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

• ClinicalTrials.gov Identifier: NCT02390050
• Recruitment Status: Completed
• First Posted: March 17, 2015
• Results First Posted: April 20, 2021
• Last Update Posted: June 29, 2021
• Sponsor: Theracos
• Information provided by (Responsible Party): Theracos

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: Bexagliflozin tablets; Drug: Bexagliflozin tablets, placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 292 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 12, 2015
• Actual Primary Completion Date: June 3, 2016
• Actual Study Completion Date: June 3, 2016

Arms and Interventions

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 Name: 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 Name: 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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Change in HbA1c After 12 Weeks of Treatment [ Time Frame: 12 weeks ]
   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.

Secondary Outcome Measures :

1. Proportion of Subjects With HbA1c < 7% [ Time Frame: Baseline to up to 12 weeks ]
   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%.
2. Change in Body Weight Over Time [ Time Frame: Baseline to Week 2, Week 6 and Week 12 ]
   The body weight was analyzed on the full analysis set using the MMRM ANCOVA model used for the primary efficacy analysis.
3. Change in Fasting Plasma Glucose (FPG) Over Time [ Time Frame: Baseline to Week 2, Week 6 and Week 12 ]
   The fasting plasma glucose (FPG) was analyzed on the full analysis set using the same MMRM ANCOVA model used in the primary efficacy analysis.
4. Change in Systolic and Diastolic Blood Pressure Over Time [ Time Frame: Baseline to Week 2, Week 6 and Week 12 ]
   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.
5. Change in HbA1c Over Time [ Time Frame: Baseline to Week 2, Week 6 and Week 12 ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Phoenix Medical Research Institute LLC

Peoria, Arizona, United States, 85381

Advanced Arizona Clinical Research

Tucson, Arizona, United States, 85712

United States, California

Hope Clinical Research, LLC

Canoga Park, California, United States, 91303

Catalina Research Institute

Chino, California, United States, 91710

National Research Institute

Huntington Park, California, United States, 90255

Long Beach Clinical Trials

Long Beach, California, United States, 90806

Synergy San Diego

National City, California, United States, 91950

Northern California Research

Sacramento, California, United States, 95821

Artemis Institute for Clinical Research, LLC

San Diego, California, United States, 92103

Infosphere Clinical Research, Inc

West Hills, California, United States, 91307

United States, Florida

M&O Clinical Research LLC

Fort Lauderdale, Florida, United States, 33316

AGA Clinical Trials

Hialeah, Florida, United States, 33012

Compass Research North

Leesburg, Florida, United States, 34748

Sweet Hope Research Specialty, Inc

Miami Lakes, Florida, United States, 33016

Sunshine Research Center

Opa-locka, Florida, United States, 33054

Compass Research LLC

Orlando, Florida, United States, 32806

Progressive Medical Research

Port Orange, Florida, United States, 32127

United States, Georgia

PICR Clinic

Atlanta, Georgia, United States, 30338

United States, Missouri

Sundance Clinical Research

Saint Louis, Missouri, United States, 63141

United States, New Jersey

Premier Research Ltd

Trenton, New Jersey, United States, 08611

United States, New York

Regional Clinical Research, Inc

Endwell, New York, United States, 13760

United States, North Carolina

Calabash Medical Center

Calabash, North Carolina, United States, 28467

Diabetes & Endocrinology Consultants PC

Morehead City, North Carolina, United States, 28557

PMG Research of Salisbury

Salisbury, North Carolina, United States, 28144

United States, Ohio

CTI Research

Cincinnati, Ohio, United States, 45255

Summit Research Group, LLC

Stow, Ohio, United States, 44224

United States, Oregon

Columbia Research Group, Inc.

Portland, Oregon, United States, 97239

United States, Pennsylvania

Detweiler Family Medicine and Associate, P.C.

Lansdale, Pennsylvania, United States, 19446

United States, South Carolina

North Myrtle Beach Family Practice

Myrtle Beach, South Carolina, United States, 29582

United States, Texas

Global Medical Research

DeSoto, Texas, United States, 75115

Rockwood Medical Clinic

Fort Worth, Texas, United States, 76164

United States, Utah

Wasatch Clinical Research

Salt Lake City, Utah, United States, 84107

Japan

Medical Corporation Hitomi-kai Motomachi Takatsuka Naika Clinic

Yokohama Naka-ku, Kanagawa, Japan, 231-0023

Medical Corporation Hayashi katagihara Clinic

Nishikyo-ku, Kyoto, Japan, 615-8125

Medical Corporation KEISEIKAI Kajiyama clinic

Ukyou-ku, Kyoto, Japan, 615-0035

Ikeoka Medical Corp. Ikeoka Clinic

Joto-ku, Osaka, Japan, 536-0008

Miyauchi Medical Center

Takatsuki-shi, Osaka, Japan, 569-1123

Medical Corporation Senrichuo Ekimae Clinic

Toyonaka-shi, Osaka, Japan, 560-0082

Medical Corporation Segawa Hospital

Hikigun Ogawamachi, Saitama, Japan, 355-0328

Medical Corporation Yukeikai Asano Clinic

Kawagoe-shi, Saitama, Japan, 350-0851

Medical Corporation Ishii Internal Medicine Clinic

Kawaguchi, Saitama, Japan, 333-0844

Medical Corporation Fusanokai Shimizu Clinic Fusa

Saitama-shi, Saitama, Japan, 336-0963

Medical Corp. SEIKOUKAI New Medical Research System Clinic

Hachioji-shi, Tokyo, Japan, 192-0046

Medical Corporation Jototowakai Shinkoiwa ekimae sogo Clinic

Katsushika-ku, Tokyo, Japan, 124-0024

Medical Corporation IHL Pedi Shiodome Medical Clinic

Minato-ku, Tokyo, Japan, 105-7390

Medical Corporation IHL Shinagawa East One Medical Clinic

Minato-ku, Tokyo, Japan, 108-0075

Kenkokan Suzuki Clinic

Ota-ku, Tokyo, Japan, 143-0015

Medical Corporation Souyu-kai Hirahata Clinic

Shibuya-ku, Tokyo, Japan, 150-0002

Medical Corporation Yuhokai Miho-Clinic

Shinagawa-ku, Tokyo, Japan, 141-0032

Ikebukuro Metropolitan Clinic

Toshima-ku, Tokyo, Japan, 171-0021

Sponsors and Collaborators

Theracos

Investigators

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

  Study Documents (Full-Text)

Documents provided by Theracos:

Study Protocol  [PDF] February 16, 2015

Statistical Analysis Plan  [PDF] October 21, 2015

More Information

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.

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.

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.

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.

• Responsible Party: Theracos
• ClinicalTrials.gov Identifier: NCT02390050
• Other Study ID Numbers: THR-1442-C-449
• First Posted: March 17, 2015
• Results First Posted: April 20, 2021
• Last Update Posted: June 29, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Bexagliflozin; Hypoglycemic Agents; Physiological Effects of Drugs