Trial Outcomes & Findings for Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension (NCT NCT00353652)

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

166 participants

Primary outcome timeframe

Measured at 3 months

Results posted on

2019-02-06

Participant Flow

119 subjects failed screening. 30 patients undergo 2-phase crossover study (chlorthalidone vs. spironolactone). 7 patients dropped out, 23 subjects completed study#1. 17 subjects undergo 3-phase study (chlorthalidone+placebo, chlorthalidone+spironolactone, and chlorthalidone+ irbesartan). 1 patients dropped out. 16 subjects completed study#2.

Participant milestones

Participant milestones
Measure	Study#1: Chlorthalidone (CTD) First Then Spironolactone (SP) Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of chlorthalidone first (12.5-25 mg/d), using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment with spironolactone (25-75 mg/d)without washout period for 3 months. Following 3 month treatment period, the procedures listed below were performed. After completion of the study procedures, the medication is discontinued.	Study #1: Spironolactone (SP) First, Then Chlorthalidone (CTD) Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months spironolactone first (25-75 mg/d), using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment with chlorthalidone(12.5-25 mg/d) without washout period. Following 3 month treatment period, the procedures listed below were performed. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Alone 1st, CTD+ SP 2nd, CTD+IR 3rd Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD (25 mg/d) plus fixed-dosespironolactone (SP) 25 mg daily for 3 months, then fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Alone 1st, CTD+IR 2nd, CTD+SP3rd Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months, followed by fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD+SP1st, CTD Alone 2nd, CTD+IR 3rd Subjects are randomized to receive fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD 25 mg/d alone for 3 months, then fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD+IR 1st, CTD Alone 2nd, CTD+SP 3rd Subjects are randomized to receive fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD 25 mg/d alone for 3 months, then fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months. After completion of the study procedures, the medication is discontinued.
First Intervention - 3 Months STARTED	15	15	6	7	3	1
First Intervention - 3 Months COMPLETED	12	11	6	7	3	1
First Intervention - 3 Months NOT COMPLETED	3	4	0	0	0	0
Second Intervention - 3 Months STARTED	12	11	6	7	3	1
Second Intervention - 3 Months COMPLETED	12	11	6	7	3	1
Second Intervention - 3 Months NOT COMPLETED	0	0	0	0	0	0
Third Intervention - 3 Months STARTED	0	0	6	7	3	1
Third Intervention - 3 Months COMPLETED	0	0	6	6	3	1
Third Intervention - 3 Months NOT COMPLETED	0	0	0	1	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Participants Study#1 n=30 Participants study #1 has 2 arms. Arm 1. chlorthalidone (CTD) first then spironolactone (SP): subjects are randomized to receive 3 months of CTD first (12.5-25 mg/d), titrated to achieve 24-h BP \< 130/80 mmHg. Then, the subject is transitioned to treatment with spironolactone (25-75 mg/d) without washout period for 3 months. Following 3 month treatment period, sympathetic nerve activity, 24 h-ambulatory BP, fasting plasma glucose, insulin, HOMA IR, and baroreflex sensitivity are measured. After completion of the study procedures, the medication is discontinued. Arm 2. spironolactone (SP) first, then chlorthalidone (CTD): subjects are randomized to receive 3 months spironolactone first (25-75 mg/d), titrated to achieve 24-h BP \< 130/80 mmHg. Then, the subject is switched to CTD (12.5-25 mg/d) without washout period. Following 3 month treatment period, sympathetic nerve activity, 24 h-ambulatory BP, fasting plasma glucose, insulin, HOMA IR, and baroreflex sensitivity are measured.	Participants Study#2 n=17 Participants study #2 has 6 arms. Arm 1. CTD alone 1st, CTD+ SP 2nd, CTD+IR 3rd: Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD (25 mg/d) plus fixed-dosespironolactone (SP) 25 mg daily for 3 months, then fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months. Arm 2. fixed-dose CTD alone 1st, CTD+IR 2nd, CTD+SP3rd Arm3. fixed-dose CTD+SP1st, CTD alone 2nd, CTD+IR 3rd Arm 4. fixed-dose CTD+SP1st, CTD+IR 2nd, CTD alone 3rd Arm 5. CTD+IR 1st, CTD alone 2nd, CTD+SP 3rd Arm 6. CTD+IR 1st, CTD+SP 2nd, CTD alone 3rd	Total n=47 Participants Total of all reporting groups
Age, Continuous	49.3 years STANDARD_DEVIATION 2.0 • n=5 Participants	50.6 years STANDARD_DEVIATION 2.3 • n=7 Participants	49.7 years STANDARD_DEVIATION 2.2 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	21 Participants n=5 Participants	13 Participants n=7 Participants	34 Participants n=5 Participants
Region of Enrollment United States	30 participants n=5 Participants	17 participants n=7 Participants	47 participants n=5 Participants

PRIMARY outcome

Timeframe: Measured at 3 months

Outcome measures

Outcome measures
Measure	Study#1: Chlorthalidone (CTD), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of chlorthalidone first (12.5-25 mg/d) or spironolactone (25-75 mg/d) first at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study #1: Spironolactone (SP), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of spironolactone (25-75 mg/d) first or chlorthalidone first (12.5-25 mg/d) at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study# 2 Chlorthalidone (CTD), Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus SP Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus IR Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.
Sympathetic Nerve Activity	46 bursts/min Standard Error 4	40 bursts/min Standard Error 3	49 bursts/min Standard Error 3	42 bursts/min Standard Error 3	52 bursts/min Standard Error 2

SECONDARY outcome

Timeframe: Measured at 3 months

Outcome measures

Outcome measures
Measure	Study#1: Chlorthalidone (CTD), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of chlorthalidone first (12.5-25 mg/d) or spironolactone (25-75 mg/d) first at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study #1: Spironolactone (SP), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of spironolactone (25-75 mg/d) first or chlorthalidone first (12.5-25 mg/d) at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study# 2 Chlorthalidone (CTD), Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus SP Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus IR Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.
24-hour Ambulatory Systolic Blood Pressure	127.4 mmHg Standard Error 2	128.6 mmHg Standard Error 2	123.5 mmHg Standard Error 2	121.6 mmHg Standard Error 3	119.8 mmHg Standard Error 3

SECONDARY outcome

Timeframe: 3 months

fasting plasma insulin

Outcome measures

Outcome measures
Measure	Study#1: Chlorthalidone (CTD), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of chlorthalidone first (12.5-25 mg/d) or spironolactone (25-75 mg/d) first at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study #1: Spironolactone (SP), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of spironolactone (25-75 mg/d) first or chlorthalidone first (12.5-25 mg/d) at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study# 2 Chlorthalidone (CTD), Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus SP Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus IR Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.
Insulin	8.24 mU/liter Interval 4.56 to 10.49	7.6 mU/liter Interval 4.68 to 8.6	7.6 mU/liter Interval 4.08 to 19.7	4.87 mU/liter Interval 3.5 to 6.78	6.8 mU/liter Interval 3.28 to 10.25

SECONDARY outcome

Timeframe: 3 months

Population: unequal randomization by chance

assessment of insulin resistance calculated by multiplying fasting plasma insulin (mU/l) with fasting plasma glucose (mmol/l) divided by 22.5.

Outcome measures

Outcome measures
Measure	Study#1: Chlorthalidone (CTD), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of chlorthalidone first (12.5-25 mg/d) or spironolactone (25-75 mg/d) first at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study #1: Spironolactone (SP), Titrated Dose n=23 Participants Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of spironolactone (25-75 mg/d) first or chlorthalidone first (12.5-25 mg/d) at the dose titrated to achieve 24-h ambulatory BP \< 130/80 mmHg, using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment the remain arm without washout period for 3 months. Following 3 month treatment period, measurement of outcomes are performed. After completion of the study procedures, the medication is discontinued.	Study# 2 Chlorthalidone (CTD), Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus SP Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.	Study# 2 CTD Fixed Dose 25 mg/d Plus IR Fixed Dose n=17 Participants Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first or fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily first or fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) first, using a single-blind 3-phase crossover design. Then, subjects are treated with the remaining one of the 2 arms for 3 months, followed by the last arm for 3 months without washout period. After completion of the study procedures, the medication is discontinued.
HOMA-IR	1.91 mU/l*mmol/l Interval 1.17 to 2.96	1.33 mU/l*mmol/l Interval 0.56 to 2.06	1.87 mU/l*mmol/l Interval 0.8 to 4.13	0.85 mU/l*mmol/l Interval 0.69 to 1.52	1.42 mU/l*mmol/l Interval 0.77 to 2.23

SECONDARY outcome

Timeframe: 3 months

slope relating percent change in SNA (% change in total activity from baseline) to diastolic BP.