A Dose Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets in Subjects With Type 2 Diabetes Mellitus

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

A Phase 2b, Multi-center, Double-blind, Placebo-controlled, Dose Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets on HbA1c in Subjects With Type 2 Diabetes Mellitus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02390050
• Other study ID #: THR-1442-C-449
• Status: Completed
• Phase: Phase 2
• Start date: May 12, 2015
• Est. completion date: June 3, 2016

Study information

• Verified date: June 2021
• Source: Theracos
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to investigate the effect of bexagliflozin in lowering hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). Bexagliflozin is an orally administered drug for the treatment of T2DM and is classified as a Sodium Glucose co-Transporter 2 (SGLT2) Inhibitor. This study was to enroll both treatment naive and those subjects previously treated with one oral hypoglycemic agent (OHA). Approximately 320 subjects eligible for randomization was to receive bexagliflozin tablets, 5, 10, 20 mg or placebo, once daily for 12 weeks in an outpatient setting.

Description:

The study was a phase 2b multicenter, double-blind, placebo-controlled parallel group study to assess the effect of once daily bexagliflozin tablets on HbA1c in either treatment-naïve T2DM subjects or in subjects who were treated with one oral anti-diabetic agent. Treatment naïve subjects were eligible if their HbA1c values were between 7% and 8.5% at the screening visit while subjects who were treated with one oral hypoglycemic agent (OHA) were eligible if their HbA1c value was between 6.5% and 8.5% at screening and underwent a 6 or 10 week washout period. In addition, all eligible subjects underwent a two week placebo run-in period and those who showed good compliance in taking study medication (i.e., missed no more than one dose during the run-in period) during this period and whose HbA1c values were between 7 and 8.5% at the end of the run-in period were eligible for randomization.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 292
• Est. completion date: June 3, 2016
• Est. primary completion date: June 3, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

The following subjects were eligible for randomization:

1. men or women = 20 years of age at screening. Women of childbearing potential must test negative by urine pregnancy test.

2. were treatment naïve or taking one oral anti-diabetic medication in combination with diet and exercise

3. were diagnosed with T2DM with HbA1c levels at screening between 7.0% and 8.5% (inclusive) if treatment naïve or with HbA1c levels between 6.5 and 8.5% (inclusive) if on one oral anti-diabetic medication

4. had a body mass index (BMI) = 40 kg/m2

5. were taking stable doses of medication for hypertension or hyperlipidemia that has not changed for at least 30 days prior to screening (if applicable)

6. were able to comprehend the study participation requirements and willing to provide written informed consent in accordance with institutional and regulatory guidelines

7. were able to maintain adequate glycemic control at the run-in visit (for subjects who complete the washout)

8. had an HbA1c between 7.0 and 8.5% (inclusive) prior to randomization (day -3 to -5)

9. were capable of adhering to the investigational product administration requirements as evidenced by omission of no more than one dose of run-in medication

Subjects who exhibited any of the following characteristics were to be ineligible for randomization:

1. Diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young

2. Used parenteral therapy for treatment of diabetes

3. Pregnancy or current breastfeeding status

4. Hemoglobinopathy or carrier status for hemoglobin alleles that affect HbA1c measurement

5. Genitourinary tract infection within 6 weeks of screening or history of =3 genitourinary infections requiring treatment within 6 months of screening

6. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at screening.

7. Uncontrolled hypertension at screening

8. A positive result on hepatitis B surface antigen, hepatitis C, or positive result from screen for drugs of abuse

9. History of human immunodeficiency virus infection

10. Life expectancy < 2 years

11. History of New York Heart Association Class 4 heart failure within 3 months of screening

12. History of myocardial infarction, unstable angina, stroke, or hospitalization for heart failure within 3 months of screening

13. History of treatment with an investigational drug within 30 days or within 7 half lives of the investigational drug, whichever is longer

14. Previous treatment with bexagliflozin

15. Had taken or within 6 months of taking any Sodium Glucose Transporter 2 (SGLT2) inhibitors prior to screening

16. Participation of another interventional trial

17. Not able to comply with the study scheduled visits

18. Affected by any condition, disease, disorder, or clinically relevant abnormality that, in the opinion of the investigator, would jeopardize the subject's appropriate participation in this study.

19. Liver function tests resulting in Alanine transaminase (ALT) or aspartate transaminase (AST) = 2.5 x upper limit of normal (ULN) or total bilirubin = 1.5 x ULN, with the exception of isolated Gilbert's syndrome ,at screening

20. Exhibited fasting plasma glucose = 250 mg/dL (13.9 mmol/L) on two or more consecutive days prior to randomization or exhibited severe clinical signs or symptoms of hyperglycemia during the washout or run-in periods, including weight loss, blurred vision, increased thirst, or increased urination, or fatigue

21. Fasting Plasma Glucose = 250 mg/dL at randomization

22. Prior renal transplantation or evidence of nephrotic syndrome, defined as a urine albumin-to-creatinine ratio (UACR) > 2000 mg/g at screening

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Bexagliflozin tablets
Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.
• Bexagliflozin tablets, placebo
Bexagliflozin tablets, placebo, are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.

Locations

Country	Name	City	State
Japan	Medical Corp. SEIKOUKAI New Medical Research System Clinic	Hachioji-shi	Tokyo
Japan	Medical Corporation Segawa Hospital	Hikigun Ogawamachi	Saitama
Japan	Ikeoka Medical Corp. Ikeoka Clinic	Joto-ku	Osaka
Japan	Medical Corporation Jototowakai Shinkoiwa ekimae sogo Clinic	Katsushika-ku	Tokyo
Japan	Medical Corporation Yukeikai Asano Clinic	Kawagoe-shi	Saitama
Japan	Medical Corporation Ishii Internal Medicine Clinic	Kawaguchi	Saitama
Japan	Medical Corporation IHL Pedi Shiodome Medical Clinic	Minato-ku	Tokyo
Japan	Medical Corporation IHL Shinagawa East One Medical Clinic	Minato-ku	Tokyo
Japan	Medical Corporation Hayashi katagihara Clinic	Nishikyo-ku	Kyoto
Japan	Kenkokan Suzuki Clinic	Ota-ku	Tokyo
Japan	Medical Corporation Fusanokai Shimizu Clinic Fusa	Saitama-shi	Saitama
Japan	Medical Corporation Souyu-kai Hirahata Clinic	Shibuya-ku	Tokyo
Japan	Medical Corporation Yuhokai Miho-Clinic	Shinagawa-ku	Tokyo
Japan	Miyauchi Medical Center	Takatsuki-shi	Osaka
Japan	Ikebukuro Metropolitan Clinic	Toshima-ku	Tokyo
Japan	Medical Corporation Senrichuo Ekimae Clinic	Toyonaka-shi	Osaka
Japan	Medical Corporation KEISEIKAI Kajiyama clinic	Ukyou-ku	Kyoto
Japan	Medical Corporation Hitomi-kai Motomachi Takatsuka Naika Clinic	Yokohama Naka-ku	Kanagawa
United States	PICR Clinic	Atlanta	Georgia
United States	Calabash Medical Center	Calabash	North Carolina
United States	Hope Clinical Research, LLC	Canoga Park	California
United States	Catalina Research Institute	Chino	California
United States	CTI Research	Cincinnati	Ohio
United States	Global Medical Research	DeSoto	Texas
United States	Regional Clinical Research, Inc	Endwell	New York
United States	M&O Clinical Research LLC	Fort Lauderdale	Florida
United States	Rockwood Medical Clinic	Fort Worth	Texas
United States	AGA Clinical Trials	Hialeah	Florida
United States	National Research Institute	Huntington Park	California
United States	Detweiler Family Medicine and Associate, P.C.	Lansdale	Pennsylvania
United States	Compass Research North	Leesburg	Florida
United States	Long Beach Clinical Trials	Long Beach	California
United States	Sweet Hope Research Specialty, Inc	Miami Lakes	Florida
United States	Diabetes & Endocrinology Consultants PC	Morehead City	North Carolina
United States	North Myrtle Beach Family Practice	Myrtle Beach	South Carolina
United States	Synergy San Diego	National City	California
United States	Sunshine Research Center	Opa-locka	Florida
United States	Compass Research LLC	Orlando	Florida
United States	Phoenix Medical Research Institute LLC	Peoria	Arizona
United States	Progressive Medical Research	Port Orange	Florida
United States	Columbia Research Group, Inc.	Portland	Oregon
United States	Northern California Research	Sacramento	California
United States	Sundance Clinical Research	Saint Louis	Missouri
United States	PMG Research of Salisbury	Salisbury	North Carolina
United States	Wasatch Clinical Research	Salt Lake City	Utah
United States	Artemis Institute for Clinical Research, LLC	San Diego	California
United States	Summit Research Group, LLC	Stow	Ohio
United States	Premier Research Ltd	Trenton	New Jersey
United States	Advanced Arizona Clinical Research	Tucson	Arizona
United States	Infosphere Clinical Research, Inc	West Hills	California

Sponsors (1)

Lead Sponsor	Collaborator
Theracos

Countries where clinical trial is conducted

United States,  Japan, 

References & Publications (10)

American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. — View Citation

Japan Diabetes Society (2012). Treatment Guidance for Diabetes 2012-2013.

Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M, Wadden TA, Wagenknecht LE, West DS, Williamson DF, Yanovski SZ. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54. doi: 10.1056/NEJMoa1212914. Epub 2013 Jun 24. Erratum in: N Engl J Med. 2014 May 8;370(19):1866. — View Citation

Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A; Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009 Jun;53(6):982-92. doi: 10.1053/j.ajkd.2008.12.034. Epub 2009 Apr 1. — View Citation

National Research Council (US) Panel on Handling Missing Data in Clinical Trials. The Prevention and Treatment of Missing Data in Clinical Trials. Washington (DC): National Academies Press (US); 2010. — View Citation

Palaniappan LP, Wong EC, Shin JJ, Fortmann SP, Lauderdale DS. Asian Americans have greater prevalence of metabolic syndrome despite lower body mass index. Int J Obes (Lond). 2011 Mar;35(3):393-400. doi: 10.1038/ijo.2010.152. Epub 2010 Aug 3. — View Citation

Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003 Nov;14(11):2873-82. — View Citation

Scheen AJ, Van Gaal LF. Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol. 2014 Nov;2(11):911-22. doi: 10.1016/S2213-8587(14)70004-X. Epub 2014 Feb 19. Review. — View Citation

Schwartz S, Fabricatore AN, Diamond A. Weight reduction in diabetes. Adv Exp Med Biol. 2012;771:438-58. Review. — View Citation

van den Heuvel LP, Assink K, Willemsen M, Monnens L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet. 2002 Dec;111(6):544-7. Epub 2002 Sep 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in HbA1c After 12 Weeks of Treatment	Mixed model repeated measures (MMRM) analysis of covariance model (ANCOVA) with baseline HbA1c as a covariate will be fit to the available data, incorporating all visits at which HbA1c was measured for each subject including scheduled visits at Weeks 2, 6, and 12 as well as unscheduled visits for measurements of HbA1c. Treatment (placebo, 5 mg, 10 mg, 20 mg), study center, prior anti-diabetic treatment status, study visit and treatment-by-visit interaction will be applied as fixed effects and subject as a random effect. The least square mean (LSM) change from baseline to Week 12 was analyzed using the Mixed-Effect Model Repeated Measure (MMRM) Analysis of Covariance (ANCOVA) model using 95% Confidence Intervals (CIs) for the between-group mean changes.	12 weeks
Secondary	Proportion of Subjects With HbA1c < 7%	To assess the efficacy of bexagliflozin based on the proportion of subjects who reach the American Diabetes Associate (ADA) and the Japan Diabetes Society target HbA1c of <7%.	Baseline to up to 12 weeks
Secondary	Change in Body Weight Over Time	The body weight was analyzed on the full analysis set using the MMRM ANCOVA model used for the primary efficacy analysis.	Baseline to Week 2, Week 6 and Week 12
Secondary	Change in Fasting Plasma Glucose (FPG) Over Time	The fasting plasma glucose (FPG) was analyzed on the full analysis set using the same MMRM ANCOVA model used in the primary efficacy analysis.	Baseline to Week 2, Week 6 and Week 12
Secondary	Change in Systolic and Diastolic Blood Pressure Over Time	The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were analyzed on the full analysis set using the same MMRM ANCOVA model used in the primary efficacy analysis.	Baseline to Week 2, Week 6 and Week 12
Secondary	Change in HbA1c Over Time	The least square mean (LSM) change from baseline to Week 2, Week 6 and Week 12 was analyzed using the Mixed-Effect Model Repeated Measure (MMRM) Analysis of Covariance (ANCOVA) model using 95% Confidence Intervals (CIs) for the between-group mean changes. The LSM change was calculated by excluding HbA1c data obtained after rescue medication.	Baseline to Week 2, Week 6 and Week 12