Effects of dapagliflozin on kidney function (glomerular filtration rate) in subjects with type 2 diabetes

Study identifier:MB102-035

ClinicalTrials.gov identifier:NCT00976495

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

An Exploratory Phase 2 Study to Assess the Effect of Dapagliflozin on Glomerular Filtration Rate (GFR) in Subjects with Type 2 Diabetes who have Inadequate Glycemic and Blood Pressure (BP) Control

Medical condition

Type 2 Diabetes Mellitus

Phase

Phase 2

Healthy volunteers

Study drug

Dapagliflozin, Placebo, Hydrochlorothiazide

Sex

All

Actual Enrollment

154

Study type

Interventional

Age

18 Years - 70 Years

Date

Study Start Date: 01 Oct 2009

Primary Completion Date: 01 Nov 2010

Study Completion Date: 01 Nov 2010

Study design

Allocation: Randomized
Endpoint Classification: Safety
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Basic Science

Verification:

Verified 01 Jan 2017 by AstraZeneca Pharmaceuticals

Collaborators

Astra-Zeneca, Bristol-Myers Squibb

Inclusion and exclusion criteria

Location

Orlando Clinical Research Center

Orlando, FL, United States, 32809

Location

Prism Research

St. Paul, MN, United States, 55114

Location

Compass Research, Llc

Orlando, FL, United States, 32806

Location

Zablocki Veterans Affairs Medical Center

Milwaukee, WI, United States, 53295

Location

Elite Research Institute

Miami, FL, United States, 33169

Location

Local Institution

Groningen, Netherlands, 9713 GZ

Location

Memorial Hospital Of Rhode Island

Pawtucket, RI, United States, 02860

Location

University Of Michigan

Ann Arbor, MI, United States, 48106

Arms	Assigned Interventions
Experimental: Dapagliflozin	Drug: Dapagliflozin Tablets, Oral, 10 mg, once daily, 12 weeks Other Name: BMS-512148 Drug: Placebo Tablets, Oral, 0 mg, once daily, 12 weeks
Active Comparator: Hydrochlorothiazide	Drug: Hydrochlorothiazide Tablets, Oral, 25 mg, once daily, 12 weeks

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Of 154 participants enrolled, 77 completed a qualification period. Of these 77 participants, 75 were randomized and received treatment. Of these 75 participants, 74 completed double-blind treatment 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
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Participant Flow: Overall Study

	Placebo	Dapagliflozin 10 mg	Hydrochlorothiazide 25 mg
STARTED	25	24	26
COMPLETED	25	23	26
NOT COMPLETED	0	1	0
Withdrawal by Subject	0	1	0

Baseline Characteristics

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

All randomized participants who received at least 1 dose of study medication

Reporting Groups

	Description
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Baseline Measures

	Placebo	Dapagliflozin 10 mg	Hydrochlorothiazide 25 mg	Total
Number of Participants [units: Participants]	25	24	26	75
Age Continuous [units: Years] Mean ± Standard Deviation	58.0 ± 9.50	53.7 ± 9.38	54.8 ± 9.87	55.5 ± 9.63
Age, Customized [units: Participants]
Younger than 65 years	19	22	21	62
65 - 75 years	6	2	5	13
Gender, Customized [units: Participants]
Male	18	16	15	49
Female	7	8	11	26
Race/Ethnicity, Customized [units: Participants]
White	17	19	20	56
Black/African American	4	4	4	12
Asian	3	0	2	5
Other	1	1	0	2

Outcome Measures

1. Primary Outcome Measure: Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF]) [ Time Frame: From Baseline to Week 12 ]

Measure Type	Primary
Measure Name	Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF])
Measure Description	Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. If no Week 12 measurement was available, the last available post-baseline measurement obtained on or after Day 23 was used regardless of rescue medication. Measurements were obtained during radomization visit, and Week 12 in the double-blind period by a central laboratory.
Time Frame	From Baseline to Week 12
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.
All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 12 (MLOCF)

Reporting Groups

	Description
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Measured Values

	Placebo	Dapagliflozin 10 mg	Hydrochlorothiazide 25 mg
Number of Participants Analyzed [units:participants]	25	22	26
Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF]) [units: % Change of Baseline GFR] Mean (Standard Error)	-2.92 ( 2.0133)	-10.76 (1.9684)	-3.40 (1.9756)

Statistical Analysis 1 for Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF])

Groups^[1]	Placebo, Dapagliflozin 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	-8.07
Standard Error of the mean	± 2.7177
95% Confidence Interval	( -13.34 to -2.49 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

Statistical Analysis 2 for Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF])

Groups^[1]	Dapagliflozin 10 mg, Hydrochlorothiazide 25 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	-7.62
Standard Error of the mean	± 2.7068
95% Confidence Interval	( -12.87 to -2.06 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

2. Secondary Outcome Measure: Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 12 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])
Measure Description	Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Measurements were obtained during lead-in, and Week 12 in the double-blind period.
Time Frame	From Baseline to Week 12
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.
All randomized participants who received study medication and had nonmissing ASBP values at baseline and Week 12 (LOCF)

Reporting Groups

	Description
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Measured Values

	Placebo	Dapagliflozin 10 mg	Hydrochlorothiazide 25 mg
Number of Participants Analyzed [units:participants]	25	22	25
Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) [units: mmHg] Mean (Standard Error)	-0.88 (1.6373)	-3.28 (1.7674)	-6.55 (1.6833)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])

Groups^[1]	Placebo, Dapagliflozin 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	-2.40
Standard Error of the mean	± 2.3613
95% Confidence Interval	( -7.11 to 2.31 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])

Groups^[1]	Dapagliflozin 10 mg, Hydrochlorothiazide 25 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	3.26
Standard Error of the mean	± 2.4112
95% Confidence Interval	( -1.55 to 8.08 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

3. Secondary Outcome Measure: Adjusted Mean Change From Baseline in Daytime (0900 to 2100 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 12 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in Daytime (0900 to 2100 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])
Measure Description	Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Measurements were obtained during lead-in, and Week 12 in the double-blind period.
Time Frame	From Baseline to Week 12
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.
All randomized participants who received study medication and had nonmissing ASBP values at baseline and Week 12 (LOCF)

Reporting Groups

	Description
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Measured Values

	Placebo	Dapagliflozin 10 mg	Hydrochlorothiazide 25 mg
Number of Participants Analyzed [units:participants]	25	22	25
Adjusted Mean Change From Baseline in Daytime (0900 to 2100 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) [units: mmHg] Mean (Standard Error)	-1.55 (1.7247)	-5.93 (1.8673)	-6.83 (1.7671)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in Daytime (0900 to 2100 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])

Groups^[1]	Placebo, Dapagliflozin 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	-4.38
Standard Error of the mean	± 2.5072
95% Confidence Interval	( -9.38 to 0.63 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in Daytime (0900 to 2100 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])

Groups^[1]	Dapagliflozin 10 mg, Hydrochlorothiazide 25 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	0.91
Standard Error of the mean	± 2.5474
95% Confidence Interval	( -4.18 to 5.99 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

4. Secondary Outcome Measure: Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 12 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])
Measure Description	Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Measurements were obtained during lead-in, and Week 12 in the double-blind period.
Time Frame	From Baseline to Week 12
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.
All randomized participants who received study medication and had nonmissing ASBP values at baseline and Week 12 (LOCF)

Reporting Groups

	Description
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Measured Values

	Placebo	Dapagliflozin 10 mg	Hydrochlorothiazide 25 mg
Number of Participants Analyzed [units:participants]	25	22	25
Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) [units: mmHg] Mean (Standard Error)	-0.61 (1.9468)	-0.45 (2.0822)	-7.76 (1.9857)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])

Groups^[1]	Placebo, Dapagliflozin 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	0.16
Standard Error of the mean	± 2.7812
95% Confidence Interval	( -5.39 to 5.71 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])

Groups^[1]	Dapagliflozin 10 mg, Hydrochlorothiazide 25 mg
Non-Inferiority/Equivalence Test^[2]	No
Mean Difference (Final Values)^[5]	7.31
Standard Error of the mean	± 2.8135
95% Confidence Interval	( 1.70 to 12.93 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	ANCOVA was applied. Given that this was a pilot study designed for exploratory analysis, formal statistical hypothesis testing was not performed.

Serious Adverse Events

Time Frame	Onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment 12 weeks plus 4 days for non-serious adverse event; plus 30 days for serious adverse event.
Additional Description	No text entered.

Reporting Groups

	Description
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Serious Adverse Events

Placebo

Dapagliflozin 10 mg

Hydrochlorothiazide 25 mg

Total, serious adverse events

# participants affected / at risk

0/25 (0.00%)

3/24 (12.50%)

0/26 (0.00%)

Infections and infestations

LOCALISED INFECTION¹,^†

# participants affected / at risk

0/25 (0.00%)

1/24 (4.17%)

0/26 (0.00%)

# events

Injury, poisoning and procedural complications

INTERVERTEBRAL DISC INJURY¹,^†

# participants affected / at risk

0/25 (0.00%)

1/24 (4.17%)

0/26 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

PLEURITIC PAIN¹,^†

# participants affected / at risk

0/25 (0.00%)

1/24 (4.17%)

0/26 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA Version: 13.1

Other Adverse Events

Time Frame	Onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment 12 weeks plus 4 days for non-serious adverse event; plus 30 days for serious adverse event.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Placebo	Tablet, oral, once daily for 12 weeks
Dapagliflozin 10 mg	Tablet, oral, once daily for 12 weeks
Hydrochlorothiazide 25 mg	Tablet, oral, once daily for 12 weeks

Other Adverse Events

Placebo

Dapagliflozin 10 mg

Hydrochlorothiazide 25 mg

Total, other (not including serious) adverse events

# participants affected / at risk

2/25 (8.00%)

6/24 (25.00%)

9/26 (34.62%)

Renal and urinary disorders

POLLAKIURIA¹,^†

# participants affected / at risk

1/25 (4.00%)

3/24 (12.50%)

1/26 (3.85%)

# events

Renal and urinary disorders

NOCTURIA¹,^†

# participants affected / at risk

1/25 (4.00%)

2/24 (8.33%)

0/26 (0.00%)

# events

Skin and subcutaneous tissue disorders

HYPERHIDROSIS¹,^†

# participants affected / at risk

0/25 (0.00%)

0/24 (0.00%)

2/26 (7.69%)

# events

Skin and subcutaneous tissue disorders

INGROWING NAIL¹,^†

# participants affected / at risk

0/25 (0.00%)

0/24 (0.00%)

2/26 (7.69%)

# events

Nervous system disorders

HEADACHE¹,^†

# participants affected / at risk

0/25 (0.00%)

1/24 (4.17%)

4/26 (15.38%)

# events

Metabolism and nutrition disorders

MALAISE¹,^†

# participants affected / at risk

0/25 (0.00%)

0/24 (0.00%)

2/26 (7.69%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA Version: 13.1

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:	Anna Maria Langkilde
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
Download
Publication
Download
MB102035_Redacted_CSR_synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

First line of email MUST contain NCT# & Site#. Only trial are recruiting have contact information at this time.

Investigators

Principal Investigator

Bristol-Myers Squibb

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Orlando Clinical Research Center

Prism Research

Compass Research, Llc

Zablocki Veterans Affairs Medical Center

Elite Research Institute

Local Institution

Memorial Hospital Of Rhode Island

University Of Michigan

For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm

Publication

MB102035_Redacted_CSR_synopsis

Trial Results Summaries