Efficacy of Chlorthalidone and Hydrochlorothiazide Combined With Amiloride on Blood Pressure in Primary Hypertension.

Efficacy of Chlorthalidone and Hydrochlorothiazide in Combination With Amiloride in Multiple Doses on Blood Pressure in Patients With Primary Hypertension: a Factorial Randomized Controlled Trial.

Thiazide diuretics have demonstrated favorable blood pressure lowering efficacy, safety profile and low cost, but it is still unclear what are the equivalence of doses of their more common agents, chlorthalidone and hydrochlorothiazide. Besides, concernments about adverse metabolic effects such as hypokalemia, hyperglycemia and hyperlipidemia do exist, which may be attenuated with the concomitant administration of a potassium-sparing diuretic, such as amiloride. In addition to control adverse effects of thiazides, amiloride could offer an additional blood pressure lowering effect, but the efficacy of different doses was not fully established. This study aims to investigate the blood pressure lowering efficacy of chlorthalidone and hydrochlorothiazide, in combination with amiloride in different doses, for the initial management in patients with primary hypertension.

Study Overview

• Status: Unknown
• Conditions: Hypertension
• Intervention / Treatment: Drug: Chlorthalidone 25 mg; Drug: Amiloride 20 mg; Drug: Amiloride 10 mg; Drug: Hydrochlorothiazide 50 mg

Detailed Description

This is a factorial (2x2) randomized double-blinded clinical trial comparing the association of a thiazide diuretic (chlorthalidone 25 mg/day or hydrochlorothiazide 50 mg/day) with a potassium-sparing diuretic (amiloride 10 mg/day or amiloride 20 mg/day) as first drug option in patients aged 30 to 75 years with primary hypertension. The thiazide diuretic and amiloride will be combined in a single capsule. The capsules will be of the same size and color, so that neither the researcher nor the patients can distinguish the treatment by their appearance. The primary outcome will be the mean change from baseline in 24-h systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM). The secondary outcomes will be the mean change from baseline in daytime and nighttime systolic and diastolic blood pressure measured by ABPM, mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure, incidence of adverse events, variation of laboratory parameters and proportion of patients who achieved blood pressure control (<140/90 mmHg and <130/80 mmHg for office blood pressure and 24-h ABPM, respectively). The follow-up will last 12 weeks. For a P alpha of 0.05, power of 80%, and standard deviation of 9 mmHg, and absolute difference of 6 mmHg on systolic blood pressure on 24-h ABPM, it will be necessary to study a total of 76 patients. The sample size will be increased by 10% to compensate losses, resulting in 84 patients being randomized in total (42 for each arm).

• Study Type: Interventional
• Enrollment (Anticipated): 84
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Flavio Fuchs, MD, PhD; Phone Number: +55 51 3359.8344; Email: ffuchs@hcpa.edu.br

Study Locations

• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90035 903
      • Recruiting
      • Hospital de Clinicas de Porto Alegre
      • Contact: Flavio Fuchs, MD, PhD; Phone Number: +55 51 3359.8344; Email: ffuchs@hcpa.edu.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults (age 30 to 75 years).
• Diagnosis of primary hypertension based on ABPM (mean 24-h systolic BP ≥130 mmHg or mean 24-h diastolic BP ≥80 mmHg).
• No current use of antihypertensive medication.

Exclusion Criteria:

• Low life expectancy.
• Other indications for the use of diuretics.
• Intolerance or contraindications to the study drugs.
• Cardiovascular disease (heart failure, myocardial infarction or stroke).
• Secondary hypertension.
• Chronic kidney disease and / or abnormal renal function (creatinine >1.5 mg/dL).
• Hyperkalemia (serum potassium >5.5 mEq/L).
• Gout.
• Previous antihypertensive treatment with more than one drug.
• Systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg measured through office blood pressure.
• Pregnancy or prospective pregnancy during the study.
• Lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chlorthalidone 25 mg + amiloride 20 mg; Chlorthalidone 25 mg plus amiloride 20 mg combined in a single capsule, taken orally in the morning, for 12 weeks.	Drug: Chlorthalidone 25 mg; Chlorthalidone 25 mg taken orally in the morning for 12 weeks.; Other Names: Chlorthalidone; Drug: Amiloride 20 mg; Amiloride 20 mg taken orally in the morning for 12 weeks.; Other Names: Amiloride
Active Comparator: Chlorthalidone 25 mg + amiloride 10 mg; Chlorthalidone 25 mg plus amiloride 10 mg combined in a single capsule, taken orally in the morning, for 12 weeks.	Drug: Chlorthalidone 25 mg; Chlorthalidone 25 mg taken orally in the morning for 12 weeks.; Other Names: Chlorthalidone; Drug: Amiloride 10 mg; Amiloride 10 mg taken orally in the morning for 12 weeks.; Other Names: Amiloride
Active Comparator: Hydrochlorothiazide 50 mg + amiloride 20 mg; Hydrochlorothiazide 50 mg plus amiloride 20 mg combined in a single capsule, taken orally in the morning, for 12 weeks.	Drug: Amiloride 20 mg; Amiloride 20 mg taken orally in the morning for 12 weeks.; Other Names: Amiloride; Drug: Hydrochlorothiazide 50 mg; Hydrochlorothiazide 50 mg taken orally in the morning for 12 weeks.; Other Names: Hydrochlorothiazide
Active Comparator: Hydrochlorothiazide 50 mg + amiloride 10 mg; Hydrochlorothiazide 50 mg plus amiloride 10 mg combined in a single capsule, taken orally in the morning, for 12 weeks.	Drug: Amiloride 10 mg; Amiloride 10 mg taken orally in the morning for 12 weeks.; Other Names: Amiloride; Drug: Hydrochlorothiazide 50 mg; Hydrochlorothiazide 50 mg taken orally in the morning for 12 weeks.; Other Names: Hydrochlorothiazide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline in 24-h systolic blood pressure measured by ABPM.	Difference between the treatment arms in mean change from baseline in 24-h systolic blood pressure measured by ABPM.	12 weeks
Mean change from baseline in 24-h diastolic blood pressure measured by ABPM.	Difference between the treatment arms in mean change from baseline in 24-h diastolic blood pressure measured by ABPM.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline in daytime and nighttime blood pressure measured by ABPM.	Difference between the treatment arms in mean change from baseline in daytime and nighttime systolic and diastolic blood pressure measured by ABPM.	12 weeks
Mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure.	Difference between the treatment arms in mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure.	12 weeks
Proportion of participants reporting adverse events.	Difference between treatment arms in the proportion of participants reporting adverse events.	12 weeks
Mean change from baseline in total cholesterol.	Difference between the treatment arms in mean change from baseline in serum total cholesterol, measured in mg/dL.	12 weeks
Mean change from baseline in HDL cholesterol (HDL-C).	Difference between the treatment arms in mean change from baseline in serum HDL cholesterol (HDL-C), measured in mg/dL.	12 weeks
Mean change from baseline in LDL cholesterol (LDL-C).	Difference between the treatment arms in mean change from baseline in serum LDL cholesterol (LDL-C), measured in mg/dL.	12 weeks
Mean change from baseline in triglycerides.	Difference between the treatment arms in mean change from baseline in serum triglycerides, measured in mg/dL.	12 weeks
Mean change from baseline in creatinine.	Difference between the treatment arms in mean change from baseline in serum creatinine, measured in mg/dL.	12 weeks
Mean change from baseline in urea.	Difference between the treatment arms in mean change from baseline in serum urea, measured in mg/dL.	12 weeks
Mean change from baseline in potassium.	Difference between the treatment arms in mean change from baseline in serum potassium, measured in mEq/L.	12 weeks
Mean change from baseline in sodium.	Difference between the treatment arms in mean change from baseline in serum sodium, measured in mg/dL.	12 weeks
Mean change from baseline in magnesium.	Difference between the treatment arms in mean change from baseline in serum magnesium, measured in mg/dL.	12 weeks
Mean change from baseline in uric acid.	Difference between the treatment arms in mean change from baseline in serum uric acid, measured in mg/dL.	12 weeks
Mean change from baseline in fasting plasma glucose.	Difference between the treatment arms in mean change from baseline in fasting plasma glucose, measured in mg/dL.	12 weeks
Mean change from baseline in hemoglobin A1c (HbA1c).	Difference between the treatment arms in mean change from baseline in hemoglobin A1c (HbA1c), measured in percentage.	12 weeks
Proportion of participants achieving blood pressure control.	Difference between treatment arms in the proportion of participants achieving blood pressure control. Blood pressure control will be defined as <140/90 mmHg and <130/80 mmHg for office BP and 24-h ABPM, respectively.	12 weeks.

Collaborators and Investigators

• Sponsor: Hospital de Clinicas de Porto Alegre
• Collaborators: Instituto de Cardiologia do Rio Grande do Sul
• Investigators: Principal Investigator: Flavio Fuchs, MD, PhD, Hospital de Clinicas de Porto Alegre

Publications and helpful links

General Publications

• Martins VM, Helal L, Ferrari F, Bottino LG, Fuchs SC, Fuchs FD. Efficacy of chlorthalidone and hydrochlorothiazide in combination with amiloride in multiple doses on blood pressure in patients with primary hypertension: a protocol for a factorial randomized controlled trial. Trials. 2019 Dec 16;20(1):736. doi: 10.1186/s13063-019-3909-z.

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2019
• Primary Completion (Anticipated): July 1, 2021
• Study Completion (Anticipated): July 1, 2021

Study Registration Dates

• First Submitted: April 22, 2019
• First Submitted That Met QC Criteria: April 24, 2019
• First Posted (Actual): April 25, 2019

Study Record Updates

• Last Update Posted (Actual): December 9, 2019
• Last Update Submitted That Met QC Criteria: December 6, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Treatment; Hypertension; Amiloride; Chlorthalidone; Hydrochlorothiazide
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Channel Blockers; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Hydrochlorothiazide; Chlorthalidone; Amiloride
• Other Study ID Numbers: 2016-0553

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: This trial is in accordance with the compliance of the reproducibility standards accordingly to the International Committee of Medical Journal Editors (ICMJE). The investigators intend to publish the results in an open-access journal, indexed at the Directory of Open Access Journals, with the copyrights transferred to the authors (CC By 4.0). Also, all materials, raw and treated data, statistical code and outputs will be publicly shared without restrictions to access the data neither expiration date. The repository was not chosen yet and will be provided in further amendments or in the final report of this study. All laboratory specimens, reports, data collection, process, and administrative forms will be identified by a coded identification number to maintain participant confidentiality. After full data analysis, all subject identifiers will be erased.
• IPD Sharing Time Frame: The individual participant dataset will become available at a public repository up to six months after the first study publication.
• IPD Sharing Access Criteria: A simple registration will grant access to study datasets. The website for these files is not defined at the time of registration.

Drug and device information, study documents

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