Open Label RCT for Chronic Severe AR : Entresto vs. CCB/ARB (REVERSE-AR)

Multicenter, Randomized, Open-label Trial to Assess the Efficacy of Sacubitril/Valsartan vs. Amlodipine/Losartan on Left Ventricular Remodeling in Patients With Chronic Severe Aortic Regurgitation

The purpose of this study is to assess the efficacy of sacubitril-valsartan compared to the combination of ARB/CCB on left ventricular remodeling in patients with chronic aortic valve regurgitation.

Study Overview

• Status: Recruiting
• Conditions: Aortic Valve Insufficiency
• Intervention / Treatment: Drug: Sacubitril-valsartan; Drug: Amlodipine-losartan

Detailed Description

After being informed consent about the study and potential risk, all patients giving written informed consent will undergo a 1 month screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in an open-label manner in a 1:1 ratio to sacubitril-valsartan or amlodipine/losartan.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Eun Kyoung Kim, MD. PhD; Phone Number: 82-2-3410-3419; Email: ekbobi.kim@samsung.com
• Study Contact Backup: Name: Sung Ji Park, MD, PhD; Phone Number: 82-2-3410-3419; Email: sungji.park@samsung.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
    • Contact: Eun Kyoung Kim, MD PhD; Phone Number: 82234103419; Email: ekbobi.kim@samsung.com
    • Contact: Ji Hoon Kim, MD; Phone Number: 82234103419; Email: jh9933.kim@samsung.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Participant over 20 years of age who has not been hospitalized for heart failure
2. Participant with hypertension or systolic blood pressure 125 mmHg or higher
3. NYHA I
4. Participant with chronic severe aortic regurgitation (VCW >0.6cm)
5. Participant with AV regurgitant volume ≥ 60mL or effective regurgitant orifice area ≥ 0.3 cm2
6. Participant with left ventricular ejection fraction ≥ 55%

Exclusion Criteria:

1. A history of hypersensitivity or allergy to clinical trial drugs or similar compounds or ARB/NEP inhibitors
2. History of angioedema
3. Patients with an ascending aorta dilated by more than 55 mm
4. Patients with aortic valve insufficiency due to hereditary aortic disease (Marfan syndrome, Ehlers-Danlos syndrome)
5. Patients with moderate to severe aortic stenosis
6. Patients with claustrophobia or with metallic implants unsuitable for magnetic resonance imaging
7. History of acute heart failure within 6 weeks and dyspnea of NYHA II or higher
8. Symptomatic hypotension or SBP < 100 mmHg at screening
9. Patients with renal failure (Estimated GFR < 30 mL/min/1.73 m2) or on dialysis
10. Significant increase in blood potassium level (Potassium > 5 mmol/L)
11. Blood AST or ALT value is more than twice the upper limit of normal or symptoms and signs of cirrhosis (history of hepatic coma, history of esophageal varices, history of symptomatic ascites)
12. In case of acute coronary syndrome, stroke, thoracic surgery, and percutaneous coronary angioplasty within 3 months
13. If aortic valve surgery is scheduled within the next 6 months
14. In case of severe mitral valve disease
15. Patients with primary hyperaldosteronism
16. If a woman of childbearing potential has not used double contraception
17. Women who are currently pregnant or lactating
18. When it is judged that there are clinically significant abnormalities in physical examination, diagnostic examination, electrocardiogram, etc. at the time of the screening visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sacubitril-Valsartan Group; Participant start Sacubitril/Valsartan tablet 50mg twice a day and uptitrate to 100mg twice a day. Participants take the maximum dose considering blood pressure for a total of 48 weeks.	Drug: Sacubitril-valsartan; 50mg~100mg twice daily; Other Names: Entresto
Placebo Comparator: Amlodipine-Losartan group; Participant start amlodipine/losartan 25/2.5mg once a day and uptitrate to 5/100mg once a day. Participants take the maximum dose considering blood pressure for a total of 48 weeks.	Drug: Amlodipine-losartan; amlodipine/losartan 2.5/25mg ~ 5/100mg once daily; Other Names: Amosartan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of left ventricular end-diastolic volume index from baseline to 12 months follow-up	Change = [LVEDV on CMR at 12 months]-[LVEDV on CMR at baseline]	Baseline and month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of regurgitant volume of aortic valve regurgitation from baseline to 12 months follow-up.	Change = [regurgitant volume at 12 months]-[regurgitant volume at baseline]	Baseline and month 12
Change of EROA of aortic valve regurgitation from baseline to 12 months follow-up.	Measurement of regurgitant volume of AR is derived from Doppler imaging on echocardiography. Change = [regurgitant volume at 12 months]-[regurgitant volume at baseline]	Baseline and month 12
Change of LV end-systolic volume from baseline to 12 months follow-up.	Change = [LVEDV at 12 months]-[LVEDV at baseline]	Baseline and month 12
Holodiastolic flow reversal in the proximal abdominal aorta and descending thoracic aorta from baseline to 12 months follow-up	presence or absence of holodiastolic flow reversal in the proximal abdominal and descending thoracic aorta on echocardiography	Baseline and month 12
Change of NT-proBNP level from baseline to 12 months follow-up.	Change =[NT-proBNP at 12 months]-[NTproBNP at baseline]	Baseline and month 12
Aortic valve replacement or repair operation	Any surgical event for correction of AR	During 12 months after enrollment

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Investigators: Principal Investigator: Eun Kyoung Kim, MD, PhD, Heart Vascular Stroke Institute, Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: January 27, 2022
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (Actual): January 28, 2022

Study Record Updates

• Last Update Posted (Actual): January 28, 2022
• Last Update Submitted That Met QC Criteria: January 27, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Aortic Valve Disease; Heart Valve Diseases; Aortic Valve Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Amlodipine; Valsartan; Losartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: reverseAR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No