Study of Dapagliflozin in Combination With Metformin XR to Initiate the Treatment of Type 2 Diabetes

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A Multicenter, Randomized, Double-Blind, Active Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin 10 mg in Combination With Metformin as Initial Therapy as Compared With Dapagliflozin 10 mg Monotherapy and Metformin Monotherapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00859898
• Other study ID #: MB102-034
• Secondary ID: Eudract #: 2008-
• Status: Completed
• Phase: Phase 3
• First received: March 10, 2009
• Last updated: February 4, 2014
• Start date: April 2009
• Est. completion date: May 2010

Study information

• Verified date: February 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Foundation for Pharmaceutical Studies, National Committee for Ethics in Science and Technology, The Argentine Association of Bioethics, Ministry of Health (ANMAT)Korea: Food and Drug AdministrationMexico: Federal Commission for Protection Against Health RisksPeru: Ministry of HealthPhilippines: Bureau of Food and DrugsPhilippines: Philippine Council for Health Research and DevelopmentRussia: Ministry of Health of the Russian FederationUkraine: State Pharmacological Center - Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The primary purpose of this study is to compare the change from baseline in hemoglobin A1C achieved with dapagliflozin 10 mg in combination with metformin XR as compared with metformin monotherapy and compared with Dapagliflozin monotherapy, after 24 weeks of oral administration of double-blind treatment. The safety of treatment with dapagliflozin will also be assessed in this study

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1093
• Est. completion date: May 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 77 Years

Eligibility

Inclusion Criteria:

• Treatment naive males and females, >= 18 years old and <= 77 years old, with type 2 diabetes mellitus

• Subjects must have central laboratory pre-randomization hemoglobin A1C >= 7.5 and <= 12.0%

• C-peptide >= 1.0 ng/mL (0.34 nmol/L)

• Body Mass Index <= 45 kg/m2

• Must be able to perform self monitoring of blood glucose

Exclusion Criteria:

• aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3X*upper limit of normal (ULN)

• Serum Total bilirubin >2 mg/dL (34.2 µmol/L)

• Creatinine kinase >3*ULN

• Serum creatinine >= 1.50 mg/dL (133 µmol/L) for male subjects, >= 1.40 mg/dL (124 µmol/L) for female subjects

• Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Dapagliflozin
Tablets, Oral, 10 mg, once daily, 24 weeks
• Metformin XR
Tablets, Oral, up to 2000 mg, once daily, 24 weeks
• Metformin XR
Tablets, Oral, 500 mg up to 2000 mg, once daily 24 weeks
• dapagliflozin matching Placebo

• metformin HCl Modified Release matching Placebo

Locations

Country	Name	City	State
India	Local Institution	Aminjikarai	Chennai
India	Local Institution	Bangalore	Karnataka
India	Local Institution	Chennai	Tamilnadu
India	Local Institution	Ghaziabad	Uttar Pradesh
India	Local Institution	Haryana	Karnal
India	Local Institution	Hyderabad	Andhra Pradesh
India	Local Institution	Indore	Madhya Pradesh
India	Local Institution	Jaipur
India	Local Institution	Nagpur	Maharashtra
India	Local Institution	Nagpur	Maharashtra
Korea, Republic of	Local Institution	Bucheon	Gyeonggi-Do
Korea, Republic of	Local Institution	Daegu
Korea, Republic of	Local Institution	Goyang-Si	Gyeonggi-Do
Korea, Republic of	Local Institution	Guri-Si	Gyeonggi-Do
Korea, Republic of	Local Institution	Incheon
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Sungnam	Gyeonggi-Do
Mexico	Local Institution	Aguascalientes
Mexico	Local Institution	Cuernavaca	Morelos
Mexico	Local Institution	Durango
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Merida	Yucatan
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Morelia	Michioacan
Mexico	Local Institution	Veracruz
Puerto Rico	Local Institution	Fajardo
Puerto Rico	Local Institution	Ponce
Puerto Rico	Local Institution	Ponce
Puerto Rico	Local Institution	San Juan
Puerto Rico	Local Institution	San Juan
Puerto Rico	Local Institution	San Juan
Russian Federation	Local Institution	Ekaterinaburg
Russian Federation	Local Institution	Kemerovo
Russian Federation	Local Institution	Krasnoyarsk
Russian Federation	Local Institution	Moscov
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Nizhniy Novgorod
Russian Federation	Local Institution	Nizhniy Novgorod
Russian Federation	Local Institution	Novosibirsk
Russian Federation	Local Institution	Novosibirsk
Russian Federation	Local Institution	Saint Petersburg
Russian Federation	Local Institution	Saint-Petersburg
Russian Federation	Local Institution	Samara
Russian Federation	Local Institution	Saratov
Russian Federation	Local Institution	Smolensk
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St.Petersburg
Russian Federation	Local Institution	Tyumen
Russian Federation	Local Institution	Vladimir
Russian Federation	Local Institution	Volgograd
Russian Federation	Local Institution	Voronezh
Russian Federation	Local Institution	Yaroslavl
Russian Federation	Local Institution	Yaroslavl
United States	Provident Clinical Research	Addison	Illinois
United States	Northwest Clinical Research Center	Bellevue	Washington
United States	Gilbert Medical Research, Llc	Bethany	Oklahoma
United States	Northwest Clinical Trials	Boise	Idaho
United States	Holston Medical Group	Bristol	Tennessee
United States	Community Health Care, Inc.	Canal Fulton	Ohio
United States	Metrolina Medical Research	Charlotte	North Carolina
United States	Cedar Crosse Research Center	Chicago	Illinois
United States	Lynn Institute Of The Rockies	Colorado Springs	Colorado
United States	John Muir Physician Network Clinical Research Center	Concord	California
United States	Clinical Therapeutics Corporation	Coral Gables	Florida
United States	Dallas Diabetes & Endocrine Center	Dallas	Texas
United States	Radiant Research, Inc.	Denver	Colorado
United States	Dingmans Medical	Dingmans Ferry	Pennsylvania
United States	Safe Harbor Clinical Research	E. Providence	Rhode Island
United States	Encompass Clinical Research-North Coast	Encinitas	California
United States	Williamette Valley Clinical Studies	Eugene	Oregon
United States	Seven Corners Medical Center	Falls Church	Virginia
United States	Parkway Medical Group	Fayetteville	Tennessee
United States	Integrated Medical Group Pc/Fleetwood Clinical Research	Fleetwood	Pennsylvania
United States	Southland Clinical Research Center, Inc.	Fountain Valley	California
United States	Valley Research	Fresno	California
United States	Holzer Clinic, Inc	Gallipolis	Ohio
United States	Pharmquest	Greensboro	North Carolina
United States	Southeastern Research Associates, Inc.	Greenville	South Carolina
United States	Lake Hartwell Family Medicine	Hartwell	Georgia
United States	Endocrine Associates	Houston	Texas
United States	Excel Clinical Research	Houston	Texas
United States	Juno Research, Llc.	Houston	Texas
United States	Non-Invasive Cardiovascular, Pa	Houston	Texas
United States	Texas Center For Drug Development	Houston	Texas
United States	Village Family Practice	Houston	Texas
United States	Del Rosario Medical Clinic, Inc.	Huntington Park	California
United States	Physicians Research Group	Indianapolis	Indiana
United States	Irvine Center For Clinical Research, Inc.	Irvine	California
United States	Borgess Research Institute	Kalamazoo	Michigan
United States	Wells Institute For Health Awareness	Kettering	Ohio
United States	Holston Medical Group	Kingsport	Tennessee
United States	Southwind Medical Specialists	Memphis	Tennessee
United States	Baptist Diabetes Associates	Miami	Florida
United States	Nextphase Clinical Trials, Inc.	Miami	Florida
United States	Midland Clinical Research Center	Midland	Texas
United States	Avastra Clinical Trials	Midvale	Utah
United States	Hill Country Medical Associates	New Braunfels	Texas
United States	Clinilabs, Inc.	New York	New York
United States	Newark Physician Associates	Newark	Ohio
United States	Olive Branch Family Medical Center	Olive Branch	Mississippi
United States	International Institute Of Clinical Research	Ozark	Alabama
United States	Middle Georgia Drug Study Center, Llc	Perry	Georgia
United States	Daniel G. Williams, Md	Perrysburg	Ohio
United States	Pacific Sleep Medicine Services (Avastra Clinical Trials)	Redlands	California
United States	Crescent Medical Research	Salisbury	North Carolina
United States	Covenant Clinical Research, Pa	San Antonio	Texas
United States	S.A.M. Clinical Research Center	San Antonio	Texas
United States	Wellmon Family Practice	Shippensburg	Pennsylvania
United States	Clinical Research Advantage, Inc.	Tempe	Arizona
United States	Clinical Research Advantage, Inc./Mesa Family Med Ctr, Pc	Tempe	Arizona
United States	Tulsa Clinical Research, Llc	Tulsa	Oklahoma
United States	Orange County Research Center	Tustin	California
United States	Deerbrook Medical Associates	Vernon Hills	Illinois
United States	Tidewater Integrated Medical Research	Virginia Beach	Virginia
United States	Metabolic Research Institute, Inc.	W Palm Beach	Florida
United States	Integris Family Care Yukon	Yukon	Oklahoma
United States	Physician Research, Inc.	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Bristol-Myers Squibb	AstraZeneca

Countries where clinical trial is conducted

United States,  India,  Korea, Republic of,  Mexico,  Puerto Rico,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 (Last Observation Carried Forward) - Randomized Treated Participants	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, ie, last observation carried forward (LOCF) was determined. HbA1c was measured as percent of hemoglobin by a central laboratory. 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. HbA1c measurements were obtained during the Qualification and Lead-In Periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the Double-Blind Period.	Week 24	No
Secondary	Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (LOCF) - Randomized, Treated Participants	Data after rescue medication was excluded from this analysis. FPG was measured as milligrams per deciliter (mg/dL) by a central laboratory. 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. FPG measurements were obtained during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the Double-Blind Period.	Week 24	No
Secondary	Percent Adjusted for Baseline HbA1c of Participants Achieving a Therapeutic Glycemic Response at Week 24 (LOCF) - Randomized, Treated Participants	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 was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.	Week 24	No
Secondary	Adjusted Mean Change From Baseline in HbA1C at Week 24 (LOCF) in Participants Whose Baseline HbA1C Category =9.0%	HbA1c was measured as percent of hemoglobin by a central laboratory. The population included those randomized, treated participants whose Baseline HbA1c was greater than, equal to (>=) 9.0%. 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.	Week 24	No
Secondary	The Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (LOCF) - Randomized, Treated Participants	Adjusted mean change from baseline in total body weight at Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available was determined. 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. Body weight was measured in kilograms (kg). Body weight measurements were obtained during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the Double-Blind Period.	Week 24	No
Secondary	Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuation Due to AEs, During the 12 Week Double Blind Period, Including Data After Rescue - All Treated Participants	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. Events captured from baseline to last dose plus 4 days for AEs, plus 30 days for SAEs during the Double Blind 12 Week Period. Data after rescue included.	Day 1 of Double Blind Period to end of Week 24 Plus 30 days	Yes
Secondary	Number of Participants With Adverse Events of Special Interest During the 12 Week Double Blind Period - All Treated Participants	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 13.0. Data after rescue included for all special AEs except hypoglycemia (excluded data after 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 recovery after glucose/glucagon; Minor: either symptomatic with glucose measurement < 63 mg/dL, regardless of need for 3rd party assistance, or asymptomatic with glucose < 63 mg/dL that does not qualify as major; Other: suggestive but not meeting criteria for major or minor.	Baseline to last dose plus 4 days in 12 Week Double Blind Period	Yes
Secondary	Mean Change From Baseline in Seated Systolic and Diastolic Blood Pressure at Week 24 - Treated Participants	Measurements were taken during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the Double Blind Period. Blood pressure values were obtained: after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Systolic and Diastolic pressures were 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 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.	Week 24	Yes
Secondary	Mean Change From Baseline in Seated Heart Rate at Week 24 - Randomized, Treated Participants	Measurements were taken during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the Double Blind Period. Heart rate values were obtained: after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently throughout the study. 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 last assessment on or prior to the date of the first dose of the double-blind study medication.	Week 24	Yes
Secondary	Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 24 (LOCF) - Randomized, Treated Participants	12-Lead electrocardiograms (ECGs) were performed at entry into Lead-In Period Day -7 visit 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 -7 for this parameter. Data after rescue included.	Week 24	Yes
Secondary	Number of Participants With Marked Laboratory Abnormalities (Not Including Liver Function) in 24 Week Double Blind Treatment Period, Including Data After Rescue - Randomized, Treated Participants	Laboratory samples: Qualification and Lead-In Periods, Day 1, Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of Double-Blind Period. Baseline (BL)=last assessment prior to start of first dose of double-blind study medication. Data after rescue included. Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); Units per liter (U/L), blood urea nitrogen (BUN). Marked abnormality Low (High) defined: hemoglobin <6 (>18 females or >20 males) g/dL; hematocrit <20% ( >55% females or >60% males); creatinine (>=1.5*preRX, >=2.5 mg/dL); glucose <54 (>350) mg/dL; creatine kinase (>5*ULN);calcium <7.5 (>=1 mg/dL from ULN and >= 0.5mg/dL from PreRX); sodium <130 or < 120 male/female (>150 mEq/L; potassium <=2.5 (>=6.0) mEq/L; bicarbonate <= 13 mEq/L; inorganic phosphorus: <=1.8 if age 17-65 or <=2.1 if age >=66, (>=5.6 if age 17-65 or >=5.1) mg/dL if age >=66; albumin <=2 (>6) g/dL; urine albumin(alb) / creatinine (creat) ratio (>1800 mg/g)	Baseline to Week 24/end of treatment plus 4 days	Yes
Secondary	Number of Participants With Marked Laboratory Abnormalities in Liver Function in 24 Week Double Blind Treatment Period, Including Data After Rescue - Randomized, Treated Participants	Safety laboratory measurements were obtained during the Qualification and Lead-In Periods and on Day 1 of the Double-Blind Period and at Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. BL was defined as the last assessment prior to the start of the first dose of the double-blind study medication. Data included from BL up to and including the last day of treatment plus 30 days. Liver function abnormality criteria: FDA Guidance for Industry: Premarketing Clinical Evaluation (July 2009). Data after rescue was also included. Abbreviations: Pretreatment (PreRX), upper limit of normal (ULN); greater than (>) less than (<); Units per liter (U/L), alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP). Marked abnormality Low (High) defined: ALP, AST and ALT (>3*ULN); bilirubin (>2*ULN if PreRX <= ULN; >3*ULN if PreRX > ULN); AST or ALT plus (+) bilirubin elevation: AST or ALT >3*ULN and bilirubin >1.5*ULN within 14 days on or after ALT elevation.	Baseline to Week 24/end of treatment plus 30 days	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
•   Investigator Inquiry form