CAVDPhase 4NCT04521452
Randomized, Open-label Trial of Inhibitory Effect of Evogliptin on Progression of CAVD
A Phase 4 study testing Evogliptin in people with CAVD, run by Asan Medical Center at 1 site in South Korea.
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. Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- CAVD
- What is being tested?
- Evogliptin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 218 participants
- Where
- 1 siteSouth Korea
- Study dates
- Sep 2020to Sep 2024
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and female aged 19 years or older
- Subjects who were diagnosed with type 2 diabetes mellitus and being treated with oral hypoglycemic drugs
- 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)
- Subjects who decided to take part in this study on his/her own volition after listening to the details of this study
Who cannot join
- 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)
- Subjects with left ventricular ejection fraction < 40%
- Heart failure patients: Subjects with heart failure of NYHA functional class II-IV
- Subjects with an estimated glomerular filtration rate (eGFR) of <30ml
- Subjects with type 1 diabetes or diabetic ketoacidosis
- Subjects with serious hypersensitivity to DPP-4 inhibitors
Show all 16Show fewer
- Subjects who have received/are receiving any of the following medication therapies:
- Vitamin K
- Calcium supplement (or osteoporosis medication)
- Subjects whose aortic valve stenosis is not caused by degenerative or bicuspid valve disease (e.g. rheumatic valve disease)
- Subjects who have received or are expected to receive (as of Visit 1) aortic valve surgery during the study.
- Subjects for whom a two-year clinical course investigation is not possible due to malignant tumor or cerebrovascular disease
- Pregnant or lactating women
- 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)
- Any other subjects deemed not eligible for this study by an investigator
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the detailed 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.
- Conditions
- CAVD
- Being tested
- Evogliptin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EvogliptinDrug
Subjects will receive evogliptin 5 mg daily
| Study group | Role | What they receive |
|---|---|---|
| Evogliptin Group | Experimental | evogliptin 5mg daily Receives: Drug: Evogliptin |
| Non-evogliptin Group | No intervention | DM medications except evogliptin and other DPP-4 inhibitors |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in aortic valve calcium volume at week 96 from baseline
Measured: 96 weeks
Secondary outcomes (7)
Change in aortic valve calcium volume at week 48 from baseline
Measured: 96 weeks
Change in aortic valve calcium score at week 48 and week 96 from baseline
Measured: 48 weeks, 96 weeks
Rate of change (%) in aortic valve calcium volume at week 48 and week 96 from baseline
Measured: 48 weeks, 96 weeks
Change in peak aortic-jet velocity at week 48 and week 96 from baseline
Measured: 48 weeks, 96 weeks
Change in aortic peak & mean pressure gradient at week 48 and week 96 from baseline
Measured: 48 weeks, 96 weeks
Change in aortic valve area at week 48 and week 96 from baseline
Measured: 48 weeks, 96 weeks
Time of major cardiovascular event
Measured: anytime during the entire follow-up of 96 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Aug 2020
- Study startSep 2020 (estimated)
- Primary completionSep 2024 (estimated)
- Study completionSep 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for CAVDStudies of the same condition, open and under way.
- More trials run by Asan Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, open-label trial
- Masking
- None (open label)
- Enrolment
- 218 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Asan Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- REDNVIA Co., Ltd.
- Responsible party
- Principal investigator, Jae-Kwan Song, Asan Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04521452
- Sponsor's protocol ID
- DIP_CAVD_DM
- Status last verified
- Aug 2020
- First submitted
- 19 Aug 2020
- Last updated
- 20 Aug 2020
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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.
PubMed 27188578Bonow 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. No abstract available.
PubMed 25691712Choi 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.
PubMed 28179397Otto 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. doi: 10.1056/NEJM199907153410302.
PubMed 10403851Aronow 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. doi: 10.1016/s0002-9149(98)00922-9.
PubMed 10073870Pawade 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.
PubMed 26227196Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez Munoz D, Rosenhek R, Sjogren 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. No abstract available.
PubMed 28886619Brandenburg VM, Reinartz S, Kaesler N, Kruger 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. No abstract available.
PubMed 28533322
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04521452
- Acronym / sponsor ID
- DIP_CAVD_DM
- Conditions
- CAVD
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 218 participants (estimated)
- Lead sponsor
- Asan Medical CenterUniversity, hospital or other
- Collaborators
- REDNVIA Co., Ltd.
- Study start
- Sep 2020 (estimated)
- Primary completion
- Sep 2024 (estimated)
- Study completion
- Sep 2024 (estimated)
- First posted
- 20 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Randomized, open-label trial
| Arm | Type | Receives |
|---|---|---|
| Evogliptin Group | Experimental | Drug: Evogliptinevogliptin 5mg daily |
| Non-evogliptin Group | No intervention | –DM medications except evogliptin and other DPP-4 inhibitors |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male and female aged 19 years or older
- Subjects who were diagnosed with type 2 diabetes mellitus and being treated with oral hypoglycemic drugs
- 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:
- Subjects who decided to take part in this study on his/her own volition after listening to the details of this study
Key exclusion criteria (16 listed)
- 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)
- Subjects with left ventricular ejection fraction < 40%
- Heart failure patients: Subjects with heart failure of NYHA functional class II-IV
- Subjects with an estimated glomerular filtration rate (eGFR) of <30ml
- Subjects with type 1 diabetes or diabetic ketoacidosis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EvogliptinSubjects will receive evogliptin 5 mg daily | Drug | Evogliptin Group |
Primary outcome
Change in aortic valve calcium volume at week 96 from baseline
Time frame: 96 weeks
7 secondary outcomes
Change in aortic valve calcium volume at week 48 from baseline
Time frame: 96 weeks
Change in aortic valve calcium score at week 48 and week 96 from baseline
Time frame: 48 weeks, 96 weeks
Rate of change (%) in aortic valve calcium volume at week 48 and week 96 from baseline
Time frame: 48 weeks, 96 weeks
Change in peak aortic-jet velocity at week 48 and week 96 from baseline
Time frame: 48 weeks, 96 weeks
Change in aortic peak & mean pressure gradient at week 48 and week 96 from baseline
Time frame: 48 weeks, 96 weeks
Change in aortic valve area at week 48 and week 96 from baseline
Time frame: 48 weeks, 96 weeks
Time of major cardiovascular event
Time frame: anytime during the entire follow-up of 96 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2020.
- Background: PubMed 27188578Lindman 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.
- Background: PubMed 25691712Bonow 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. No abstract available.
- Background: PubMed 28179397Choi 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.
- Background: PubMed 10403851Otto 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. doi: 10.1056/NEJM199907153410302.
- Background: PubMed 10073870Aronow 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. doi: 10.1016/s0002-9149(98)00922-9.
- Background: PubMed 26227196Pawade 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.
- Background: PubMed 28886619Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez Munoz D, Rosenhek R, Sjogren 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. No abstract available.
- Background: PubMed 28533322Brandenburg VM, Reinartz S, Kaesler N, Kruger 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. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Evogliptin in people with CAVD, run by Asan Medical Center at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 20 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in aortic valve calcium volume at week 96 from baseline (time frame: 96 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04521452, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2020.