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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Chronic Kidney Diseases

Intervention / Treatment
-----------------
* Drug: N-acetylcysteine (NAC)
* Drug: Placebo
* Biological: Blood sample
* Biological: Blood sample


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: N-acetylcysteine (NAC) group<br> | Drug: N-acetylcysteine (NAC)<br>* Intravenous injection of 2 gram of N-acetylcysteine (NAC) during 4 weeks, 3 times per week during the first three hours of dialysis.<br>Biological: Blood sample<br>* Circulating tissue factor assay<br>Biological: Blood sample<br>* The test of pro-coagulant activity of the tissue factor<br>|
| Placebo Comparator: Placebo group<br> | Drug: Placebo<br>* Intravenous injection of 2 gram of Placebo during 4 weeks, 3 times per week during the first three hours of dialysis.<br>Biological: Blood sample<br>* Circulating tissue factor assay<br>Biological: Blood sample<br>* The test of pro-coagulant activity of the tissue factor<br>|

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 |