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.
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
1 other identifier
interventional
85
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1 type-2-diabetes-mellitus
Started May 2017
Shorter than P25 for phase_1 type-2-diabetes-mellitus
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 23, 2017
CompletedStudy Start
First participant enrolled
May 29, 2017
CompletedFirst Posted
Study publicly available on registry
May 30, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 3, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
August 3, 2017
CompletedAugust 14, 2017
August 1, 2017
2 months
May 23, 2017
August 11, 2017
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
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)
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)
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 Outcomes (15)
Time to reach maximum observed plasma concentration (tmax)
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 (λz) of a semi-logarithmic concentration-time curve (t1/2)
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)
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
Terminal elimination rate constant (λz)
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 total body clearance of drug from plasma after extravascular administration (CL/F)
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
- +10 more secondary outcomes
Study Arms (12)
Cohort 1: Sequence 1 (ABC)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. A= Reference product - 2.5mg ONGLYZA (2.5mg saxagliptin) and 5/1000mg XIGDUO XR (5 mg dapagliflozin / 1000mg Metformin XR) after food. B = Test product - Triple FCDP consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR after food. C = Test product - Triple FCDP tablet consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 1: Sequence 2 (ACB)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ACB: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. A= Reference product - 2.5mg ONGLYZA (2.5mg saxagliptin) and 5/1000mg XIGDUO XR (5 mg dapagliflozin / 1000mg Metformin XR) after food. B = Test product - Triple FCDP consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR after food. C = Test product - Triple FCDP tablet consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 1: Sequence 3 (BAC)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. A= Reference product - 2.5mg ONGLYZA (2.5mg saxagliptin) and 5/1000mg XIGDUO XR (5 mg dapagliflozin / 1000mg Metformin XR) after food. B = Test product - Triple FCDP consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR after food. C = Test product - Triple FCDP tablet consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 1: Sequence 4 (BCA)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. A= Reference product - 2.5mg ONGLYZA (2.5mg saxagliptin) and 5/1000mg XIGDUO XR (5 mg dapagliflozin / 1000mg Metformin XR) after food. B = Test product - Triple FCDP consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR after food. C = Test product - Triple FCDP tablet consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 1: Sequence 5 (CAB)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. A= Reference product - 2.5mg ONGLYZA (2.5mg saxagliptin) and 5/1000mg XIGDUO XR (5 mg dapagliflozin / 1000mg Metformin XR) after food. B = Test product - Triple FCDP consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR after food. C = Test product - Triple FCDP tablet consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 1: Sequence 6 (CBA)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. A= Reference product - 2.5mg ONGLYZA (2.5mg saxagliptin) and 5/1000mg XIGDUO XR (5 mg dapagliflozin / 1000mg Metformin XR) after food. B = Test product - Triple FCDP consisting of 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR after food. C = Test product - Triple FCDP tablet consisting of 2.5mg saxagliptin / 5mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 2: Sequence 1 (DEF)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. D= Reference product - 5mg ONGLYZA (5mg saxagliptin) and 10/1000mg XIGDUO XR (10 mg dapagliflozin / 1000mg Metformin XR) after food. E = Test product - Triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR after food. F = Test product - Triple FCDP tablet consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 2: Sequence 2 (DFE)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. D= Reference product - 5mg ONGLYZA (5mg saxagliptin) and 10/1000mg XIGDUO XR (10 mg dapagliflozin / 1000mg Metformin XR) after food. E = Test product - Triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR after food. F = Test product - Triple FCDP tablet consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 2: Sequence 3 (EDF)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. D= 5mg ONGLYZA (5mg saxagliptin) and 10/1000mg XIGDUO XR (10 mg dapagliflozin / 1000mg Metformin XR) after food. E = Triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR after food. F = Triple FCDP tablet consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 2: Sequence 4 (EFD)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. D= Reference product - 5mg ONGLYZA (5mg saxagliptin) and 10/1000mg XIGDUO XR (10 mg dapagliflozin / 1000mg Metformin XR) after food. E = Test product - Triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR after food. F = Test product - Triple FCDP tablet consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR without food.
Cohort 2: Sequence 5 (FDE)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. D= Reference product - 5mg ONGLYZA (5mg saxagliptin) and 10/1000mg XIGDUO XR (10 mg dapagliflozin / 1000mg Metformin XR) after food. E = Test product - Triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR after food. F = Test product - Triple FCDP tablet consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR without food.
COhort 2: Sequence 6 (FED)
EXPERIMENTALSubjects were randomized to treatment sequence 1 ABC: On Day 1, each subjects will receive orally single-dose of the treatment assigned to that treatment period. D= Reference product - 5mg ONGLYZA (5mg saxagliptin) and 10/1000mg XIGDUO XR (10 mg dapagliflozin / 1000mg Metformin XR) after food. E = Test product - Triple FCDP consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR after food. F = Test product - Triple FCDP tablet consisting of 5 mg saxagliptin / 10 mg dapagliflozin / 1000 mg metformin XR without food.
Interventions
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).
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.
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.
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.
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.
Eligibility Criteria
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 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.
- 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.
- 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 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.
- 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.
- 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 caffeine-containing 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, 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.
- \. 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.
- \. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of Screening.
- \. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- AstraZenecalead
- Parexelcollaborator
Study Sites (1)
Research Site
Baltimore, Maryland, 21225, United States
Related Publications (1)
Tang W, Engman H, Zhu Y, Dayton B, Boulton DW. Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects. Clin Ther. 2019 Aug;41(8):1545-1563. doi: 10.1016/j.clinthera.2019.05.015. Epub 2019 Jun 29.
PMID: 31266654DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
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
May 23, 2017
First Posted
May 30, 2017
Study Start
May 29, 2017
Primary Completion
August 3, 2017
Study Completion
August 3, 2017
Last Updated
August 14, 2017
Record last verified: 2017-08
Data Sharing
- IPD Sharing
- Will share