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

Antiphospholipid Syndrome (APS) Clinical Trial

— APLAQUINE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02595346
• Other study ID #: 2015/074/HP
• Status: Recruiting
• Phase: Phase 2
• First received: November 2, 2015
• Last updated: December 6, 2016
• Start date: June 2016
• Est. completion date: December 2018

Study information

• Verified date: December 2016
• Source: University Hospital, Rouen
• Contact: Sébastien MIRANDA, MD
• Email: sebastien.miranda[@]chu-rouen.fr
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Antiphospholipid Syndrome
• Antiphospholipid Syndrome (APS)
• Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
France	Rouen University Hospital	Rouen

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Rouen

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	change from baseline in endothelial glycocalyx thickness	indirect measure of the glycocalyx thickness by using sublingual SDF (sidestream dark field) imaging	6 months	No
Secondary	change from baseline in oxydative stress	plasma levels of nitrites and TBARS (thiobarbituric acid reactive substance)	6 months	No
Secondary	change from baseline in systemic inflammation	plasma levels of TNFalpha	6 months	No
Secondary	change from baseline in coagulation parameter	Tissue factor plasmatic level	6 months	No
Secondary	change from baseline in plasmatic level in hydroxychloroquine	plasma level of hydroxychloroquine	6 months	No