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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Theracos
ClinicalTrials.gov Identifier:
NCT02390050
First received: March 11, 2015
Last updated: February 1, 2017
Last verified: January 2017
  Purpose
The purpose of this study is 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 will enroll both treatment naive and those subjects previously treated with one oral hypoglycemic agent (OHA). Approximately 320 subjects eligible for randomization will receive bexagliflozin tablets, 5, 10, 20 mg or placebo, once daily for 12 weeks in an outpatient setting.

Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: Bexagliflozin tablets
Drug: Bexagliflozin tablets, placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: 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

Further study details as provided by Theracos:

Primary Outcome Measures:
  • Dose Identification [ Time Frame: 12 weeks ]
    The primary objective of this study is to identify dose(s) for further clinical study through the comparison of HbA1c change from baseline in each active group that will receive bexagliflozin tablets, 5 mg, 10 mg, or 20 mg, to the placebo group over 12 weeks of treatment. To examine the dose response, tests for linear and quadratic dose-response relationships between the doses (0 [placebo], 5, 10 and 20 mg bexagliflozin) and the change from baseline in HbA1c at week 12 will be conducted using a general linear model and appropriate orthogonal polynomial contrasts.


Secondary Outcome Measures:
  • Change in HbA1c over time [ Time Frame: 12 weeks ]
    To assess the change in HbA1c over time. In addition to the week 12 comparisons, the change from baseline to week 2 and week 6 will also be analyzed from the same Mixed-Effect Model Repeated Measure (MMRM) Analysis of Covariance (ANCOVA) model using 95% Confidence Intervals (CIs) for the between- group mean changes. The secondary efficacy endpoint, changes in HbA1c over time will be assessed descriptively using graphical methods

  • Proportion of subjects with HbA1c <7% [ Time Frame: 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%

  • Change in body weight over time [ Time Frame: 12 weeks ]
    To assess change in body weight over time. Fasting plasma glucose, systolic and diastolic blood pressure, and weight will be analyzed using the same MMRM ANCOVA model used in the primary efficacy analysis.

  • Change in Fasting Plasma Glucose (FPG) over time [ Time Frame: 12 weeks ]
    To assess change in fasting plasma glucose over time. Fasting plasma glucose, systolic and diastolic blood pressure, and weight will be analyzed using the same MMRM ANCOVA model used in the primary efficacy analysis.

  • Change in systolic and diastolic blood pressure over time [ Time Frame: 12 weeks ]
    To assess change in systolic and diastolic blood pressure over time. Fasting plasma glucose, systolic and diastolic blood pressure, and weight will be analyzed using the same MMRM ANCOVA model used in the primary efficacy analysis.

  • Safety of bexagliflozin in subjects with T2DM (adverse events) [ Time Frame: 12 weeks ]
    Safety will be assessed based on an analysis of the adverse events record; of laboratory data, including hematology, serum chemistry, urinalysis, urinary electrolytes and creatinine; of electrocardiograms (ECGs), vital signs and physical examinations; and of concomitant medication use. All subjects who are randomized and take at least one dose of double-blind study medication will be included in the Safety Analysis Set. Safety analyses will be based on the medication that was actually dispensed to each subject.


Other Outcome Measures:
  • Population pharmacokinetic evaluation of bexagliflozin plasma concentration (bexagliflozin plasma concentration over time (sparsely sampled) [ Time Frame: 12 weeks ]
    Measurement of bexagliflozin plasma concentration over time (sparsely sampled) will also be conducted at 20 centers and will include approximately 240 study subjects as part of a bexagliflozin population PK study.


Enrollment: 292
Study Start Date: May 2015
Study Completion Date: June 2016
Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Detailed Description:

THR-1442-C-449 is a phase 2b multicenter, double-blind, placebo-controlled, dose range finding study to assess the efficacy and safety of once daily bexagliflozin in either treatment- naïve type 2 diabetic subjects or subjects previously treated with one oral hypoglycemic agent (OHA). The primary efficacy endpoint will be placebo-adjusted reduction in HbA1c, measured after 12 weeks of treatment. Treatment naïve subjects are those who have never received prescription anti-diabetic medications or who have received no more than 14 days of prescription medications for diabetes in the 12 weeks prior to enrollment. The study will enroll men and women with type 2 diabetes mellitus (T2DM) and with HbA1c between 7% and 8.5% (inclusive) at the screening visit (for subjects who are treatment naïve) or with T2DM and with HbA1c between 6.5% and 8.5% (inclusive) at screening visit (for subjects who have received one OHA and who are willing and able to undergo a washout period.) Approximately 400 subjects who meet all the inclusion criteria, none of the exclusion criteria, and who consent to participate in the study are eligible to be enrolled to complete a 6 to 10 week washout if needed and a 2 week run-in period prior to being randomized. Subjects who can adhere to the run-in medication dosing schedule (i.e., miss no more than one dosage in 2 weeks) and who have HbA1c between 7 and 8.5% at baseline (visit S5) will be eligible for randomization and receive investigational product. A 20% screen fail rate is expected by the end of run-in, leading to approximately 320 subjects eligible for randomization to receive oral bexagliflozin tablets, 5, 10, 20 mg or placebo once daily for 12 weeks in an outpatient setting. Subjects who experience hyperglycemia during the study may receive approved anti-diabetic medication. Subjects will visit their study site at weeks 2, 6, and 12 for safety and efficacy evaluation, with a follow up visit at week 14.

Measurement of bexagliflozin plasma concentration over time (sparsely sampled) will be conducted at 20 centers and will include approximately 240 subjects who consent to participate the pharmacokinetics (PK) study. Three samples from each subject will be drawn at weeks 2, 6, or 12.

  Eligibility

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

Inclusion Criteria:

  1. Men or women ≥ 20 years of age at screening. Women of childbearing potential must test negative by urine pregnancy test.
  2. Treatment naïve or currently taking one oral anti-diabetic medication in combination with diet and exercise
  3. 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. Currently having a body mass index (BMI) ≤ 40 kg/m2
  5. Taking stable doses of medication for hypertension or hyperlipidemia that has not changed for at least 30 days prior to screening (if applicable)
  6. Able to comprehend the study participation requirements and willing to provide written informed consent in accordance with institutional and regulatory guidelines
  7. Able to maintain adequate glycemic control at the run-in visit (for subjects who complete the washout)
  8. Having an HbA1c between 7.0 and 8.5% (inclusive) prior to randomization (day -3 to -5)
  9. Capable of adhering to the investigational product administration requirements as evidenced by omission of no more than one dose of run-in medication

Exclusion Criteria:

  1. A diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young
  2. Current use of 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 or study drug EGT0001474
  15. Currently or within 6 months of taking any Sodium Glucose Transporter 2 (SGLT2) inhibitors from screening
  16. Currently participating in 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. Exhibiting fasting plasma glucose ≥ 250 mg/dL (13.9 mmol/L) on two or more consecutive days prior to randomization or exhibiting 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02390050

  Show 50 Study Locations
Sponsors and Collaborators
Theracos
Investigators
Study Director: J Paul Lock, M.D. Theracos
  More Information

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

Responsible Party: Theracos
ClinicalTrials.gov Identifier: NCT02390050     History of Changes
Other Study ID Numbers: THR-1442-C-449
Study First Received: March 11, 2015
Last Updated: February 1, 2017
Individual Participant Data  
Plan to Share IPD: No

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on April 27, 2017