Drug Interaction Study of Saxagliptin in Combination With Dapagliflozin in Healthy Participants

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01662999
First received: August 9, 2012
Last updated: June 4, 2014
Last verified: June 2014
Results First Received: November 1, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Crossover Assignment;   Masking: Open Label
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: Saxagliptin
Drug: Dapagliflozin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
20 August 2012 to 29 November 2012. Phase 1 Clinical Pharmacology center with healthy, fasted participants.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
89 participants enrolled; 42 randomized and treated with study drug. 47 not randomized for following reasons: 3 withdrew consent, 38 no longer met study criteria, 6 had other reasons. Treatment was administered on Day 1 of each period after fast of 10 hours; Washout began after single dose in the period and was for at least 6 days.

Reporting Groups
  Description
A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin)

Single dose of:

Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral

A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin

Single dose of:

Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral

B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin)

Single dose of:

Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral

B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin

Single dose of:

Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral

C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin

Single dose of:

Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral

C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin

Single dose of:

Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment A: Saxagliptin 5mg, Tablet


Participant Flow for 3 periods

Period 1:   Period 1
    A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin)     A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin     B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin)     B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin     C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin     C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin  
STARTED     7     7     7     7     7     7  
COMPLETED     7     7     7     7     7     7  
NOT COMPLETED     0     0     0     0     0     0  

Period 2:   Period 2
    A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin)     A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin     B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin)     B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin     C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin     C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin  
STARTED     7     7     7     7     7     7  
COMPLETED     7     7     7     7     7     7  
NOT COMPLETED     0     0     0     0     0     0  

Period 3:   Period 3
    A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin)     A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin     B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin)     B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin     C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin     C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin  
STARTED     7     7     7     7     7     7  
COMPLETED     7     6 [1]   7     7     7     7  
NOT COMPLETED     0     1     0     0     0     0  
Withdrawal by Subject                 0                 1                 0                 0                 0                 0  
[1] Participant did not provide 36, 48, or 60 hour samples in this period for Treatment B.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin) Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral.
A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral.
B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin) Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral
B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral.
C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets,Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral.
C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral.
Total Total of all reporting groups

Baseline Measures
    A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin)     A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin     B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin)     B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin     C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin     C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin     Total  
Number of Participants  
[units: participants]
  7     7     7     7     7     7     42  
Age  
[units: participants]
             
<=18 years     0     0     0     0     0     0     0  
Between 18 and 65 years     7     7     7     7     7     7     42  
>=65 years     0     0     0     0     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  36.1  ± 6.47     28.7  ± 5.02     27.7  ± 6.99     32.0  ± 6.51     34.4  ± 5.74     33.3  ± 7.95     32.0  ± 6.81  
Gender  
[units: participants]
             
Female     2     2     2     3     2     2     13  
Male     5     5     5     4     5     5     29  
Region of Enrollment  
[units: participants]
             
United States     7     7     7     7     7     7     42  
Body Surface Area (m^2) [1]
[units: m^2]
Mean ± Standard Deviation
  1.90  ± 0.187     1.92  ± 0.145     1.91  ± 0.208     1.95  ± 0.170     1.94  ± 0.166     1.85  ± 0.108     1.91  ± 0.160  
Body Weight (kg) [2]
[units: kg]
Mean ± Standard Deviation
  77.94  ± 12.250     78.94  ± 8.100     76.01  ± 14.589     80.73  ± 11.903     79.64  ± 11.223     71.71  ± 6.404     77.50  ± 10.813  
[1] Body surface area was measured in meters squared (m^2) prior to first dose of study drug (Day -1).
[2] Body weight was measured in kilograms (k) prior to first dose of study drug (Day -1).



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin From a Single Dose of Dapagliflozin Versus Cmax of Dapagliflozin From Co-administered Saxagliptin Plus Dapagliflozin - Pharmacokinetic Evaluable Population   [ Time Frame: Day 1 (0 h to 60 h post dose) in each period ]

2.  Primary:   Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity [AUC(INF)] of Dapagliflozin From a Single Dose of Dapagliflozin Versus AUC (INF) of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

3.  Primary:   Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus AUC(0-T) for Dapagliflozin When Co-administered With 5 mg Saxagliptin   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

4.  Primary:   Maximum Observed Concentration (Cmax) of a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

5.  Primary:   AUC(0-T) of Saxagliptin From Single Dose 5 mg Saxagliptin Versus AUC(0-T) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

6.  Primary:   AUC(INF) of Saxagliptin From a Single Dose of 5 mg Saxagliptin Versus AUC(INF) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

7.  Secondary:   Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus Tmax of Dapagliflozin When Co-administered With 5 mg Saxagliptin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

8.  Secondary:   Half-life (T-HALF) of Dapagliflozin From a Single Dose of Dapagliflozin Versus T-Half of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

9.  Secondary:   Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

10.  Secondary:   Cmax of 5-Hydroxy (5-OH) Saxagliptin From a Single Dose Saxagliptin Versus Cmax of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

11.  Secondary:   AUC(0-T) of 5-OH Saxagliptin From Single Dose Saxagliptin Versus AUC(0-T) of 5-OH From Saxagliptin Co-administered With Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

12.  Secondary:   AUC(INF) of 5-OH Saxagliptin From a Single Dose Saxagliptin Versus AUC(INF) of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

13.  Secondary:   Cmax of the Saxagliptin Total Active Moiety From a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

14.  Secondary:   AUC(INF) and AUC(0-T) of the Saxagliptin Total Active Moiety From a Single Dose 5 mg Saxagliptin Versus AUC(INF) and AUC(0-T) of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

15.  Secondary:   Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

16.  Secondary:   Half-life (T-HALF) of Saxagliptin, and 5-OH Saxagliptin From Single Dose 5 mg Saxagliptin Versus T-HALF of Saxagliptin and 5-OH From Co-administered Saxagliptin With 10 mg Dapagliflozin - PK Evaluable Population   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

17.  Secondary:   Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable   [ Time Frame: Day 1 (0h to 60h post dose) in each period ]

18.  Secondary:   Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population   [ Time Frame: Day 1 to end of study (16 days) ]

19.  Secondary:   Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population   [ Time Frame: Baseline to Day 1 of each period ]

20.  Secondary:   Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population   [ Time Frame: Baseline to Day 1 of each period ]
  Hide Outcome Measure 20

Measure Type Secondary
Measure Title Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population
Measure Description Blood pressure was taken while the participant was quietly seated for at least 5 minutes. Blood pressure was measured in millimeters of mercury (mmHg). Baseline was Day -1 in Period 1; study drug was administered on Day 1 of each crossover period.
Time Frame Baseline to Day 1 of each period  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population = All participants who received at least one dose of any study drug.

Reporting Groups
  Description
Treatment A: Saxagliptin 5mg Single dose oral tablet of 5 mg saxagliptin.
Treatment B: Dapagliflozin 10mg Single dose oral tablet of 10 mg dapagliflozin.
Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg Co-administration of a single dose oral tablet of 10 mg dapagliflozin plus a single dose of oral tablet 5mg saxagliptin.

Measured Values
    Treatment A: Saxagliptin 5mg     Treatment B: Dapagliflozin 10mg     Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg  
Number of Participants Analyzed  
[units: participants]
  42     42     42  
Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population  
[units: mmHg]
Mean ± Standard Deviation
     
Systolic Blood Pressure     -6.0  ± 7.41     -4.6  ± 8.13     -7.2  ± 8.35  
Diastolic Blood Pressure     -2.6  ± 4.94     -2.0  ± 4.86     -3.3  ± 6.23  

No statistical analysis provided for Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population



21.  Secondary:   Mean Change From Baseline in Heart Rate - Safety Population   [ Time Frame: Baseline to Day 1 in each period ]

22.  Secondary:   Mean Change From Baseline in Respiration Rate - Safety Population   [ Time Frame: Baseline to Day 1 in each period ]

23.  Secondary:   Mean Change From Baseline in Temperature - Safety Population   [ Time Frame: Baseline to Day 1 in each period ]

24.  Secondary:   Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population   [ Time Frame: Baseline to Day 1 in each period ]

25.  Secondary:   Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population   [ Time Frame: Baseline to Day 1 of each period ]

26.  Secondary:   Number of Participants With Change From Baseline in ECG Interval - Safety Population   [ Time Frame: Baseline to end of study (16 days) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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