Bioequivalence Study Coadministered to Healthy Subjects in the Fasted State

Study identifier:CV181-364

ClinicalTrials.gov identifier:NCT02223065

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Bioequivalence Study of Fixed-dose Combination Tablet of 5 milligrams Saxagliptin/10 milligrams Dapagliflozin Relative to Their Respective Individual Components Coadministered to Healthy Subjects in the Fasted State

Medical condition

Type 2 Diabetes Mellitus

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Saxagliptin, Dapagliflozin

Sex

All

Actual Enrollment

Study type

Interventional

Age

19 Years - 55 Years

Date

Study Start Date: 01 Sept 2014

Primary Completion Date: 01 Dec 2014

Study Completion Date: 01 Dec 2014

Study design

Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science

Verification:

Verified 01 Mar 2016 by AstraZeneca Pharmaceuticals

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

1. Signed Informed Consent Form
- Signed written informed consent must be obtained from the subjects in accordance with requirements of the study center's IRB or IEC before the initiation of any protocol-required procedures.
2.Target Population
- Healthy subjects as determined by no clinically significant deviation from normal in medical history, psychiatric history, physical examination findings, vital sign measurements, 12-lead ECG measurements, physical measurements, and clinical laboratory test results.
3.Age and Reproductive Status
- Males and females, ages 19 to 55 years, inclusive. To extent possible, the distribution of men and women between the sequences will be balanced
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
- Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs saxagliptin and dapagliflozin plus 5 half lives of study drug dapagliflozin (the longer half life between the 2 drugs; 3 days) for a total of 3 days following treatment completion.
e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs saxagliptin and dapagliflozin plus 5 half lives of dapagliflozin (the longer half life between the 2 drugs;
3 days) for a total of 3 days following treatment completion.
f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section

Exclusion Criteria

- Any significant acute or chronic medical illness.
- Current or recent (within 3 months of study drug administration) gastrointestinal disease that could impact upon the absorption of study drug
- Any other sound medical, psychiatric, and/or social reason as determined by the investigator
- Any major surgery within 4 weeks of study drug administration.
- Any prior GI surgery including cholecystectomy (remote history of appendectomy will not be exclusionary).
- Current, recent (within 3 months of study drug administration), or remote history of pancreatitis.
- Donation of blood or plasma to a blood bank or in a clinical study (except at screening visit) within 4 weeks before study drug administration.
- Blood transfusion within 4 weeks of study drug administration. h) Inability to tolerate oral medication.
- Inability to be venipunctured performed and/or tolerate venous access.
- Use of tobacco- or nicotine-containing products (including, but not limited to, cigarettes, pipes, e-cigarettes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months before check-in.
- Drug or alcohol abuse (within 2 years of study drug administration) as defined in the Diagnostic and Statistical Manual of Mental Disorders - 4th Edition, Diagnostic Criteria for Drug and Alcohol Abuse
History of glucose intolerance or diabetes mellitus.
- For females, history of chronic or recurrent urinary tract infection (UTI) (defined as
3 occurrences per year) or UTI in the past 3 months. For males, any UTI within the previous 5 years that has not been thoroughly evaluated and for which an explanation is not clear.
- History of recurrent (defined as 3 occurrences per year) or recent vulvovaginal mycotic infections.
- Any other sound medical, psychiatric, and/or social reason as determined by the investigator.
Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECGs, or clinical laboratory determinations beyond what is consistent with the target population.
b) Abnormal urinalysis at screening (may repeat once). If the urinalysis is abnormal on Day -1 of Period 1, continuation in the study is up to the investigator’s discretion. The CRO medical monitor should be consulted.
c) Glucosuria or hematoria at screening or Day -1 of Period 1, repeat is not permitted. d) A positive nicotine test (ie, cotinine).
e) Abnormal liver function tests (alanine or aspartate aminotransferase [ALT or AST, respectively], or total bilirubin).
f) Any of the following on 12-lead ECG prior to study drug administration, confirmed by repeat.
i) PR ≥ 210 ms ii) QRS ≥ 120 ms iii) QT ≥ 500 ms
iv) QTcF ≥ 450 ms
g) Positive urine screen for drugs of abuse. h) Positive urine alcohol test.
i) Positive blood screen for hepatitis C virus (HCV) antibody, hepatitis B surface antigen
(HBsAg), or human immunodeficiency virus (HIV)-1 or HIV-2 antibodies at screening.
4. Allergies and Adverse Drug Reaction
a) History of allergy or adverse reactions to DPP4 or SGLT inhibitors or related compounds.
b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infectious disease) illness.
c) Inability to comply with restrictions and prohibited activities/treatments

No locations available

Arms	Assigned Interventions
Experimental: Treatment A Single oral dose of saxagliptin tablet coadministered with dapagliflozin tablet	-
Experimental: Treatment B Single oral dose of FDC (fixed-dose combination) tablet	-

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Open-label, randomized, single-dose, 2-treatment, 2-period crossover study in 36 healthy subjects. A single dose was administered on Day 1 and Day 8 under fasted conditions. Blood samples for the plasma pharmacokinetic analysis collected over a 60-hour interval after dosing in each period

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
Treatment AB	Treatment A: Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions. Treatment B: Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.
Treatment BA	Treatment B: Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions. Treatment A: Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.

Participant Flow: Overall Study

	Treatment AB	Treatment BA
STARTED	18	18
COMPLETED	18	18
NOT COMPLETED	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Treatment AB	Treatment A: Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions. Treatment B: Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.
Treatment BA	Treatment B: Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions. Treatment A: Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.

Baseline Measures

	Treatment AB	Treatment BA	Total
Number of Participants [units: Participants]	18	18	36
Age Continuous [units: YEARS] Mean ( Standard deviation )	33.6 (19 to 53)	32.9 (19 to 52)	33.3 (19 to 53)
Age, Customized [units: Participants] < 65	18	18	36
Ethnicity, Customized [units: Participants]
BLACK/AFRICAN AMERICAN	2	1	3
WHITE	16	17	33
Gender, Male/Female [units: Participants]
FEMALE	8	10	18
MALE	10	8	18

Outcome Measures

1. Primary Outcome Measure: Saxagliptin Maximum Observed Concentrations (Cmax) [ Time Frame: Day 1-3 (Period 1) and Day 8-10 (Period 2) ]

Measure Type	Primary
Measure Name	Saxagliptin Maximum Observed Concentrations (Cmax)
Measure Description	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time Frame	Day 1-3 (Period 1) and Day 8-10 (Period 2)
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.
Evaluable PK Population

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Measured Values

	Treatment A	Treatment B
Number of Participants Analyzed [units:participants]	36	36
Saxagliptin Maximum Observed Concentrations (Cmax) [units: ng/mL] Geometric Mean (90% Confidence Interval)	26.2 (24.6 to 27.8)	25.5 (24.0 to 27.1)

Statistical Analysis 1 for Saxagliptin Maximum Observed Concentrations (Cmax)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	Yes
Method^[3]	ANOVA
P-Value^[4]	0.4950
Other^[5]	0.975
90% Confidence Interval	( 0.915 to 1.038 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The specified bioequivalence limits (0.80, 1.25) for PK measures
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Dapagliflozin Maximum Observed Concentrations (Cmax) [ Time Frame: Day 1 to 3 (Period 1) and Day 8 to 10 (Period 2) ]

Measure Type	Primary
Measure Name	Dapagliflozin Maximum Observed Concentrations (Cmax)
Measure Description	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time Frame	Day 1 to 3 (Period 1) and Day 8 to 10 (Period 2)
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.
Evaluable PK Population

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Measured Values

	Treatment A	Treatment B
Number of Participants Analyzed [units:participants]	36	36
Dapagliflozin Maximum Observed Concentrations (Cmax) [units: ng/mL] Geometric Mean (90% Confidence Interval)	142 (132 to 153)	141 (132 to 152)

Statistical Analysis 1 for Dapagliflozin Maximum Observed Concentrations (Cmax)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	Yes
Method^[3]	ANOVA
P-Value^[4]	0.8650
Other^[5]	0.993
90% Confidence Interval	( 0.932 to 1.060 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The specified bioequivalence limits (0.80, 1.25) for PK measures
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) [ Time Frame: Day 1-3 (Period 1) and Day 8-10 (Period 2) ]

Measure Type	Primary
Measure Name	Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])
Measure Description	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time Frame	Day 1-3 (Period 1) and Day 8-10 (Period 2)
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.
Evaluable PK Population

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Measured Values

	Treatment A	Treatment B
Number of Participants Analyzed [units:participants]	36	36
Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) [units: ng.h/mL] Geometric Mean (90% Confidence Interval)	95.9 (90.0 to 102)	98.0 (92.0 to 104)

Statistical Analysis 1 for Saxagliptin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	Yes
Method^[3]	ANOVA
P-Value^[4]	0.2344
Other^[5]	1.022
90% Confidence Interval	( 0.991 to 1.054 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The specified bioequivalence limits (0.80, 1.25) for PK measures
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Primary Outcome Measure: Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) [ Time Frame: Day 1-3 (Period 1) and Day 8-10 (Period 2) ]

Measure Type	Primary
Measure Name	Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])
Measure Description	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time Frame	Day 1-3 (Period 1) and Day 8-10 (Period 2)
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.
Evaluable PK Population

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Measured Values

	Treatment A	Treatment B
Number of Participants Analyzed [units:participants]	36	36
Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T]) [units: ng.h/mL] Geometric Mean (90% Confidence Interval)	537 (504 to 573)	546 (512 to 582)

Statistical Analysis 1 for Dapagliflozin AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	Yes
Method^[3]	ANOVA
P-Value^[4]	0.2458
Other^[5]	1.016
90% Confidence Interval	( 0.993 to 1.038 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The specified bioequivalence limits (0.80, 1.25) for PK measures
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Primary Outcome Measure: Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) [ Time Frame: Day 1-3 (Period 1) and Day 8-10 (Period 2) ]

Measure Type	Primary
Measure Name	Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])
Measure Description	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time Frame	Day 1-3 (Period 1) and Day 8-10 (Period 2)
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.
Evaluable PK Population

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Measured Values

	Treatment A	Treatment B
Number of Participants Analyzed [units:participants]	36	36
Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) [units: ng.h/mL] Geometric Mean (90% Confidence Interval)	97.0 (91.1 to 103)	99.4 (93.3 to 106)

Statistical Analysis 1 for Saxagliptin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	Yes
Method^[3]	ANOVA
P-Value^[4]	0.1947
Other^[5]	1.024
90% Confidence Interval	( 0.993 to 1.056 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The specified bioequivalence limits (0.80, 1.25) for PK measures
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Primary Outcome Measure: Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) [ Time Frame: Day 1-3 (Period 1) and Day 8-10 (Period 2) ]

Measure Type	Primary
Measure Name	Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])
Measure Description	5-mg saxagliptin/10-mg dapagliflozin as a Fixed-dose Combination (FDC) and as Individual Tablets together in the fasted state
Time Frame	Day 1-3 (Period 1) and Day 8-10 (Period 2)
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.
Evaluable PK Population

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Measured Values

	Treatment A	Treatment B
Number of Participants Analyzed [units:participants]	36	36
Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) [units: ng.h/mL] Geometric Mean (90% Confidence Interval)	553 (518 to 591)	561 (525 to 599)

Statistical Analysis 1 for Dapagliflozin AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf])

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	Yes
Method^[3]	ANOVA
P-Value^[4]	0.3191
Other^[5]	1.013
90% Confidence Interval	( 0.992 to 1.034 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The specified bioequivalence limits (0.80, 1.25) for PK measures
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Serious Adverse Events

	Treatment A	Treatment B
Total, serious adverse events
# participants affected / at risk	0/36 (0.00%)	0/36 (0.00%)

Other Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Treatment A	Single oral dose of 5-mg saxagliptin tablet coadministered with 10-mg dapagliflozin tablet under fasted conditions.
Treatment B	Single oral dose of 5-mg saxagliptin/10-mg dapagliflozin FDC tablet under fasted conditions.

Other Adverse Events

	Treatment A	Treatment B
Total, other (not including serious) adverse events
# participants affected / at risk	0/36 (0.00%)	0/36 (0.00%)

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.

Limitations and Caveats

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
No text entered.

Results Point of Contact

Name/Title:	Eva Johnsson, Clinical Science Lead, GLOBAL_MEDICINES_DEV
Organization:	AstraZeneca AB, S-151 85 Södertälje, Sweden
Phone	+46 31 7762484 Ext: 762 484
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center Telephone no (US and Outside the US):

1-877-240-9479

Investigators

Principal Investigator

Michael Gartner

Celerion

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Trial Results Summaries