Phase III Insulin Add-On Asia Regional Program - ST

Study identifier:MB102-137

ClinicalTrials.gov identifier:NCT02096705

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A 24-week Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Trial to Evaluate Efficacy and Safety of Dapagliflozin Added to Therapy of Asian Subjects with Type 2 Diabetes Who Have Inadequate Glycemic Control on Insulin

Medical condition

diabetes

Phase

Phase 3

Healthy volunteers

Study drug

Dapagliflozin, Dapagliflozin Placebo

Sex

All

Actual Enrollment

477

Study type

Interventional

Age

18 Years +

Date

Study Start Date: 31 Mar 2014

Primary Completion Date: 28 Jan 2016

Study Completion Date: 28 Jan 2016

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Jul 2017 by AstraZeneca

Collaborators

Bristol-Myers Squibb

Inclusion and exclusion criteria

Location

Local Institution

Seoul, Republic of Korea, 134-727

Location

Local Institution

Tianjin, China

Location

Local Institution

Guangzhou, Guangdong, China, 510080

Location

Local Institution

Xi'an, Shanxi, China, 710061

Location

Local Institution

Nanjing, Jiangsu, China, 210012

Location

Local Institution

Busan, Republic of Korea, 49241

Location

Local Institution

Singapore, Singapore, 169856

Location

Local Institution

Seoul, Republic of Korea, 06351

Arms	Assigned Interventions
Experimental: Group 1: Dapagliflozin Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin	Drug: Dapagliflozin Tablet Other Name: BMS-512148
Placebo Comparator: Group 2: Dapagliflozin Placebo Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin	Drug: Dapagliflozin Placebo 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
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
477 participants were enrolled; 313 entered lead-in period; 272 participants were randomized to a treatment group. Of the 205 participants not randomized to a treatment group: 190 No longer met study criteria, 11 withdrew consent, 2 were lost to follow-up, and 2 were removed for administrative reasons.

Reporting Groups

	Description
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin

Participant Flow for 2 periods

Period 1: Treatment

	Placebo	Dapagliflozin
STARTED	133	139
COMPLETED	124	134
NOT COMPLETED	9	5
Adverse Event	6	3
Subject request to discontinue treatment	1	1
Withdrawal by Subject	1	0
Unspecified	1	1

Period 2: Follow-up

	Placebo	Dapagliflozin
STARTED	129^[1]	139^[2]
COMPLETED	125	135
NOT COMPLETED	4	4
Withdrawal by Subject	1	0
Adverse Event	2	2
Subjects not reporting status	1	2

[1]	5 participants in this arm did not complete the treatment period and rejoined for follow-up
[2]	5 participants in this arm did not complete the treatment period and rejoined for follow-up

Baseline Characteristics

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

All Randomized Participants

Reporting Groups

	Description
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin

Baseline Measures

	Placebo	Dapagliflozin	Total
Number of Participants [units: Participants]	133	139	272
Age Categorical [units: Participants]
<=18 years	0	0	0
Between 18 and 65 years	97	117	214
>=65 years	36	22	58
Age Continuous [units: years] Mean ± Standard Deviation	58.6 ± 8.91	56.5 ± 8.39	57.5 ± 8.70
Gender, Male/Female [units: Participants]
Female	69	73	142
Male	64	66	130

Outcome Measures

1. Primary Outcome Measure: Adjusted mean change in HbA1c from baseline to Week 24 [ Time Frame: Baseline (Day 1) and 24 weeks ]

Measure Type	Primary
Measure Name	Adjusted mean change in HbA1c from baseline to Week 24
Measure Description	The adjusted mean change in the percentage of Hemoglobin A1c (HbA1c) from baseline to Week 24 was reported for each arm.
Time Frame	Baseline (Day 1) and 24 weeks
Safety Issue?

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 with non-missing baseline and at least one post-baseline value

Reporting Groups

	Description
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin

Measured Values

	Placebo	Dapagliflozin
Number of Participants Analyzed [units:participants]	129	137
Adjusted mean change in HbA1c from baseline to Week 24 [units: percentage of hemoglobin] Mean (Standard Error)	0.03 (0.0707)	-0.87 (0.0666)

Statistical Analysis 1 for Adjusted mean change in HbA1c from baseline to Week 24

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measure analysis]
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.90
Standard Error of the mean	± 0.0968
95% Confidence Interval	( -1.09 to -0.71 )

[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.
[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:
	P-value for Dapagliflozin vs. placebo
[5]	Other relevant estimation information:
	Difference of Dapagliflozin from placebo

2. Secondary Outcome Measure: Adjusted mean change in fasting plasma glucose (FPG) from baseline to Week 24 [ Time Frame: Baseline (Day 1) and 24 weeks ]

Measure Type	Secondary
Measure Name	Adjusted mean change in fasting plasma glucose (FPG) from baseline to Week 24
Measure Description	The adjusted mean change from baseline to 24 weeks in Fasting Plasma Glucose (FPG) was reported for each arm in milligrams per deciliter (mg/dL).
Time Frame	Baseline (Day 1) and 24 weeks
Safety Issue?

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 with non-missing baseline and at least one post-baseline value

Reporting Groups

	Description
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin

Measured Values

	Placebo	Dapagliflozin
Number of Participants Analyzed [units:participants]	133	138
Adjusted mean change in fasting plasma glucose (FPG) from baseline to Week 24 [units: mg/dL] Mean (Standard Error)	0.07 (3.3803)	-30.62 (3.1314)

Statistical Analysis 1 for Adjusted mean change in fasting plasma glucose (FPG) from baseline to Week 24

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measure analysis]
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-30.69
Standard Error of the mean	± 4.6050
95% Confidence Interval	( -39.76 to -21.61 )

[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.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	P-value for Dapagliflozin vs. placebo
[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:
	Difference of Dapagliflozin from placebo

3. Secondary Outcome Measure: Adjusted mean change in body weight from baseline to week 24 [ Time Frame: Baseline (Day 1) and 24 weeks ]

Measure Type	Secondary
Measure Name	Adjusted mean change in body weight from baseline to week 24
Measure Description	Adjusted mean change in body weight from baseline to week 24 was reported for each arm in kilograms (kg).
Time Frame	Baseline (Day 1) and 24 weeks
Safety Issue?

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 with non-missing baseline and at least one post-baseline value

Reporting Groups

	Description
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin

Measured Values

	Placebo	Dapagliflozin
Number of Participants Analyzed [units:participants]	133	138
Adjusted mean change in body weight from baseline to week 24 [units: kilograms] Mean (Standard Error)	0.37 (0.2224)	-1.00 (0.2103)

Statistical Analysis 1 for Adjusted mean change in body weight from baseline to week 24

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measure analysis]
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-1.38
Standard Error of the mean	± 0.3057
95% Confidence Interval	( -1.98 to -0.77 )

[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.
[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:
	P-value for Dapagliflozin vs. placebo
[5]	Other relevant estimation information:
	Difference of Dapagliflozin from placebo

4. Secondary Outcome Measure: Adjusted mean change in absolute calculated mean total daily dose of insulin (TDDI) from baseline to week 24 [ Time Frame: Baseline (Day 1) and 24 weeks ]

Measure Type	Secondary
Measure Name	Adjusted mean change in absolute calculated mean total daily dose of insulin (TDDI) from baseline to week 24
Measure Description	The adjusted mean change in absolute calculated mean Total Daily Dose of Insulin (TDDI) from baseline to week 24 was reported for each arm in International Units (IU).
Time Frame	Baseline (Day 1) and 24 weeks
Safety Issue?

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 with non-missing baseline and at least one post-baseline value

Reporting Groups

	Description
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin

Measured Values

	Placebo	Dapagliflozin
Number of Participants Analyzed [units:participants]	133	139
Adjusted mean change in absolute calculated mean total daily dose of insulin (TDDI) from baseline to week 24 [units: International Units (IU)] Mean (Standard Error)	0.74 (0.3723)	-0.70 (0.3592)

Statistical Analysis 1 for Adjusted mean change in absolute calculated mean total daily dose of insulin (TDDI) from baseline to week 24

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measure analysis]
P-Value^[4]	0.0059
Mean Difference (Final Values)^[5]	-1.43
Standard Error of the mean	± 0.5171
95% Confidence Interval	( -2.45 to -0.42 )

[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.
[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:
	P-value for Dapagliflozin vs. placebo
[5]	Other relevant estimation information:
	Difference of Dapagliflozin from placebo

Serious Adverse Events

Time Frame	24 week treatment period + 30 days
Additional Description	Includes serious adverse events with onset on or after the first date/time of double-blind treatment and on or prior to the last day of double blind treatment plus 30 days. Includes non-serious adverse events with onset on or after the first date/time of double-blind treatment and on or prior to the last day of double blind treatment plus 4 days.

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin

Serious Adverse Events

Dapagliflozin

Placebo

Total, serious adverse events

# participants affected / at risk

8/139 (5.76%)

18/133 (13.53%)

Cardiac disorders

ACUTE MYOCARDIAL INFARCTION¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Cardiac disorders

ANGINA PECTORIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Cardiac disorders

CORONARY ARTERY DISEASE¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Congenital, familial and genetic disorders

MYOCARDIAL BRIDGING¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Eye disorders

CATARACT¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Eye disorders

UVEITIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Gastrointestinal disorders

GASTRITIS¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Infections and infestations

LUNG INFECTION¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Infections and infestations

NEUROSYPHILIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Injury, poisoning and procedural complications

HUMERUS FRACTURE¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Metabolism and nutrition disorders

ACIDOSIS¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Metabolism and nutrition disorders

HYPERGLYCAEMIA¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Musculoskeletal and connective tissue disorders

FOOT DEFORMITY¹,^†

# participants affected / at risk

0/139 (0.00%)

2/133 (1.50%)

# events

Musculoskeletal and connective tissue disorders

OSTEOARTHRITIS¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Musculoskeletal and connective tissue disorders

PERIARTHRITIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Musculoskeletal and connective tissue disorders

SPINAL OSTEOARTHRITIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

BILE DUCT CANCER¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

COLORECTAL CANCER¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

PROSTATE CANCER¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Nervous system disorders

ARACHNOID CYST¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Nervous system disorders

CEREBRAL INFARCTION¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Nervous system disorders

DIABETIC NEUROPATHY¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Nervous system disorders

SEIZURE¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Nervous system disorders

SYNCOPE¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Nervous system disorders

VIITH NERVE PARALYSIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/133 (0.75%)

# events

Pregnancy, puerperium and perinatal conditions

ECTOPIC PREGNANCY¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Renal and urinary disorders

CALCULUS URETERIC¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

Renal and urinary disorders

HYDRONEPHROSIS¹,^†

# participants affected / at risk

1/139 (0.72%)

0/133 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (18.1)

Other Adverse Events

Time Frame	24 week treatment period + 30 days
Additional Description	Includes serious adverse events with onset on or after the first date/time of double-blind treatment and on or prior to the last day of double blind treatment plus 30 days. Includes non-serious adverse events with onset on or after the first date/time of double-blind treatment and on or prior to the last day of double blind treatment plus 4 days.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg oral Tablet once daily for 24 weeks + Background Insulin
Placebo	Dapagliflozin Placebo 0 mg oral Tablet once daily for 24 weeks + Background Insulin

Other Adverse Events

Dapagliflozin

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

61/139 (43.88%)

61/133 (45.86%)

Infections and infestations

NASOPHARYNGITIS¹,^†

# participants affected / at risk

5/139 (3.60%)

7/133 (5.26%)

# events

Infections and infestations

UPPER RESPIRATORY TRACT INFECTION¹,^†

# participants affected / at risk

8/139 (5.76%)

9/133 (6.77%)

# events

Infections and infestations

URINARY TRACT INFECTION¹,^†

# participants affected / at risk

5/139 (3.60%)

7/133 (5.26%)

# events

Metabolism and nutrition disorders

DYSLIPIDAEMIA¹,^†

# participants affected / at risk

9/139 (6.47%)

12/133 (9.02%)

# events

Metabolism and nutrition disorders

HYPERLIPIDAEMIA¹,^†

# participants affected / at risk

31/139 (22.30%)

31/133 (23.31%)

# events

Metabolism and nutrition disorders

HYPERURICAEMIA¹,^†

# participants affected / at risk

12/139 (8.63%)

12/133 (9.02%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (18.1)

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.

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

FDA Safety Alerts and Recalls
Download
Trial Results Summaries
Available here

Contacts

Contact

Recruiting sites have contact information. Please contact directly. If there is no contact information, please email:

Clinical.Trials@bms.com

Contact Backup

First line of the email MUST contain and Site #.

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Local Institution

Local Institution

Local Institution

Local Institution

Local Institution

Local Institution

Local Institution

Local Institution

FDA Safety Alerts and Recalls

Trial Results Summaries