Clinical trial NCT01535677: To Compare the Similarity of a Combination Dapagliflozin/Metformin Tablet With the Two Drugs Administered Separately
Official title: A Bioequivalence Study of the Fixed Dose Combination Dapagliflozin/Metformin Tablet (5 mg/850 mg) Relative to a 5 mg Dapagliflozin Tablet and an 850 mg Metformin (Glucophage® Marketed in Canada by Sanofi-Aventis) Tablet Co-Administered to Healthy Subjects in the Fasted and Fed States
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 2 Diabetes Mellitus
Keywords: Phase 1
healthy volunteers
cross-over study
Bioavailability
Bioequivalence
Cmax
tmax
AUC
AUC(0-t)
λz
tlast
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2012-02-20
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: This is an open-label, randomised study to compare the similarity of a combination Dapagliflozin/Metformin tablet with the two drugs administered separately under fasting and fed conditions in healthy volunteers.

Detailed description: A Bioequivalence Study of the Fixed Dose Combination Dapagliflozin/Metformin Tablet (5.0 mg/850 mg) Relative to a 5.0 mg Dapagliflozin Tablet and an 850 mg Metformin (Glucophage® Marketed in Canada by Sanofi-Aventis) Tablet Co-Administered to Healthy Subjects in the Fasted and Fed States

Eligibility criteria: Inclusion Criteria:

* Healthy volunteers aged 18 to 55 years inclusive with suitable veins for cannulation or repeated vein puncture
* Male subjects should be willing to use barrier contraception ie, condoms and spermicide, from the day of dosing until at least 3 months after dosing with the investigational product
* Non-pregnant, non-lactating female subjects who if pre-menopausal are using adequate birth control eg, oral, injectable, transdermal or implanted hormonal contraceptives, vaginal contraceptive ring, intrauterine device (IUD)/intrauterine systems
* Have a body mass index (BMI) between 18.5 and 30.0 kg/m2 inclusive (ie, within 15% of normal range) and weigh at least 50 kg and no more than 100 kg.

Exclusion Criteria:

* History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs
* Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with individual safety evaluation Current smokers who smoke more than 5 cigarettes per day (or equivalent use of tobacco products) or cannot give up smoking during the study
* Excessive intake of caffeine containing drinks eg, coffee, tea, caffeine containing energy drinks and cola (more than 5 cups of coffee or equivalent per day)
* Plasma donation within one month of screening or any blood donation/blood loss \>500 mL during the 3 months prior to screening

Primary outcomes:
measure: Area under the curve over the time (AUC)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: AUC from time zero to the time of last quantifiable analyte concentration (AUC(0-t))
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Maximum concentration (Cmax)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
Secondary outcomes:
measure: Time to reach maximum analyte concentration (tmax)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Terminal rate constant (λz)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Time of last quantifiable analyte concentration (tlast)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Terminal half-life (t1/2)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Observed maximum analyte concentration (Cmax)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC(0 t))
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Elimination terminal half-life (t1/2)
timeFrame: pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose
measure: Safety profile description in term of Adverse Events
timeFrame: from first dose in treatment period 1 up to 10 days after final dose
measure: Safety profile description in term of Blood Pressure
timeFrame: at screening, once daily during the residential period (5 days each) and up to 10 days after final dose
measure: Safety profile description in term of Physical Examination
timeFrame: at screening, Day -1 and Day 4 at Visits 2 to 5 and up to 10 days after final dose
measure: Safety profile description in term of Electrocardiogram ECG
timeFrame: at screening and up to 10 days after final dose
measure: Safety profile description in term of Heart Rate
timeFrame: at screening, once daily during the residential period (5 days each) and up to 10 days after final dose
measure: Safety profile description in term of Safety Labs
timeFrame: at screening, on Day -1 and Day 4 (72 hours post-dose) at Visits 2 to 5 and up to 10 days after final dose
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca Research and Development SE-431 83 Mölndal Sweden
name: Eva Johnsson, MD
role: STUDY_DIRECTOR
affiliation: Quintiles Drug Research Unit at Guy's Hospital, 6 Newcomen St, London SE1 1YR
name: Saeed Kahn, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: AstraZeneca Research and DevelopmentSE-431 83 Mölndal Sweden
name: Mirjana Kujacic, PHD
role: STUDY_CHAIR
References:
citation: Chang M, Liu X, Cui D, Liang D, LaCreta F, Griffen SC, Lubin S, Quamina-Edghill D, Boulton DW. Bioequivalence, Food Effect, and Steady-State Assessment of Dapagliflozin/Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects. Clin Ther. 2015 Jul 1;37(7):1517-28. doi: 10.1016/j.clinthera.2015.05.004. Epub 2015 Jun 3.