A Study to Evaluate the Efficacy and Safety of DA-1229 (Evogliptin) in Patient's Calcific Aortic Valve Disease With Mild to Moderate Aortic Stenosis (EVOID-AS)

Study Overview
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Brief Summary
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This is an adaptive Phase 2/3 multicenter, double-blind, placebo-controlled, randomized, parallel, 3 arm study to evaluate the efficacy and safety of DA-1229 compared to placebo in patients with calcific aortic valve disease with mild to moderate aortic stenosis. There are 3 arms in this study to which patients will be randomized in a ratio of 1:1:1 to receive the DA-1229 or placebo orally once daily for a period of 104 weeks . the 3 arms are: placebo, DA-1229 5mg GroupDA-1229 10 mg Group. The study will have three phases: Screening Period (up to 4 weeks), Treatment Period (104 weeks), and Follow-Up Period (2-4 weeks). Total Study Duration is112 Weeks.

Official Title
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An Adaptive Phase 2/3 Multicenter, Double-Blind, Placebo-Controlled, Randomized, Parallel, 3 Arm Study to Evaluate the Efficacy and Safety of DA-1229 (Evogliptin) in Patient's Calcific Aortic Valve Disease With Mild to Moderate Aortic Stenosis (EVOID-AS)

Conditions
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Calcific Aortic Valve Disease

Intervention / Treatment
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* Drug: Evogliptin
* Drug: Evogliptin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adult ≥ 35 years of age at time of screening. Subject has calcific aortic valve disease with mild to moderate aortic stenosis as defined by Doppler echocardiography results: Aortic Valve mean pressure gradient between 10-30 mmHg and Aortic Valve Area ≥ 1.2 and ≤ 2.0 cm2 on TTE within 2 weeks prior to randomization and, Cardiac Compute Tomography (CT) test results: aortic valve calcium score (Agatston score) ≥ 200 AU at baseline cardiac CT within 1 month prior to randomization Subject provides written informed consent prior to initiation of any study procedures. Subject understands and agrees to comply with planned study procedures. Exclusion Criteria: Subject has concomitant moderate or more aortic valve regurgitation. Subject has concomitant moderate or severe mitral or tricuspid valve disease. Subjects has left ventricular ejection fraction < 50%. Subject previous history of aortic valve surgery. Subject has NYHA class III or IV heart failure. Subjects whose alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 times the upper limit of normal range. Subjects who cannot undergo Cardiac CT. Subjects whose life expectancy is < 2 years. Subjects with ESRD (End-stage Renal Disease) defined as eGFR (calculated using MDRD equation) ≤ 30 mL/min/1.73m2 or in need of dialysis. Subject has diabetes mellitus. Subject has history of pancreatitis. Subjects who are currently taking or anticipated to take any of the following medications for the duration of the study: Insulin, DPP4 inhibitor, oral hypoglycemic agent The use of SGLT2 inhibitors is allowed as long as the indication for its use is for treatment of heart failure and not diabetes mellitus. Injectable GLP-1 agonists indicated for weight loss treatment in nondiabetics are also allowed. Vitamin K ▪ Subjects taking over-the-counter multivitamins containing ≤ 90 mcg/day vitamin K will be allowed to continue use during the study. Bisphosphonate Any medications that impact hepatic metabolism, by way of inducing CYP3A4 system, giving rise to drug-drug interaction (with the exception of focal treatment) ▪ CYP3A4 inducer: barbiturates (phenobarbital), rifampicin/rifabutin, carbamazepine, phenytoin, primidone, St. John's Wort, Efavirenz, griseofulvin, and chronic (>1 month) supraphysiologic glucocorticoid use (>7.5 mg/day prednisone or equivalent glucocorticoid dosing). Subjects with history of severe allergic reaction to DPP4 inhibitors including anaphylaxis and angioedema Subjects with galactose intolerance, lapp lactase deficiency, and glucose-galactose malabsorption Subjects with history of severe cerebrovascular diseases (such as cerebral infarction or transient ischemic attack), severe cardiovascular diseases (such as unstable angina, myocardial infarction and life-threatening arrhythmia) within 6 months of screening. Subjects with history of malignant tumor within the past 3 years prior to Screening Visit (Visit 1) unless cure is expected. Subjects with history of drug or alcohol abuse. History of cannabis/Marijuana use including recreational use in the last 6 months and an unwillingness to abstain during the course of the study. o Note: Alcohol abuse is a pattern of drinking that result in harm to one's health, interpersonal relationships, or ability to work. Manifestations of alcohol abuse include the following: Failure to fulfill major responsibilities at work, school, or home, drinking in dangerous situations, such as drinking while driving or operating machinery, legal problems related to alcohol, such as being arrested for drinking while driving or for physically hurting someone while drunk and continued drinking despite ongoing relationship problems that are caused or worsened by drinking Subjects with history of medication non-compliance Pregnant or lactating women Subjects who used investigational drugs or devices within 4 weeks prior to screening or investigational biologics within the last 6 months prior to screening. Inability to provide informed consent or to comply with test requirements Subjects with physical (severe hepatic, cardiac, renal, pulmonary, hematological, endocrine, gastrointestinal, etc. conditions) or mental (cognitive, psychiatric, etc. conditions) conditions that may impact their ability to take part in the study. Consideration by the investigator, for safety reasons, that the subject is an unsuitable candidate to receive study treatment Women of child-bearing age who are sexually active but decline to take proper contraceptive measures during the study period Note: To be eligible for the study, Women of childbearing potential (WOCBP) and Women not of childbearing potential are eligible to participate. Both women of childbearing potential and women of no childbearing potential should use an approved method of birth control and agrees to continue to use this method for the duration of the study (and for 30 days after taking the last dose of investigational product). Acceptable methods of contraception include abstinence, female subject/partner's use of hormonal contraceptive (oral, implanted, or injected) in conjunction with a barrier method (WOCBP only), female subject/partner's use of an intrauterine device (IUD), or if the female subject/partner is surgically sterile or 2 years post-menopausal. All male subjects/partners must agree to consistently and correctly use a condom for the duration of the study and for 30 days after taking the study drug. In addition, subjects may not ova or donate sperm for the duration of the study and for 30 days after taking the last dose investigational product.

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* DA-1229 Placebo, 1 tab<br>|
| Active Comparator: DA-1229 5mg<br> | Drug: Evogliptin<br>* DA-1229 5mg, 1 tab<br>* Other names: DA-1229;|
| Active Comparator: DA-1229 10 mg<br> | Drug: Evogliptin<br>* DA-1229 10 mg, 1 tab<br>* Other names: DA-1229;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aortic valve calcification as measured by change from baseline in Agatston arbitrary unit (AU) using cardiac computed tomography (CT) at 104 weeks |  | at 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-major adverse cardiovascular events of cardiac death, non- fatal myocardial infarction, heart failure hospitalization and stroke |  | 104 weeks | 
| Time-to-symptom onset |  | 104 weeks | 
| Time-to-AV intervention to treat aortic stenosis including AV replacement |  | 104 weeks | 
| Aortic valve calcification as measured by Agatston AU using cardiac computed tomography (CT) at week 52 |  | at week 52 | 
| Change in aortic stenosis severity as measured by aortic valve area (AVA) using echocardiography at week 52 as compared to baseline |  | at week 52 as compared to baseline | 
| Change in aortic stenosis severity as measured by aortic valve area (AVA) using echocardiography at week 104 as compared to baseline |  | at week 104 as compared to baseline | 
| Change in aortic stenosis severity as measured by peak transaortic velocity using echocardiography at week 52 as compared to baseline |  | at week 52 as compared to baseline | 
| Change in aortic stenosis severity as measured by peak transaortic velocity using echocardiography at week 104 as compared to baseline |  | at week 104 as compared to baseline | 
| Change in aortic stenosis severity as measured by mean pressure gradient using echocardiography at week 52 as compared to baseline |  | at week 52 as compared to baseline | 
| Change in aortic stenosis severity as measured by mean pressure gradient using echocardiography at week 104 as compared to baseline |  | at week 104 as compared to baseline | 
| Change in aortic stenosis severity as measured by dimensionless velocity using echocardiography at week 52 as compared to baseline |  | at week 52 as compared to baseline | 
| Change in aortic stenosis severity as measured by dimensionless velocity using echocardiography at week 104 as compared to baseline |  | at week 104 as compared to baseline | 
| Change in coronary artery and mitral annulus calcium score at week 52 as compared to baseline |  | at week 52 as compared to baseline | 
| Change in coronary artery and mitral annulus calcium score at week 104 as compared to baseline |  | at week 104 as compared to baseline |