Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to demonstrate bioequivalence of coadministered drugs on healthy subjects.
Interventions
DRUGSaxagliptin
DRUGDapagliflozin
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Signed Informed Consent Form * Signed written informed consent must be obtained from the subjects in accordance with requirements of the study center's IRB or IEC before the initiation of any protocol-required procedures. 2. Target Population * Healthy subjects as determined by no clinically significant deviation from normal in medical history, psychiatric history, physical examination findings, vital sign measurements, 12-lead ECG measurements, physical measurements, and clinical laboratory test results. 3. Age and Reproductive Status * Males and females, ages 19 to 55 years, inclusive. To extent possible, the distribution of men and women between the sequences will be balanced * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. * Women must not be breastfeeding. d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs saxagliptin and dapagliflozin plus 5 half lives of study drug dapagliflozin (the longer half life between the 2 drugs; 3 days) for a total of 3 days following treatment completion. e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs saxagliptin and dapagliflozin plus 5 half lives of dapagliflozin (the longer half life between the 2 drugs; 3 days) for a total of 3 days following treatment completion. f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section
Exclusion criteria
* Any significant acute or chronic medical illness. * Current or recent (within 3 months of study drug administration) gastrointestinal disease that could impact upon the absorption of study drug * Any other sound medical, psychiatric, and/or social reason as determined by the investigator * Any major surgery within 4 weeks of study drug administration. * Any prior GI surgery including cholecystectomy (remote history of appendectomy will not be exclusionary). * Current, recent (within 3 months of study drug administration), or remote history of pancreatitis. * Donation of blood or plasma to a blood bank or in a clinical study (except at screening visit) within 4 weeks before study drug administration. * Blood transfusion within 4 weeks of study drug administration. h) Inability to tolerate oral medication. * Inability to be venipunctured performed and/or tolerate venous access. * Use of tobacco- or nicotine-containing products (including, but not limited to, cigarettes, pipes, e-cigarettes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months before check-in. * Drug or alcohol abuse (within 2 years of study drug administration) as defined in the Diagnostic and Statistical Manual of Mental Disorders - 4th Edition, Diagnostic Criteria for Drug and Alcohol Abuse History of glucose intolerance or diabetes mellitus. * For females, history of chronic or recurrent urinary tract infection (UTI) (defined as 3 occurrences per year) or UTI in the past 3 months. For males, any UTI within the previous 5 years that has not been thoroughly evaluated and for which an explanation is not clear. * History of recurrent (defined as 3 occurrences per year) or recent vulvovaginal mycotic infections. * Any other sound medical, psychiatric, and/or social reason as determined by the investigator. Physical and Laboratory Test Findings 1. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECGs, or clinical laboratory determinations beyond what is consistent with the target population. 2. Abnormal urinalysis at screening (may repeat once). If the urinalysis is abnormal on Day -1 of Period 1, continuation in the study is up to the investigator's discretion. The CRO medical monitor should be consulted. 3. Glucosuria or hematoria at screening or Day -1 of Period 1, repeat is not permitted. d) A positive nicotine test (ie, cotinine). e) Abnormal liver function tests (alanine or aspartate aminotransferase \[ALT or AST, respectively\], or total bilirubin). f) Any of the following on 12-lead ECG prior to study drug administration, confirmed by repeat. i) PR ≥ 210 ms ii) QRS ≥ 120 ms iii) QT ≥ 500 ms iv) QTcF ≥ 450 ms g) Positive urine screen for drugs of abuse. h) Positive urine alcohol test. i) Positive blood screen for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV)-1 or HIV-2 antibodies at screening. 4. Allergies and Adverse Drug Reaction 1. History of allergy or adverse reactions to DPP4 or SGLT inhibitors or related compounds. 2. History of any significant drug allergy (such as anaphylaxis or hepatotoxicity). 5. Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Saxagliptin Maximum Observed Concentrations (Cmax) | Day 1-3 (Period 1) and Day 8-10 (Period 2) | 5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state |
| Dapagliflozin Maximum Observed Concentrations (Cmax) | Day 1 to 3 (Period 1) and Day 8 to 10 (Period 2) | 5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state |
| Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) | Day 1-3 (Period 1) and Day 8-10 (Period 2) | 5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state |
| Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) | Day 1-3 (Period 1) and Day 8-10 (Period 2) | 5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state |
| Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | Day 1-3 (Period 1) and Day 8-10 (Period 2) | 5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state |
| Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | Day 1-3 (Period 1) and Day 8-10 (Period 2) | 5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state |
Participant flow
Recruitment details
Open-label, randomized, single-dose, 2-treatment, 2-period crossover study in 36 healthy subjects. A single dose was administered on Day 1 and Day 8 under fasted conditions. Blood samples for the plasma pharmacokinetic analysis collected over a 60-hour interval after dosing in each period
Participants by arm
| Arm | Count |
|---|---|
| Treatment AB Treatment A: Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B: Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions. | 18 |
| Treatment BA Treatment B: Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.
Treatment A: Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions. | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | Treatment AB | Treatment BA | Total |
|---|---|---|---|
| Age, Continuous | 33.6 YEARS STANDARD_DEVIATION 11.63 | 32.9 YEARS STANDARD_DEVIATION 11.34 | 33.3 YEARS STANDARD_DEVIATION 11.32 |
| Age, Customized < 65 | 18 Participants | 18 Participants | 36 Participants |
| Race/Ethnicity, Customized BLACK/AFRICAN AMERICAN | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized WHITE | 16 Participants | 17 Participants | 33 Participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 18 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 36 | 0 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])
5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time frame: Day 1-3 (Period 1) and Day 8-10 (Period 2)
Population: Evaluable PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 553 ng.h/mL | 90% Confidence Interval 5.723 |
| Treatment B | Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 561 ng.h/mL | 90% Confidence Interval 5.763 |
p-value: 0.319190% CI: [0.992, 1.034]ANOVA
Primary
Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])
5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time frame: Day 1-3 (Period 1) and Day 8-10 (Period 2)
Population: Evaluable PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) | 537 ng.h/mL | 90% Confidence Interval 5.723 |
| Treatment B | Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) | 546 ng.h/mL | 90% Confidence Interval 5.763 |
p-value: 0.245890% CI: [0.993, 1.038]ANOVA
Primary
Dapagliflozin Maximum Observed Concentrations (Cmax)
5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time frame: Day 1 to 3 (Period 1) and Day 8 to 10 (Period 2)
Population: Evaluable PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Dapagliflozin Maximum Observed Concentrations (Cmax) | 142 ng/mL | 90% Confidence Interval 28.93 |
| Treatment B | Dapagliflozin Maximum Observed Concentrations (Cmax) | 141 ng/mL | 90% Confidence Interval 37.1 |
p-value: 0.86590% CI: [0.932, 1.06]ANOVA
Primary
Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])
5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time frame: Day 1-3 (Period 1) and Day 8-10 (Period 2)
Population: Evaluable PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 97.0 ng.h/mL | 90% Confidence Interval 5.723 |
| Treatment B | Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 99.4 ng.h/mL | 90% Confidence Interval 5.763 |
p-value: 0.194790% CI: [0.993, 1.056]ANOVA
Primary
Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])
5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time frame: Day 1-3 (Period 1) and Day 8-10 (Period 2)
Population: Evaluable PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) | 95.9 ng.h/mL | 90% Confidence Interval 5.723 |
| Treatment B | Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) | 98.0 ng.h/mL | 90% Confidence Interval 5.763 |
p-value: 0.234490% CI: [0.991, 1.054]ANOVA
Primary
Saxagliptin Maximum Observed Concentrations (Cmax)
5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time frame: Day 1-3 (Period 1) and Day 8-10 (Period 2)
Population: Evaluable PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Saxagliptin Maximum Observed Concentrations (Cmax) | 26.2 ng/mL | 90% Confidence Interval 5.723 |
| Treatment B | Saxagliptin Maximum Observed Concentrations (Cmax) | 25.5 ng/mL | 90% Confidence Interval 5.763 |
p-value: 0.49590% CI: [0.915, 1.038]ANOVA