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

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ClinicalTrials.gov Identifier: NCT02595346
Recruitment Status : Unknown
Verified December 2016 by University Hospital, Rouen.
Recruitment status was:  Recruiting
First Posted : November 3, 2015
Last Update Posted : December 7, 2016
Sponsor:
Information provided by (Responsible Party):
University Hospital, Rouen

Brief 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.


Condition or disease Intervention/treatment Phase
Antiphospholipid Syndrome (APS) Drug: Hydroxychloroquine Drug: placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficiency of Hydroxychloroquine on the Endothelial Dysfunction in Antiphospholipid Syndrome (APLAQUINE)
Study Start Date : June 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


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 Name: 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.





Primary Outcome Measures :
  1. Change from baseline flow mediated dilatation of brachial artery [ Time Frame: 6 months ]
    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.


Secondary Outcome Measures :
  1. change from baseline in endothelial glycocalyx thickness [ Time Frame: 6 months ]
    indirect measure of the glycocalyx thickness by using sublingual SDF (sidestream dark field) imaging

  2. change from baseline in oxydative stress [ Time Frame: 6 months ]
    plasma levels of nitrites and TBARS (thiobarbituric acid reactive substance)

  3. change from baseline in systemic inflammation [ Time Frame: 6 months ]
    plasma levels of TNFalpha

  4. change from baseline in coagulation parameter [ Time Frame: 6 months ]
    Tissue factor plasmatic level

  5. change from baseline in plasmatic level in hydroxychloroquine [ Time Frame: 6 months ]
    plasma level of hydroxychloroquine



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02595346


Contacts
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Contact: Sébastien MIRANDA, MD sebastien.miranda@chu-rouen.fr
Contact: Julien BLOT +3323288 ext 8265 julien.blot@chu-rouen.fr

Locations
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France
Rouen University Hospital Recruiting
Rouen, France, 76031
Sub-Investigator: Ygal BENHAMOU, MD         
Sponsors and Collaborators
University Hospital, Rouen
Investigators
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Principal Investigator: Sébastien MIRANDA, MD Rouen University Hospital

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Responsible Party: University Hospital, Rouen
ClinicalTrials.gov Identifier: NCT02595346     History of Changes
Other Study ID Numbers: 2015/074/HP
First Posted: November 3, 2015    Key Record Dates
Last Update Posted: December 7, 2016
Last Verified: December 2016
Additional relevant MeSH terms:
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Antiphospholipid Syndrome
Syndrome
Disease
Pathologic Processes
Autoimmune Diseases
Immune System Diseases
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents