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
  Hide 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 ]

Measure Type Primary
Measure Title 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
Measure Description The geometric mean of the maximum observed plasma concentration (Cmax) is presented below; serial blood samples for determination of study drug were collected predose (0 hours (h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h,and 60 h postdose, relative to dosing on Day 1 in each cross over period and these data are summarized in the Pharmacokinetic (PK) parameter of Cmax presented here. Plasma samples were analyzed for dapagliflozin by High Performance Liquid chromatography–Mass Spectrometry (HPLC-MS/MS) using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Dapagliflozin Cmax was derived from plasma concentration versus time data using a non-compartmental method, using a validated PK analysis program ™. Actual sampling times were used for PK calculations. Cmax was reported in ng/mL.
Time Frame Day 1 (0 h to 60 h post dose) in each period  
Safety Issue No  

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.
Pharmacokinetic (PK) Evaluable: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  41     42  
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  
[units: ng/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  133  
  ( 23% )  
  125  
  ( 27% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 0.943
90% Confidence Interval ( 0.867 to 1.026 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Primary
Measure Title 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
Measure Description AUC(INF) is area under the plasma concentration-time curve from time 0 extrapolated to infinity. Serial blood samples for determination of study drug were collected predose (0 hours (h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Actual sampling times were used for PK calculations. AUC(INF) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms*hours per milliliter (ng*h/mL).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  41     42  
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  
[units: ng*h/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  547  
  ( 23% )  
  539  
  ( 20% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ration of adjusted geometric mean [3] 0.984
90% Confidence Interval ( 0.961 to 1.008 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment B versus C in AUC(INF). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Primary
Measure Title 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
Measure Description AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method). Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Actual sampling times were used for PK calculations. AUC(0-T) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms*hours per milliliter (ng*h/mL).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  41     42  
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  
[units: ng*h/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  529  
  ( 23% )  
  523  
  ( 19% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 0.990
90% Confidence Interval ( 0.966 to 1.014 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment B versus C in AUC(0-T). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Primary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by Liquid chromatography–Mass Spectrometry (LC-MS/MS) using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). Cmax for Saxagliptin was derived from plasma concentration versus time data using a validated PK analysis program ™ and was measured in nanograms per milliliter (ng/mL).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: ng/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  23.6  
  ( 31% )  
  21.9  
  ( 33% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 0.927
90% Confidence Interval ( 0.883 to 0.972 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Primary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by Liquid chromatography–Mass Spectrometry (LC-MS/MS) using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). AUC(0-T), the area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms*hours per milliliter (ng*h/mL).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: ng*h/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  87.8  
  ( 23% )  
  87.0  
  ( 23% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 0.991
90% Confidence Interval ( 0.960 to 1.022 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Primary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). AUC(INF) was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in nanograms*hours per milliliter (ng*h/mL).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: ng*h/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  89.0  
  ( 23% )  
  88.2  
  ( 23% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 0.991
90% Confidence Interval ( 0.961 to 1.022 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. Tmax was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours.
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. 1 participant (ACB treatment sequence) withdrew consent after having received all 3 treatments and did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B). This did not impact T-HALF.

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  41     42  
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  
[units: hours]
Median ( Full Range )
  1.00  
  ( 0.50 to 2.02 )  
  1.00  
  ( 0.50 to 2.00 )  

No statistical analysis provided for 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



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. T-HALF was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours.
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. 1 participant (ACB treatment sequence) withdrew consent after having received all 3 treatments and did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B). This did not impact T-HALF.

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

Measured Values
    10mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: hours]
Mean ± Standard Deviation
  15.9  ± 7.32     13.8  ± 4.81  

No statistical analysis provided for 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



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 ]

Measure Type Secondary
Measure Title Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. CLT/F was calculated as Dose/AUC(INF)and was measured in milliliters per minute (mL/min).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  41     42  
Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population  
[units: mL/min]
Geometric Mean ( Geometric Coefficient of Variation )
  305  
  ( 24% )  
  309  
  ( 20% )  

No statistical analysis provided for Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). Actual sampling times were used for PK calculations. Cmax for 5-OH Saxagliptin (the major active metabolite of Saxagliptin) was derived from plasma concentration versus time data using a validated PK analysis program ™ and was measured in ng/mL.
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: ng/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  47.0  
  ( 30% )  
  49.6  
  ( 27% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 1.055
90% Confidence Interval ( 1.004 to 1.109 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of 5-OH saxagliptin (metabolite of saxagliptin). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method)and was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™. AUC (0-T) was measured in nanograms*hours per milliliter (ng*h/mL).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: ng*h/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  267  
  ( 22% )  
  289  
  ( 22% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 1.085
90% Confidence Interval ( 1.058 to 1.113 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of 5-OH saxagliptin (metabolite). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). AUC(INF) was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in nanograms*hours per milliliter (ng*h/mL).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    10 mg Dapagliflozin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: ng*h/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  273  
  ( 22% )  
  296  
  ( 22% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
ratio of adjusted geometric mean [3] 1.085
90% Confidence Interval ( 1.058 to 1.113 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of 5-OH saxagliptin (metabolite). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Cmax of saxagliptin total active moiety (molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin) was derived from the plasma concentration versus time profile for the saxagliptin total active moiety. Measurement was in nano Molars (nM).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: nM]
Geometric Mean ( Geometric Coefficient of Variation )
  138  
  ( 20% )  
  137  
  ( 21% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 0.994
90% Confidence Interval ( 0.960 to 1.030 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin total active moiety. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method. AUC(INF) is area under the plasma concentration-time curve from time zero extrapolated to infinity; AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method) and both were derived from the plasma concentration versus time profile using a validated PK analysis program ™. Total moiety (molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin), AUC(0-T)and AUC(INF) were measured in nano Molars*hours (nM*h).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: nM*h]
Geometric Mean ( Geometric Coefficient of Variation )
   
AUC(INF) for Saxagliptin Total Active Moiety     702  
  ( 15% )  
  735  
  ( 15% )  
AUC(0-T) for Saxagliptin Total Active Moiety     694  
  ( 15% )  
  727  
  ( 15% )  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Mixed Models Analysis
Ratio of adjusted geometric mean [3] 1.046
90% Confidence Interval ( 1.029 to 1.064 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis assesses the effect of concomitant administration of dapagliflozin on the AUC(0-T) of saxagliptin total active moiety. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin and 5-OH by LC-MS/MS using a validated method. Tmax was derived from the plasma concentration versus time profile for study drug and was measured in hours (h). Saxagliptin was the drug, 5-OH saxagliptin was the metabolite, and Saxagliptin total Active Moiety was molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin.
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: h]
Median ( Full Range )
   
Tmax of Saxagliptin     0.50  
  ( 0.50 to 2.00 )  
  1.00  
  ( 0.50 to 2.00 )  
Tmax of 5-OH Saxagliptin     1.50  
  ( 1.00 to 2.00 )  
  1.50  
  ( 1.00 to 3.00 )  
Tmax of Saxagliptin Total Active Moiety     1.00  
  ( 0.50 to 2.00 )  
  1.00  
  ( 0.50 to 2.00 )  

No statistical analysis provided for 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



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method. T-HALF was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours (h).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: h]
Mean ± Standard Deviation
   
T-HALF for Saxagliptin     5.86  ± 2.23     5.38  ± 2.17  
T-HALF for 5-OH Saxagliptin     15.9  ± 3.06     17.0  ± 2.97  

No statistical analysis provided for 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



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 ]

Measure Type Secondary
Measure Title 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
Measure Description Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Saxagliptin is the parent drug and 5-OH saxagliptin is the metabolite. The molecular weights to be used for the molar ratios were 315.42 and 331.42 for saxagliptin and 5-OH, respectively. Plasma samples were analyzed for saxagliptin and for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL and 0.200 ng/mL to 100.0 ng/mL for saxagliptin and 5-OH, respectively).
Time Frame Day 1 (0h to 60h post dose) in each period  
Safety Issue No  

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.
PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.

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

Measured Values
    5 mg Saxagliptin     5 mg Saxagliptin + 10 mg Dapagliflozin  
Number of Participants Analyzed  
[units: participants]
  42     42  
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  
[units: Molar ratio]
Geometric Mean ( Geometric Coefficient of Variation )
   
MR_Cmax     1.90  
  ( 37% )  
  2.16  
  ( 37% )  
MR_AUC(INF)     2.92  
  ( 33% )  
  3.19  
  ( 33% )  
MR_AUC(0-T)     2.89  
  ( 33% )  
  3.16  
  ( 34% )  

No statistical analysis provided for 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



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) ]

Measure Type Secondary
Measure Title Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population
Measure Description Adverse event (AE)=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE)=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. End of study was approximately 16 days and was the time for a participant to conclude each of the 3 periods (including the 6 day washout between periods).
Time Frame Day 1 to end of study (16 days)  
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 Treatment A: Single dose oral tablet of 5 mg saxagliptin..
Treatment B: Dapagliflozin 10mg Treatment B: A single oral tablet dose of 10 mg Dapagliflozin.
Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg Treatment C: Co-administration of a single dose oral tablet of 10 mg dapagliflozin plus a single dose of oral tablet of 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  
Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population  
[units: participants]
     
Participants with AEs     6     9     8  
Participants with treatment-related AEs     4     4     7  
Participants with SAEs     0     0     0  
Participants discontinuing due to AEs     0     0     0  
Deaths     0     0     0  

No statistical analysis provided for Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population



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

Measure Type Secondary
Measure Title Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population
Measure Description Fasted for 10 hours prior to samples taken. Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Lower limit of normal (LLN); upper limit of normal (ULN); pretreatment(pre-RX); treatment (RX). Hemoglobin (g/L): <0.85* pre-RX; hematocrit (vol): <0.85*pre-RX; erythrocytes (*10^12 c/L): <0.85*pre-RX; platelet count (*10^9 c/L): <0.85*LLN if pre-RX>=LLN, or if Pre-Tx <LLN; leukocytes (*10^9 c/L): <0.85*LLN if pre-RX <LLN,or <0.9*LLN if LLN<=Pre-RX<=ULN; neutrophils+bands (*10^9 c/L): <0.85*Pre-RX if Pre-RX <1.5 or <1.5 if Pre-RX >=1.5; eosinophils (*10^9 c/L): if value >0.75; basophils (*10^9 c/L): if value >0.4; monocytes (*10^9c/L): if value >2; lymphocytes (*10^9 c/L): if value <0.750 or if value >7.50.
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 A single oral tablet dose 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  
Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population  
[units: participants]
     
Leukocytes Low     0     0     1  
Neutrophils (absolute) Low     1     1     1  

No statistical analysis provided for Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population



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

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 ]

Measure Type Secondary
Measure Title Mean Change From Baseline in Heart Rate - Safety Population
Measure Description Heart rates were taken while the participant was sitting quietly for at least 5 minutes and were measured in beats per minute (bpm). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period.
Time Frame Baseline to Day 1 in 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 Heart Rate - Safety Population  
[units: bpm]
Mean ± Standard Deviation
  -4.4  ± 7.04     -4.0  ± 9.64     -4.3  ± 10.52  

No statistical analysis provided for Mean Change From Baseline in Heart Rate - Safety Population



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

Measure Type Secondary
Measure Title Mean Change From Baseline in Respiration Rate - Safety Population
Measure Description Respiration rates were taken while the participant was sitting quietly for at least 5 minutes and were measured in breaths per minute (bpm). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period.
Time Frame Baseline to Day 1 in 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.
No text entered.

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 Respiration Rate - Safety Population  
[units: bpm]
Mean ± Standard Deviation
  -0.4  ± 3.46     -1.2  ± 2.89     -0.9  ± 3.13  

No statistical analysis provided for Mean Change From Baseline in Respiration Rate - Safety Population



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

Measure Type Secondary
Measure Title Mean Change From Baseline in Temperature - Safety Population
Measure Description Participant had their temperature taken after quietly sitting for at least 5 minutes and it was measured as degrees of centigrade (C). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period.
Time Frame Baseline to Day 1 in 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 Temperature - Safety Population  
[units: degrees of centigrade]
Mean ± Standard Deviation
  -0.15  ± 0.393     -0.23  ± 0.383     -0.16  ± 0.385  

No statistical analysis provided for Mean Change From Baseline in Temperature - Safety Population



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

Measure Type Secondary
Measure Title Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population
Measure Description Fasted for 10 hours prior to samples taken. Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Lower limit of normal(LLN); upper limit of normal (ULN); pre-treatment(Pre-Rx). Alkaline phosphatase U/L:>1.25*Pre-RX if Pre-Rx >ULN or >1.25*ULN if Pre-Rx <=ULN; aspartate aminotransferase (AST) U/L: >1.25*Pre-Rx if Pre-Rx > ULN or 1.25*ULN if Pre-Rx <= ULN;alanine aminotransferase (ALT) U/L: >1.25*Pre-Rx if Pre-Rx>ULN or 1.25*ULN if Pre-Rx<=ULN;blood urea nitrogen (BUN)mmol/L: >1.1*ULN if Pre-Rx <=ULN or >1.2*Pre-Rx if Pre-Rx >ULN; total bilirubin µmol/L: >1.1*ULN if Pre-Rx <=ULN or >1.25*Pre-Rx if Pre-Rx >ULN;direct bilirubin µmol/L: >1.1*ULN if Pre-Rx <= ULN or >1.25*Pre-Rx if Pre-Rx > ULN; creatine phosphokinase (CK) U/L: >1.5*Pre-Rx if Pre-Rx >ULN or >1.5*ULN if Pre-Rx <= ULN.
Time Frame Baseline to Day 1 in 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 of 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  
Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population  
[units: participants]
     
Total Bilirubin High     1     1     1  
Direct Bilirubin High     1     1     1  
ALT High     1     0     1  
BUN High     1     0     0  
CK High     0     0     1  

No statistical analysis provided for Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population



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

Measure Type Secondary
Measure Title Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population
Measure Description Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Fasted for 10 hours prior to samples taken. LLN=lower limit of normal; ULN=upper limit of normal; pretreatment (Pre-Rx). Normals: Urine glucose qualitative: dipstick >=1 if Pre-Rx <1 or 2*Pre-Rx if Pre-Rx>=1; urine microscopic white blood cell count (WBC): >=2 if Pre-Rx <2 or >=4 if Pre-Rx >=2;urine red blood cell count (RBC):>=2 if Pre-Rx <2 or >=4 if Pre-Rx >=2.
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. Urine WBC and RBC were not done for all 42 participants. Number of participants analyzed (N) for the 3 treatments for WBC/RBC urine were 4, 8, 6, in treatment A, B, C, respectively.

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  
Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population  
[units: participants]
     
Urine Glucose High (N=42, 42, 42)     0     2     5  
Urine WBC and RBC High (N= 4, 8, 6)     0     0     1  

No statistical analysis provided for Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population



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

Measure Type Secondary
Measure Title Number of Participants With Change From Baseline in ECG Interval - Safety Population
Measure Description A 12-Lead electrocardiogram (ECG) was performed and recorded after the participant had been supine for at least 5 minutes. ECGs done at baseline (Day-1 of Period 1) and at end of study; therefore the results are presented by sequence, and cannot be presented by treatment. QT interval (measure between Q wave and T wave in the heart's electrical cycle); and QT interval corrected for heart rate using Fridericia's formula (QTcF) were measured in milliseconds (msec). Abnormality criteria: QT/QTcF QT or QTcF >450 msec and <=480 msec at any postdose time point and not present at baseline. QT or QTcF >480 msec and <=500 msec at any postdose time point and not present at baseline QT or QTcF >500 msec at any postdose time point and not present at baseline. QT/QTcF Increase from baseline >60 msec for at least 1 postdose measurement. Increase from baseline in QT or QTcF >30 msec for at least 1 postdose measurement, but <=60 msec for all postdose measurements.
Time Frame Baseline to end of study (16 days)  
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
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.

Measured Values
    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  
Number of Participants Analyzed  
[units: participants]
  7     7     7     7     7     7  
Number of Participants With Change From Baseline in ECG Interval - Safety Population  
[units: participants]
           
QT change from baseline >60 msec     0     0     0     1     0     0  
QT change from baseline >30 msec; <=60 msec     0     4     0     0     0     0  
QTcF change from baseline >60 msec     0     0     0     0     0     0  
QTcF change from baseline >30 msec; <=60 msec     0     0     0     0     0     0  

No statistical analysis provided for Number of Participants With Change From Baseline in ECG Interval - Safety Population




  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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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01662999     History of Changes
Other Study ID Numbers: CV181-191
Study First Received: August 9, 2012
Results First Received: November 1, 2013
Last Updated: June 4, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board