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A Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes With Inadequately Controlled Hypertension on an ACEI or ARB and an Additional Antihypertensive Medication

This study has been completed.
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01195662
First received: September 3, 2010
Last updated: December 2, 2015
Last verified: December 2015
Results First Received: February 7, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Condition: Type 2 Diabetes
Interventions: Drug: Dapagliflozin
Drug: Placebo matching 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
Recruitment: 29-Oct-2010 to 04-Oct-2012. Original study had 3 arms but 5 mg dapagliflozin arm was discontinued with Protocol Amendment 8 (implemented 01-Nov-2011) because totality of data in development program showed that once daily 10-mg dapagliflozin provides optimal efficacy with safety and tolerance. Study continued to enroll with 2 arms.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
2245 enrolled. 1213 completed enrollment;1032 not completed:1 adverse event (AE), 65 withdrew consent (WC), 7 lost to follow up (LTF), 2 administrative (admin), 934 criteria not met, 2 non-compliant, 21 other. Lead-In: 588 randomized; 625 not randomized: 6 AE, 69 WC, 13 LTF, 8 admin, 2 at request, 497 criteria not met, 11 non-compliant, 19 other.

Reporting Groups
  Description
Placebo Matching Dapagliflozin Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Dapagliflozin 10 mg Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)

Dapagliflozin: Tablets, Oral, 5 mg, once a day for up to12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.

This arm was discontinued with Amendment 8 to the protocol (implemented 1 November 2011) and the other 2 arms continued to enroll. This arm is not included in primary and secondary efficacy analysis.


Participant Flow for 2 periods

Period 1:   Double Blind Treatment Period
    Placebo Matching Dapagliflozin   Dapagliflozin 10 mg   Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
STARTED   224   225   133 
COMPLETED   202   211   119 
NOT COMPLETED   22   14   14 
Adverse Event                4                1                2 
Withdrawal by Subject                6                4                4 
Lost to Follow-up                3                2                3 
Administrative reason                2                1                1 
Requested discontinue treatment                1                0                1 
No Longer Meets Criteria                1                5                2 
Lack of Efficacy                2                0                0 
Non-specified                3                0                0 
Missing disposition information                0                1                1 

Period 2:   Follow-Up(Week 13/1 Week Post Last Dose)
    Placebo Matching Dapagliflozin   Dapagliflozin 10 mg   Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
STARTED   203 [1]   209 [2]   120 [3] 
COMPLETED   200   209   119 
NOT COMPLETED   3   0   1 
Withdrawal by Subject                2                0                1 
non-specified                1                0                0 
[1] 1 participant discontinued drug but remained in study and entered Follow-Up.
[2] 2 participants completed treatment period but chose not to enter follow up period.
[3] 1 participant discontinued drug but remained in the study and entered the follow up period.



  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.
Participants in Double-Blind Period who were randomized and treated with at least one dose of double-blind study medication.

Reporting Groups
  Description
Placebo Matching Dapagliflozin Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Dapagliflozin 10 mg Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Dagagliflozin 5 mg (Arm Discontinued With Amendment 8) Dapagliflozin: Tablets, Oral, 5 mg, once daily, Up to 12 weeks. This arm discontinued with implementation of Amendment 8 to the protocol (1 November 2011). Study continued to enroll participants in other 2 arms post Amendment 8. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Total Total of all reporting groups

Baseline Measures
   Placebo Matching Dapagliflozin   Dapagliflozin 10 mg   Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)   Total 
Overall Participants Analyzed 
[Units: Participants]
 224   225   133   582 
Age, Customized 
[Units: Participants]
       
Less than (<) 65 years   198   198   118   514 
Greater than, equal (>=) to 65 and < 75 years   25   23   14   62 
>= 75 years   1   4   1   6 
Gender 
[Units: Participants]
       
Female   95   107   52   254 
Male   129   118   81   328 
Race/Ethnicity, Customized [1] 
[Units: Participants]
       
White   157   160   84   401 
Black or African American   17   19   9   45 
Asian   38   34   36   108 
Other Race   12   12   4   28 
Ethnicity Hispanic/Latino   41   47   21   109 
Ethnicity Not Hispanic/Latino   40   38   16   94 
Ethnicity Not Reported   143   140   96   379 
[1] Ethnicity was collected and summarized only for USA participants.
Body Mass Index (BMI) [1] 
[Units: Participants]
       
< 25 kg/m^2   21   17   9   47 
>=25 kg/m^2   203   208   124   535 
>=27 kg/m^2   179   178   101   458 
>=30 kg/m^2   147   141   73   361 
[1] BMI is measured by weight in kilograms (kg) divided by height in meters (m) squared (kg/m^2). Less than (<); Greater than, equal to (>=).
Hypertension Medication [1] 
[Units: Participants]
       
Thiazide or thiazide-like diuretics, no insulin   94   95   54   243 
Calcium channel and beta blockers, no insulin   114   112   79   305 
Thiazide or thiazide-like diuretics, insulin   5   6   0   11 
Calcium channel and beta blockers, insulin   11   12   0   23 
[1]

The following categories served as a randomization stratification factor:

category 1: thiazide or thiazide-like diuretics and no insulin category 2: calcium channel blockers, beta blockers, central alpha adrenergic agonist or alpha adrenergic blockers and no insulin category 3: thiazide or thiazide-like diuretics and insulin category 4: calcium channel blockers, beta blockers, central alpha adrenergic agonist or alpha adrenergic blockers and insulin



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure for 12 Week Double-Blind Treatment Period - Randomized Participants   [ Time Frame: Baseline to Week 12 ]

2.  Primary:   Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) for 12 Week Double-Blind Treatment Period - Randomized Participants   [ Time Frame: Baseline to Week 12 ]

3.  Secondary:   Adjusted Mean Change From Baseline in 24-hour Ambulatory Systolic Blood Pressure at Week 12 Last Observation Carried Forward (LOCF)   [ Time Frame: Baseline, Week 12 ]

4.  Secondary:   Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure (DBP) for 12 Week Double-Blind Treatment Period - Randomized Participants   [ Time Frame: Baseline to Week 12 ]

5.  Secondary:   Adjusted Mean Change From Baseline in 24-hr Ambulatory Diastolic Blood Pressure at Week 12 (LOCF)   [ Time Frame: Baseline, Week 12 ]

6.  Secondary:   Adjusted Mean Change From Baseline in Serum Uric Acid at Week 12 in Double-Blind Treatment Period - Randomized Participants   [ Time Frame: Baseline, Week 12 ]

7.  Secondary:   Number of Participants With Deaths,Serious Adverse Events (SAEs), Adverse Events (AEs), Hypoglycemia Events, Discontinuation Due to AEs, SAEs and Hypoglycemia, During the 12 Week Double Blind Period, Including Data After Rescue   [ Time Frame: Baseline to last dose of 12 weeks of double blind medication plus 30 days if SAE or plus 4 days if AE/hypoglycemic event ]

8.  Secondary:   Number of Participants With Marked Chemistry Laboratory Abnormalities in 12 Week Double Blind Treatment Period, Including Data After Rescue   [ Time Frame: Baseline (Day 1) to last dose double blind medication (Week 12) plus 4 days ]

9.  Secondary:   Number of Participants With Elevated Liver Laboratory Tests in Participants Treated With Double Blind 10 mg Dapagliflozin or Placebo , Including Data After Rescue   [ Time Frame: Baseline (Day 1) to last dose double blind medication (Week 12) Plus 30 days ]

10.  Secondary:   Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 12 (LOCF), Including Data After Rescue   [ Time Frame: Baseline, Week 12 ]

11.  Secondary:   Proportion of Participants With Orthostatic Hypotension at Baseline and Week 12, Including Data After Rescue   [ Time Frame: Baseline (Day 1), Week 12 ]


  Serious Adverse Events
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Time Frame 12 Weeks plus 30 days
Additional Description Baseline to last dose of 12 weeks of double blind medication plus 30 days if SAE or plus 4 days if AE/hypoglycemic event

Reporting Groups
  Description
Placebo Matching Dapagliflozin Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Dapagliflozin 10 mg Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)

Dapagliflozin: Tablets, Oral, 5 mg, once a day for up to12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.

This arm was discontinued with Amendment 8 to the protocol (implemented 1 November 2011) and the other 2 arms continued to enroll. This arm is not included in primary and secondary efficacy analysis.


Serious Adverse Events
    Placebo Matching Dapagliflozin   Dapagliflozin 10 mg   Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
Total, serious adverse events       
# participants affected / at risk   2/224 (0.89%)   6/225 (2.67%)   1/133 (0.75%) 
Cardiac disorders       
Angina pectoris † 1       
# participants affected / at risk   1/224 (0.45%)   0/225 (0.00%)   0/133 (0.00%) 
Gastrointestinal disorders       
Diverticular perforation † 1       
# participants affected / at risk   0/224 (0.00%)   1/225 (0.44%)   0/133 (0.00%) 
Infections and infestations       
Hepatitis E † 1       
# participants affected / at risk   0/224 (0.00%)   1/225 (0.44%)   0/133 (0.00%) 
Osteomyelitis † 1       
# participants affected / at risk   0/224 (0.00%)   1/225 (0.44%)   0/133 (0.00%) 
Bronchitis † 1       
# participants affected / at risk   0/224 (0.00%)   1/225 (0.44%)   0/133 (0.00%) 
Injury, poisoning and procedural complications       
Avulsion fracture † 1       
# participants affected / at risk   0/224 (0.00%)   1/225 (0.44%)   0/133 (0.00%) 
Lumbar vertebral fracture † 1       
# participants affected / at risk   0/224 (0.00%)   0/225 (0.00%)   1/133 (0.75%) 
Respiratory, thoracic and mediastinal disorders       
Asthma † 1       
# participants affected / at risk   0/224 (0.00%)   1/225 (0.44%)   0/133 (0.00%) 
Dyspnoea exertional † 1       
# participants affected / at risk   0/224 (0.00%)   1/225 (0.44%)   0/133 (0.00%) 
Skin and subcutaneous tissue disorders       
Angioedema † 1       
# participants affected / at risk   1/224 (0.45%)   0/225 (0.00%)   0/133 (0.00%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 15.1




  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
Totality of data from dapagliflozin development program as of 1 NOV 2011 showed 10 mg dapagliflozin dose provided optimal efficacy, was safe and well tolerated for the general Type 2 diabetes population, allowing the 5 mg arm to be discontinued.


  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


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01195662     History of Changes
Other Study ID Numbers: MB102-077 ST
2010-019798-13 ( EudraCT Number )
Study First Received: September 3, 2010
Results First Received: February 7, 2014
Last Updated: December 2, 2015
Health Authority: United States: Food and Drug Administration
Mexico: Secretaria de Salud
Australia: Department of Health and Ageing Therapeutic Goods Administration
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Hungary: National Institute of Pharmacy
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of the Russian Federation
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Denmark: Ministry of Health