Randomized, Open-label Trial of Inhibitory Effect of Evogliptin on Progression of CAVD

CAVD Clinical Trial

Official title:

An Open-label, Randomized Study of Inhibitory Effect of Evogliptin, the Dipeptidyl Peptidase-4 Inhibitor, on the Progression of Aortic Valve Calcification in Patients With Type 2 Diabetes Mellitus and Mild-to-moderate Aortic Stenosis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04521452
• Other study ID #: DIP_CAVD_DM
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: September 2020
• Est. completion date: September 2024

Study information

• Verified date: August 2020
• Source: Asan Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 218
• Est. completion date: September 2024
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

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

Related Conditions & MeSH terms

• CAVD
• Disease Progression

Intervention

Drug:
• Evogliptin
Subjects will receive evogliptin 5 mg daily

Locations

Country	Name	City	State
Korea, Republic of	Asan Medical Center	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Asan Medical Center	REDNVIA

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (8)

Aronow WS, Ahn C, Shirani J, Kronzon I. Comparison of frequency of new coronary events in older subjects with and without valvular aortic sclerosis. Am J Cardiol. 1999 Feb 15;83(4):599-600, A8. — View Citation

Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez Muñoz D, Rosenhek R, Sjögren J, Tornos Mas P, Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL; ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017 Sep 21;38(36):2739-2791. doi: 10.1093/eurheartj/ehx391. — View Citation

Bonow RO, Greenland P. Population-wide trends in aortic stenosis incidence and outcomes. Circulation. 2015 Mar 17;131(11):969-71. doi: 10.1161/CIRCULATIONAHA.115.014846. Epub 2015 Feb 17. — View Citation

Brandenburg VM, Reinartz S, Kaesler N, Krüger T, Dirrichs T, Kramann R, Peeters F, Floege J, Keszei A, Marx N, Schurgers LJ, Koos R. Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation: Results From a Prospective Interventional Proof-of-Concept Study. Circulation. 2017 May 23;135(21):2081-2083. doi: 10.1161/CIRCULATIONAHA.116.027011. Erratum in: Circulation. 2020 Jan 21;141(3):e54. — View Citation

Choi B, Lee S, Kim SM, Lee EJ, Lee SR, Kim DH, Jang JY, Kang SW, Lee KU, Chang EJ, Song JK. Dipeptidyl Peptidase-4 Induces Aortic Valve Calcification by Inhibiting Insulin-Like Growth Factor-1 Signaling in Valvular Interstitial Cells. Circulation. 2017 May 16;135(20):1935-1950. doi: 10.1161/CIRCULATIONAHA.116.024270. Epub 2017 Feb 8. — View Citation

Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, Pibarot P. Calcific aortic stenosis. Nat Rev Dis Primers. 2016 Mar 3;2:16006. doi: 10.1038/nrdp.2016.6. Review. — View Citation

Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med. 1999 Jul 15;341(3):142-7. — View Citation

Pawade TA, Newby DE, Dweck MR. Calcification in Aortic Stenosis: The Skeleton Key. J Am Coll Cardiol. 2015 Aug 4;66(5):561-77. doi: 10.1016/j.jacc.2015.05.066. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in aortic valve calcium volume at week 96 from baseline		96 weeks
Secondary	Change in aortic valve calcium volume at week 48 from baseline		96 weeks
Secondary	Change in aortic valve calcium score at week 48 and week 96 from baseline		48 weeks, 96 weeks
Secondary	Rate of change (%) in aortic valve calcium volume at week 48 and week 96 from baseline		48 weeks, 96 weeks
Secondary	Change in peak aortic-jet velocity at week 48 and week 96 from baseline		48 weeks, 96 weeks
Secondary	Change in aortic peak & mean pressure gradient at week 48 and week 96 from baseline		48 weeks, 96 weeks
Secondary	Change in aortic valve area at week 48 and week 96 from baseline		48 weeks, 96 weeks
Secondary	Time of major cardiovascular event		anytime during the entire follow-up of 96 weeks