Clinical trial NCT03115112: Safety and Efficacy of Bexagliflozin Compared to Sitagliptin as Add-on Therapy to Metformin in Type 2 Diabetes Subjects
Official title: A Phase 3, Randomized, Double-Blind, Active-Controlled Study to Evaluate the Effects of Bexagliflozin Versus Sitagliptin in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control by Metformin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Theracos
Sponsor class: INDUSTRY
First posted: 2017-04-14
Enrollment: 386
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate the effect of bexagliflozin compared to sitagliptin as an add-on therapy to metformin in lowering hemoglobin A1c (HbA1c) levels in subjects with type 2 diabetes mellitus (T2DM).

Detailed description: This was a phase 3, multi-center, randomized, double-blind, parallel-group study to demonstrate that bexagliflozin was non-inferior to sitagliptin as add-on therapy in subjects whose T2DM was not adequately controlled by metformin treatment alone. The primary effectiveness endpoint was the change in HbA1c from baseline at week 24.

At the time of screening, all subjects were to have taken metformin at a stable dose of ≥ 1500 mg per day for ≥ 8 weeks and have received diet and exercise counseling. A total of 374 eligible subjects were to be enrolled in the study. Subjects who successfully completed a 1-week run-in and who met all eligibility criteria were to be randomized in a 1:1 ratio to receive once daily double-blind treatment of either active bexagliflozin tablets with placebo sitagliptin tablets or placebo bexagliflozin tablets and active sitagliptin tablets. The study subjects were to continue receiving open-labeled metformin during the entire study at a stable dose and frequency. The treatment period was 24 weeks and was conducted in an outpatient setting.

Randomization was stratified by HbA1c (≤ 8.5% vs. ˃ 8.5%) values. Symptoms and blood sugars related to the occurrence of hyperglycemia, hypoglycemic events or symptoms that could indicate ketoacidosis were to be recorded. Bexagliflozin tablets, 20 mg or placebo, and sitagliptin tablets, 100 mg or placebo, were to be taken once daily at approximately the same time each day either before or after breakfast. Background metformin was to be taken at the same dose and frequency from screening throughout the entire study.

Each subject was advised to return to the clinic at weeks 6, 12, 18 and 24 for efficacy assessment and safety monitoring, including review of AEs and concomitant medication, vital signs, ECG, physical examination and blood and urine specimen collections. Subjects were to return to the clinic for a follow-up exit visit at week 26 or 2 weeks after the last dose of study drugs if subjects withdrew from the study prior to week 24.

Eligibility criteria: Each subject was required to meet the following criteria at the time of enrollment to be eligible for the study:

1. To have been male or female adults ≥ 18 years of age.
2. To have been negative on the urine pregnancy test and agreed to abstain from coitus or use contraception during the entire study if a subject was female of childbearing potential.
3. To have had a diagnosis of T2DM with HbA1c levels between 7.0% and 11% (inclusive) at the time of screening.
4. To have been treated with a stable dose of ≥ 1500 mg/day metformin only along with diet and exercise counseling for at least 8 weeks at the time of screening.
5. To have had a BMI ≤ 45 kg per m2 at the time of screening.
6. To have been taking stable doses of treatment for dyslipidemia and/or hypertension for 30 days if applicable.
7. To have been willing and able to return for all clinic visits and to complete all study-required procedures.
8. To have adhered to the investigational product administration requirements as evidenced by missing no more than 1 day of run-in medications.

Potential subjects who exhibited any of the following characteristics were to be excluded from the study:

1. Diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young (MODY)
2. Hemoglobinopathy that affected HbA1c measurement
3. Any contraindication to the safe use of DPP-4 therapy or sitagliptin, including known hypersensitivity reaction
4. History of pancreatitis
5. Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within 6 months from the time of screening
6. Cancer, active or in remission, for \< 3 years
7. History of alcohol or illicit drug abuse in the past 2 years
8. Triglycerides \> 500 mg dL-1 at Visit V1
9. Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase \> 1.5 x upper limit of normal (ULN) with the exception of isolated Gilbert's syndrome); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 x ULN
10. Estimated GFR, as calculated by the modification of diet in renal disease study equation (MDRD), \< 60 mL min-1 per 1.73 m2 at the time of screening.
11. Uncontrolled hypertension (SBP \> 160 mm Hg or diastolic BP \> 95 mm Hg) at Visit V1
12. Life expectancy \< 2 years
13. History of MI, unstable angina, stroke or hospitalization for heart failure within 3 months at the time of screening
14. History of treatment with an investigational drug within 30 days or within 7 half-lives of the investigational drug, whichever is longer
15. Previous treatment with bexagliflozin or EGT0001474 study drug
16. Currently or within 3 months of taking any SGLT2 inhibitor
17. Currently participating in another interventional trial
18. Prior renal transplantation or evidence of nephrotic syndrome (defined as a urine albumin-to-creatinine ratio (UACR) \> 1500 mg g-1 at the time of screening).
19. Any condition, disease, disorder or clinically relevant abnormality that could have jeopardized the subject's appropriate participation in this study or obscure the effects of treatment
20. Female subjects who were pregnant or nursing
21. Two or more consecutive SMBG measures ≥ 250 mg dL-1 (13.9 mmol L-1) prior to randomization accompanied by clinical signs or symptoms of hyperglycemia prior to randomization, including weight loss, blurred vision, increased thirst increased urination, or fatigue

Primary outcomes:
measure: Change in HbA1c From Baseline to Week 24
timeFrame: Baseline to week 24
Secondary outcomes:
measure: Change in FPG From Baseline at Week 24
timeFrame: Baseline to week 24
measure: Change in Body Weight in Subjects With Baseline BMI ≥ 25 kg/m2 at Week 24
timeFrame: Baseline to week 24
measure: Change in SBP in Subjects From Baseline at Week 24
timeFrame: Baseline to week 24
Other outcomes:
Locations:
city: Lincoln
country: United States
facility: Clinical Research Site 1357
state: California
city: Long Beach
country: United States
facility: Clinical Research Site 1358
state: California
city: San Dimas
country: United States
facility: Clinical Research Site 1361
state: California
city: Port Orange
country: United States
facility: Clinical Research Site 1031
state: Florida
city: Chicago
country: United States
facility: Clinical Research Site 1271
state: Illinois
city: Topeka
country: United States
facility: Clinical Research Site 1359
state: Kansas
city: Berlin
country: United States
facility: Clinical Research Site 1009
state: New Jersey
city: Trenton
country: United States
facility: Clinical Research Site 1037
state: New Jersey
city: Munroe Falls
country: United States
facility: Clinical Research Site 1008
state: Ohio
city: San Antonio
country: United States
facility: Clinical Research Site 1360
state: Texas
city: Hodonín
country: Czechia
facility: Clinical Research Site 3119
city: Mladá Boleslav
country: Czechia
facility: Clinical Research Site 3123
city: Olomouc
country: Czechia
facility: Clinical Research Site 3120
city: Praha
country: Czechia
facility: Clinical Research Site 3112
city: Prostějov
country: Czechia
facility: Clinical Research Site 3122
city: Balatonfüred
country: Hungary
facility: Clinical Research Site 9102
city: Balatongyörök
country: Hungary
facility: Clinical Research Site 9101
city: Budapest
country: Hungary
facility: Clinical Research Site 9106
city: Szeged
country: Hungary
facility: Clinical Research Site 9107
city: Zalaegerszeg
country: Hungary
facility: Clinical Research Site 9105
city: Zamardi
country: Hungary
facility: Clinical Research Site 9103
city: Chiba
country: Japan
facility: Clinical Research Site 6031
city: Chiba
country: Japan
facility: Clinical Research Site 6037
city: Chiba
country: Japan
facility: Clinical Research Site 6042
city: Fukuoka
country: Japan
facility: Clinical Research Site 6040
city: Fukuoka
country: Japan
facility: Clinical Research Site 6035
city: Ibaraki
country: Japan
facility: Clinical Research Site 6034
city: Ibaraki
country: Japan
facility: Clinical Research Site 6039
city: Ibaraki
country: Japan
facility: Clinical Research Site 6041
city: Ibaraki
country: Japan
facility: Clinical Research Site 6032
city: Shizuoka
country: Japan
facility: Clinical Research Site 6036
city: Tochigi
country: Japan
facility: Clinical Research Site 6038
city: Ōsaka
country: Japan
facility: Clinical Research Site 6033
city: Gdańsk
country: Poland
facility: Clinical Research Site 7137
city: Kraków
country: Poland
facility: Clinical Research Site 7144
city: Kraków
country: Poland
facility: Clinical Research Site 7142
city: Kraków
country: Poland
facility: Clinical Research Site 7139
city: Kraków
country: Poland
facility: Clinical Research Site 7141
city: Lublin
country: Poland
facility: Clinical Research Site 7120
city: Lublin
country: Poland
facility: Clinical Research Site 7138
city: Olsztyn
country: Poland
facility: Clinical Research Site 7131
city: Poznań
country: Poland
facility: Clinical Research Site 7143
city: Poznań
country: Poland
facility: Clinical Research Site 7140
city: Poznań
country: Poland
facility: Clinical Research Site 7136
city: Puławy
country: Poland
facility: Clinical Research Site 7107
city: Toruń
country: Poland
facility: Clinical Research Site 7128
city: Alicante
country: Spain
facility: Clinical Research Site 9002
city: Almería
country: Spain
facility: Clinical Research Site 9016
city: Alzira
country: Spain
facility: Clinical Research Site 9005
city: Barcelona
country: Spain
facility: Clinical Research Site 9017
city: Barcelona
country: Spain
facility: Clinical Research Site 9013
city: Madrid
country: Spain
facility: Clinical Research Site 9012
city: Sevilla
country: Spain
facility: Clinical Research Site 9011
city: Sevilla
country: Spain
facility: Clinical Research Site 9014
city: Sevilla
country: Spain
facility: Clinical Research Site 9015
city: Valencia
country: Spain
facility: Clinical Research Site 9018
Study officials:
affiliation: Theracos Sub, LLC
name: J. Paul Lock, MD
role: STUDY_DIRECTOR
References: