Beneficial Effect of Amiloride on Progression of Chronic Kidney Disease (A-CKD)

This is a randomized, placebo-controlled, double-blinded crossover trial testing the effects of amiloride in patients with chronic kidney disease (CKD) and proteinuria.

In CKD with proteinuria, there is aberrant filtration of serine proteases and complement precursors into the tubular lumen. The interaction of these factors leads to proinflammatory complement activation, which may promote inflammation, opsonization, and formation of the membrane-attack complex, causing cell injury.

With the aim of preserving kidney function, reducing cardiovascular morbidity, and delaying renal replacement therapy in CKD, this study tests whether amiloride (10 mg/day) protects the filtration barrier, lowers albuminuria, and mitigates kidney inflammation through urokinase inhibition, independent of blood pressure effects.

Participants are randomized to receive amiloride (10 mg/day) or placebo for one week, with a 2-3-week washout period in between. Blood and urine samples are collected before and after each treatment period. Additionally, ECG, body composition measurements, blood pressure, and body weight are monitored.

The primary outcome measures are urinary C3a, soluble C5-9 (sTCC/MAC), and kidney injury biomarkers KIM-1 and NGAL. Secondary endpoints include the urinary albumin/creatinine ratio, protein/creatinine ratio, and blood pressure.

Study Overview

• Status: Recruiting
• Conditions: Proteinuria; Chronic Kidney Disease(CKD)
• Intervention / Treatment: Drug: amiloride; Drug: Placebo

Detailed Description

Please refer to the protocol

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gitte Rye Hinrichs, MD, PhD; Phone Number: 004521695186; Email: gitte.rye.hinrichs2@rsyd.dk

Study Locations

• Denmark
  • Odense, Denmark, 5000
    • Recruiting
    • Department of Nephrology, Odense University Hospital
    • Contact: Claus Bistrup, MD, Professor; Phone Number: +45-23368077; Email: claus.bistrup@rsyd.dk
    • Contact: Gitte Rye Hinrichs, MD, PhD; Phone Number: +4521695186; Email: gitte.rye.hinrichs2@rsyd.dk
    • Sub-Investigator: Gitte Rye Hinrichs, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

Participants are eligible to be included in the study, only if all the following criteria apply:

1. Participant must be 18 years of age including at the time of signing the informed consent.

2. A clinical diagnosis of chronic kidney disease and:

   1. eGFR ≥ 25 mL/min/1.73m2 and < 60mL/ min/1.73m2 at screening
   2. UACR of ≥ 300mg/g at screening
3. Participants must be on stable antihypertensive treatment 2 weeks before start of study drug and throughout study duration.
4. Office blood pressure at screening meeting (visit 1), > 110/60mmHg and < 150/90mmHg. If BP > 150/90mmHg at visit 1, screening phase can be prolonged to 4 weeks#.
5. Capable of giving signed informed consent.

6. Women with childbearing potential* can only be included if a pregnancy test is negative at the screening visit. Moreover, women should be using contraception during the study.

   • If the office blood pressure varies by approximately ±10 mmHg and is deemed acceptable by the investigator, the participant can be included.

     • Women are considered of childbearing potential following menarche and until becoming post-menopausal (12 consecutive months without a menstrual period) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy or bilateral oophorectomy (According to the Clinical Trial Facilitation Group, 2014-09-15).

Exclusion criteria

Participants are excluded from the study is any of the following criteria apply:

1. Treatment with amiloride alone or in combination or use of other types of K-sparing diuretics, MR antagonists (Spironolactone, eplerenone, finerenone)
2. Ongoing cancer treatment
3. Treatment with immunosuppressive therapy within 6 months prior to screening
4. History of organ transplantation
5. Evidence of current infection (CRP> 50 and temperature > 38◦C)
6. History of unstable or rapidly progressing renal disease (eGFR decreasing > 5ml/min/1.73m2 the last 2 months)
7. Severe hepatic insufficiency classified as Child-Pugh C
8. Patients on hypertension treatment who is not on stable antihypertensive treatment 2 weeks before start of study drug.
9. Pregnancy or breastfeeding participants
10. Congestive heart failure NYHA class IV, unstable or acute congestive heart failure.

11. Recent cardiovascular events in a patient:

    1. Less than two months post coronary artery revascularization.
    2. Acute stroke or TIA within two months prior to screening
    3. Acute coronary syndrome within two months prior to screening
12. Patients who, in the judgement of the investigator may be at risk for dehydration.
13. Known hypersensitivity to the study treatment (active substance or excipients)
14. Known hypersensitivity to resonium
15. Addison´s disease
16. Gastric bypass operation
17. Participation in other interventional trials
18. Lactose intolerance
19. Plasma potassium >4.9 mmol/l at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amiloride; Amiloride 5mg twice daily for 7 days followed by 2-3 weeks of washout and then placebo twice daily for 7 days	Drug: amiloride; 5mg twice daily for 7 days
Placebo Comparator: Placebo; Placebo twice daily for 7 days followed by 2-3 weeks of washout and then Amilorid 5 mg twice daily for 7 days	Drug: Placebo; 1 tablet twice daily for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine-C3a (ng/ml)	Urine-C3a is measured in spot urine samples and expressed as u-C3a/creatinine (µg/g) to account for the dilution factor.	Measured before (day one) and after (day 8) each treatment period
Urine C5-9-sTCC/MAC (U/ml)	Membrane Attack Complex (MAC) of the complement system, specifically targeting the C5 to C9 proteins. u-C5-9 is measured in spot urine samples and expressed as u-C5-9/creatinine U/µmol to account for the dilution factor.	Measured before (day one) and after (day 8) each treatment period
Kidney Injury Molecule-1 (KIM-1) pg/ml	KIM-1 is a protein that serves as a biomarker used particularly in the context of kidney injury	Measured before (day one) and after (day 8) each treatment period
Neutrophil Gelatinase-Associated Lipocalin (NGAL) (pg/mL)	NGAL is a protein associated with neutrophils used as a biomarker in the context of kidney injury.	Measured before and after each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine albumin/creatinin ratio (mg/g)	In spot urine samples, albumin and creatinin are measured	Measured before (day one) and after (day 8) each treatment period
Urine protein/creatinin ratio	In spot urine samples, albumin and creatinin are measured	Measured before (day one) and after (day 8) each treatment period
Home blood pressure (mmHg)	Home blood pressure are measured according to standard guidelines	Measured before (day one) and after (day 8) each treatment period

Collaborators and Investigators

• Sponsor: Odense University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: April 2, 2025
• First Submitted That Met QC Criteria: April 10, 2025
• First Posted (Actual): April 11, 2025

Study Record Updates

• Last Update Posted (Actual): April 11, 2025
• Last Update Submitted That Met QC Criteria: April 10, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Urination Disorders; Urological Manifestations; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Proteinuria; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium Channel Blockers; Membrane Transport Modulators; Diuretics; Natriuretic Agents; Diuretics, Potassium Sparing; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Amiloride
• Other Study ID Numbers: EUCT: 2022-500692-31-00; 2022-500692-31-00 (Ctis)

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: No
• Studies a U.S. FDA-regulated device product: No