Treatment of Vascular Stiffness in ADPKD

Autosomal Dominant Polycystic Kidney Clinical Trial

— TRAMPOLINE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05228574
• Other study ID #: NL72836.340.10
• Status: Recruiting
• Phase: Phase 4
• Start date: March 11, 2022
• Est. completion date: December 31, 2024

Study information

• Verified date: September 2023
• Source: Erasmus Medical Center
• Contact: L. Xue, MSc
• Phone: (0031)107040704
• Email: l.xue[@]erasmusmc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 54
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Autosomal Dominant Polycystic Kidney
• Polycystic Kidney Diseases
• Polycystic Kidney, Autosomal Dominant

Intervention

Dietary Supplement:
• Sodium chloride (NaCl)
Sodium chloride capsules 6 grams per day for 4 weeks.
• Placebo
Placebo capsules, 6 grams per day for 4 weeks.

Drug:
• Amiloride Hcl 5mg Tab
Amiloride 5mg tablets, 20 mg per day for two weeks in open-label setting.

Locations

Country	Name	City	State
Netherlands	Erasmus University Medical Centre Rotterdam	Rotterdam	South-Holland

Sponsors (1)

Lead Sponsor	Collaborator
Erasmus Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Blood pressure	24-hours ambulatory blood pressure measurement (Mobil-O-Graph).	At week 3, week 5 and at at week 7
Secondary	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
Secondary	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
Secondary	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-a, 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