Study of the Efficiency of Hydroxychloroquine on the Endothelial Dysfunction and Its Vascular Consequences During the Antiphospholipid Syndrome (APLAQUINE)

Efficiency of Hydroxychloroquine on the Endothelial Dysfunction in Antiphospholipid Syndrome (APLAQUINE)

This study evaluates the benefits of hydroxychloroquine on arterial function in antiphospholipid syndrome.

Briefly, the patients will be randomized in two groups, one will receive hydroxychloroquine and standard treatment, the other will receive placebo in addition of standard treatment.

Study Overview

• Status: Unknown
• Conditions: Antiphospholipid Syndrome (APS)
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: placebo

Detailed Description

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by recurrent thrombotic events and miscarriages, with persistently positive antiphospholipid antibodies (aPL). APS may be isolated (primary APS) or associated to a connective tissue disease, most often systemic lupus erythematous (SLE).

Pathogenic effects of aPL were first described by the demonstration that in vitro incubation of endothelial cells or monocytes with aPL induce an endothelial dysfunction characterized by pro-coagulant (overexpression of tissue factor and modulation of protein C and S), pro-inflammatory (increased level of IL-6(interleukin 6) , IL-1β and TNFα) and pro-adhesive (increased levels of ICAM-1(intercellular adhesion molecule ), VCAM-1 (vascular endothelial cell adhesion molecule) and E-selectin) phenotypes. In parallel the investigators and others reported that endothelial function, assessed by flow mediated dilatation, is altered in patients with primary and secondary forms of APS. Although a role for TLR (toll-like receptor )-mediated NFkB translocation has been advanced, the pathogenic mechanisms that lead to in vivo endothelial injury in APS are incompletely understood.

In an experimental model, the investigators demonstrated that passive transfer of human aPL to mice induced a marked endothelial dysfunction assessed ex vivo in small resistance arteries, and an increase in TNFα levels. Moreover, the investigators group have demonstrated that patients with primary arterial APS display endothelial dysfunction and structural arterial changes, associated with a pro-oxidative and pro-coagulant state and with activation of the TLR2 and TLR4 signalling pathways.

Recently, in a preliminary study the investigators have found that endothelial glycocalyx which is an important part of the vascular barrier and which is intimately linked to the homeostatic functions of the endothelium was altered in APL patients.

Hydroxychloroquine (HCQ) is an antimalarial drug, also used to treat rheumatic diseases such as SLE. There is experimental evidence to suggest a direct role of hydroxychloroquine on the pathophysiology of APS: it directly reduces the binding of antibodies on the phospholipid bilayers, protects the annexin A5 anticoagulant shield and it reverses platelet adhesion induced by aPL.

Furthermore it is known to decrease the expression of lysosomal TLRs, but also extra lysosomal TLR2 and TLR4.

The aim of this study is to investigate whether treatment with hydroxychloroquine modulates vascular endothelial function in patients.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sébastien MIRANDA, MD; Email: sebastien.miranda@chu-rouen.fr

Study Locations

• France
  • Rouen, France, 76031
    • Recruiting
    • ROUEN university hospital
    • Sub-Investigator: Ygal BENHAMOU, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients who fulfilled Sidney criteria for APS (antiphospholipid Syndrome
• Women of childbearing potential must have a contraceptive method
• Written informed consent
• no severe, progressive, or uncontrolled kidney, liver, blood, stomach, lung, heart, or brain disease.

Exclusion Criteria:

• secondary antiphospholipid syndrome
• Pregnancy and breastfeeding
• Patients with a history of severe depression, psychosis, or suicidal ideation
• story of intolerance or contra-indication to hydroxychloroquine, lactose, trinitrin
• Prior use of hydroxychloroquine in the last 6 months
• Chronic heart failure
• atrial fibrillation
• severe pulmonary hypertension
• severe kidney failure clearance < 30ml/mn
• uncontrolled arterial hypertension
• secondary arterial hypertension
• diabetes mellitus diagnosed in the last 3 months
• body mass index > 35
• Patient has been committed to an institution by legal or regulatory order

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: hydroxychlorquine; hydroxychloroquine 200 mg twice a day for 6 months	Drug: Hydroxychloroquine; endothelial function is assessed by measuring the flow mediated dilatation of humeral artery in response to ischemia. the dilatation is evaluated by echotracking. glycocalyx thickness is measured by the study of sublingual microcirculation with SDF imaging. oxydative, inflammatory and coagulation parameters is assessed on plasma samples.; Other Names: plaquenil
Placebo Comparator: control; placebo 2 pills a day for 6 months	Drug: placebo; endothelial function is assessed by measuring the flow mediated dilatation of humeral artery in response to ischemia. the dilatation is evaluated by echotracking. glycocalyx thickness is measured by the study of sublingual microcirculation with SDF imaging. oxydative, inflammatory and coagulation parameters is assessed on plasma samples.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline flow mediated dilatation of brachial artery	The brachial artery diameter and blood flow are measured by echotracking and Doppler before and just after and ischemic test. Result expressed in percentage of diameter variation.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change from baseline in endothelial glycocalyx thickness	indirect measure of the glycocalyx thickness by using sublingual SDF (sidestream dark field) imaging	6 months
change from baseline in oxydative stress	plasma levels of nitrites and TBARS (thiobarbituric acid reactive substance)	6 months
change from baseline in systemic inflammation	plasma levels of TNFalpha	6 months
change from baseline in coagulation parameter	Tissue factor plasmatic level	6 months
change from baseline in plasmatic level in hydroxychloroquine	plasma level of hydroxychloroquine	6 months

Collaborators and Investigators

• Sponsor: University Hospital, Rouen
• Investigators: Principal Investigator: Sébastien MIRANDA, MD, ROUEN university hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: November 2, 2015
• First Submitted That Met QC Criteria: November 2, 2015
• First Posted (Estimate): November 3, 2015

Study Record Updates

• Last Update Posted (Estimate): December 7, 2016
• Last Update Submitted That Met QC Criteria: December 6, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease; Syndrome; Antiphospholipid Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 2015/074/HP