Treatment of Vascular Stiffness in ADPKD (TRAMPOLINE)

Treatment of Vascular Stiffness in Patients With Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease characterized by cystic kidneys and caused by mutations in the polycystic kidney disease and other rare genes. It is associated with salt-sensitive hypertension, which accounts for the majority of morbidity and mortality. About 70% of patients with ADPKD develop hypertension, prior to the onset of kidney function decline. Early onset hypertension, despite its treatment, is independently associated with rapid kidney function decline. The investigators hypothesize that a high-sodium diet in patients with ADPKD is required for the development of vascular stiffness, which precedes hypertension, and that treatment with amiloride reverses this phenomenon.

Study Overview

• Status: Recruiting
• Conditions: Autosomal Dominant Polycystic Kidney
• Intervention / Treatment: Dietary supplement: Sodium chloride (NaCl); Drug: Amiloride Hcl 5mg Tab; Dietary supplement: Placebo

Detailed Description

Objective of the study:

The investigators aim to investigate if arterial stiffness is exacerbated due to a high-salt diet in patients with ADPKD. The investigators also aim to explore whether treatment with amiloride prevents the arterial stiffness caused by a high-salt diet.

Study design:

Randomized, double blinded and placebo-controlled clinical trial with open-label treatment with amiloride

Study population:

Adults with ADPKD with an estimated glomerular filtration rate (CKD-EPI) of ≥ 60 ml/min/1.73m2

Intervention:

All participants will be subjected to a low-salt diet (3,5 grams/day) throughout the study for a total of 6 weeks. After a run-in period of 2 weeks, participants will be randomized into two treatment groups:

Group 1: Sodium chloride capsules (6 grams/day) for 2 weeks, combined with amiloride (20 mg/day) in last 2 weeks Group 2: Placebo capsules for 2 weeks, combined with amiloride (20 mg/day) in last 2 weeks.

Primary study parameters/outcome of the study:

The three primary outcomes of this study are a difference in central arterial stiffness (pulse wave velocity, PWV) between:

1. The high-salt group versus low-salt group;
2. The high-salt group: before versus after amiloride treatment;
3. The low-salt group: before versus after amiloride treatment.

The burden of participation includes:

• A dietary salt restriction of 3.5 grams/day for a total period of 6 weeks
• Salt supplementation or placebo for a total period of 4 weeks
• Drug intervention with amiloride during the last 2 weeks
• Hospital visits

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: L. Xue, MSc; Phone Number: (0031)107040704; Email: l.xue@erasmusmc.nl

Study Locations

• Netherlands
  • South-Holland
    • Rotterdam, South-Holland, Netherlands, 3015GD
      • Recruiting
      • Erasmus University Medical Centre Rotterdam
      • Contact: L. Xue, MSc; Phone Number: 003130906182; Email: l.xue@erasmusmc.nl
      • Principal Investigator: M. Salih, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults with typical ADPKD diagnosed based on Ravine criteria and/or a documented Pkd 1 or 2 mutation
• Chronic kidney disease epidemiology collaboration equation estimated glomerular filtration rate ≥60 ml/min/1.73m2
• Ability to provide informed consent

Exclusion Criteria:

• Uncontrolled hypertension, defined as an office blood pressure of ≥160/ ≥90 mmHg with or without antihypertensive treatment
• Concomitant use of ≥ 3 antihypertensive medications
• When antihypertensive treatment is prescribed for any other treatment indication than hypertension (e.g. cardia arrhythmia)
• Serum potassium levels >5.5 mmol/L (measured within last 6 months)
• History of liver disease (excluding liver cysts due to ADPKD)
• History of heart failure (cardiac ejection fraction < 35%) or cardiac arrhythmia
• History of diabetes mellitus
• Active infection or antibiotic therapy
• Immunosuppressive therapy within the last year
• Concomitant use of drugs that could influence blood pressure and/or disease progression (Tolvaptan/non-steroidal anti-inflammatory drugs (NSAIDs)/chemotherapy), excluding < 3 antihypertensive drugs
• Actual pregnancy or unwillingness to adhere to reproductive precautions during the duration of the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High-salt group (group 1); All participants will be subjected to a low-salt diet (3.5 grams/day) for six weeks. Group 1 will receive sodium chloride capsules (6 grams/day) for four weeks. In the last two weeks of the trial, all participants will be treated with amiloride tablets (20 mg daily) in open-label setting.	Dietary supplement: Sodium chloride (NaCl); Sodium chloride capsules 6 grams per day for 4 weeks.; Other Names: Table salt; Drug: Amiloride Hcl 5mg Tab; Amiloride 5mg tablets, 20 mg per day for two weeks in open-label setting.; Other Names: Amiloride
Placebo Comparator: Low-salt group (group 2); All participants will be subjected to a low-salt diet (3.5 grams/day) for six weeks. Group 2 will receive placebo capsules (6 grams/day) for four weeks. In the last two weeks of the trial, all participants will be treated with amiloride tablets (20 mg daily) in open-label setting.	Drug: Amiloride Hcl 5mg Tab; Amiloride 5mg tablets, 20 mg per day for two weeks in open-label setting.; Other Names: Amiloride; Dietary supplement: Placebo; Placebo capsules, 6 grams per day for 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial stiffness induced by high salt diet	Difference in central arterial stiffness, measured as the pulse wave velocity (PWV), in high-salt group versus low-salt group.	At week 3, week 5
Effect of treatment with amiloride on arterial stiffness in high-salt group	Difference in central arterial stiffness, measured as the pulse wave velocity (PWV), before versus after amiloride treatment in high-salt group.	At week 5 and at week 7
Effect of treatment with amiloride on arterial stiffness in low-salt group	Difference in central arterial stiffness, measured as the pulse wave velocity (PWV), before versus after amiloride treatment in low-salt group.	At week 5 and at week 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure	24-hours ambulatory blood pressure measurement (Mobil-O-Graph).	At week 3, week 5 and at at week 7
Salt tasting thresholds	Sodium chloride (NaCl) solutions with different concentrations to assess the salt tasting thresholds.	At inclusion, week 3, week 5 and at week 7
Skin sodium accumulation	In a subgroup of participants, tissue sodium concentration (23Na) will be assessed noninvasively using a contrast-free 23 Na-MRI scan.	At week 3, week 5 and at week 7
Markers of (vascular) inflammation and endothelial dysfunction	Blood biomaterials will be collected at the visits. We will measure inflammatory markers including the high-sensitivity C-reactive protein, interleukin-6 and tumor necrosis factor-α, and other relevant markers for endothelial dysfunction including the adhesion molecules intercellular cell adhesion molecules-1, vascular cell adhesion molecules-1 and endothelin-1.	At inclusion, week 3, week 5 and at week 7

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Investigators: Principal Investigator: M. Salih, MD, PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 12, 2022
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (Actual): February 8, 2022

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Hypertension; Polycystic kidney disease; Amiloride; Salt
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Channel Blockers; Diuretics, Potassium Sparing; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Amiloride
• Other Study ID Numbers: NL72836.340.10

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