Clinical trial NCT02836873: Safety and Efficacy of Bexagliflozin in Type 2 Diabetes Mellitus Patients With Moderate Renal Impairment
Official title: A Double Blind Placebo Controlled Study to Evaluate the Effect of Bexagliflozin Tablets on Hemoglobin A1c in Patients With Type 2 Diabetes Mellitus and Moderate Renal Impairment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Theracos
Sponsor class: INDUSTRY
First posted: 2016-07-19
Enrollment: 312
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of oral administration of bexagliflozin at 20 mg versus placebo in subjects with T2DM, moderate renal impairment and inadequate glycemic control.

Detailed description: The phase 3, double-blind, placebo-controlled parallel-group study was conducted at investigative sites in the US, Japan, France and Spain. Approximately 300 subjects were to be randomly assigned to receive bexagliflozin tablets, 20 mg, or placebo in equal ratio for 24 weeks.

The study was to enrolled male and female participants who had T2DM with an HbA1c between 7.0 and 10.5% (inclusive) and stage 3 chronic kidney disease (CKD) as defined by an eGFR of ≥ 30 and\< 60 mL min-1 per 1.73 m2 at the screening visit and one additional time of measurement between 1 and 12 months prior to screening. Subjects were either treatment naïve or were treated with a stable regimen of anti-diabetic medications.

All eligible subjects were to enter a one-week single-blind, placebo run-in period. Subjects who were compliant in taking run-in medication, had screening eGFR ≥ 30 and\< 60 mL min-1 per 1.73 m2, and had stable GFR (no more than 20% change in eGFR between a historical value and the value determined at the screening visit) were eligible for randomization. Randomization was stratified by HbA1c level (7.0 to 8.5% or 8.6 to 10.5%), anti-diabetic treatment regimen and eGFR (30 - 44 mL min-1 per 1.73 m2 or 45 - 59 mL min-1 per 1.73 m2). At least 135 subjects in each of the eGFR groups were planned.

Study subjects were to schedule clinic visits at weeks 2, 6, 12, 18, and 24 for safety and efficacy evaluation. At weeks 2 and 18, the visits were to be conducted via phone interviews unless an in-person visit was considered clinically advisable. A final follow-up visit was to be conducted at week 26 or two weeks after the last dose of investigational product if the subject withdrew 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 non-pregnant female ≥ 20 years of age. Women of childbearing potential were required to agree to use contraception throughout the study to avoid any possible pregnancy. Females who were surgically sterile (hysterectomy, oophorectomy) or postmenopausal (absence of menses for greater than 12 months and age \> 45 years) were eligible if they tested negative on the urine pregnancy test.
2. To have had a diagnosis of T2DM with an HbA1c between 7.0 and 10.5% (inclusive) at the time of screening.
3. To have been treatment naïve or to have been treated with a stable regimen of anti-diabetic medications. At the time of screening, the doses and frequency of all anti-diabetic medications were to have been stable for 8 weeks.
4. To have had an eGFR ≥ 30 and \< 60 mL min-1 per 1.73 m2 at 2 time points: screening (V1), and 1 additional time point between 1 and 12 months of screening (may be obtained from available medical records). The eGFR was calculated by the MDRD equation.
5. To have had a body mass index (BMI) ≤ 45 kg per m2 (inclusive).
6. To have been taking stable doses of medications for hypertension or hyperlipidemia (if applicable) for at least 30 days prior to randomization
7. To have had stable eGFR between the historic value and day of screening (no more than 20% change in eGFR between the most recent historical value and the value determined at the screening visit V1).

9.3.2 Exclusion Criteria

Potential participants who exhibited any of the following characteristics were excluded from the study:

1. A diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young (MODY)
2. A hemoglobinopathy that could affect HbA1c measurement
3. Frequent symptomatic hypoglycemia (greater than one episode per week on average)
4. A history of genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within the last 6 months
5. A cancer, active or in remission for \< 3 years (Non-melanoma skin cancer or basal cell carcinoma or carcinoma in situ of the cervix were not grounds for exclusion)
6. A history of alcohol or illicit drug abuse in the past 2 years
7. Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase \> 1.5 × upper limit of normal (ULN) with the exception of isolated Gilbert's syndrome); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 × ULN
8. A history of MI, stroke or hospitalization for heart failure, or hospitalization for unstable angina in the prior 3 months
9. Evidence of NYHA class IV heart failure at screening or randomization
10. A history of taking an SGLT2 inhibitor within 3 months of screening
11. Any condition, disease, disorder, or clinically relevant laboratory abnormality that, in the opinion of the PI, would jeopardize the subject's appropriate participation in this study or obscure the effects of treatment
12. A current status of pregnancy or breastfeeding
13. A current status of renal replacement therapy (peritoneal or hemodialysis) or a history of renal transplantation
14. A corrected serum calcium \< 8 mg dL-1 at screening (V1) or randomization (V3)
15. Uncontrolled hypertension (systolic blood pressure \>170 mm Hg or diastolic blood pressure \>110 mm Hg)
16. Participation in another interventional trial or exposure to an investigational drug within 30 days or 7 half-lives of screening, whichever was longer
17. Previous exposure to bexagliflozin or EGT0001474
18. Evidence of having skipped dosing more than once during the run-in period
19. A fasting blood glucose value during the run-in period ≥ 250 mg dL-1 (13.9 mmol L-1) associated with severe clinical signs or symptoms of hyperglycemia
20. Any episode of symptomatic hypoglycemia during the run-in period in which symptoms were severe
21. An inability to comprehend or unwillingness to provide written informed consent in accordance with institutional and regulatory guidelines

Primary outcomes:
measure: Change From Baseline in HbA1c at 24 Weeks
timeFrame: 24 weeks
Secondary outcomes:
measure: Change in Body Weight From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2
timeFrame: 24 weeks
measure: Change From Baseline in Systolic Blood Pressure (SBP) in Subjects With Baseline SBP ≥ 130 mm Hg at Week 24
timeFrame: 24 weeks
measure: Change From Baseline in HbA1c in Subjects With Stage 3a CKD (eGFR 45 to 59 mL/Min/1.73 m2) at Week 24
timeFrame: 24 weeks
measure: Change From Baseline in HbA1c in Subjects With Stage 3b CKD (eGFR 30 to 44 mL/Min/1.73 m2) at Week 24
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Fresno
country: United States
facility: Research Site
state: California
city: La Palma
country: United States
facility: Research Site
state: California
city: Lincoln
country: United States
facility: Research Site
state: California
city: Riverside
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site
state: California
city: San Dimas
country: United States
facility: Research Site
state: California
city: Monument
country: United States
facility: Research Site
state: Colorado
city: Norwalk
country: United States
facility: Research Site
state: Connecticut
city: Hollywood
country: United States
facility: Research Site
state: Florida
city: Tampa
country: United States
facility: Research Site
state: Florida
city: West Palm Beach
country: United States
facility: Research Site
state: Florida
city: Paducah
country: United States
facility: Research Site
state: Kentucky
city: Auburn
country: United States
facility: Research Site
state: Maine
city: Rockport
country: United States
facility: Research Site
state: Maine
city: Nashua
country: United States
facility: Research Site
state: New Hampshire
city: Bronx
country: United States
facility: Research Site
state: New York
city: Stow
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Austin
country: United States
facility: Research Site
state: Texas
city: Austin
country: United States
facility: Research Site
state: Texas
city: North Richland Hills
country: United States
facility: Research Site
state: Texas
city: Round Rock
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Dijon
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pierre Benite
country: France
facility: Research Site
city: Poitiers
country: France
facility: Research Site
city: Venissieux
country: France
facility: Research Site
city: Atsugi-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Kamakura-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Kawasaki-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Yokohama-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Yokohama-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Yokohama-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Kyoto-shi
country: Japan
facility: Research Site
state: Kyoto
city: Kyoto-shi
country: Japan
facility: Research Site
state: Kyoto
city: Kawagoe-shi
country: Japan
facility: Research Site
state: Saitama
city: Kawaguchi-shi
country: Japan
facility: Research Site
state: Saitama
city: Sayama-shi
country: Japan
facility: Research site
state: SAitama
city: Hachioji-shi
country: Japan
facility: Research Site
state: Tokyo
city: Hachioji-shi
country: Japan
facility: Research Site
state: Tokyo
city: Minato-ku
country: Japan
facility: Research Site
state: Tokyo
city: Ota-ku
country: Japan
facility: Research Site
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: Research Site
state: Tokyo
city: Toshima-ku
country: Japan
facility: Research Site
state: Toyko
city: Alcala de Henares
country: Spain
facility: Research Site
city: Alicante
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
Study officials:
affiliation: Massachusetts General Hospital
name: Andrew Allegretti, M.D.
role: STUDY_DIRECTOR
References: