Spironolactone in CKD Enabled by Chlorthalidone: PILOT (SPICE PILOT)

Spironolactone in Chronic Kidney Disease Enabled by Chlorthalidone: A Pilot Randomized Control Trial

Highly prevalent among patients with chronic kidney disease (CKD) and poorly controlled blood pressure (BP), is a modifiable risk factor to abrogate both kidney failure progression and cardiovascular (CV) disease. Spironolactone (SPL), a mineralocorticoid receptor antagonist, is widely used to treat resistant hypertension, however one of the most common side effects is an increase of serum potassium (K). This side effect occurs frequently in those who suffer from CKD. Alternatively, chlorthalidone (CTD) is a thiazide-like diuretic used for treating hypertension and decreases serum K. In this pilot study, our goal is to assess whether the combination of SPL and CTD can improve BP control, while also reducing the risk of hyperkalemia over a period of 12 weeks. We hypothesize that among patients with CKD and poorly controlled hypertension, compared to SPL and placebo, treatment over 12 weeks with CTD will counter the hyperkalemia effect of SPL, and therefore the combination of SPL with CTD will result in a lower BP. This pilot study will be performed at Richard L. Roudebush VA in Indianapolis, Indiana.

Study Overview

• Status: Recruiting
• Conditions: Renal Insufficiency; Chronic Hypertension
• Intervention / Treatment: Drug: Spironolactone; Drug: Placebo; Drug: Chlorthalidone

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rajiv Agarwal, MD; Phone Number: 317-988-2241; Email: ragarwal@iu.edu
• Study Contact Backup: Name: Timothy l Ramsey, MS/MBA; Phone Number: 317-988-9544; Email: timothy.ramsey2@va.gov

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Richard L Roudebush VA Medical Center
      • Contact: Timothy l ramsey, ms; Phone Number: 317-988-9544; Email: timothy.ramsey2@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 110 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age greater than 18 years.
2. GFR estimated by CKD-EPI formula < 45 ml/min/1.73 m2 but ≥ 15 mL/min/1.73 m2 using IDMS-calibrated creatinine.
3. Hypertension. Using AOBP monitoring, BP of ≥ 130/80 mmHg.
4. Treatment with antihypertensive drugs: This would require the use of at least one antihypertensive drug. One of the drugs should be either an ACE inhibitor or ARB or a beta-blocker at the time of randomization.
5. Serum K 3.5 to 5.2 mEq/L at the time of randomization. In patients with eGFR < 45 ml/min/1.73 m2 and serum K > 5.2 mEq/L

Exclusion Criteria:

1. Use of spironolactone, eplerenone, amiloride, triamterene, thiazides, or thiazide-like drugs or the use of K supplements or K binders in the previous 12 weeks.
2. Expected to receive renal replacement therapy within the next 6 months.
3. Myocardial infarction, heart failure hospitalization, or stroke ≤ 12 weeks prior to randomization.
4. 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).
5. Known hypersensitivity to thiazide or spironolactone.
6. Clinic AOBP <110 mmHg systolic at their first visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Spironolactone + Placebo; Subjects with stage 3B/4 chronic kidney disease and poorly controlled hypertension will be randomized into two groups: one receiving spironolactone and placebo and one receiving spironolactone and chlorthalidone. At randomization, subjects will begin at 25 mg spironolactone and 6.25 mg placebo/chlorthalidone daily.	Drug: Spironolactone; Study drugs will be increased if goal blood pressure is not achieved and/or serum potassium is not in safe clinical range (dosage of chlorthalidone/placebo not to exceed 25 mg daily; dosage of spironolactone not to exceed 50 mg daily).; Drug: Placebo; Study drugs will be increased if goal blood pressure is not achieved and/or serum potassium is not in safe clinical range (dosage of chlorthalidone/placebo not to exceed 25 mg daily; dosage of spironolactone not to exceed 50 mg daily).
Experimental: Spironolactone + Chlorthalidone; Subjects with stage 3B/4 chronic kidney disease and poorly controlled hypertension will be randomized into two groups: one receiving spironolactone and placebo and one receiving spironolactone and chlorthalidone. At randomization, subjects will begin at 25 mg spironolactone and 6.25 mg placebo/chlorthalidone daily.	Drug: Spironolactone; Study drugs will be increased if goal blood pressure is not achieved and/or serum potassium is not in safe clinical range (dosage of chlorthalidone/placebo not to exceed 25 mg daily; dosage of spironolactone not to exceed 50 mg daily).; Drug: Chlorthalidone; Study drugs will be increased if goal blood pressure is not achieved and/or serum potassium is not in safe clinical range (dosage of chlorthalidone/placebo not to exceed 25 mg daily; dosage of spironolactone not to exceed 50 mg daily).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Systolic Automated Office Blood Pressure from baseline to 12 weeks between arms	Baseline to 12 Weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in logarithmically transformed albumin/creatinine ratio from baseline to 12 weeks between arms	Baseline to 12 Weeks

Collaborators and Investigators

• Sponsor: Indiana Institute for Medical Research
• Investigators: Principal Investigator: Rajiv Agarwal, MD, Indiana Institute for Medical Research; Roudebush VA Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Estimated): December 12, 2023
• Study Completion (Estimated): December 12, 2023

Study Registration Dates

• First Submitted: January 18, 2022
• First Submitted That Met QC Criteria: February 1, 2022
• First Posted (Actual): February 3, 2022

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 11, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Hypertension; Chronic Kidney Disease; Spironolactone; Chlorthalidone; Thiazide Diuretic; Potassium Sparring Diuretic
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hypertension; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Spironolactone; Chlorthalidone
• Other Study ID Numbers: 12672

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No