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

Study Overview
=================
Brief Summary
-----------------
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.

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).

Official Title
-----------------
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.

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: Chlorthalidone 25 mg
* Drug: Hydrochlorothiazide 50 mg
* Drug: Amiloride 20 mg
* Drug: Amiloride 10 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: The trial has a factorial design, where participants will receive two simultaneous interventions: a thiazide diuretic (chlorthalidone 25 mg or hydrochlorothiazide 50 mg) and a potassium-sparing diuretic (amiloride 10 mg or amiloride 20 mg). Randomization will be done in 1:1:1:1 ratio, and participants will be randomly assigned to four groups: a) chlorthalidone 25 mg + amiloride 10 mg; b) chlorthalidone 25 mg + amiloride 20 mg; c) hydrochlorothiazide 50 mg + amiloride 10 mg; and d) hydrochlorothiazide 50 mg + amiloride 20 mg.
Masking: Quadruple


Arms and Interventions

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

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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hypertension, Treatment, Chlorthalidone, Hydrochlorothiazide, Amiloride