Tissue Sodium in Pre-hypertensive Patients

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02236520
• Collaborator: American Heart Association (Other)
• Enrollment: 71
• Location: 1
• Arms: 4
• Actual Duration (Months): 44
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

Cardiovascular disease is the first common cause of death worldwide. Hypertension is the number one driving risk factor. Hypertension has long been associated with dietary salt intake. We believe that the accumulation of salt in the interstitium and inside cells represents a neglected risk factor, which initiates a pro-inflammatory state, chronically increases blood pressure, and leads to systemic energy imbalance. We will explore the concept that Na+ storage in the skin and in muscle is associated with increased blood pressure, a pro-inflammatory state, and reduced insulin sensitivity. We will do so by addressing the following specific aims:

• Specific Aim 1: To test the hypothesis that African Americans are characterized by increased tissue Na+ storage, which is paralleled by higher blood pressure, reduced forearm blood flow, and enhanced pulse wave velocity

• Specific Aim 2: To test the hypothesis that treatment with spironolactone reduces tissue Na+ content

• Specific Aim 3: To test the hypothesis that Na+ storage leads to immune cell activation

• Specific Aim 4: To test the hypothesis that the accumulation of salt in skin and muscle is associated with decreased insulin sensitivity and propensity to diabetes mellitus

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Spironolactone; Drug: Chlorthalidone; Dietary Supplement: Diet; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Tissue Sodium in Pre-hypertensive Patients
• Actual Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Spironolactone 50 mg capsule of Spironolactone administered orally 1 per day for 8 weeks	Drug: Spironolactone
Active Comparator: Chlorthalidone 25 mg capsule of Chlorthalidone administered orally 1 per day for 8 weeks	Drug: Chlorthalidone
Active Comparator: Diet diet of 6 g salt per day for 8 weeks	Dietary Supplement: Diet
Placebo Comparator: Placebo placebo capsule administered orally 1 per day for 8 weeks	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change in Tissue Sodium Concentration Measured Using Sodium Magnetic Resonance Imaging (NaMRI) [baseline and 8 weeks]

   NaMRI is a sensitive laboratory assessment of the concentration of sodium in tissue

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age 30 to 80 years old;

• Systolic blood pressures between 110 to 150 mmHg and/or diastolic blood pressure between 80-99 mmHg;

• Ability to give informed consent.

Exclusion Criteria:

• Pregnancy;

• Intolerance to study protocols;

• Acute cardiovascular events within the previous 6 months;

• Impaired renal function [estimated glomerular filtration rate (GFR) < 45 ml/min/1.73m^2];

• Current or recent treatment with systemic glucocorticoid therapy (within 1 month of enrollment);

• Current use of anti-hypertensive medication (except calcium channel blockers and beta blockers);

• Diabetes mellitus requiring medical therapy;

• Morbid obesity (BMI > 45);

• Prior adverse reaction to a thiazide or spironolactone;

• Claustrophobia preventing the patient from having an MRI or other contraindications to MRI;

• Impaired hepatic function (aspartate amino transaminase and/or alanine amino transaminase > 1.5x upper limit of normal range);

• Current illicit drug use;

• Sexually active women of childbearing potential** who are unwilling to practice adequate contraception during the study [adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device (IUD); bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly].

• Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of child bearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University
• American Heart Association

Investigators

• Principal Investigator: Alp Ikizler, MD, Vanderbilt University
• Principal Investigator: Jens Titze, MD, Vanderbilt University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 15, 2018

More Information

Publications

None provided.

• Responsible Party: Alp Ikizler, Professor, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT02236520
• Other Study ID Numbers: 141382
• First Posted: Sep 10, 2014
• Last Update Posted: May 22, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Alp Ikizler, Professor, Vanderbilt University Medical Center: Na+ MRI; salt stores
• Additional relevant MeSH terms: Hypertension; Chlorthalidone; Spironolactone

Study Results

Participant Flow

Arm/Group Title	Spironolactone	Chlorthalidone	Diet	Placebo
Arm/Group Description	50 mg capsule of Spironolactone administered orally 1 per day for 8 weeks Spironolactone	25 mg capsule of Chlorthalidone administered orally 1 per day for 8 weeks Chlorthalidone	diet of 6 g salt per day for 8 weeks Diet	placebo capsule administered orally 1 per day for 8 weeks Placebo
Period Title: Overall Study
STARTED	16	13	15	15
COMPLETED	14	8	15	14
NOT COMPLETED	2	5	0	1

Baseline Characteristics

Arm/Group Title	Spironolactone	Chlorthalidone	Diet	Placebo	Total
Arm/Group Description	50 mg capsule of Spironolactone administered orally 1 per day for 8 weeks Spironolactone	25 mg capsule of Chlorthalidone administered orally 1 per day for 8 weeks Chlorthalidone	diet of 6 g salt per day for 8 weeks Diet	placebo capsule administered orally 1 per day for 8 weeks Placebo	Total of all reporting groups
Overall Participants	16	13	15	15	59
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48 (11)	49 (9)	49 (13)	48 (14)	48 (12)
Sex: Female, Male (Count of Participants)
Female	11 68.8%	10 76.9%	9 60%	10 66.7%	40 67.8%
Male	5 31.3%	3 23.1%	6 40%	5 33.3%	19 32.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.3%	0 0%	0 0%	0 0%	1 1.7%
Not Hispanic or Latino	15 93.8%	13 100%	15 100%	15 100%	58 98.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	7 43.8%	5 38.5%	8 53.3%	6 40%	26 44.1%
White	9 56.3%	8 61.5%	7 46.7%	9 60%	33 55.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	16 100%	13 100%	15 100%	15 100%	59 100%

Outcome Measures

1. Primary Outcome

Title	Change in Tissue Sodium Concentration Measured Using Sodium Magnetic Resonance Imaging (NaMRI)
Description	NaMRI is a sensitive laboratory assessment of the concentration of sodium in tissue
Time Frame	baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Chlorthalidone	Diet	Placebo
Arm/Group Description	50 mg capsule of Spironolactone administered orally 1 per day for 8 weeks Spironolactone	25 mg capsule of Chlorthalidone administered orally 1 per day for 8 weeks Chlorthalidone	diet of 6 g salt per day for 8 weeks Diet	placebo capsule administered orally 1 per day for 8 weeks Placebo
Measure Participants	14	8	15	14
Median (Inter-Quartile Range) [mmol/L]	-0.202	0.430	-1.745	-0.407

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Spironolactone		Chlorthalidone		Diet		Placebo
Arm/Group Description	50 mg capsule of Spironolactone administered orally 1 per day for 8 weeks Spironolactone		25 mg capsule of Chlorthalidone administered orally 1 per day for 8 weeks Chlorthalidone		diet of 6 g salt per day for 8 weeks Diet		placebo capsule administered orally 1 per day for 8 weeks Placebo
All Cause Mortality
	Spironolactone		Chlorthalidone		Diet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/13 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Spironolactone		Chlorthalidone		Diet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/13 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Spironolactone		Chlorthalidone		Diet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/16 (25%)		2/13 (15.4%)		1/15 (6.7%)		0/15 (0%)
Cardiac disorders
tachycardia	1/16 (6.3%)	1	0/13 (0%)	0	0/15 (0%)	0	0/15 (0%)	0
Endocrine disorders
hypoglycemia	1/16 (6.3%)	1	0/13 (0%)	0	0/15 (0%)	0	0/15 (0%)	0
Gastrointestinal disorders
gastrointestinal upset	1/16 (6.3%)	1	0/13 (0%)	0	0/15 (0%)	0	0/15 (0%)	0
nausea	1/16 (6.3%)	1	0/13 (0%)	0	0/15 (0%)	0	0/15 (0%)	0
Metabolism and nutrition disorders
hypokalemia	0/16 (0%)	0	1/13 (7.7%)	1	1/15 (6.7%)	1	0/15 (0%)	0
hyponatremia	0/16 (0%)	0	1/13 (7.7%)	1	0/15 (0%)	0	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.