Sacubitril/Valsartan Treats Patients With Essential Hypertension and Type 2 Diabetic Nephropathy (Hyper-Save)

A Prospective, Randomized, Controlled, Multicenter Study of Sacubitril/Valsartan in the Treatment of Patients With Mild to Moderate Essential Hypertension and Type 2 Diabetic Nephropathy: The Hyper-Save Study

This study aims to compare the efficacy and safety of Sacubitril/Valsartan versus Valsartan in patients with essential hypertension and type 2 diabetic nephropathy over a 12-week treatment period, including two treatment groups, with a total of 297 eligible subjects randomly assigned in a 2:1 ratio to either the experimental group or the control group.Subjects will participate in the study through two phases: the screening period and the follow-up period.The primary outcome measure is the change in systolic blood pressure from baseline after 12 weeks of treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 2 Diabetes; Essential Hypertension; Nephropathy
• Intervention / Treatment: Drug: Sacubitril/Valsartan; Drug: Valsartan

• Study Type: Interventional
• Enrollment (Estimated): 297
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Wenjie Tian Chief Physician; Phone Number: 086-17708130310; Email: tianwenjie1976@hotmail.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610072
      • Sichuan Academy of Medical Sciences · Sichuan Provincial People's Hospital
      • Contact: Hospital Operator; Phone Number: 086-028-87393401; Email: syyirb@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 years or older, no gender restriction;
• Diagnosed with mild to moderate primary hypertension (140 ≤ SBP < 180 mmHg and/or 90 ≤ DBP < 110 mmHg), including newly diagnosed or inadequately treated patients (those who have not followed previous medical advice and have uncontrolled blood pressure according to the investigator);
• Diagnosed with type 2 diabetes (according to Guideline for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition)), and meeting the following conditions: a) Continuously on ≥ 1 glucose control medication regimens (which may include long-acting insulin) for at least 12 weeks before screening, with a stable treatment regimen (i.e., the same medication and dosage) for at least 28 days before screening, and maintaining this regimen during the study. At the investigator's discretion, the dose of supplemental short-acting insulin can be adjusted as needed to achieve adequate glucose control; b) HbA1c level ≤ 10.5% and fasting (≥ 8 hours) plasma glucose level ≤ 13.3 mmol/L (if fasting glucose > 13.3 mmol/L, the investigator may repeat the test to determine eligibility);
• Urine albumin/creatinine ratio (UACR) ≥ 30 mg/g in two measurements taken on separate days or eGFR < 60 mL/min/1.73 m²;
• Non-pregnant or fertile patients (male or female) using reliable contraception;
• Female patients with potential for pregnancy must have a negative pregnancy test at screening;
• Subjects must voluntarily agree to comply strictly with the study protocol requirements and sign a written informed consent form.

Exclusion Criteria:

• Presence of severe hypertension, malignant hypertension, hypertensive emergencies, or hypertensive crises;
• History or evidence of secondary hypertension within 12 months before screening, including but not limited to any of the following: renovascular hypertension, renal parenchymal hypertension, unilateral or bilateral renal artery stenosis, coarctation of the aorta, primary aldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension;
• History of angioedema (drug-related or other causes) within 12 months before screening;
• Presence of diabetic ketoacidosis;
• History or evidence of secondary diabetes within 12 months before screening, including but not limited to any of the following: endocrine disorders causing carbohydrate metabolism disorders, pancreatogenic diabetes, hepatogenic diabetes, nephrogenic diabetes, etc.;
• History of malignancy in any organ system (excluding localized basal cell carcinoma of the skin);
• History of acute stroke, lacunar infarction, or dementia within 6 months before screening;
• History of coronary artery bypass graft surgery or any percutaneous coronary intervention (PCI) within 6 months before screening;
• Previously diagnosed or currently diagnosed heart failure (NYHA Class III-IV) or clinically significant valvular heart disease;
• History or current diagnosis of cardiac abnormalities: (1) second or third-degree atrioventricular block without a pacemaker; (2) clinically significant arrhythmias, including atrial fibrillation with a ventricular rate ≥ 120 bpm; (3) family history of long QT syndrome or torsades de pointes ventricular tachycardia;
• Chronic kidney disease stage 4 or higher (eGFR < 30 mL/min/1.73 m²), receiving renal dialysis, or history of kidney transplantation;
• Significant abnormalities in laboratory tests, such as potassium levels > 5.5 mmol/L or < 3.5 mmol/L, sodium levels < 130 mmol/L, liver function (ALT, AST) results > 3 times the upper limit of normal;
• History of allergy to antihypertensive drugs such as ARBs, Angiotensin-Converting Enzyme (ACE) inhibitors, or renin inhibitors;
• Clear history of intolerance to drugs similar to the study medication (e.g., ACE inhibitors, ARBs);
• Use of traditional Chinese or Western medicines that could affect the study's efficacy during the study period (see appendix for list);
• Any surgery or medical condition that significantly alters the absorption, distribution, metabolism, or excretion of any medication, including but not limited to the following: clinically significant gastrointestinal surgery within 12 months before the screening (e.g., gastrectomy, gastrointestinal anastomosis, bowel resection, gastric bypass, gastroenterostomy, or gastric banding), current active inflammatory bowel disease or history of active inflammatory bowel disease;
• Pregnant or breastfeeding women, or patients of childbearing potential unwilling or unable to use effective contraception during the study period;
• Participation in another clinical study using any investigational drug or observational study within 30 days before screening;
• Other conditions that, in the investigator's judgment, may affect the conduct of the clinical study or the determination of study results.

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
Experimental: Experimental; Initial Dose: The starting dose of Sacubitril/Valsartan is 200 mg once daily. Dose Adjustment: If blood pressure targets (SBP < 130 mmHg and DBP < 80 mmHg) are not achieved after 2 weeks of treatment, the dose of Sacubitril/Valsartan should be doubled to 400 mg once daily. Additional Treatment: If blood pressure targets are still not met after an additional 2 weeks of treatment, Nifedipine controlled-release tablets (30 mg once daily) should be added to the regimen.	Drug: Sacubitril/Valsartan; Sacubitril/Valsartan is a novel antihypertensive medication composed of an angiotensin II receptor blocker (ARB) Valsartan and a neprilysin inhibitor Sacubitril in a 1:1 molar co-crystal form. Sacubitril is a prodrug that, once ingested, is metabolized by esterases into its active form, which inhibits neprilysin activity. Neprilysin has various substrates, including natriuretic peptides and angiotensin II (Ang II). By inhibiting neprilysin, the levels of natriuretic peptides that have antihypertensive and organ-protective effects are increased. The other component, Valsartan, effectively inhibits the Ang II type 1 receptor (AT1R), providing additional antihypertensive and organ-protective effects. The co-crystal structure ensures that Sacubitril and Valsartan have similar absorption and elimination rates, thereby synchronizing their pharmacological effects.
Active Comparator: Comparator; Initial Dose: The starting dose of Valsartan is 80 mg once daily. Dose Adjustment: If blood pressure targets (SBP < 130 mmHg and DBP < 80 mmHg) are not achieved after 2 weeks of treatment, the dose of Valsartan should be doubled to 160 mg once daily. Additional Treatment: If blood pressure targets are still not met after an additional 2 weeks of treatment, Nifedipine controlled-release tablets (30 mg once daily) should be added to the regimen.	Drug: Valsartan; Valsartan, effectively inhibits the Ang II type 1 receptor (AT1R), providing both antihypertensive and organ-protective effects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in 24-hour ambulatory systolic blood pressure(SBP)	The comparison of the reduction in 24-hour ambulatory systolic blood pressure from baseline between the two groups	From enrollment to the end of treatment at 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in 24-hour ambulatory diastolic blood pressure(DBP)	The comparison of the reduction in 24-hour ambulatory diastolic blood pressure from baseline between the two groups	From enrollment to the end of treatment at 12 weeks
Changes in daytime and nighttime ambulatory blood pressure	The comparison of the changes in daytime and nighttime ambulatory blood pressure between the two groups. (The mean daytime blood pressure is defined as the average of hourly measurements taken between 6:00 and 22:00, and the mean nighttime is defined as the average of hourly measurements taken between 22:00 and 6:00.)	From enrollment to the end of treatment at 12 weeks
Rate of dipper blood pressure restoration	The comparison of the proportion of subjects in each group who achieve a dipper blood pressure pattern, defined as a nighttime blood pressure reduction of 10-20% in both systolic and diastolic blood pressure.	From enrollment to the end of treatment at 12 weeks
Rate of blood pressure achievement	The comparison of the proportion of subjects in each group who achieve blood pressure targets (SBP < 130 mmHg and DBP < 80 mmHg)	From enrollment to the end of treatment at 12 weeks
Rate of hypertension treatment response	The comparison of the proportion of subjects in each group who achieve hypertension treatment response, defined as: SBP < 140 mmHg and/or a reduction from baseline of ≥ 20 mmHg; DBP < 90 mmHg and/or a reduction from baseline of ≥ 10 mmHg; both of them	From enrollment to the end of treatment at 12 weeks
Improvement in diabetes condition	Comparison of reductions in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) between the two groups	From enrollment to the end of treatment at 12 weeks
Improvement in Renal Function	The comparison of reductions in serum creatinine, urine albumin/creatinine ratio, and blood urea nitrogen between the two groups	From enrollment to the end of treatment at 12 weeks
Medication utilization	The comparison of dose escalation proportions and the proportion of subjects requiring adjunctive nifedipine controlled-release tablets between the two groups	From enrollment to the end of treatment at 12 weeks
Safety assessments	Safety assessments included monitoring of all adverse events (AEs), serious AEs (SAEs), and regular monitoring of vital signs and clinical laboratory tests.	From enrollment to the end of treatment at 12 weeks

Collaborators and Investigators

• Sponsor: Sichuan Academy of Medical Sciences
• Collaborators: The Second Affiliated Hospital of Chongqing Medical University; Chengdu First People's Hospital; The People's Hospital of Leshan; Nanchong Central Hospital; Dazhou Central Hospital; Meishan Traditional Chinese Medicine Hospital; The Affiliated Traditional Chinese Medicine Hospital Of Southwest Medical University; Mianyang People's Hospital; Guan'an People's Hospital; Qijiang District People's Hospital; Meishan People's Hospital; The First People's Hospital of Guangyuan

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): April 10, 2025
• Study Completion (Estimated): April 10, 2025

Study Registration Dates

• First Submitted: June 28, 2024
• First Submitted That Met QC Criteria: July 9, 2024
• First Posted (Actual): July 15, 2024

Study Record Updates

• Last Update Posted (Actual): July 15, 2024
• Last Update Submitted That Met QC Criteria: July 9, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Essential hypertension; Nephropathy; Sacubitril/Valsartan
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hypertension; Diabetes Mellitus, Type 2; Kidney Diseases; Diabetic Nephropathies; Essential Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: Ethical Review 2024(15-1)

Drug and device information, study documents

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