Low-dose Quadruple Combination Therapy in Patients With Hypertension

Hypertension Clinical Trial

— QUADUAL  

Official title:

Initial Treatment With a Single Capsule Containing Quadruple Combination of Half Doses of Blood Pressure Medicines Versus Standard Dose Dual Therapy in Patients With Hypertension: A Single-center, Randomized, Double-blind, Crossover Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05377203
• Other study ID #: R22023
• Secondary ID: MR-43-23-020339
• Status: Completed
• Phase: Phase 4
• Start date: July 13, 2022
• Est. completion date: July 4, 2023

Study information

• Verified date: July 2023
• Source: The Third Xiangya Hospital of Central South University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to compare the antihypertensive effect of initial treatment with a single capsule containing quadruple combination of half-dose of blood pressure medicines or standard dose dual combination in patients with hypertension.

Description:

This is a single-center, randomized, double-blind, crossover trial, planning to enroll 90 patients with grade 1 and 2 hypertension in the Third Xiangya Hospital of Central South University. The participants will be divided into two groups randomly and treated with half-dose quadruple antihypertensive therapy (irbesartan 75mg+ metoprolol 23.75mg+ amlodipine 2.5mg+ indapamide 1.25mg) or with full-dose dual antihypertensive therapy (irbesartan 150mg+ amlodipine 5mg) for four weeks. After washing out with placebo for two weeks, the participants of the two groups will exchange their medication and be treated for another four weeks. The changes of blood pressure (including 24-hour ambulatory blood pressure, office blood pressure, and home blood pressure) and related adverse effects of the two groups will be compared.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: July 4, 2023
• Est. primary completion date: July 4, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Age =18 years, < 80 years old;

• Have never taken antihypertensive medications or have not taken antihypertensive medications in the past 1 month;

• Patients with hypertension (meet the following two parameters to avoid white coat hypertension):a. Office Blood Pressure: systolic blood pressure =140 mmHg and/or diastolic blood pressure =90 mmHg measured 3 times on different days;b. ABPM: average blood pressure of 24h =130/80 mmHg; Or average blood pressure of daytime =135/85 mmHg; Or average blood pressure of night =120/70 mmHg;

• Participate voluntarily and sign written informed consent.

Exclusion Criteria:

• Confirmed or highly suspected secondary hypertension, such as primary aldosteronism, Cushing's syndrome, pheochromocytoma or paraganglioma, aortic constriction, renal arterial stenosis, renal hypertension, hyperthyroidism, etc.;

• Severe hypertension: systolic blood pressure =180 mmHg and/or diastolic blood pressure =110 mmHg in the consulting room or hypertensive emergency or urgency at the time of visit;

• Differences in blood pressure of both upper limbs =20/10mmHg;

• Allergic to irbesartan, metoprolol, amlodipine, indapamide and sulfonamides;

• Cannot swallow tablets;

• Pregnant and lactating women;

• Possible reproductive needs during the trial;

• Uncorrected electrolyte disorder (serum potassium > 5.5mmol/L or < 3.5mmol/L, serum sodium < 135mmol/L);

• Severe organ dysfunction, including impaired renal function (GFR < 60mL /min/1.73m^2), impaired liver function (aspartate aminotransferase or alanine aminotransferase = 3 times the upper limit of normal), NYHF classification class IV for cardiac function;

• Comorbidities lead to inaccurate blood pressure measurement, such as arrhythmia, etc.;

• Comorbidities result in the prohibition or caution of the experimental drugs, such as:

aortic stenosis, mitral valve stenosis, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis or renal artery stenosis with solitary kidney, gout, hyperuricemia (serum uric acid >420µmol/L in men or 360µmol/L in women), acute coronary syndrome, sick sinus syndrome, degree II-III of atrioventricular block, severe peripheral vascular disease with high risk of gangrene, history or family history of angioedema;

• Comorbidities affect the absorption, distribution, metabolism and excretion of the experimental drugs such as: gastrointestinal resection, gastrointestinal bypass surgery, sympathetic nerve resection or other operations, active inflammatory bowel disease, malignant tumors undergoing or planning to undergo radiotherapy or chemotherapy or targeted therapy, etc.;

• Medications in use or about to be used may lead to the prohibition or caution of experimental drugs: such as ACEI, Aliskiren, lithium agent, etc.;

• Medications in use or about to be used will interfere the results of this study, such as: hormones, Sacubitril valsartan and spironolactone for patients with chronic heart failure, Dapagliflozin and Liraglutide for patients with diabetes, and long-term medication for patients with chronic coronary heart disease, etc.;

• Not appropriate for antihypertensive therapies of this trial evaluated by physician;

• Participating in other clinical research that may affect the conduct of this study.

Related Conditions & MeSH terms

• Arterial Hypertension
• Hypertension

Intervention

Drug:
• Quadruple combination of half doses therapy?Dual combination of standard dose therapy
Quadruple combination of half doses therapy: a single capsule containing quadruple combination of half doses of blood pressure medicines (amlodipine besylate tablet 2.5mg, amlodipine besylate tablet simulator 2.5mg, irbesartan tablets 75mg, irbesartan tablets simulator 75mg, metoprolol succinate sustained-release tablets 23.75mg, indapamide tablets 1.25mg), take orally, one capsule once a day. Dual combination of standard dose therapy: a single capsule containing dual combination of standard dose of blood pressure medicines (amlodipine besylate tablets 2.5mg×2, irbesartan tablets 75mg×2, metoprolol succinate sustained-release tablets simulator 23.75mg, indapamide tablets simulator 1.25mg), take orally, one capsule once a day.
• Dual combination of standard dose therapy? Quadruple combination of half doses therapy
Dual combination of standard dose therapy: a single capsule containing dual combination of standard dose of blood pressure medicines (amlodipine besylate tablets 2.5mg×2, irbesartan tablets 75mg×2, metoprolol succinate sustained-release tablets simulator 23.75mg, indapamide tablets simulator 1.25mg), take orally, one capsule once a day. Quadruple combination of half doses therapy: a single capsule containing quadruple combination of half doses of blood pressure medicines (amlodipine besylate tablet 2.5mg, amlodipine besylate tablet simulator 2.5mg, irbesartan tablets 75mg, irbesartan tablets simulator 75mg, metoprolol succinate sustained-release tablets 23.75mg, indapamide tablets 1.25mg), take orally, one capsule once a day.

Locations

Country	Name	City	State
China	The Third Xiangya Hospital of Central South University	Changsha	Hunan

Sponsors (1)

Lead Sponsor	Collaborator
The Third Xiangya Hospital of Central South University

Country where clinical trial is conducted

China, 

References & Publications (6)

An J, Luong T, Qian L, Wei R, Liu R, Muntner P, Brettler J, Jaffe MG, Moran AE, Reynolds K. Treatment Patterns and Blood Pressure Control With Initiation of Combination Versus Monotherapy Antihypertensive Regimens. Hypertension. 2021 Jan;77(1):103-113. doi: 10.1161/HYPERTENSIONAHA.120.15462. Epub 2020 Nov 16. — View Citation

Chow CK, Gupta R. Blood pressure control: a challenge to global health systems. Lancet. 2019 Aug 24;394(10199):613-615. doi: 10.1016/S0140-6736(19)31293-0. Epub 2019 Jul 18. No abstract available. — View Citation

Joint Committee for Guideline Revision. 2018 Chinese Guidelines for Prevention and Treatment of Hypertension-A report of the Revision Committee of Chinese Guidelines for Prevention and Treatment of Hypertension. J Geriatr Cardiol. 2019 Mar;16(3):182-241. doi: 10.11909/j.issn.1671-5411.2019.03.014. No abstract available. — View Citation

Lu J, Lu Y, Wang X, Li X, Linderman GC, Wu C, Cheng X, Mu L, Zhang H, Liu J, Su M, Zhao H, Spatz ES, Spertus JA, Masoudi FA, Krumholz HM, Jiang L. Prevalence, awareness, treatment, and control of hypertension in China: data from 1.7 million adults in a population-based screening study (China PEACE Million Persons Project). Lancet. 2017 Dec 9;390(10112):2549-2558. doi: 10.1016/S0140-6736(17)32478-9. Epub 2017 Nov 5. Erratum In: Lancet. 2017 Nov 14;: — View Citation

Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, Wainford RD, Williams B, Schutte AE. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020 Jun;75(6):1334-1357. doi: 10.1161/HYPERTENSIONAHA.120.15026. Epub 2020 May 6. No abstract available. — View Citation

Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, Benetos A, Biffi A, Boavida JM, Capodanno D, Cosyns B, Crawford C, Davos CH, Desormais I, Di Angelantonio E, Franco OH, Halvorsen S, Hobbs FDR, Hollander M, Jankowska EA, Michal M, Sacco S, Sattar N, Tokgozoglu L, Tonstad S, Tsioufis KP, van Dis I, van Gelder IC, Wanner C, Williams B; ESC National Cardiac Societies; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021 Sep 7;42(34):3227-3337. doi: 10.1093/eurheartj/ehab484. No abstract available. Erratum In: Eur Heart J. 2022 Nov 7;43(42):4468. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of participants with severe adverse events (SAE)	Percentage of participants with any SAE according to Good Clinical Practice definition.	Four weeks
Other	Percentage of participants with side effects	Percentage of participants with occurrence of any potentially relevant side effect (pre-specified as in study protocol).	Four weeks
Other	Rate of relevant side effects	Rate of relevant side effects (pre-specified as in study protocol) at the participant level.	Four weeks
Other	Mean change in serum potassium	Mean change (from baseline) in serum potassium after 4 weeks of medication.	Four weeks
Other	Mean change in serum sodium	Mean change (from baseline) in serum sodium after 4 weeks of medication.	Four weeks
Other	Mean change in blood urea nitrogen	Mean change (from baseline) in blood urea nitrogen after 4 weeks of medication.	Four weeks
Other	Mean change in serum creatinine	Mean change (from baseline) in serum creatinine after 4 weeks of medication.	Four weeks
Other	Mean change in serum uric acid	Mean change (from baseline) in serum uric acid after 4 weeks of medication.	Four weeks
Other	Mean change in serum glutamic-oxalacetic transaminase	Mean change (from baseline) in serum glutamic-oxalacetic transaminase after 4 weeks of medication.	Four weeks
Other	Mean change in serum glutamic-pyruvic transaminase	Mean change (from baseline) in serum glutamic-pyruvic transaminase after 4 weeks of medication.	Four weeks
Other	Mean change in serum bilirubin	Mean change (from baseline) in serum bilirubin (total and direct bilirubin) after 4 weeks of medication.	Four weeks
Other	Mean change in blood glucose	Mean change (from baseline) in blood glucose after 4 weeks of medication.	Four weeks
Other	Mean change in urinary protein	Mean change (from baseline) in urinary protein (-, +, ++, +++) after 4 weeks of medication.	Four weeks
Other	Change in electrocardiogram QT Interval	Change (from baseline) in electrocardiogram QT Interval after 4 weeks of medication.	Four weeks
Primary	Mean systolic blood pressure of 24-hour	The reduction of mean systolic blood pressure of 24-hour in Ambulatory Blood Pressure Monitoring (ABPM) after 4 weeks of medication (from baseline).	Four weeks
Secondary	Mean systolic blood pressure of daytime and night	The reduction of mean systolic blood pressure of daytime and night in ABPM after 4 weeks of medication (from baseline).	Four weeks
Secondary	Mean diastolic blood pressure of 24-hour, daytime and night	The reduction of mean diastolic blood pressure of 24-hour, daytime and night in ABPM after 4 weeks of medication (from baseline).	Four weeks
Secondary	Morning blood pressure surge	The change of morning blood pressure surge in ABPM after 4 weeks of medication (from baseline).	Four weeks
Secondary	Office blood pressure	The reduction of office blood pressure after 4 weeks of medication (from baseline).	Four weeks
Secondary	Home blood pressure	The reduction of home blood pressure after 4 weeks of medication (from baseline).	Four weeks
Secondary	Heart rate	The change in heart rate after 4 weeks of medication (from baseline).	Four weeks
Secondary	Controlled rate of blood pressure	Controlled rate of blood pressure after 4 weeks of medication (from baseline).	Four weeks