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

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ClinicalTrials.gov Identifier: NCT03928145
Recruitment Status : Recruiting
First Posted : April 25, 2019
Last Update Posted : December 9, 2019
Sponsor:
Collaborator:
Instituto de Cardiologia do Rio Grande do Sul
Information provided by (Responsible Party):
Hospital de Clinicas de Porto Alegre

Tracking Information
First Submitted Date  ICMJE April 22, 2019
First Posted Date  ICMJE April 25, 2019
Last Update Posted Date December 9, 2019
Actual Study Start Date  ICMJE November 13, 2019
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 24, 2019)
  • Mean change from baseline in 24-h systolic blood pressure measured by ABPM. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in 24-h systolic blood pressure measured by ABPM.
  • Mean change from baseline in 24-h diastolic blood pressure measured by ABPM. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in 24-h diastolic blood pressure measured by ABPM.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 24, 2019)
  • Mean change from baseline in daytime and nighttime blood pressure measured by ABPM. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in 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. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure.
  • Proportion of participants reporting adverse events. [ Time Frame: 12 weeks ]
    Difference between treatment arms in the proportion of participants reporting adverse events.
  • Mean change from baseline in total cholesterol. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum total cholesterol, measured in mg/dL.
  • Mean change from baseline in HDL cholesterol (HDL-C). [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum HDL cholesterol (HDL-C), measured in mg/dL.
  • Mean change from baseline in LDL cholesterol (LDL-C). [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum LDL cholesterol (LDL-C), measured in mg/dL.
  • Mean change from baseline in triglycerides. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum triglycerides, measured in mg/dL.
  • Mean change from baseline in creatinine. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum creatinine, measured in mg/dL.
  • Mean change from baseline in urea. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum urea, measured in mg/dL.
  • Mean change from baseline in potassium. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum potassium, measured in mEq/L.
  • Mean change from baseline in sodium. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum sodium, measured in mg/dL.
  • Mean change from baseline in magnesium. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum magnesium, measured in mg/dL.
  • Mean change from baseline in uric acid. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in serum uric acid, measured in mg/dL.
  • Mean change from baseline in fasting plasma glucose. [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in fasting plasma glucose, measured in mg/dL.
  • Mean change from baseline in hemoglobin A1c (HbA1c). [ Time Frame: 12 weeks ]
    Difference between the treatment arms in mean change from baseline in hemoglobin A1c (HbA1c), measured in percentage.
  • Proportion of participants achieving blood pressure control. [ Time Frame: 12 weeks. ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Chlorthalidone and Hydrochlorothiazide Combined With Amiloride on Blood Pressure in Primary Hypertension.
Official Title  ICMJE 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.
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
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.
Primary Purpose: Treatment
Condition  ICMJE Hypertension
Intervention  ICMJE
  • Drug: Chlorthalidone 25 mg
    Chlorthalidone 25 mg taken orally in the morning for 12 weeks.
    Other Name: Chlorthalidone
  • Drug: Hydrochlorothiazide 50 mg
    Hydrochlorothiazide 50 mg taken orally in the morning for 12 weeks.
    Other Name: Hydrochlorothiazide
  • Drug: Amiloride 20 mg
    Amiloride 20 mg taken orally in the morning for 12 weeks.
    Other Name: Amiloride
  • Drug: Amiloride 10 mg
    Amiloride 10 mg taken orally in the morning for 12 weeks.
    Other Name: Amiloride
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Chlorthalidone 25 mg
    • Drug: Amiloride 20 mg
  • 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.
    Interventions:
    • Drug: Chlorthalidone 25 mg
    • Drug: Amiloride 10 mg
  • 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.
    Interventions:
    • Drug: Hydrochlorothiazide 50 mg
    • Drug: Amiloride 20 mg
  • 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.
    Interventions:
    • Drug: Hydrochlorothiazide 50 mg
    • Drug: Amiloride 10 mg
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 24, 2019)
84
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Flavio Fuchs, MD, PhD +55 51 3359.8344 ffuchs@hcpa.edu.br
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03928145
Other Study ID Numbers  ICMJE 2016-0553
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Time Frame: The individual participant dataset will become available at a public repository up to six months after the first study publication.
Access Criteria: A simple registration will grant access to study datasets. The website for these files is not defined at the time of registration.
Responsible Party Hospital de Clinicas de Porto Alegre
Study Sponsor  ICMJE Hospital de Clinicas de Porto Alegre
Collaborators  ICMJE Instituto de Cardiologia do Rio Grande do Sul
Investigators  ICMJE
Principal Investigator: Flavio Fuchs, MD, PhD Hospital de Clinicas de Porto Alegre
PRS Account Hospital de Clinicas de Porto Alegre
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP