Effects and Safety of Sacubitril/Valsartan on Refractory Hypertension

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Resistant Hypertension

Intervention / Treatment
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* Drug: Sacubitril/valsartan
* Drug: valsartan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sacubitril/valsartan group<br>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<br>* 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.<br>* Other names: amlodipine 10mg, hydrochlorothiazide 25 mg, spironolactone 20 mg;|
| Active Comparator: valsartan group<br>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<br>* 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.<br>* Other names: amlodipine 10mg, hydrochlorothiazide 25 mg, spironolactone 20 mg;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resistant hypertension, ambulatory blood pressure, sacubitril/valsartan, valsartan