Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 diabetes mellitus, saxagliptin, dapagliflozin, metformin XR, fixed-dose combination, healthy subjects, crossover, cohorts.
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.
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
Interventions
DRUG2.5 mg saxagliptin / 5 mg dapagliflozin / 850 mg metformin XR FDC tablet
Used in Treatment B and Treatment E.
DRUG2.5 mg saxagliptin / 5 mg dapagliflozin / 1000 mg metformin XR FDC tablet
Used in Treatment A and Treatment D.
DRUG5 mg dapagliflozin / 850 mg metformin XR FDC
Used in Treatment H.
DRUG5 mg dapagliflozin / 1000 mg metformin XR FDC
Used in Treatment G.
DRUG2.5 mg ONGLYZA® (saxagliptin) tablet
Used in treatments C and F.
DRUG5 mg Forxiga® (dapagliflozin) tablet
Used in treatments C, F and I.
DRUG500 mg Glucophage XR®
Used in treatments C, F and I.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* For inclusion in the study subjects should fulfill the following criteria: 1. Provision of signed and dated, written informed consent prior to any study specific procedures. 2. Healthy male and/or female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture. 3. 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. * 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.
Exclusion criteria
* Subjects will not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK assessment: AUC (Area under plasma concentration-time curve from time zero to infinity) | 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) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| Secondary PK parameter: CL/F (Apparent total body clearance of drug from plasma after extravascular administration (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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| Secondary PK parameter: Vz/F (Apparent volume of distribution during terminal phase after extravascular administration (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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| Secondary PK parameters: AUC/D (Dose normalized AUC (metformin 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| Secondary PK parameter: AUC0-t/D (Dose normalized AUC0-t (metformin 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| Secondary PK parameter: Cmax/D (Dose normalized Cmax (metformin 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| Vital signs (systolic and diastolic blood pressure [BP]) | At Screening, Day -1, Pre-dose and 48 hours (Days 1 to 4), 5 to 7 days post-final dose] | To assess the vital signs as a criteria of safety and tolerability variables. |
| Vital signs (pulse rate) | At Screening, Day -1, Pre-dose and 48 hours (Days 1 to 4), 5 to 7 days post-final dose] | To assess the vital sign as a criteria of safety and tolerability variables. |
| Twelve-lead electrocardiograms (ECGs) | At Screening, 5 to 7 days post-final dose ] | To assess the cardiovascular system functioning as a criteria of safety and tolerability variables. |
| Physical examination | At Screening, Day -1 (brief) , Day 4, 72 hours (brief) post-dose (Days 1 to 4), 5 to 7 days post-final dose ] | To assess the physical conditions as a criteria of safety and tolerability variables. |
| Body weight | At Screening, Day -1, 5 to 7 days post-final dose ] | To assess the body weight as a criteria of safety and tolerability variables. |
| Laboratory assessments (hematology, clinical chemistry and urinalysis) | At Screening, Day -1, Day 4 (72 hours post-dose), Post-study 5 to 7 days post-final dose | To assess hematology, clinical chemistry and urinalysis as a criteria of safety and tolerability variables. |
| Number of patients with Adverse Events (AEs) | 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 | To assess the adverse events as a criteria of safety and tolerability variables. |
| 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
| 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) | To measure the PK exposure for saxagliptin, 5-hydroxy saxagliptin (where applicable), dapagliflozin and metformin using plasma concentrations in subjects following IMP administration. |
Countries
United Kingdom
Outcome results
None listed