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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Bexagliflozin tablets; Drug: Bexagliflozin tablets, placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 292
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Kanagawa
    • Yokohama Naka-ku, Kanagawa, Japan, 231-0023
      • Medical Corporation Hitomi-kai Motomachi Takatsuka Naika Clinic
  • Kyoto
    • Nishikyo-ku, Kyoto, Japan, 615-8125
      • Medical Corporation Hayashi Katagihara Clinic
    • Ukyou-ku, Kyoto, Japan, 615-0035
      • Medical Corporation KEISEIKAI Kajiyama Clinic
  • Osaka
    • Joto-ku, Osaka, Japan, 536-0008
      • Ikeoka Medical Corp. Ikeoka Clinic
    • Takatsuki-shi, Osaka, Japan, 569-1123
      • Miyauchi Medical Center
    • Toyonaka-shi, Osaka, Japan, 560-0082
      • Medical Corporation Senrichuo Ekimae Clinic
  • Saitama
    • Hikigun Ogawamachi, Saitama, Japan, 355-0328
      • Medical Corporation Segawa Hospital
    • Kawagoe-shi, Saitama, Japan, 350-0851
      • Medical Corporation Yukeikai Asano Clinic
    • Kawaguchi, Saitama, Japan, 333-0844
      • Medical Corporation Ishii Internal Medicine Clinic
    • Saitama-shi, Saitama, Japan, 336-0963
      • Medical Corporation Fusanokai Shimizu Clinic Fusa
  • Tokyo
    • Hachioji-shi, Tokyo, Japan, 192-0046
      • Medical Corp. SEIKOUKAI New Medical Research System Clinic
    • Katsushika-ku, Tokyo, Japan, 124-0024
      • Medical Corporation Jototowakai Shinkoiwa ekimae sogo Clinic
    • Minato-ku, Tokyo, Japan, 105-7390
      • Medical Corporation IHL Pedi Shiodome Medical Clinic
    • Minato-ku, Tokyo, Japan, 108-0075
      • Medical Corporation IHL Shinagawa East One Medical Clinic
    • Ota-ku, Tokyo, Japan, 143-0015
      • Kenkokan Suzuki Clinic
    • Shibuya-ku, Tokyo, Japan, 150-0002
      • Medical Corporation Souyu-kai Hirahata Clinic
    • Shinagawa-ku, Tokyo, Japan, 141-0032
      • Medical Corporation Yuhokai Miho-Clinic
    • Toshima-ku, Tokyo, Japan, 171-0021
      • Ikebukuro Metropolitan Clinic
• United States
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Phoenix Medical Research Institute LLC
    • Tucson, Arizona, United States, 85712
      • Advanced Arizona Clinical Research
  • California
    • Canoga Park, California, United States, 91303
      • Hope Clinical Research, LLC
    • Chino, California, United States, 91710
      • Catalina Research Institute
    • Huntington Park, California, United States, 90255
      • National Research Institute
    • Long Beach, California, United States, 90806
      • Long Beach Clinical Trials
    • National City, California, United States, 91950
      • Synergy San Diego
    • Sacramento, California, United States, 95821
      • Northern California Research
    • San Diego, California, United States, 92103
      • Artemis Institute for Clinical Research, LLC
    • West Hills, California, United States, 91307
      • Infosphere Clinical Research, Inc
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • M&O Clinical Research LLC
    • Hialeah, Florida, United States, 33012
      • AGA Clinical Trials
    • Leesburg, Florida, United States, 34748
      • Compass Research North
    • Miami Lakes, Florida, United States, 33016
      • Sweet Hope Research Specialty, Inc
    • Opa-locka, Florida, United States, 33054
      • Sunshine Research Center
    • Orlando, Florida, United States, 32806
      • Compass Research LLC
    • Port Orange, Florida, United States, 32127
      • Progressive Medical Research
  • Georgia
    • Atlanta, Georgia, United States, 30338
      • PICR Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Sundance Clinical Research
  • New Jersey
    • Trenton, New Jersey, United States, 08611
      • Premier Research Ltd
  • New York
    • Endwell, New York, United States, 13760
      • Regional Clinical Research, Inc
  • North Carolina
    • Calabash, North Carolina, United States, 28467
      • Calabash Medical Center
    • Morehead City, North Carolina, United States, 28557
      • Diabetes & Endocrinology Consultants PC
    • Salisbury, North Carolina, United States, 28144
      • PMG Research of Salisbury
  • Ohio
    • Cincinnati, Ohio, United States, 45255
      • CTI Research
    • Stow, Ohio, United States, 44224
      • Summit Research Group, LLC
  • Oregon
    • Portland, Oregon, United States, 97239
      • Columbia Research Group, Inc.
  • Pennsylvania
    • Lansdale, Pennsylvania, United States, 19446
      • Detweiler Family Medicine and Associate, P.C.
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29582
      • North Myrtle Beach Family Practice
  • Texas
    • DeSoto, Texas, United States, 75115
      • Global Medical Research
    • Fort Worth, Texas, United States, 76164
      • Rockwood Medical Clinic
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Wasatch Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bexagliflozin tablets, 5 mg; Bexagliflozin tablets, 5 mg, once daily by mouth before breakfast	Drug: Bexagliflozin tablets; Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.; Other Names: Code name: EGT0001442
Active Comparator: Bexagliflozin tablets, 10 mg; Bexagliflozin tablets, 10 mg, once daily by mouth before breakfast	Drug: Bexagliflozin tablets; Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.; Other Names: Code name: EGT0001442
Active Comparator: Bexagliflozin tablets, 20 mg; Bexagliflozin tablets, 20 mg, once daily by mouth before breakfast	Drug: Bexagliflozin tablets; Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.; Other Names: Code name: EGT0001442
Placebo Comparator: Bexagliflozin tablets, placebo; Bexagliflozin tablets, placebo, once daily by mouth before breakfast	Drug: Bexagliflozin tablets, placebo; Bexagliflozin tablets, placebo, are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Theracos
• Investigators: Study Director: J Paul Lock, M.D., Theracos

Publications and helpful links

General Publications

• American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. No abstract available.
• 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.
• 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.
• 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. Available from http://www.ncbi.nlm.nih.gov/books/NBK209904/
• 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.
• 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. doi: 10.1097/01.asn.0000092790.89332.d2.
• 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.
• Schwartz S, Fabricatore AN, Diamond A. Weight reduction in diabetes. Adv Exp Med Biol. 2012;771:438-58. doi: 10.1007/978-1-4614-5441-0_31.
• 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. doi: 10.1007/s00439-002-0820-5. Epub 2002 Sep 27.
• Japan Diabetes Society (2012). Treatment Guidance for Diabetes 2012-2013.

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2015
• Primary Completion (Actual): June 3, 2016
• Study Completion (Actual): June 3, 2016

Study Registration Dates

• First Submitted: March 11, 2015
• First Submitted That Met QC Criteria: March 16, 2015
• First Posted (Estimate): March 17, 2015

Study Record Updates

• Last Update Posted (Actual): June 29, 2021
• Last Update Submitted That Met QC Criteria: June 11, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Bexagliflozin
• Other Study ID Numbers: THR-1442-C-449

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No