Effects and Safety of Sacubitril/Valsartan on Refractory Hypertension

Effects and Safety of Sacubitril/Valsartan Versus Valsartan on Refractory Hypertension: The EOSORH Trial

Resistant hypertension (RH) accounted for a considerable proportion of patients with hypertension. It has been revealed to impose certain adverse effects on the prognosis of patients with cardiovascular diseases. The antihypertensive effect of sacubitril/valsartan being fully confirmed in previous studies, there were no related randomized controlled trials (RCT) about this potency among Chinese patients with RH. The investigators designed this study to evaluated effects and safety of sacubitril/valsartan versus valsartan on Chinese patients with RH.

Study Overview

• Status: Recruiting
• Conditions: Resistant Hypertension
• Intervention / Treatment: Drug: Sacubitril/valsartan; Drug: valsartan

Detailed Description

Background Resistant hypertension (RH) accounted for a considerable proportion of patients with hypertension. It has been revealed to impose certain adverse effects on the prognosis of patients with cardiovascular diseases. The antihypertensive effect of sacubitril/valsartan being fully confirmed in previous studies, there were no related randomized controlled trials (RCT) about this potency among Chinese patients with RH.

Purpose Describing the design of the Effects of Sacubitril/valsartan Versus Valsartan on Refractory Hypertension (EOSORH) trial.

Methods and analysis This is a monocentric, randomized, parallel-group, controlled trial which will investigate the efficacy and safety of sacubitril/valsartan in the treatment of Chinese patients with RH. A total of 138 patients will be enrolled who are diagnosed with RH according to the Guidelines for Prevention and Treatment of Hypertension in China (2018 revision). After a washout period, subjects will be randomized to sacubitril/valsartan group or valsartan group in a 1:1 ratio. The primary outcome is the change in 24 hours average ambulatory systolic blood pressure (SBP) from baseline to 8 weeks after randomization, comparing the sacubitril/valsartan group with valsartan group. The secondary outcomes including change in 24 hours average ambulatory diastolic blood pressure (DBP), clinic blood pressure and series of cardiac and renal hematologic indicators. Safety endpoints will also be evaluated, covered changes in blood potassium level, renal function, hypotension, etc. Full Analysis Set (FAS), per-protocol set (PPS) and safety set (SS) will be defined. Baseline data will be analyzed by using data from FAS whereas the analysis of primary outcome will be based on FAS and PPS but the conclusions of FAS are dominant.

Ethics and dissemination The research protocol has been approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University. This research is designed to investigate the efficacy and safety of sacubitril/valsartan in Chinese RH patients. Findings will be shared by Sun Yat-sen Memorial Hospital, policymakers and the academic community to promote the clinical pharmacal therapy of RH in China.

Discussion The effects of sacubitril/valsartan on hypertension have been widely reported by a series of large RCT in recent years, while its application in RH patients is still elusive. The study will provide a new pharmacal strategy for the treatment of RH.

• Study Type: Interventional
• Enrollment (Anticipated): 138
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Dengfeng Geng, Dr.; Phone Number: 020-81332623; Email: dr.dfengg@hotmail.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510120
      • Recruiting
      • Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
      • Contact: Dengfeng Geng, Dr.; Phone Number: 020-81332623; Email: dr.dfengg@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical diagnosis of resistant hypertension
• ≥18 and ≤75 years old at the time of randomization
• Must agree to comply with all requirements and sign the informed consent form

Exclusion Criteria:

• unwilling to sign informed consent.
• Severe renal insufficiency
• Research related drug contraindications
• secondary hypertension
• Cardiovascular event
• Persistent arrhythmia, valvular heart disease, and class III-IV heart failure or left ventricular ejection fraction <45%.
• Severe liver function impairment (Child-Pugh C), biliary cirrhosis and/or cholestasis
• History of angioedema and asthma
• Woman of childbearing age who do not take effective contraceptive measures or pregnant or breastfeeding
• Allergic to drugs related to the study
• Suffering from serious tumor-related diseases, receives tumor-related treatment, or has a life expectancy of less than 2 years
• Planning to join other clinical trials
• Anticipated changes in medical conditions
• Need to take study-related drugs for reasons other than hypertension
• Suffering from other diseases that may prevent the patient from participating fully period of the study
• Other any concomitant conditions
• Must continuously take any drugs that affect the results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sacubitril/valsartan group; The experimental group will be sacubitril/valsartan group. Patients assigned to this group will receive sacubitril/valsartan 200mg added to existing medication regimens before randomization including amlodipine 10mg per day, hydrochlorothiazide 25 mg per day, spironolactone 20 mg per day. The initial dose of sacubitril/valsartan will be 100mg per day and will be doubled to 200mg per day after 2 weeks then maintain until the end of the 8-week treatment period.	Drug: Sacubitril/valsartan; In sacubitril/valsartan group, patients will receive amlodipine 10mg, hydrochlorothiazide 25 mg, spironolactone 20 mg, sacubitril/valsartan 200mg to treat. The initial dose of sacubitril/valsartan will be 100mg per day and will be doubled to 200mg per day after 2 weeks then maintain until the end of the 8-week treatment period.; Other Names: amlodipine 10mg, hydrochlorothiazide 25 mg, spironolactone 20 mg
Active Comparator: valsartan group; The control group will be valsartan group, which patients will receive valsartan 160mg added to existing medication regimens before randomization including amlodipine 10mg per day, hydrochlorothiazide 25 mg per day, spironolactone 20 mg per day. The initial dose of valsartan will be 80mg per day and will be doubled to 160mg per day 2 weeks later and then maintain until the end of the 8-week treatment period.	Drug: valsartan; In valsartan group, patients will receive amlodipine 10mg, hydrochlorothiazide 25 mg, spironolactone 20 mg and valsartan 160mg. The initial dose of valsartan will be 80mg per day and will be doubled to 160mg per day 2 weeks later and then maintain until the end of the 8-week treatment period.; Other Names: amlodipine 10mg, hydrochlorothiazide 25 mg, spironolactone 20 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the change in 24 hours average ambulatory systolic pressure from baseline to 8 weeks after randomization	the change in 24 hours average ambulatory systolic blood pressure (in mmHg) from baseline to 8 weeks after randomization	8 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 24 hours average ambulatory diastolic blood pressure, daytime and night-time blood pressure and office blood pressure	Change in 24 hours average ambulatory diastolic blood pressure, daytime systolic blood pressure, night-time systolic blood pressure, daytime diastolic blood pressure, night-time diastolic blood pressure, office systolic blood pressure and office diastolic blood pressure	8 weeks after randomization
Change in level of cardiac marker reflecting the heart failure	serum N-terminal pro-brain natriuretic peptide (NT-proBNP in pg/ml)	8 weeks after randomization
Change in level of cardiac marker reflecting myocardial damage	cardiac troponin T (cTnT in pg/ml)	8 weeks after randomization
Change in level of novel cardiac marker reflecting the heart failure	suppression of Tumorigenicity 2 (sST2 in ng/ml)	8 weeks after randomization
Change in level of cardiac marker reflectting myocardial metabolism	cyclic guanosine monophosphate (cGMP in pmol/l)	8 weeks after randomization
Change in level of estimated glomerular filtration rate	Change in level of estimated glomerular filtration rate (eGFR in mL/min/1.73m^2).	8 weeks after randomization
Change in level of urinary albumin to creatinine ratio	Change in level of urinary albumin to creatinine ratio (in mg/mmol).	8 weeks after randomization
the control rate of blood pressure	The control rate of blood pressure. Blood pressure control was defined as a blood pressure of less than 140/90 mmHg after medical treatment.	8 weeks after randomization
Change in left atrium diameter determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in left atrium diameter (LA in mm) determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in left ventricular mass index determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in left ventricular mass index (LVMI in g/m^2) determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in left ventricular end diastolic volume index determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in left ventricular end diastolic volume index (LVEDVI in ml/m^2) determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in left ventricular end systolic volume index determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in left ventricular end systolic volume index (LVESVI in ml/m^2) determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in left ventricular ejection fraction determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in left ventricular ejection fraction (LVEF in %) determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in E/A determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in E/A determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.The E/A ratio is an echocardiographic index that reflects the diastolic function of the heart Under normal circumstances, E/A > 1.	8 weeks after randomization
Change in E/e' determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in E/e' determined by ultrasonic cardiogram and three-dimensional .The E/E' ratio is of great clinical significance in determining the diastolic function of the heart. If the E/E' ratio is <8, diastolic dysfunction can generally be ruled out. If the E/E' ratio is > 15, it generally indicates the existence of diastolic dysfunction.	8 weeks after randomization
Change in left ventricular overall longitudinal peak strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in left ventricular overall longitudinal peak strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in overall radial peak strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in overall radial peak strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in overall circumstantial peak strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in overall circumstantial peak strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization
Change in area strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging	Change in area strain determined by ultrasonic cardiogram and three-dimensional speckle tracking imaging.	8 weeks after randomization

Collaborators and Investigators

• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Investigators: Principal Investigator: Dengfeng Geng, Dr., Sun Yat-sen Memorial Hospital,Sun Yat-sen University

Publications and helpful links

General Publications

• Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM; American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008 Jun 24;117(25):e510-26. doi: 10.1161/CIRCULATIONAHA.108.189141.
• Lamirault G, Artifoni M, Daniel M, Barber-Chamoux N, Nantes University Hospital Working Group On Hypertension. Resistant Hypertension: Novel Insights. Curr Hypertens Rev. 2020;16(1):61-72. doi: 10.2174/1573402115666191011111402.
• Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016 Mar 5;387(10022):957-967. doi: 10.1016/S0140-6736(15)01225-8. Epub 2015 Dec 24.
• Kario K, Shin J, Chen CH, Buranakitjaroen P, Chia YC, Divinagracia R, Nailes J, Hoshide S, Siddique S, Sison J, Soenarta AA, Sogunuru GP, Tay JC, Teo BW, Turana Y, Zhang Y, Park S, Van Minh H, Wang JG. Expert panel consensus recommendations for ambulatory blood pressure monitoring in Asia: The HOPE Asia Network. J Clin Hypertens (Greenwich). 2019 Sep;21(9):1250-1283. doi: 10.1111/jch.13652.
• Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, Zhang Y, Gotou H, Lefkowitz M, Zhang J. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014 Apr;63(4):698-705. doi: 10.1161/HYPERTENSIONAHA.113.02002. Epub 2014 Jan 20.

Study record dates

Study Major Dates

• Study Start (Anticipated): September 24, 2022
• Primary Completion (Anticipated): October 28, 2022
• Study Completion (Anticipated): March 31, 2023

Study Registration Dates

• First Submitted: January 5, 2022
• First Submitted That Met QC Criteria: September 16, 2022
• First Posted (Actual): September 19, 2022

Study Record Updates

• Last Update Posted (Actual): September 19, 2022
• Last Update Submitted That Met QC Criteria: September 16, 2022
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: ambulatory blood pressure; valsartan; sacubitril/valsartan; Resistant hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Amlodipine; Valsartan; Spironolactone; Hydrochlorothiazide; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2020-KY-126

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No