Chlorthalidone in Chronic Kidney Disease

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02841280

Acronym

CLICK

Enrollment

160

Registered

2016-07-22

Start date

2016-07-31

Completion date

2021-04-30

Last updated

2023-05-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertension, Renal Insufficiency, Chronic

Brief summary

It is estimated that in the United States there are approximately 8 million individuals who have moderate to severe chronic kidney disease (CKD). Among them hypertension is common and is often poorly controlled due to an expanded volume state; diuretics are frequently prescribed. Loop diuretics are potent and effective in lowering blood pressure (BP) but their use is associated with acute kidney injury. Thiazide diuretics, on the other hand, are less potent, their use may be associated with less acute kidney injury, but as yet there are no firm data to support that thiazide diuretic therapy can improve BP among subjects with advanced CKD. The investigators found 13 studies on the use of thiazide diuretics in advanced CKD either alone or in combination with loop diuretics and concluded that thiazides may be useful. Thiazides cause a negative Na balance, increase Na excretion by 10-15% and weight loss by 1-2 kg in observational studies. Observational data show that thiazides lead to an improvement in seated clinic BP of about 10-15 mmHg systolic and 5-10 mmHg diastolic whereas randomized trials show about a 15 mmHg reduction in mean BP. Randomized trials had only between 7 and 23 subjects each; accordingly, larger studies are needed to evaluate their safety and efficacy in moderate to advanced CKD.

Detailed description

This is a placebo-controlled, double-blind, randomized controlled trial of chlorthalidone (CTD) in patients with CKD and poorly controlled hypertension

Interventions

DRUGChlorthalidone

This is a forced-titration study and the study drug will be increased if goal BP is not achieved (dosage of chlorthalidone not to exceed 50 mg)

DRUGPlacebo

This is a forced-titration study and placebo will be increased if goal BP is not achieved.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Age greater than 18 years. 2. Calculated glomerular filtration rate (GFR) by 4-component Modification of Diet in Renal Disease (MDRD) formula \< 30 ml/min/1.73m2 but ≥15 mL/min/1.73m2. The hospital laboratory uses isotope dilution mass spectrometry (IDMS) calibrated creatinine and the appropriate formula is used to estimate GFR. 3. Hypertension. This is defined as BP of either ≥130 systolic or ≥80 mmHg by 24-hour ambulatory BP monitoring. 4. Treatment with antihypertensive drugs: This would require the use of at least one antihypertensive drug. One of the drugs should be either an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). If these are contraindicated then use of a beta-blocker is required prior to randomization.

Exclusion criteria

1. Use of thiazide or thiazide-like drugs in the previous 12 weeks. 2. Use of furosemide in a dose \>200 mg/d. 3. BP of either ≥160 systolic or ≥100 mmHg by 24-hour ambulatory BP monitoring. 4. Expected to receive renal replacement therapy within the next 3 months. 5. Myocardial infarction, heart failure hospitalization, or stroke ≤3 months prior to randomization. 6. Pregnant or breastfeeding women or women who are planning to become pregnant or those not using a reliable form of contraception (oral contraceptives. condoms and diaphragms will be considered reliable). 7. Known hypersensitivity to thiazide or sulfa drugs. 8. Organ transplant recipient or therapy with immunosuppressive agents.

Design outcomes

Primary

Measure	Time frame
Change From Baseline to 12 Weeks in Systolic Ambulatory Blood Pressure in the Chlorthalidone Group Compared to Placebo.	Baseline to 12 weeks

Secondary

Measure	Time frame
Changes in Albuminuria From Baseline at Each 4 Week Visit in the Log Transformed Albumin/Creatinine Ratio in the Chlorthalidone Group Compared to Placebo	Baseline to 12 weeks
Change From Baseline at Each 4 Week Visit in Log of Aldosterone and Log of Renin in the Chlorthalidone Group Compared to Placebo. No Adjustments Will be Made for Multiple Comparisons.	Baseline to 12 weeks
Change From Baseline at Each 4 Week Visit in Log of N-terminal Pro B-type Natriuretic Peptide (NTproBNP) in the Chlorthalidone Group Compared to Placebo. No Adjustments Will be Made for Multiple Comparisons.	Baseline to 12 weeks
Change From Baseline at Each 4 Week Visit in Body Volume in the Chlorthalidone Group Compared to Placebo. No Adjustments Will be Made for Multiple Comparisons.	Baseline to 12 weeks

Countries

United States

Participant flow

Recruitment details

Patients were recruited by screening for potential participants for eligibility at 3 medical centers between June 29, 2016 and January 7, 2021. The first participant consented on July 14, 2016, and the last participant was randomized on January 20, 2021.

Pre-assignment details

Of the 403 consented patients, 160 met inclusion criteria and were randomized to treatment. Thus, 160 are considered enrolled for the purposes of this report.

Participants by arm

Arm	Count
Chlorthalidone Subjects with stage 4 chronic kidney disease (CKD) and poorly controlled hypertension confirmed by 24 hour ambulatory blood pressure monitoring will be randomized into two groups, one receiving placebo and one receiving a diuretic called chlorthalidone (12.5 mg at randomization). Doubling of the dose of the diuretic (up to 50 mg) or placebo will occur every 4 weeks if required by home blood pressure (BP) results. Chlorthalidone: This is a forced-titration study and the study drug or placebo will be increased if goal BP is not achieved (dosage of chlorthalidone not to exceed 50 mg)	81
Placebo Subjects with stage 4 CKD and poorly controlled hypertension confirmed by 24 hour ambulatory blood pressure monitoring will be randomized into two groups, one receiving placebo and one receiving a diuretic called chlorthalidone (12.5 mg at randomization). Doubling of the dose of the diuretic (up to 50 mg) or placebo will occur every 4 weeks if required by home BP results. Placebo: This is a forced-titration study and the study drug or placebo will be increased if goal BP is not achieved (dosage of chlorthalidone not to exceed 50 mg)	79
Total	160

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	1
Overall Study	Death	1	0
Overall Study	Lost to Follow-up	2	2
Overall Study	Stop Point: BP above threshold	2	0
Overall Study	Withdrawal by Subject	7	3

Baseline characteristics

Characteristic	Placebo	Chlorthalidone	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	46 Participants	47 Participants	93 Participants
Age, Categorical Between 18 and 65 years	33 Participants	34 Participants	67 Participants
Age, Continuous	66.7 years STANDARD_DEVIATION 10.8	66.2 years STANDARD_DEVIATION 10.8	66.4 years STANDARD_DEVIATION 10.8
Body-Mass Index	32.0 kg/m^2 STANDARD_DEVIATION 7.4	33.0 kg/m^2 STANDARD_DEVIATION 7	32.5 kg/m^2 STANDARD_DEVIATION 7.2
Cause of Chronic Kidney Disease Diabetes	42 Participants	42 Participants	84 Participants
Cause of Chronic Kidney Disease Glomerulonephritis	5 Participants	3 Participants	8 Participants
Cause of Chronic Kidney Disease Hypertension	26 Participants	26 Participants	52 Participants
Cause of Chronic Kidney Disease Obstructive Uropathy	2 Participants	3 Participants	5 Participants
Cause of Chronic Kidney Disease Other	3 Participants	6 Participants	9 Participants
Cause of Chronic Kidney Disease Polycystic Kidney Disease	1 Participants	1 Participants	2 Participants
Current Smoking	19 Participants	21 Participants	40 Participants
Diastolic Blood Pressure	67.9 mm Hg STANDARD_DEVIATION 13.9	69.2 mm Hg STANDARD_DEVIATION 12.3	68.6 mm Hg STANDARD_DEVIATION 13.1
Estimated Glomerular Filtration Rate	22.8 ml/min/1.73 m^2 STANDARD_DEVIATION 4.2	23.5 ml/min/1.73 m^2 STANDARD_DEVIATION 4.2	23.2 ml/min/1.73 m^2 STANDARD_DEVIATION 4.2
Height	173.0 cm STANDARD_DEVIATION 8.6	171.7 cm STANDARD_DEVIATION 11.3	172.3 cm STANDARD_DEVIATION 10.1
Hip Circumference	114.6 cm STANDARD_DEVIATION 15	115.9 cm STANDARD_DEVIATION 14.9	115.3 cm STANDARD_DEVIATION 14.9
Medical History of Diabetes Mellitus	61 Participants	60 Participants	121 Participants
Pulse Rate	64.3 beats/min STANDARD_DEVIATION 11.1	66.5 beats/min STANDARD_DEVIATION 11.7	65.4 beats/min STANDARD_DEVIATION 11.4
Race/Ethnicity, Customized Race or Ethnic Group Asian	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Race or Ethnic Group Black	32 Participants	32 Participants	64 Participants
Race/Ethnicity, Customized Race or Ethnic Group Hispanic	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Race or Ethnic Group White	47 Participants	46 Participants	93 Participants
Region of Enrollment United States	79 participants	81 participants	160 participants
Sex: Female, Male Female	17 Participants	19 Participants	36 Participants
Sex: Female, Male Male	62 Participants	62 Participants	124 Participants
Systolic Blood Pressure	138.7 mm Hg STANDARD_DEVIATION 16	141.2 mm Hg STANDARD_DEVIATION 15.1	140.0 mm Hg STANDARD_DEVIATION 15.6
Waist Circumference	115.4 cm STANDARD_DEVIATION 16.6	115.3 cm STANDARD_DEVIATION 17	115.3 cm STANDARD_DEVIATION 16.8
Waist-to-Hip Ratio	0.998 ratio STANDARD_DEVIATION 0.074	1.011 ratio STANDARD_DEVIATION 0.078	1.005 ratio STANDARD_DEVIATION 0.076
Weight	95.8 kg STANDARD_DEVIATION 23.5	97.4 kg STANDARD_DEVIATION 23.6	96.6 kg STANDARD_DEVIATION 23.6

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 81	0 / 79
other Total, other adverse events	74 / 81	68 / 79
serious Total, serious adverse events	8 / 81	11 / 79