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.
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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
126
Used in Treatment B and Treatment E.
Used in Treatment A and Treatment D.
Used in Treatment H.
Research Site
Harrow, United Kingdom
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.
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)
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.
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)
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.
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: 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.
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)
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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Used in Treatment G.
Used in treatments C and F.
Used in treatments C, F and I.
Used in treatments C, F and I.
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)
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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)
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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))
To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration.
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)
To assess the adverse events as a criteria of safety and tolerability variables.
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])
To assess the vital signs as a criteria of safety and tolerability variables.
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)
To assess the vital sign as a criteria of safety and tolerability variables.
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)
To assess the cardiovascular system functioning as a criteria of safety and tolerability variables.
Time frame: At Screening, 5 to 7 days post-final dose ]
Physical examination
To assess the physical conditions as a criteria of safety and tolerability variables.
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
To assess the body weight as a criteria of safety and tolerability variables.
Time frame: 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.
Time frame: At Screening, Day -1, Day 4 (72 hours post-dose), Post-study 5 to 7 days post-final dose