RENACTIF: Reduction of the Thrombotic Phenotype in Renal Insufficiency With N-AcetylCysteine (RENACTIF)

RENACTIF: Reduction of the Thrombotic Phenotype in Renal Insufficiency With N-AcetylCysteine A Randomized, Double-blind, Placebo-controlled, Cross-over Trial

Chronic Kidney Disease (CKD) is a known risk factor of cardiovascular morbidity and mortality.

In CKD, decline of renal function results in the accumulation of uremic toxins in blood and tissue, such as Indoxyl Sulfate (IS). IS plasma level is predictive of mortality and cardiovascular disease (CVD). Patients with CKD have increased oxidative stress and circulating tissue factor (TF) levels. In vitro, IS induces an inflammatory, pro-oxidative and pro-coagulant phenotype on endothelial cells and activates TF. N-acetylcysteine (NAC) protects endothelial cells from the effects of IS. NAC reduces oxidative stress and production of activated TF. A prospective study evaluating an oral NAC treatment versus placebo in chronic hemodialysis patients showed a better cardiovascular outcome but the physiopathology was unclear.

The hypothesis is that NAC reduces cardiovascular risk by its effect on uremic toxin-induced pro-coagulant TF production.

The primary objective is to compare the effect of NAC intravenously administered at each dialysis session (2gram on 3 dialysis sessions per week) to placebo on circulating TF levels in patients with CKD on chronic hemodialysis after 4 weeks of treatment. The objective is to show a 33% decrease in circulating tissue factor (TF) levels in the NAC group compared to the control group.

It is a randomized, double-blind, placebo-controlled crossover trial that includes chronic hemodialysis patients from La Conception Hospital (AP-HM) in Marseilles, France. This is an interventional biomedical research project.

20 patients will be included in each group and will receive during 4 weeks intravenous injection.

This study will give a pathophysiological rationale for the use of NAC to reduce thrombotic and cardiovascular risk in patients with CKD. This step will provide the rationale for a clinical trial to reduce the occurrence of major cardiovascular events with IV NAC in hemodialysis (HD) patients.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Drug: N-acetylcysteine (NAC); Biological: Blood sample; Biological: Blood sample; Drug: Placebo

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

Contacts and Locations

• Study Contact: Name: Marion SALLEE, PH; Phone Number: +33 491383042; Email: marion.sallee@ap-hm.fr

Study Locations

• France
  • Marseille, France, 13354
    • Assistance Publique Hopitaux de Marseille

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Hemodialysis patients regardless of the etiology of their renal insufficiency for more than 3 months on a cycle of 3 sessions per week
• Hemodialysis patients at least 4 hours per dialysis session
• Patients with a weight of more than 40 kilogram
• Patients capable of giving informed consent, agreeing to participate in the study and having signed a consent
• Patient able to understand a written questionnaire

Exclusion Criteria:

• Pregnant or lactating women
• Persons deprived of their liberty or hospitalized without consent
• Majors under legal protection or unable to express their consent
• Possibility of recovery of renal function (scleroderma for example)
• Chronic progressive infection that may affect their thrombotic risk
• Patients under 40 kilogram
• Patient taking oral anticoagulants
• Patient with a known allergy to the active molecule or to any of its excipients

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
Placebo Comparator: Placebo group	Biological: Blood sample; Circulating tissue factor assay; Biological: Blood sample; The test of pro-coagulant activity of the tissue factor; Drug: Placebo; Intravenous injection of 2 gram of Placebo during 4 weeks, 3 times per week during the first three hours of dialysis.
Active Comparator: N-acetylcysteine (NAC) group	Drug: N-acetylcysteine (NAC); Intravenous injection of 2 gram of N-acetylcysteine (NAC) during 4 weeks, 3 times per week during the first three hours of dialysis.; Biological: Blood sample; Circulating tissue factor assay; Biological: Blood sample; The test of pro-coagulant activity of the tissue factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
compare the effect of N-acetylcysteine (NAC) intravenously administered	show a 33% decrease in circulating tissue factor levels in the N-acetylcysteine (NAC) group	12 months

Collaborators and Investigators

• Sponsor: Assistance Publique Hopitaux De Marseille
• Investigators: Study Director: Jean-Olivier ARNAUD, Director, Assistance Publique Hopitaux de Marseille

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2019
• Primary Completion (Actual): February 4, 2021
• Study Completion (Actual): May 23, 2023

Study Registration Dates

• First Submitted: August 16, 2018
• First Submitted That Met QC Criteria: August 16, 2018
• First Posted (Actual): August 17, 2018

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 23, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 2017-71; 2018-003232-80 (EudraCT Number)

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