Type 2 Diabetes MellitusPhase 1NCT03138356

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

A Phase 1 study testing 2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tablet, 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tablet and 5 mg dapagliflozin / 850 mg metformin XR FDC in people with Type 2 Diabetes Mellitus, run by AstraZeneca at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for: Type 2 Diabetes Mellitus
What is being tested?: 2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tablet, 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tablet and 5 mg dapagliflozin / 850 mg metformin XR FDC
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 126 participants
Where: 1 siteUnited Kingdom
Study dates: 25 May 2017to 28 Nov 2017
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

For inclusion in the study subjects should fulfill the following criteria:
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:
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.

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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.

Who cannot join

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

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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.
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.
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.
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.
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
Use of saxagliptin, dapagliflozin and/or metformin within 3 months prior to the first administration of IMP.
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.
Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
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.
Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.
Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

Research Site
Harrow, HA1 3UJ

Other trials in United Kingdom

About this study

Official 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

Read the detailed description

This study will be an open-label, randomized, 3-period, 3-treatment, single-dose crossover study in healthy subjects (males and females), performed at a single study center, conducted in 3 cohorts. A total of 126 healthy male or female subjects (3 cohorts of 42 subjects each [each cohort consisting of 3 treatments]) will be randomized in this study to ensure that at least 108 subjects (36 in each cohort) are evaluable. Each 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 of 6 treatment sequences with 7 subjects prescribing the ordered sequence of 3 administered treatments in each treatment sequence, and will receive the IMPs in either a fasted or fed-state according to the assigned treatment. For fed-state cohorts, all doses of study drug will be administered to subjects after consuming a standard meal (light fat, low calorie) in the morning. Subjects will start consuming the meal 30 minutes prior to the dose and will finish the meal within 25 minutes. Dosing will then start after 30 minutes after the start of the meal. Subjects in the fasted state cohort will be fasted overnight (at least 10 hours) before dosing

The study will comprise:

A Screening period of maximum 28 days;
Three treatment periods during which subjects will be resident in the Unit from the day before dosing with the IMP (Day -1) until at least 72 hours after dosing; discharged on the morning of Day 4; and
A final Follow-up Visit within 5 to 7 days after the last administration of the IMP.

There will be a minimum washout period of 7 to 14 days between each dose administration

Conditions: Type 2 Diabetes Mellitus
Being tested: 2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tablet, 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tablet, 5 mg dapagliflozin / 850 mg metformin XR FDC, 5 mg dapagliflozin / 1000 mg metformin XR FDC, 2.5 mg ONGLYZA® (saxagliptin) tablet
Keywords: Type 2 diabetes mellitus, saxagliptin, dapagliflozin, metformin XR, fixed-dose combination, healthy subjects, crossover, cohorts.
Medical subject headings: Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tabletDrug
Used in Treatment B and Treatment E.
2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tabletDrug
Used in Treatment A and Treatment D.
5 mg dapagliflozin / 850 mg metformin XR FDCDrug
Used in Treatment H.
5 mg dapagliflozin / 1000 mg metformin XR FDCDrug
Used in Treatment G.
2.5 mg ONGLYZA® (saxagliptin) tabletDrug
Used in treatments C and F.
5 mg Forxiga® (dapagliflozin) tabletDrug
Used in treatments C, F and I.
500 mg Glucophage XR®Drug
Used in treatments C, F and I.

Study groups in NCT03138356
Study group	Role	What they receive
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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: Drug: 5 mg Forxiga® (dapagliflozin) tablet; Drug: 500 mg Glucophage XR®

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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)
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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)
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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)
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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)
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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: CL/F (Apparent total body clearance of drug from plasma after extravascular administration (parent drug only))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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: AUC0-t/D (Dose normalized AUC0-t (metformin only))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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: Cmax/D (Dose normalized Cmax (metformin only))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
Measured: 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)
To assess the adverse events as a criteria of safety and tolerability variables.
Measured: 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
Vital signs (systolic and diastolic blood pressure [BP])
To assess the vital signs as a criteria of safety and tolerability variables.
Measured: At Screening, Day -1, Pre-dose and 48 hours (Days 1 to 4), 5 to 7 days post-final dose]
Vital signs (pulse rate)
To assess the vital sign as a criteria of safety and tolerability variables.
Measured: At Screening, Day -1, Pre-dose and 48 hours (Days 1 to 4), 5 to 7 days post-final dose]
Twelve-lead electrocardiograms (ECGs)
To assess the cardiovascular system functioning as a criteria of safety and tolerability variables.
Measured: At Screening, 5 to 7 days post-final dose ]
Physical examination
To assess the physical conditions as a criteria of safety and tolerability variables.
Measured: 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
To assess the body weight as a criteria of safety and tolerability variables.
Measured: At Screening, Day -1, 5 to 7 days post-final dose ]
Laboratory assessments (hematology, clinical chemistry and urinalysis)
To assess hematology, clinical chemistry and urinalysis as a criteria of safety and tolerability variables.
Measured: At Screening, Day -1, Day 4 (72 hours post-dose), Post-study 5 to 7 days post-final dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

25 May 201728 Nov 2017

First posted3 May 2017
Study start25 May 2017
Primary completion28 Nov 2017
Study completion28 Nov 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
More trials run by AstraZenecaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Enrolment: 126 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03138356
Sponsor's protocol ID: D168AC00002
Status last verified: Dec 2017
First submitted: 21 Apr 2017
Last updated: 7 Dec 2017
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Undecided

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 7 Dec 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

Official 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
ClinicalTrials.gov ID: NCT03138356
Acronym / sponsor ID: D168AC00002
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 diabetes mellitus, saxagliptin, dapagliflozin, metformin XR, fixed-dose combination, healthy subjects, crossover, cohorts.
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 126 participants (actual)
Lead sponsor: AstraZenecaIndustry (pharma, biotech, devices)
Study start: 25 May 2017 (actual)
Primary completion: 28 Nov 2017 (actual)
Study completion: 28 Nov 2017 (actual)
First posted: 3 May 2017 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

The study will comprise:

A Screening period of maximum 28 days;
Three treatment periods during which subjects will be resident in the Unit from the day before dosing with the IMP (Day -1) until at least 72 hours after dosing; discharged on the morning of Day 4; and
A final Follow-up Visit within 5 to 7 days after the last administration of the IMP.

There will be a minimum washout period of 7 to 14 days between each dose administration

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 9

Arm	Type	Receives
Cohort 1 Treatment A	Experimental	Drug: 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tabletSingle-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).
Cohort 1 Treatment B	Experimental	Drug: 2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tabletSingle-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).
Cohort 1 Treatment C (Reference product)	Active comparator	Drug: 2.5 mg ONGLYZA® (saxagliptin) tablet, Drug: 5 mg Forxiga® (dapagliflozin) tablet, Drug: 500 mg Glucophage XR®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).
Cohort 2 Treatment D	Experimental	Drug: 2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tabletSingle-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).
Cohort 2 Treatment E	Experimental	Drug: 2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tabletSingle-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).
Cohort 2 Treatment F (Reference Product)	Active comparator	Drug: 2.5 mg ONGLYZA® (saxagliptin) tablet, Drug: 5 mg Forxiga® (dapagliflozin) tablet, Drug: 500 mg Glucophage XR®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).
Cohort 3 Treatment G	Experimental	Drug: 5 mg dapagliflozin / 1000 mg metformin XR FDCSingle-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).
Cohort 3 Treatment H	Experimental	Drug: 5 mg dapagliflozin / 850 mg metformin XR FDCSingle-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).
Cohort 3 Treatment I (Reference Product)	Active comparator	Drug: 5 mg Forxiga® (dapagliflozin) tablet, Drug: 500 mg Glucophage XR®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).

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (10 listed)

For inclusion in the study subjects should fulfill the following criteria:
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).

Key exclusion criteria (27 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tabletUsed in Treatment B and Treatment E.	Drug	Cohort 1 Treatment B, Cohort 2 Treatment E
2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tabletUsed in Treatment A and Treatment D.	Drug	Cohort 1 Treatment A, Cohort 2 Treatment D
5 mg dapagliflozin / 850 mg metformin XR FDCUsed in Treatment H.	Drug	Cohort 3 Treatment H
5 mg dapagliflozin / 1000 mg metformin XR FDCUsed in Treatment G.	Drug	Cohort 3 Treatment G
2.5 mg ONGLYZA® (saxagliptin) tabletUsed in treatments C and F.	Drug	Cohort 1 Treatment C (Reference product), Cohort 2 Treatment F (Reference Product)
5 mg Forxiga® (dapagliflozin) tabletUsed in treatments C, F and I.	Drug	Cohort 1 Treatment C (Reference product), Cohort 2 Treatment F (Reference Product), Cohort 3 Treatment I (Reference Product)
500 mg Glucophage XR®Used in treatments C, F and I.	Drug	Cohort 1 Treatment C (Reference product), Cohort 2 Treatment F (Reference Product), Cohort 3 Treatment I (Reference Product)

Primary outcome

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

17 secondary outcomes

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: t½,λz (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: 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 parameter: λz (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)
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)
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)
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)
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: 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)
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
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]
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]
Twelve-lead electrocardiograms (ECGs)
Time frame: At Screening, 5 to 7 days post-final dose ]
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 ]
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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 7 Dec 2017.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Pablo ForteSoto, MD, MSc, PhD principal investigator

PAREXEL Early Phase Clinical Unit London

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03138356.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2017.