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| Name | Class |
|---|---|
| Instituto de Cardiologia do Rio Grande do Sul | OTHER |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Chlorthalidone 25 mg + amiloride 20 mg | Experimental | Chlorthalidone 25 mg plus amiloride 20 mg combined in a single capsule, taken orally in the morning, for 12 weeks. |
|
| Chlorthalidone 25 mg + amiloride 10 mg | Active Comparator | Chlorthalidone 25 mg plus amiloride 10 mg combined in a single capsule, taken orally in the morning, for 12 weeks. |
|
| Hydrochlorothiazide 50 mg + amiloride 20 mg | Active Comparator | Hydrochlorothiazide 50 mg plus amiloride 20 mg combined in a single capsule, taken orally in the morning, for 12 weeks. |
|
| Hydrochlorothiazide 50 mg + amiloride 10 mg | Active Comparator | Hydrochlorothiazide 50 mg plus amiloride 10 mg combined in a single capsule, taken orally in the morning, for 12 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Chlorthalidone 25 mg | Drug | Chlorthalidone 25 mg taken orally in the morning for 12 weeks. |
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| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Flavio Fuchs, MD, PhD | Contact | +55 51 3359.8344 | ffuchs@hcpa.edu.br |
| Name | Affiliation | Role |
|---|---|---|
| Flavio Fuchs, MD, PhD | Hospital de Clinicas de Porto Alegre | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital de Clinicas de Porto Alegre | Recruiting | Porto Alegre | Rio Grande do Sul | 90035 903 | Brazil |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31843024 | Derived | 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. |
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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.
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The individual participant dataset will become available at a public repository up to six months after the first study publication.
A simple registration will grant access to study datasets. The website for these files is not defined at the time of registration.
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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.
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The study medication will have the same color, taste, consistency, odor and appearance. In this way, patients, care providers, outcome assessors and the entire research team will be blinded regarding the allocation to the treatment groups throughout the study.
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| Hydrochlorothiazide 50 mg | Drug | Hydrochlorothiazide 50 mg taken orally in the morning for 12 weeks. |
|
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| Amiloride 20 mg | Drug | Amiloride 20 mg taken orally in the morning for 12 weeks. |
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| Amiloride 10 mg | Drug | Amiloride 10 mg taken orally in the morning for 12 weeks. |
|
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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. |
| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D002752 | Chlorthalidone |
| D006852 | Hydrochlorothiazide |
| D000584 | Amiloride |
| ID | Term |
|---|---|
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D001577 | Benzophenones |
| D010797 | Phthalimides |
| D007094 | Imides |
| D007659 | Ketones |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D054833 | Isoindoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D002740 | Chlorothiazide |
| D001581 | Benzothiadiazines |
| D049971 | Thiazides |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
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