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

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

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.
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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 ]

Show Outcome Measure 1

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 ]

Show Outcome Measure 2

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 ]

Show Outcome Measure 3

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 ]

Show Outcome Measure 4

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 ]

Show Outcome Measure 5

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 ]

Show Outcome Measure 6

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 ]

Show Outcome Measure 7

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 ]

Show Outcome Measure 8

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 ]

Show Outcome Measure 9

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 ]

Show Outcome Measure 10

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 ]

Show Outcome Measure 11

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 ]

Show Outcome Measure 12

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 ]

Show Outcome Measure 13

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 ]

Show Outcome Measure 14

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 ]

Show Outcome Measure 15

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 ]

Show Outcome Measure 16

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 ]

Show Outcome Measure 17

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) ]

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19. Secondary:

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

Show Outcome Measure 19

20. Secondary:

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

Show Outcome Measure 20

21. Secondary:

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

Show Outcome Measure 21

22. Secondary:

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

Show Outcome Measure 22

23. Secondary:

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

Show Outcome Measure 23

24. Secondary:

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

Show Outcome Measure 24

25. Secondary:

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

Show Outcome Measure 25

26. Secondary:

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

Show Outcome Measure 26

Serious Adverse Events

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Other Adverse Events

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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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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

Results Point of Contact:

Name/Title: Boaz Hirschberg
Organization: AstraZeneca Pharmaceuticals
e-mail: ClinicalTrialTransparency@astrazeneca.com

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:	April 21, 2015
Health Authority:	United States: Food and Drug Administration United States: Institutional Review Board