Randomized, Open-label Trial of Inhibitory Effect of Evogliptin on Progression of CAVD
Randomized, Open-label Trial of Inhibitory Effect of Evogliptin on Progression of CAVD
The purpose of this study is to assess an inhibitory effect of Evogliptin on the progression
 of mild-to-moderate aortic stenosis in patients with T2DM and calcific aortic stenosis.
Despite a lot of clinician's efforts to develop an effective medical treatment of calcific
 aortic valve disease (CAVD) for decades, there is no scientifically-proved medical treatment
 yet. Since the pathological features of CAVD are characterized by inflammatory cell
 infiltration and lipid deposition, as in atherosclerosis, statin drugs that are proved to be
 effective in the treatment of cardiovascular disease, have been used in the most recent
 randomized clinical trials; however, different types of medications showed negative results
 and thus, CAVD represents an unmet clinical need.

 Researchers of Asan Medical Center have proved that dipeptidyl-peptidase-4 (DPP-4)-IGF
 (insulin-like growth factor)-1 axis is important for pathologic osteoblast transformation of
 valvular interstitial cell (VIC), and reported that the administration of DPP-4 inhibitor
 prevents the calcification effectively in the actual animal model of CAVD. Under a normal
 condition, IGF-1 suppresses the pathologic transformation of VIC; however, when endothelial
 cells are damaged due to aging or various pathological conditions, DPP-4 expression is
 increased in valvular tissue. Since DPP-4 acts as an enzyme that degrades IGF-1, it reduces
 normal IGF-1 activity and increases transformation of VIC to osteoblast, causing pathological
 calcification and worsening CAVD.

 After comparing six different DPP-4 inhibitors, researchers of Asan Medical Center discovered
 that evogliptin has higher cardiac tissue distribution compared to other DPP-4 inhibitors. In
 addition, the DPP-4 inhibitors with high cardiac tissue distribution have shown decreased
 incidence rate of severe CAVD in the retrospective study. Based on these findings, this study
 will examine the effect of evogliptin on progression of CAVD.

 The study is a randomized, open-label trial of evogliptin in subjects with T2DM and
 moderate-to-severe CAVD. Subjects who have agreed to participate in the study and signed the
 ICF will undergo a screening period and those who meet the eligibility criteria will be
 randomized in a 1:1 ratio to evogliptin or non-evogliptin group. The subjects will take the
 drug for 96 weeks and will be closely monitored for efficacy. The effectiveness of evogliptin
 on inhibition of CAVD progression will be evaluated by comparing the change in aortic valve
 calcium volume in the evogliptin group against that of the non-evogliptin group.
Inclusion Criteria:

 1. Male and female aged 19 years or older

 2. Subjects who were diagnosed with type 2 diabetes mellitus and being treated with oral
 hypoglycemic drugs

 3. Subjects whose Doppler echocardiography or Heart CT performed within 8 weeks prior to
 or during Screening Visit (Visit 1) is satisfying any of the followings:

 -  Doppler echocardiogrphy (aortic valve calcification and/or hypertrophy with
 aortic peak velocity≥2.0 m/s); or

 -  Heart CT (aortic valve calcium score≥300 AU)

 4. Subjects who decided to take part in this study on his/her own volition after
 listening to the details of this study

 Exclusion Criteria:

 1. Subjects with severe aortic valve stenosis (aortic peak velocity>4.0 m/s, mean
 pressure gradient >40 mmHg, or aortic valve area≤0.75 cm2)

 2. Subjects with left ventricular ejection fraction < 40%

 3. Heart failure patients: Subjects with heart failure of NYHA functional class II-IV

 4. Subjects with an estimated glomerular filtration rate (eGFR) of <30ml

 5. Subjects with type 1 diabetes or diabetic ketoacidosis

 6. Subjects with serious hypersensitivity to DPP-4 inhibitors

 7. Subjects who have received/are receiving any of the following medication therapies:

 -  Vitamin K

 -  Calcium supplement (or osteoporosis medication)

 8. Subjects whose aortic valve stenosis is not caused by degenerative or bicuspid valve
 disease (e.g. rheumatic valve disease)

 9. Subjects who have received or are expected to receive (as of Visit 1) aortic valve
 surgery during the study.

 10. Subjects for whom a two-year clinical course investigation is not possible due to
 malignant tumor or cerebrovascular disease

 11. Pregnant or lactating women

 12. Women of childbearing potential who are sexually active and do not agree to use proper
 contraception during the study

 -  Proper contraception means physical barrier method including condom,
 contraceptive diaphragm or cervix cap. The use of contraceptive or oral
 contraceptive containing hormones that may induce drug-drug interaction with the
 investigational product is not allowed during the study (with the exception of an
 oral contraceptive administered to cure menopausal symptoms, only if the dosage
 has been consistent for the past 8 weeks)

 13. Any other subjects deemed not eligible for this study by an investigator