrations in a glucose-dependent manner in subjects with T2DM. Dapagliflozin - An inhibitor of SGLT-2, reduces re-absorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin - Lowers both basal and post-prandial plasma glucose by decreasing hepatic glucose production and intestinal absorption of glucose; improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
• 5 mg saxagliptin
A competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, slows the inactivation of the incretin hormones, thereby increases their bloodstream concentrations and reduces fasting and post-prandial glucose concentrations in a glucose-dependent manner in subjects with T2DM.
• 10 mg dapagliflozin / 1000 mg metformin XR tablet
Dapagliflozin - An inhibitor of SGLT-2, reduces re-absorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin - Lowers both basal and post-prandial plasma glucose by decreasing hepatic glucose production and intestinal absorption of glucose; improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
• Triple FCDP - 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR
Saxagliptin - A competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, slows the inactivation of the incretin hormones, thereby increases their bloodstream concentrations and reduces fasting and post-prandial glucose concentrations in a glucose-dependent manner in subjects with T2DM. Dapagliflozin - An inhibitor of SGLT-2, reduces re-absorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin - Lowers both basal and post-prandial plasma glucose by decreasing hepatic glucose production and intestinal absorption of glucose; improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Locations

Country	Name	City	State
United States	Research Site	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under plasma concentration-time curve from time zero to infinity (AUC)	To assess pharmacokinetics (PK) in terms of AUC in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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)
Primary	Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC0-t)	To assess PK in terms of AUC0-t in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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)
Primary	Maximum observed plasma concentration (Cmax)	To assess PK in terms of Cmax in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Time to reach maximum observed plasma concentration (tmax)	To assess PK in terms of tmax in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Half-life associated with terminal slope (?z) of a semi-logarithmic concentration-time curve (t1/2)	To assess PK in terms of t1/2 in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (parent drug only) (MRT)	To assess PK in terms of MRT in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Terminal elimination rate constant (?z)	To assess PK in terms of ?z in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Apparent total body clearance of drug from plasma after extravascular administration (CL/F)	To assess PK in terms of CL/F in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Apparent volume of distribution (V/F)	To assess PK in terms of V/F in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Ratio of metabolite AUC to parent AUC (MRAUC)	To assess PK in terms of MRAUC in Cohort 1 after administration of Treatment A, B (under fed condition), C (under fasted condition) and Cohort 2 after administration of Treatment D, E (under fed condition) and F (under fasted condition) in healthy volunteers.	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	Number of subjects with Adverse Events (AEs)	To assess AEs as a criteria of safety and tolerability variables.	A Day -1, spontaneous plus pre-dose, 1, 2, 3, 24, and 48 hours post-dose
Secondary	Systolic and diastolic blood pressure [BP]	To assess the systolic and diastolic blood pressure as a criteria of safety and tolerability variables	At screening (Day -28), Day -1, pre-dose, 71 hours post-dose and 5 to 7 days post-final dose follow-up
Secondary	Pulse rate	To assess the pulse rate as a criteria of safety and tolerability variables	From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)
Secondary	Twelve-lead electrocardiograms (ECGs)	To assess the cardiovascular system functioning as a criteria of safety and tolerability variables.	From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)
Secondary	Physical examination	To assess a complete physical examinations (general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal and neurological systems) and a brief physical examinations (general appearance, skin, abdomen, cardiovascular system and respiratory) as a criteria of safety and tolerability variables.; A complete physical examination will be performed at the screening visit.	From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)
Secondary	Laboratory assessments of Hematology	To assess the count of white blood cell (WBC), red blood cell (RBC) and platelets; absolute count of neutrophils, lymphocytes, monocytes, eosinophils, basophils and reticulocytes; levels of Hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) in blood as a criteria of safety and tolerability variables.	From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)
Secondary	Laboratory assessments of Clinical chemistry	To assess the levels of electrolytes (sodium, potassium, magnesium, chloride, calcium, phosphate), urea, creatinine, albumin, glucose (fasting), C-reactive protein (CRP), thyroxine (T4), thyroid-stimulating hormone (TSH), liver enzymes (alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and Gamma glutamyl transpeptidase (GGT)), bilirubin (total and unconjugated) and follicle-stimualting hormone (FSH) in serum as a criteria of safety and tolerability variables.	From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)
Secondary	Laboratory assessments of urinalysis	To assess the presence of glucose, protein, blood and microscopy (RBC, WBC, casts (cellualr, granular, hyaline) in urine as a criteria of safety and tolerability variables.	From Screening (Day -28 to Day -1) to Follow-up (5-7days post final dose)