Clinical trial NCT02841280: Chlorthalidone in Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Renal Insufficiency, Chronic
Hypertension
Lead sponsor: Indiana University
Sponsor class: OTHER
First posted: 2016-07-22
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline to 12 Weeks in Systolic Ambulatory Blood Pressure in the Chlorthalidone Group Compared to Placebo.
timeFrame: Baseline to 12 weeks
Secondary outcomes:
measure: Changes in Albuminuria From Baseline at Each 4 Week Visit in the Log Transformed Albumin/Creatinine Ratio in the Chlorthalidone Group Compared to Placebo
timeFrame: Baseline to 12 weeks
measure: 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.
timeFrame: Baseline to 12 weeks
measure: 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.
timeFrame: Baseline to 12 weeks
measure: 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.
timeFrame: Baseline to 12 weeks
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University School of Medicine, Division of Nephrology
state: Indiana
Study officials:
affiliation: Indiana University
name: Rajiv Agarwal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Agarwal R, Sinha AD, Cramer AE, Balmes-Fenwick M, Dickinson JH, Ouyang F, Tu W. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease. N Engl J Med. 2021 Dec 30;385(27):2507-2519. doi: 10.1056/NEJMoa2110730. Epub 2021 Nov 5.
citation: Agarwal R, Cramer AE, Balmes-Fenwick M, Sinha AD, Ouyang F, Tu W. Design and Baseline Characteristics of the Chlorthalidone in Chronic Kidney Disease (CLICK) Trial. Am J Nephrol. 2020;51(7):542-552. doi: 10.1159/000508700. Epub 2020 Jul 14.