Safety and Effect Study of SHR0532 (Drug Code) Tablets in Patients With Mild Hypertension

A Phase I, Randomized, Double-Blind, Placebo-hydrochlorothiazide Parallel Controlled, Multiple-Ascending Dose Study to Evaluate the Safety, Efficacy of SHR 0532 Oral Tablets in Mild Hypertension Subjects

The study is being conducted to evaluate the safety and efficacy and Pharmacokinetics/Pharmacodynamics of SHR0532 in subjects with mild hypertension for 4 weeks.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: SHR0532; Drug: SHR placebo; Drug: Hydrochlorothiazide 25 mg

Detailed Description

This is a randomized, double-blind, multiple ascending dose, placebo- and Hydrochlorothiazide-controlled study to evaluate the safety and tolerability, Pharmacokinetics and Pharmacodynamics and effect on blood pressure of SHR0532 tablets in patients with mild hypertension.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hangzhou
    • Hangzhou, Hangzhou, China, 310009
      • The Second Affiliated Hospital Zhejiang University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females between 18 to 65 years old
• Diagnosis of mild hypertension
• 18.5 kg/m2≤Body mass index (BMI) ≤35 kg/m^2
• Understand the study procedure and method, willing to participate the study and Informed consent form (ICF) signed in writing

Exclusion Criteria:

• History of significant drug allergy or allergic diseases (asthma, urticaria, eczematous dermatitis), or known allergy to anti hypertension drugs
• Anti-hypertensive drugs were taken within 1 month before screening
• History or at present patient has orthostatic hypotension
• History or at screening Participant has plasma sodium lower than 135mmol/L
• History or at screening visit/baseline patient has elevated serum uric acid (serum uric acid higher than ULN)
• Patients with type 1 diabetes mellitus need insulin therapy or poor blood glucose control (HbA1c > 9%, or oral anti diabetic drug dosage is not stable within 4 weeks before screening)
• History of arrhythmia or patient has clinically significant abnormalities of 12-lead ECG or prolonged corrected QT (QTc) interval (male > 450ms; female > 460ms) at screening visit
• History of New York Heart Association (NYHA) Definition II-IV Heart Failure
• Severe cardiovascular diseases occurred within 6 months before screening, including ischemic heart disease, peripheral vascular disease, significant ventricular tachycardia, atrial fibrillation, atrial flutter or other serious arrhythmias, hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, aortic or mitral valve disease of great hemodynamic significance, and severe cerebrovascular disease
• History of percutaneous intervention (PCI) or coronary artery bypass graft (CABG)
• History or active stroke, chronic seizures, or major neurological disorder
• History of osteoporosis, nephrocalcinosis, nephrolithiasis or hypercalciuria
• History or active malignant neoplastic disease. Exceptions: malignancies which have been successfully treated and non-recurrence >10 years prior to the screening visit
• Patients having following diseases may affect drug absorption, distribution, metabolism and excretion:

Gastrointestinal diseases such as irritable bowel syndrome, inflammatory bowel diseases including ulcerative colitis, Crohn's disease, malabsorption syndrome, microbial dysbiosis, intestinal infection; History of gastrointestinal operations, such as gastric resection and bypass, small intestinal resection and colonic resection which may affect drug absorption

• History of acute or chronic kidney diseases
• Dehydration or volume-depletion
• Clinically significant chronic or acute infectious diseases occur within 2 weeks before the start of the study (enrolment);
• Major surgery within 3 months before dosing
• Donation of blood/plasma within 1 month before dosing or blood/plasma (≥400 mL) within 3 months before dosing
• Unstable or severe urinary, digestive, psychiatric, neural, hematological and other diseases, or lab abnormalities, the investigators determine that participants in the study will be at unacceptable risk

Taking or having the following medication history:

• Participant need taking Cytochrome P450 3A4 (CYP3A4) inhibitors (such as ritonavir, indinavir, nelfinavir, erythromycin, telithromycin, clarithromycin, chloramphenicol, fluconazole, ketoconazole, itraconazole, verapamil or diltiazem) as well as strong/moderate CYP3A4 inducers (such as phenytoin, carbamazepine, oxcarbazepine, phenobarbital, efavirenz, nevirapine, rifampicin, modafinil, cyproterone or progestin) at least 2 weeks or 5 half-lives prior to administration of the initial dose of study drug until the post study visit
• Use of non-steroidal anti-inflammatory drugs (NSAIDs) at least 2 weeks before 1st dose of study drug until the post study visit
• use of systemic glucocorticoid therapy

Any laboratory examination result meet the following criteria at screening/baseline:

• Serum potassium < 3.5mmol/L or > 5.5mmol/L
• Serum creatinine more than ULN, Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 2.0 x ULN or total bilirubin more than 1.5 x ULN at screening/baseline visit
• Creatinine kinase (CK) more than 3.0 x ULN at screening/baseline visit;
• Clinically significant abnormalities of coagulation and thyroid function
• HbsAg and Hepatitis B Virus (HBV)-DNA> 1000 cps/ml, Hepatitis C Virus Antibody (HCVAb), syphilis and HIV antibodies were positive at screening visit
• Serum pregnant test positive at screening/baseline visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: SHR0532 tablet; up to 3 cohorts of subjects will receive multiple dose of oral tablets	Drug: SHR0532; once daily(QD) for 4weeks
PLACEBO_COMPARATOR: SHR0532 placebo; up to 3 cohorts of subjects will receive multiple dose of oral SHR0532 placebo	Drug: SHR placebo; once daily(QD) for 4weeks
ACTIVE_COMPARATOR: Hydrochlorothiazide; up to 3 cohorts of subjects will receive multiple dose of oral Hydrochlorothiazide 25mg	Drug: Hydrochlorothiazide 25 mg; once daily(QD) for 4weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events(AEs) and Serious Adverse Events （SAEs）	Incidence of AEs and SAEs, incidence of Treatment-Emergent Adverse Events, incidence of drug related adverse events (safety and tolrability)	from informed consent form signature to the end of the study (up to 2 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinic Systolic Blood Pressure (SBP) and Clinic Diastolic Blood Pressure (DBP)	Each subject has their office blood pressure every day of each treatment period (total of 28 days of treatment). The difference between baseline and D28 of each office BP value are calculated and recorded.	Baseline to end of the study (up to 32 days)
Change from baseline in 24h Urine sodium	Urine sodium (Na) levels were measured over 24-hours and different time period of 24 hours on Day -1 (baseline) and on Day 1to Day 7, Day28 to Day 32. The total amount of Na excreted in the Urine for Day-1 (baseline) and Day1 to Day 7, Day 28 to Day 32 were calculated and recorded and the difference between the 2 values are recorded.	from baseline to Day 8; from D28 to D32 (up to 32 days)
Change from baseline in 24h Urine Volume	Urine Volume were measured over 24-hours and different time period of 24 hours on Day -1 (baseline) and on Day 1to Day 7, Day28 to Day 32.The total amount of Urine excreted for Day-1 (baseline) and Day1 to Day 7, Day 28 to Day 32 were calculated and recorded and the difference between the 2 values are recorded.	from baseline to Day 8; from D28 to D32 (up to 32 days)

Collaborators and Investigators

• Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 31, 2019
• Primary Completion (ACTUAL): September 3, 2020
• Study Completion (ACTUAL): September 3, 2020

Study Registration Dates

• First Submitted: May 28, 2019
• First Submitted That Met QC Criteria: May 31, 2019
• First Posted (ACTUAL): June 3, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 18, 2021
• Last Update Submitted That Met QC Criteria: October 8, 2021
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide
• Other Study ID Numbers: SHR0532-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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