Clinical trial NCT03928145: Efficacy of Chlorthalidone and Hydrochlorothiazide Combined With Amiloride on Blood Pressure in Primary Hypertension.
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Hypertension
Keywords: Hypertension
Treatment
Chlorthalidone
Hydrochlorothiazide
Amiloride
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
Collaborators: name: Instituto de Cardiologia do Rio Grande do Sul
First posted: 2019-04-25
Enrollment: 84
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention 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.
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Mean change from baseline in 24-h systolic blood pressure measured by ABPM.
timeFrame: 12 weeks
measure: Mean change from baseline in 24-h diastolic blood pressure measured by ABPM.
timeFrame: 12 weeks
Secondary outcomes:
measure: Mean change from baseline in daytime and nighttime blood pressure measured by ABPM.
timeFrame: 12 weeks
measure: Mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure.
timeFrame: 12 weeks
measure: Proportion of participants reporting adverse events.
timeFrame: 12 weeks
measure: Mean change from baseline in total cholesterol.
timeFrame: 12 weeks
measure: Mean change from baseline in HDL cholesterol (HDL-C).
timeFrame: 12 weeks
measure: Mean change from baseline in LDL cholesterol (LDL-C).
timeFrame: 12 weeks
measure: Mean change from baseline in triglycerides.
timeFrame: 12 weeks
measure: Mean change from baseline in creatinine.
timeFrame: 12 weeks
measure: Mean change from baseline in urea.
timeFrame: 12 weeks
measure: Mean change from baseline in potassium.
timeFrame: 12 weeks
measure: Mean change from baseline in sodium.
timeFrame: 12 weeks
measure: Mean change from baseline in magnesium.
timeFrame: 12 weeks
measure: Mean change from baseline in uric acid.
timeFrame: 12 weeks
measure: Mean change from baseline in fasting plasma glucose.
timeFrame: 12 weeks
measure: Mean change from baseline in hemoglobin A1c (HbA1c).
timeFrame: 12 weeks
measure: Proportion of participants achieving blood pressure control.
timeFrame: 12 weeks.
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
state: RS
Study officials:
affiliation: Hospital de Clinicas de Porto Alegre
name: Flavio Fuchs, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.