Chlorthalidone in Chronic Kidney Disease

Study Overview
=================
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

Conditions
-----------------
Renal Insufficiency, Chronic, Hypertension

Intervention / Treatment
-----------------
* Drug: Chlorthalidone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age greater than 18 years. 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. Hypertension. This is defined as BP of either ≥130 systolic or ≥80 mmHg by 24-hour ambulatory BP monitoring. 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: Use of thiazide or thiazide-like drugs in the previous 12 weeks. Use of furosemide in a dose >200 mg/d. BP of either ≥160 systolic or ≥100 mmHg by 24-hour ambulatory BP monitoring. Expected to receive renal replacement therapy within the next 3 months. Myocardial infarction, heart failure hospitalization, or stroke ≤3 months prior to randomization. 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). Known hypersensitivity to thiazide or sulfa drugs. Organ transplant recipient or therapy with immunosuppressive agents.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chlorthalidone<br>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. | Drug: Chlorthalidone<br>* 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)<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* This is a forced-titration study and placebo will be increased if goal BP is not achieved.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | 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 |