Mitral Valve InsufficiencyPhase 4PRIMENCT02687932
Pharmacological Reduction of Functional, Ischemic Mitral REgurgitation
A Phase 4 study testing LCZ696 and Valsartan in people with Mitral Valve Insufficiency and Left Ventricular Dysfunction, run by Asan Medical Center at 4 sites in South Korea.
Trial summary
Functional MR is caused by adverse left ventricular remodeling after myocardial injury and associated with an increased incidence of heart failure and death. Because secondary functional MR usually develops as a result of LV dysfunction, diuretics, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors or… Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Mitral Valve Insufficiency, Left Ventricular Dysfunction
- What is being tested?
- LCZ696 and Valsartan
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 118 participants
- Where
- 4 sitesSouth Korea
- Study dates
- Mar 2016to 2 Jan 2018
- 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 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must agree to the study protocol and provide written informed consent
- Outpatients ≥ 20 years of age, male or female
- Patients with secondary functional MR (stage B and C) and LV dysfunction
- Symptoms due to coronary ischemia or heart failure may be present but symptoms due to MR should be absent
- Normal mitral valve leaflets and chords
- Regional or global wall motion abnormalities with mild or severe tethering of leaflet
Show all 10Show fewer
- ERO > 0.10 cm2
- 25% < LV ejection fraction < 50%
- Dyspnea of NYHA functional class II or III
- Patients must be on stable, optimized dose of an ACE inhibitors or ARBs for at least 4 weeks prior to study entry
Who cannot join
- History of hypersensitivity or allergy to the study drug, drugs of similar chemical classes, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drug
- Known history of angioedema
- Any evidence of structural mitral valve disease, including prolapse of mitral leaflets and rupture of chords or papillary muscles
- Current acute decompensated heart failure or dyspnea of NYHA functional class IV
- Medical history of hospitalization within 6 weeks
- Symptomatic hypotension and/or a SBP < 100 mmHg at screening
Show all 18Show fewer
- Estimated GFR < 30 mL/min/1.73m2
- Serum potassium > 5 mmol/L at screening
- Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x upper limit of normal (ULN) at screening visit (Visit 0), history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt
- Acute coronary syndrome, stroke, major CV surgery, PCI within 3 months
- Planned coronary revascularization or mitral valve intervention within 1 year
- Heart transplantation or implantation of cardiac resynchronization therapy
- History of severe pulmonary disease
- Significant aortic valve disease
- Primary aldosteronism
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using a barrier method plus a hormonal method
- Pregnant or nursing (lactating) women
- Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the investigator, would preclude safe completion of the study
Trial locations and contacts
4 sites in 1 country.
South Korea4 sites
Inha University Hospital
Incheon
Asan Medical Center
Seoul, 138-736
Samsung Medical Center
Seoul
Yonsei University Medical Center
Seoul
About this study
Official title: Multicenter, Randomized, Double-blind, Active-controlled Study to Assess the Efficacy of LCZ696 Compared to Valsartan on Reduction of Mitral Regurgitation in Patients With Left Ventricular Dysfunction and Secondary Functional Mitral Regurgitation of Stage B and C
Functional MR is caused by adverse left ventricular remodeling after myocardial injury and associated with an increased incidence of heart failure and death. Because secondary functional MR usually develops as a result of LV dysfunction, diuretics, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and aldosterone antagonists are given to patients with functional MR in line with the guidelines in the management of heart failure. However, functional MR appears to remain common despite use of these drugs and current medical treatment is usually insufficient for reducing MR or reversing the adverse LV remodeling. As LCZ696 is a dual-acting inhibitor of the renin-angiotensin-aldosterone system (RAAS) and neutral endopeptidase (NEP), LCZ696 has greater hemodynamic and neurohormonal effects than ARB alone. Investigators try to examine the hypothesis that LCZ696 is superior to ARB alone in improving functional MR in patients with LV dysfunction and functional MR.
Read the detailed description
Functional ischemic mitral regurgitation (MR) has been reported to occur in up to 40% of patients after myocardial infarction, and the prevalence of functional MR is likely to increase with an aging population and improved survival rates for myocardial infarction. The presence of functional MR is associated with an increased incidence of heart failure and death, and patients with significant functional MR incur about a two-fold increase in the risk of mortality and about a four-fold increase in the risk of heart failure. Functional MR is caused by adverse left ventricular remodeling after myocardial injury with enlargement of the left ventricle (LV), apical and lateral displacement of papillary muscles, leaflet tethering and reduced closing forces. The leaflets are normal in secondary functional MR and the treatment is considerably different between functional and primary MR. Surgery is the only definitive therapy for primary severe MR and primary MR can usually be cured by surgical valve repair. However, surgical indications are unclear in severe functional MR, because outcomes after surgery for functional MR remain suboptimum. Operative mortality, long-term mortality and heart failure rates are still high in patients with severe functional MR despite surgical improvements. According to the current guidelines, mitral valve surgery may be considered only for severely symptomatic patients with severe secondary functional MR who have persistent symptoms despite optimal medical therapy for heart failure.
Because secondary functional MR usually develops as a result of LV dysfunction, diuretics, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and aldosterone antagonists are given to patients with functional MR in line with the guidelines in the management of heart failure. However, functional MR appears to remain common despite use of these drugs and current medical treatment is usually insufficient for reducing MR or reversing the adverse LV remodeling. Persistence of functional MR due to the insufficient effectiveness of current medical treatment significantly increases morbidity and mortality, and compared with surgical or percutaneous revascularization, significantly higher mortality was observed in patients managed with medical therapy.
Quantitative assessment of MR is strongly recommended in the guidelines and the regurgitant volume and the effective regurgitant orifice area (EROA) of MR can be measured accurately and reproducibly by Doppler echocardiography. The EROA of MR has an important prognostic value in primary and secondary functional MR. Because functional MR carries an adverse prognosis with a graded relationship between MR severity and reduced survival, therapies that induce beneficial reverse remodeling of the LV and reduce MR, may improve survival. ACE inhibitors and ARBs could partially attenuate LV dilatation and remodeling after myocardial injury, but there are no published data from prospective trials regarding whether attenuation of remodeling by ACE inhibitors or ARBs reduces functional MR.
LCZ696 is a dual-acting inhibitor of the renin-angiotensin-aldosterone system (RAAS) and neutral endopeptidase (NEP). As LCZ696 offers the therapeutic advantages of concomitantly blocking both RAAS and NEP, LCZ696 was more effective in reducing the risk of death from cardiovascular causes or hospitalization for heart failure in patients with chronic heart failure than ACE inhibitor. Because NEP is involved in the metabolism of a number of vasoactive peptides such as natriuretic peptides, NEP inhibitor has vasodilating effects, facilitates sodium excretion and has profound effects on LV remodeling. Trials of hypertension and heart failure with a preserved ejection fraction also showed that LCZ696 had greater hemodynamic and neurohormonal effects than ARB alone. To date, there has been no proven pharmacological therapy to improve functional MR, and the development of medical therapy should be at the forefront of research considering the limited role of surgery in managing functional MR. Investigators hypothesize that LCZ696 is superior to ARB alone in improving functional MR in patients with LV dysfunction and functional MR via synergistic effects of NEP and RAAS inhibition on LV remodeling, and try to examine this hypothesis in a multicenter, double-blind, randomized comparison study using echocardiography.
- Being tested
- LCZ696, Valsartan
- Keywords
- Functional Mitral Regurgitation, Ischemic Mitral Regurgitation
- Medical subject headings
- Mitral Valve Insufficiency, Ventricular Dysfunction, Left
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LCZ696Drug
ValsartanDrug
| Study group | Role | What they receive |
|---|---|---|
| LCZ696 | Experimental | LCZ696 for 12 months Receives: Drug: LCZ696 |
| Valsartan | Active comparator | Valsartan for 12 months Receives: Drug: Valsartan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change of effective regurgitant orifice area (EROA) of functional mitral regurgitation from baseline to 12 months follow-up
Measured: 12 months
Secondary outcomes (4)
Change of regurgitant volume from baseline to 12 months follow-up
Measured: 12 months
Change of left ventricular end-systolic volume from baseline to 12 months follow-up
Measured: 12 months
Change of left ventricular end-diastolic volume from baseline to 12 months follow-up
Measured: 12 months
Change of incomplete mitral leaflet closure area from baseline to 12 months follow-up
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Feb 2016 (estimated)
- Study startMar 2016
- Primary completion2 Jan 2018
- Study completion2 Jan 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Mitral Valve InsufficiencyStudies 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 118 participants (actual)
Sponsor and investigators
- Lead sponsor
- Asan Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis
- Responsible party
- Principal investigator, Duk-Hyun Kang, Asan Medical Center
- Investigators
- Duk-Hyun Kang, M.D., Principal investigator, Asan Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02687932
- Sponsor's protocol ID
- 2015-0938
- Acronym
- PRIME
- Status last verified
- Jan 2018
- First submitted
- 17 Feb 2016
- Last updated
- 9 Jan 2018
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Kang DH, Park SJ, Shin SH, Hong GR, Lee S, Kim MS, Yun SC, Song JM, Park SW, Kim JJ. Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation. Circulation. 2019 Mar 12;139(11):1354-1365. doi: 10.1161/CIRCULATIONAHA.118.037077.
PubMed 30586756
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Multicenter, Randomized, Double-blind, Active-controlled Study to Assess the Efficacy of LCZ696 Compared to Valsartan on Reduction of Mitral Regurgitation in Patients With Left Ventricular Dysfunction and Secondary Functional Mitral Regurgitation of Stage B and C
- ClinicalTrials.gov ID
- NCT02687932
- Acronym / sponsor ID
- PRIME / 2015-0938
- Keywords
- Functional Mitral Regurgitation, Ischemic Mitral Regurgitation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 118 participants (actual)
- Lead sponsor
- Asan Medical CenterUniversity, hospital or other
- Collaborators
- Novartis
- Study start
- Mar 2016 (actual)
- Primary completion
- 2 Jan 2018 (actual)
- Study completion
- 2 Jan 2018 (actual)
- First posted
- 22 Feb 2016 (estimated)
- 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.
Functional MR is caused by adverse left ventricular remodeling after myocardial injury and associated with an increased incidence of heart failure and death. Because secondary functional MR usually develops as a result of LV dysfunction, diuretics, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and aldosterone antagonists are given to patients with functional MR in line with the guidelines in the management of heart failure. However, functional MR appears to remain common despite use of these drugs and current medical treatment is usually insufficient for reducing MR or reversing the adverse LV remodeling. As LCZ696 is a dual-acting inhibitor of the renin-angiotensin-aldosterone system (RAAS) and neutral endopeptidase (NEP), LCZ696 has greater hemodynamic and neurohormonal effects than ARB alone. Investigators try to examine the hypothesis that LCZ696 is superior to ARB alone in improving functional MR in patients with LV dysfunction and functional MR.
Detailed description
Functional ischemic mitral regurgitation (MR) has been reported to occur in up to 40% of patients after myocardial infarction, and the prevalence of functional MR is likely to increase with an aging population and improved survival rates for myocardial infarction. The presence of functional MR is associated with an increased incidence of heart failure and death, and patients with significant functional MR incur about a two-fold increase in the risk of mortality and about a four-fold increase in the risk of heart failure. Functional MR is caused by adverse left ventricular remodeling after myocardial injury with enlargement of the left ventricle (LV), apical and lateral displacement of papillary muscles, leaflet tethering and reduced closing forces. The leaflets are normal in secondary functional MR and the treatment is considerably different between functional and primary MR. Surgery is the only definitive therapy for primary severe MR and primary MR can usually be cured by surgical valve repair. However, surgical indications are unclear in severe functional MR, because outcomes after surgery for functional MR remain suboptimum. Operative mortality, long-term mortality and heart failure rates are still high in patients with severe functional MR despite surgical improvements. According to the current guidelines, mitral valve surgery may be considered only for severely symptomatic patients with severe secondary functional MR who have persistent symptoms despite optimal medical therapy for heart failure.
Because secondary functional MR usually develops as a result of LV dysfunction, diuretics, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and aldosterone antagonists are given to patients with functional MR in line with the guidelines in the management of heart failure. However, functional MR appears to remain common despite use of these drugs and current medical treatment is usually insufficient for reducing MR or reversing the adverse LV remodeling. Persistence of functional MR due to the insufficient effectiveness of current medical treatment significantly increases morbidity and mortality, and compared with surgical or percutaneous revascularization, significantly higher mortality was observed in patients managed with medical therapy.
Quantitative assessment of MR is strongly recommended in the guidelines and the regurgitant volume and the effective regurgitant orifice area (EROA) of MR can be measured accurately and reproducibly by Doppler echocardiography. The EROA of MR has an important prognostic value in primary and secondary functional MR. Because functional MR carries an adverse prognosis with a graded relationship between MR severity and reduced survival, therapies that induce beneficial reverse remodeling of the LV and reduce MR, may improve survival. ACE inhibitors and ARBs could partially attenuate LV dilatation and remodeling after myocardial injury, but there are no published data from prospective trials regarding whether attenuation of remodeling by ACE inhibitors or ARBs reduces functional MR.
LCZ696 is a dual-acting inhibitor of the renin-angiotensin-aldosterone system (RAAS) and neutral endopeptidase (NEP). As LCZ696 offers the therapeutic advantages of concomitantly blocking both RAAS and NEP, LCZ696 was more effective in reducing the risk of death from cardiovascular causes or hospitalization for heart failure in patients with chronic heart failure than ACE inhibitor. Because NEP is involved in the metabolism of a number of vasoactive peptides such as natriuretic peptides, NEP inhibitor has vasodilating effects, facilitates sodium excretion and has profound effects on LV remodeling. Trials of hypertension and heart failure with a preserved ejection fraction also showed that LCZ696 had greater hemodynamic and neurohormonal effects than ARB alone. To date, there has been no proven pharmacological therapy to improve functional MR, and the development of medical therapy should be at the forefront of research considering the limited role of surgery in managing functional MR. Investigators hypothesize that LCZ696 is superior to ARB alone in improving functional MR in patients with LV dysfunction and functional MR via synergistic effects of NEP and RAAS inhibition on LV remodeling, and try to examine this hypothesis in a multicenter, double-blind, randomized comparison study using echocardiography.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| LCZ696 | Experimental | Drug: LCZ696LCZ696 for 12 months |
| Valsartan | Active comparator | Drug: ValsartanValsartan for 12 months |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Patients must agree to the study protocol and provide written informed consent
- Outpatients ≥ 20 years of age, male or female
- Patients with secondary functional MR (stage B and C) and LV dysfunction
- Dyspnea of NYHA functional class II or III
- Patients must be on stable, optimized dose of an ACE inhibitors or ARBs for at least 4 weeks prior to study entry
Key exclusion criteria (18 listed)
- History of hypersensitivity or allergy to the study drug, drugs of similar chemical classes, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drug
- Known history of angioedema
- Any evidence of structural mitral valve disease, including prolapse of mitral leaflets and rupture of chords or papillary muscles
- Current acute decompensated heart failure or dyspnea of NYHA functional class IV
- Medical history of hospitalization within 6 weeks
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 |
|---|---|---|
| LCZ696 | Drug | LCZ696 |
| Valsartan | Drug | Valsartan |
Primary outcome
Change of effective regurgitant orifice area (EROA) of functional mitral regurgitation from baseline to 12 months follow-up
Time frame: 12 months
4 secondary outcomes
Change of regurgitant volume from baseline to 12 months follow-up
Time frame: 12 months
Change of left ventricular end-systolic volume from baseline to 12 months follow-up
Time frame: 12 months
Change of left ventricular end-diastolic volume from baseline to 12 months follow-up
Time frame: 12 months
Change of incomplete mitral leaflet closure area from baseline to 12 months follow-up
Time frame: 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2018.
- Derived from this study: PubMed 30586756Kang DH, Park SJ, Shin SH, Hong GR, Lee S, Kim MS, Yun SC, Song JM, Park SW, Kim JJ. Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation. Circulation. 2019 Mar 12;139(11):1354-1365. doi: 10.1161/CIRCULATIONAHA.118.037077.
- Individual participant dataSharing planned: No
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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.
Duk-Hyun Kang, M.D. principal investigator
Asan Medical Center
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing LCZ696 and Valsartan in people with Mitral Valve Insufficiency and Left Ventricular Dysfunction, run by Asan Medical Center at 4 sites 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 10 inclusion and 18 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: finished, as of the sponsor's last update on 9 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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 of effective regurgitant orifice area (EROA) of functional mitral regurgitation from baseline to 12 months follow-up (time frame: 12 months). 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 NCT02687932, which also lists 1 linked publication.
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 9 Jan 2018; AzTrials last refreshed its copy on 7 Nov 2026.