NCT00736879

Safety and Efficacy of Dapagliflozin as Monotherapy in Subjects With Type 2 Diabetes

Completed Phase 3 Results posted Last updated 20 April 2017

What this trial tests

Phase 3 trial testing Dapagliflozin in Type 2 Diabetes Mellitus in 497 participants. Completed in 29 December 2009.

Timeline

22 September 2008

Primary endpoint
29 December 2009

29 December 2009

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	497
Start date	22 September 2008
Primary completion	29 December 2009
Estimated completion	29 December 2009
Sites	62 locations across South Africa, Russia, Mexico, Canada, Puerto Rico, United States, India

Drugs / interventions tested

• Dapagliflozin (DAPAGLIFLOZIN) — full drug profile →
• Placebo

Conditions studied

• Type 2 Diabetes Mellitus — all drugs for Type 2 Diabetes Mellitus →

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 77, any sex, with Type 2 Diabetes Mellitus. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 Last Observation Carried Forward (LOCF) - All Randomized Participants Primary · Baseline (Day 1), Week 24

Adjusted mean change in HbA1c from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available was determined(LOCF). HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication (metformin) 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 o

Group	Value	95% CI
Placebo	0.02	-0.22 – 0.25
Dapagliflozin 1mg	-0.68	-0.91 – -0.45
Dapagliflozin 2.5 mg	-0.72	-0.95 – -0.49
Dapagliflozin 5 mg	-0.82	-1.06 – -0.58

Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (LOCF) - Randomized Participants Secondary · Baseline (Day 1), Week 24

Adjusted mean change in total body weight from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available LOCF was determined. Data after rescue medication (metformin) 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. Bod

Group	Value	95% CI
Placebo	-0.96	± 0.3942
Dapagliflozin 1mg	-2.69	± 0.3820
Dapagliflozin 2.5 mg	-2.64	± 0.3776
Dapagliflozin 5 mg	-2.69	± 0.3961

Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 (LOCF) - Randomized Participants Secondary · Baseline (Day 1), Week 24

Adjusted mean change in fasting plasma glucose (FPG) from baseline at Week 24 (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. FPG was measured as milligrams per deciliter (mg/dL) by a central laboratory at qualification, lead-in, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 during double-blind period. 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

Group	Value	95% CI
Placebo	4.1	± 4.200
Dapagliflozin 1mg	-11.0	± 4.082
Dapagliflozin 2.5 mg	-21.6	± 4.025
Dapagliflozin 5 mg	-28.5	± 4.230

Adjusted Mean Change From Baseline in Effect on 2-hour Post Liquid Meal Glucose at Week 24 (LOCF) - Randomized Participants Secondary · Baseline (Day 1), Week 24

Liquid meal tolerance tests (MTTs) were scheduled to occur at Day 1 visit (MTT was to be completed 2 hours prior to first dose of treatment) and at Week 24 / End of treatment visit, or Rescue visit for participants meeting criteria for rescue due to lack of glycemic control. At Week 24, study treatment was given 1 hour before MTT was administered. Participant fasted for at least 10 hours (h) prior to both visits and abstained from tobacco, alcohol, and caffeine for 24 h prior to the MTT. The liquid meal supplement was administered over 10 minutes, starting immediately after Time 0 blood sample

Group	Value	95% CI
Placebo	8.81	± 6.4925
Dapagliflozin 1mg	-33.3	± 6.0390
Dapagliflozin 2.5 mg	-39.3	± 6.5025
Dapagliflozin 5 mg	-51.8	± 6.4973

Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response at Week 24 (LOCF) - Randomized Participants Secondary · Baseline (Day 1), Week 24

Therapeutic glycemic response was defined as HbA1c less than 7.0%. n=Number of participants with HBA1c less than (\<) 7 % at Week 24, last observation carried forward (LOCF) while N=number of randomized participants with non-missing baseline and Week 24 (LOCF) values. Percent=n/N and was adjusted for Baseline HbA1c. Data after rescue medication (metformin) was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.

Group	Value	95% CI
Placebo	34.6
Dapagliflozin 1mg	53.6
Dapagliflozin 2.5 mg	43.4
Dapagliflozin 5 mg	49.1

Adjusted Mean Change From Baseline in Waist Circumference at Week 24 (LOCF) - Randomization Participants Secondary · Baseline (Day 1), Week 24

Adjusted mean waist circumference values from baseline to Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available, last observation carried forward, (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. Waist circumference was measured centimeters (cm) and obtained at lead-in, Day 1, and Week 24 of the double-blind period. 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

Group	Value	95% CI
Placebo	-1.70	± 0.5718
Dapagliflozin 1mg	-2.50	± 0.5540
Dapagliflozin 2.5 mg	-2.31	± 0.5775
Dapagliflozin 5 mg	-3.17	± 0.5933

Number of Participants With Deaths, Serious AEs (SAEs), Adverse Events (AEs), Discontinuation Due to AEs, During the 12 Week Double Blind Period, Including Data After Rescue - All Treated Participants Secondary · Day 1 of Double Blind Period to end of Week 24 Plus 30 days

Medical Dictionary for Regulatory Activities (MedDRA), version 12.1 AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug as per the investigator. Baseline to

Death

Group	Value	95% CI
Placebo	0
Dapagliflozin 1mg	0
Dapagliflozin 2.5 mg	0
Dapagliflozin 5 mg	0

Serious Adverse Event (SAE)

Group	Value	95% CI
Placebo	0
Dapagliflozin 1mg	2
Dapagliflozin 2.5 mg	2
Dapagliflozin 5 mg	0

Related SAE

Group	Value	95% CI
Placebo	0
Dapagliflozin 1mg	2
Dapagliflozin 2.5 mg	0
Dapagliflozin 5 mg	0

Adverse Event (AE)

Group	Value	95% CI
Placebo	41
Dapagliflozin 1mg	42
Dapagliflozin 2.5 mg	43
Dapagliflozin 5 mg	39

Related Adverse Event

Group	Value	95% CI
Placebo	8
Dapagliflozin 1mg	5
Dapagliflozin 2.5 mg	9
Dapagliflozin 5 mg	5

Discontinued due to AE

Group	Value	95% CI
Placebo	0
Dapagliflozin 1mg	1
Dapagliflozin 2.5 mg	1
Dapagliflozin 5 mg	0

Number of Participants With Adverse Events of Special Interest During the 12 Week Double Blind Period - All Treated Participants Secondary · Baseline to last dose plus 4 days in 12 Week Double Blind Period

Participants with AEs of hypoglycemia, cardiac/vascular disorders, renal impairment or failure, volume depletion (hypotension/dehydration/hypovolemia), fractures, urinary stones, and other reports suggestive of genital infection or urinary tract infection (UTI) were summarized using MedDRA version 12.1. Data after rescue included for all AEs of special interest except hypoglycemia; hypoglycemia AEs were prior to rescue. Major hypoglycemic episode: symptomatic requiring 3rd party assistance due to severe impairment in consciousness or behavior with a glucose value \< 54 mg/dL and prompt recover

Cardiac Disorders AEs

Group	Value	95% CI
Placebo	0
1mg Dapagliflozin	0
2.5 mg Dapagliflozin	4
5 mg Dapagliflozin	0

Vascular Disorders AEs

Group	Value	95% CI
Placebo	4
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	2
5 mg Dapagliflozin	1

Hypoglycemia AEs (excluding data after rescue)

Group	Value	95% CI
Placebo	0
1mg Dapagliflozin	0
2.5 mg Dapagliflozin	1
5 mg Dapagliflozin	1

Major hypoglycemic episode

Group	Value	95% CI
Placebo	0
1mg Dapagliflozin	0
2.5 mg Dapagliflozin	0
5 mg Dapagliflozin	0

Minor hypoglycemic episode

Group	Value	95% CI
Placebo	0
1mg Dapagliflozin	0
2.5 mg Dapagliflozin	0
5 mg Dapagliflozin	0

Other hypoglycemic episode

Group	Value	95% CI
Placebo	0
1mg Dapagliflozin	0
2.5 mg Dapagliflozin	1
5 mg Dapagliflozin	1

AE Suggestive of Genital Infection

Group	Value	95% CI
Placebo	2
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	5
5 mg Dapagliflozin	2

AE Suggestive of UTI

Group	Value	95% CI
Placebo	1
1mg Dapagliflozin	3
2.5 mg Dapagliflozin	1
5 mg Dapagliflozin	2

Mean Change From Baseline in Seated Systolic and Diastolic Blood Pressure at Week 24, Including Data After Rescue - Treated Participants Secondary · Baseline (Day 1), Week 24

Blood pressure values were obtained on Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double blind period, after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. Blood pressure was measured in millimeters of mercury (mmHg). Data after rescue were also included. 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

Systolic Blood Pressure (n=65, 68, 65, 62)

Group	Value	95% CI
Placebo	0.8	± 1.462
Dapagliflozin 1mg	-3.7	± 1.449
Dapagliflozin 2.5 mg	-3.1	± 1.603
Dapagliflozin 5 mg	-4.6	± 1.531

Diastolic Blood Pressure (n=65, 68, 65, 62)

Group	Value	95% CI
Placebo	0.2	± 0.981
Dapagliflozin 1mg	-1.1	± 1.040
Dapagliflozin 2.5 mg	-2.0	± 0.980
Dapagliflozin 5 mg	-1.9	± 1.036

Mean Change From Baseline in Seated Heart Rate at Week 24 - Treated Participants Secondary · Baseline (Day 1), Week 24

Heart rate values were obtained after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. Heart rate was measured in beats per minute (bpm). Data after rescue were also included. 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

Group	Value	95% CI
Placebo	-1.3	± 1.178
1mg Dapagliflozin	-2.0	± 0.882
2.5 mg Dapagliflozin	-1.6	± 0.845
5 mg Dapagliflozin	-1.4	± 1.080

Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 24 (LOCF) - Treated Participants Secondary · Week 24

12-Lead electrocardiograms (ECGs) were performed at Day -14 and Week 24/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator. Baseline (BL) was Day -14 for this parameter.

Normal at BL, Normal at Week 24 (N=68, 72, 74, 68)

Group	Value	95% CI
Placebo	34
1mg Dapagliflozin	38
2.5 mg Dapagliflozin	43
5 mg Dapagliflozin	38

Abnormal BL, Normal at Week 24(N=68, 72, 74, 68)

Group	Value	95% CI
Placebo	10
1mg Dapagliflozin	5
2.5 mg Dapagliflozin	4
5 mg Dapagliflozin	7

Normal BL, Abnormal at Week 24(N=68, 72, 74, 68)

Group	Value	95% CI
Placebo	4
1mg Dapagliflozin	3
2.5 mg Dapagliflozin	4
5 mg Dapagliflozin	1

Abnormal BL, Abnormal at Week 24(N=68, 72, 74, 68)

Group	Value	95% CI
Placebo	16
1mg Dapagliflozin	23
2.5 mg Dapagliflozin	14
5 mg Dapagliflozin	16

Reported at BL, Not Reported at Week 24

Group	Value	95% CI
Placebo	4
1mg Dapagliflozin	3
2.5 mg Dapagliflozin	9
5 mg Dapagliflozin	6

Number of Participants With Marked Laboratory Abnormalities in 24 Week Double Blind Treatment Period - Treated Participants Secondary · Baseline to Week 24/end of treatment plus 4 days

Safety laboratory measurements were obtained at Day 1, Weeks 1, 2, 4, 8, 12, 20, and 24 in the double blind Period. Baseline was defined as the last assessment prior to the start of the first dose of the double-blind study medication. Data included from baseline up to and including the last day of treatment plus 4 days. Data after rescue was also included. Abbreviations; Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); greater than (\>) less than (\<); Units per liter (U/L), alanine aminotransferase (ALT); aspartate aminotransfer

Hematocrit High >55% (N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	0
1mg Dapagliflozin	0
2.5 mg Dapagliflozin	1
5 mg Dapagliflozin	0

Hemoglobin High >18 g/dL(N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	1
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	1
5 mg Dapagliflozin	1

Creatinine High >=1.5*PreRX(N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	2
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	1
5 mg Dapagliflozin	4

AST 3*ULN (N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	1
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	0
5 mg Dapagliflozin	0

ALT 3*ULN (N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	1
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	0
5 mg Dapagliflozin	0

ALT 5*ULN (N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	1
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	0
5 mg Dapagliflozin	0

AST or ALT >3*ULN (N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	1
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	0
5 mg Dapagliflozin	0

AST or ALT >5*ULN (N=68, 72, 74, 67)

Group	Value	95% CI
Placebo	1
1mg Dapagliflozin	1
2.5 mg Dapagliflozin	0
5 mg Dapagliflozin	0

Adverse events — posted to ClinicalTrials.gov

Time frame: 24 Weeks plus 30 days; Day 1 of double blind treatment to last patient, last visit.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Dapagliflozin 1mg

Serious: 2/72 (3%)

Deaths: —

Dapagliflozin 2.5 mg

Serious: 2/74 (3%)

Deaths: —

Dapagliflozin 5 mg

Serious: 0/68 (0%)

Deaths: —

Placebo

Serious: 0/68 (0%)

Deaths: —

Serious adverse events (4 terms)

Reaction	System	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg	Placebo
Convulsion	Nervous system disorders	—	—	—	—
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—
Tuberculosis	Infections and infestations	—	—	—	—

Other adverse events (6 terms — click to expand)

Reaction	System	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg	Placebo
Headache	Nervous system disorders	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Pharyngitis	Infections and infestations	—	—	—	—
Hypercholesterolaemia	Metabolism and nutrition disorders	—	—	—	—
Hypertriglyceridaemia	Metabolism and nutrition disorders	—	—	—	—

Most-reported serious reactions: Convulsion, Uterine leiomyoma, Pneumonia, Tuberculosis.

Data from ClinicalTrials.gov NCT00736879 adverse events section.

Sponsor's own description

The purpose of this clinical research study is to learn if BMS-512148 (Dapagliflozin) can help reduce the blood sugar levels in subjects with Type 2 Diabetes who are not well controlled on diet and exercise alone. The safety of this treatment will also be studied

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes.
   Nauck MA. · · 2014 · cited 227× · PMID 25246775 · DOI 10.2147/dddt.s50773
2. Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials.
   Jabbour S, Seufert J, Scheen A, Bailey CJ, et al · · 2018 · cited 114× · PMID 28950419 · DOI 10.1111/dom.13124
3. The effect of dapagliflozin on renal function in patients with type 2 diabetes.
   Kohan DE, Fioretto P, Johnsson K, Parikh S, et al · · 2016 · cited 59× · PMID 26894924 · DOI 10.1007/s40620-016-0261-1
4. Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.
   Täger T, Atar D, Agewall S, Katus HA, et al · · 2021 · cited 30× · PMID 32314085 · DOI 10.1007/s10741-020-09954-8
5. Model-Informed Pediatric Dose Selection for Dapagliflozin by Incorporating Developmental Changes.
   Jo H, Pilla Reddy V, Parkinson J, Boulton DW, et al · · 2021 · cited 17× · PMID 33439535 · DOI 10.1002/psp4.12577
6. 53 &lt;sup&gt;rd&lt;/sup&gt; EASD Annual Meeting of the European Association for the Study of Diabetes : Lisbon, Portugal, 11 - 15 September 2017.
   · 2017 · cited 17× · PMID 28795195 · DOI 10.1007/s00125-017-4350-z
7. Hypersensitivity Events, Including Potentially Hypersensitivity-Related Skin Events, with Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.
   Mellander A, Billger M, Johnsson E, Träff AK, et al · · 2016 · cited 14× · PMID 27461213 · DOI 10.1007/s40261-016-0438-3
8. Abstracts of the 49th EASD (European Association for the Study of Diabetes) Annual Meeting. September 23-27, 2013. Barcelona, Spain.
   · 2013 · cited 3× · PMID 23949610 · DOI 10.1007/s00125-013-3012-z