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

NCT03138356 | Completed Phase 1

• 1 other identifier: D168AC00002
• Study Type: interventional
• Target: 126
• Locations: 1 country
• Sites: 1

Brief Summary

In this integrated, Phase I study, the safety, tolerability, food effect, and pharmacokinetic (PK) properties of Fixed-Dose Combination Tablets of Saxagliptin / Dapagliflozin / Metformin XR and Dapagliflozin / Metformin XR Relative to Individual Components in Healthy Subjects will be investigated.

Conditions

Type 2 Diabetes Mellitus

Keywords

Type 2 diabetes mellitus, saxagliptin, dapagliflozin, metformin XR, fixed-dose combination, healthy subjects, crossover, cohorts.

Outcome Measures

Primary Outcomes (3)

• PK assessment: AUC (Area under plasma concentration-time curve from time zero to infinity)

  To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.

  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)

  To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.

  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: Cmax (Maximum observed plasma concentration)

  To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.

  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 Outcomes (17)

• Secondary PK parameter: tmax (Time to reach maximum observed plasma concentration)

  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,λz (Terminal elimination half-life)

  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)

  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))

  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: λz (Terminal elimination rate constant)

  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)

Study Arms (9)

Cohort 1 Treatment A

EXPERIMENTAL

Single-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (1000 mg) XR (Extended-release) FDC (Fixed-dose combination) tablet administered orally under fasted condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (ABC), (ACB), (BAC), (BCA), (CAB) or (CBA).

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

Cohort 1 Treatment B

EXPERIMENTAL

Single-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (850 mg) XR FDC tablet, administered orally under fasted condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (ABC), (ACB), (BAC), (BCA), (CAB) or (CBA).

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

Cohort 1 Treatment C (Reference product)

ACTIVE COMPARATOR

Single-dose of Onglyza® (2.5 mg saxagliptin), Forxiga® (5 mg dapagliflozin) and Glucophage XR® (2 x 500 mg metformin XR) co-administered under fasted condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (ABC), (ACB), (BAC), (BCA), (CAB) or (CBA).

Drug: 2.5 mg ONGLYZA® (saxagliptin) tablet; Drug: 5 mg Forxiga® (dapagliflozin) tablet; Drug: 500 mg Glucophage XR®

Cohort 2 Treatment D

EXPERIMENTAL

Single-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (1000 mg) XR FDC tablet administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state The treatment sequences are (DEF), (DFE), (EDF), (EFD), (FDE) or (FED).

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

Cohort 2 Treatment E

EXPERIMENTAL

Single-dose of saxagliptin (2.5 mg), dapagliflozin (5 mg), metformin (850 mg) XR FDC tablet, administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (DEF), (DFE), (EDF), (EFD), (FDE) or (FED).

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

Cohort 2 Treatment F (Reference Product)

ACTIVE COMPARATOR

Single-dose of Onglyza® (2.5 mg saxagliptin), Forxiga® (5 mg dapagliflozin) and Glucophage XR® (2 x 500 mg metformin) co-administered under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (DEF), (DFE), (EDF), (EFD), (FDE) or (FED).

Drug: 2.5 mg ONGLYZA® (saxagliptin) tablet; Drug: 5 mg Forxiga® (dapagliflozin) tablet; Drug: 500 mg Glucophage XR®

Cohort 3 Treatment G

EXPERIMENTAL

Single-dose dapagliflozin (5 mg) / metformin (1000 mg) XR FDC tablet administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (GHI), (GIH), (HGI), (HIG), (IHG) or (IGH).

Drug: 5 mg dapagliflozin / 1000 mg metformin XR FDC

Cohort 3 Treatment H

EXPERIMENTAL

Single-dose dapagliflozin (5 mg) / metformin (850 mg) XR FDC tablet administered orally under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (GHI), (GIH), (HGI), (HIG), (IHG) or (IGH).

Drug: 5 mg dapagliflozin / 850 mg metformin XR FDC

Cohort 3 Treatment I (Reference Product)

ACTIVE COMPARATOR

Single-dose Forxiga® (5 mg dapagliflozin) and Glucophage XR® (2 x 500 mg metformin) co-administered under fed condition. Within each cohort, subjects will be randomized to 1 of 6 treatment sequences, each subject will receive 3 single-dose treatments in either a fasted or fed-state. The treatment sequences are (GHI), (GIH), (HGI), (HIG), (IHG) or (IGH).

Drug: 5 mg Forxiga® (dapagliflozin) tablet; Drug: 500 mg Glucophage XR®

Interventions

2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tablet DRUG

Used in Treatment B and Treatment E.

Cohort 1 Treatment B; Cohort 2 Treatment E

2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tablet DRUG

Used in Treatment A and Treatment D.

Cohort 1 Treatment A; Cohort 2 Treatment D

5 mg dapagliflozin / 850 mg metformin XR FDC DRUG

Used in Treatment H.

Cohort 3 Treatment H

5 mg dapagliflozin / 1000 mg metformin XR FDC DRUG

Used in Treatment G.

Cohort 3 Treatment G

2.5 mg ONGLYZA® (saxagliptin) tablet DRUG

Used in treatments C and F.

Cohort 1 Treatment C (Reference product); Cohort 2 Treatment F (Reference Product)

5 mg Forxiga® (dapagliflozin) tablet DRUG

Used in treatments C, F and I.

Cohort 1 Treatment C (Reference product); Cohort 2 Treatment F (Reference Product); Cohort 3 Treatment I (Reference Product)

500 mg Glucophage XR® DRUG

Used in treatments C, F and I.

Cohort 1 Treatment C (Reference product); Cohort 2 Treatment F (Reference Product); Cohort 3 Treatment I (Reference Product)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male and/or female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
• Female subject must either:
• 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.

You may not qualify if:

• 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.
• 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.
• Any major surgery, as determined by the investigator, within 4 weeks of first IMP dosing.
• 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.
• Blood transfusion within 4 weeks of first IMP dosing.
• Inability to tolerate oral medication.
• Inability to tolerate venipuncture or inadequate venous access as determined by the investigator.
• 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.
• Subjects who drink more than 3 cups of coffee or other caffeinecontaining products a day, or 5 cups of tea a day.
• 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.
• History of diabetes mellitus.
• History of heart failure.
• History of chronic or recurrent urinary tract infection (defined as 3 occurrences per year)
• Recent vulvovaginal mycotic infection (within 2 months prior to first IMP dosing).
• Any other sound medical, psychiatric and/or social reason as determined by the investigator.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Harrow, HA1 3UJ, United Kingdom

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

saxagliptin; dapagliflozin; Tablets; Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Pablo ForteSoto, MD, MSc, PhD

  PAREXEL Early Phase Clinical Unit London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2017
• First Posted: May 3, 2017
• Study Start: May 25, 2017
• Primary Completion: November 28, 2017
• Study Completion: November 28, 2017
• Last Updated: December 7, 2017

Record last verified: 2017-12

Locations

GB (1)