Hydroxychloroquine Versus Placebo: Impact on Thrombotic Relapse in Primary Antiphospholipid Syndrome

Study Overview
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Brief Summary
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Antiphospholipid syndrome (APS) combines thrombotic (venous and/or arterial) and/or obstetrical manifestations, along with biological anomalies related to the presence of antiphospholipid antibodies. Despite actual treatment recommended by international guidelines, the relapse rate in APS is high and survival is 65% at 15 years. Hydroxychloroquine has demonstrated its efficacy and benefits in the treatment of Systemic Lupus Erythematosus, but there is no current consensus concerning the efficacy of this treatment in the secondary prevention of thrombotic events in primary APS, even though several in vitro experimental and animal model data, along with several clinical studies have suggested a beneficial effect of this drug in this indication. Considering the prevalence of primary APS in the general population and of the number of clinical events observed in patients with primary APS and receiving conventional treatment with vitamin K anticoagulants (VKA), the consortium expects a minimum clinically relevant difference of 70%. Considering a prevalence of thrombotic events for the entire studied primary APS population of 10% at 2 years, the consortium expects a 70% decrease in thrombotic events under Hydroxychloroquine treatment administered in addition to VKA treatment in primary APS, i.e. a 3% prevalence in the Hydroxychloroquine group at 2 years. The consortium proposes a drug trial, phase III, national multicentric, comparative, randomized, superiority, double-blind, controlled with 2 compared groups (Hydroxychloroquine versus placebo) study. The enrolment period will be 24 months. The main aim of this trial is to comparatively assess at 24 months the number of new thrombotic events (venous and arterial) in primary antiphospholipid syndrome in patients treated with VKA plus Hydroxychloroquine versus VKA plus placebo, in a multicentre, prospective randomized, double-blind, versus placebo study.

Official Title
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Hydroxychloroquine Versus Placebo: Impact on Thrombotic Relapse in Primary Antiphospholipid Syndrome

Conditions
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Primary Antiphospholipid Syndrome

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Presence of a primary antiphospholipid syndrome with previous venous/arterial thrombosis and which needs a treatment with VKA Patients with a signed commitment Exclusion Criteria: Secondary APS Ocular diseases : retinal disease contraindicating the prescription of hydroxychloroquine cataract monophtalmic Past history of intolerance or allergy to hydroxychloroquine Known deficit in G6PDase Hemolytic anemia Porphyria Chronic hepatic disease Severe renal failure (creatinin clearence <30ml/min) Chronic alcoholism Patient with QT interval >440 ms on the ECG Concomitant treatment with drugs raising the QT interval Epilepsy Pregnant or breastfeeding women Women refusing an effective contraception Active cancer or malignant hemopathy Psychiatric disease unabling the compliance to treatment Unaffiliated person or not beneficiary of a social security system Concomitant participation at a biomedical trial able to interfere with the actual trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydroxychloroquine<br>All patients randomised in this arm will receive hydroxychloroquine with their usual treatment, which is antivitamin K anticoagulants | Drug: Hydroxychloroquine<br>* The patients will additionally receive this drug with their usual treatment to evaluate its efficiency to prevent new thrombotic events in primary antiphospholipid syndrome patients<br>* Other names: HCQ;|
| Placebo Comparator: Placebo<br>All patients randomised in this arm will receive a placebo with their usual treatment, which is antivitamin K anticoagulants | Drug: Placebo<br>* The patients will receive placebo with their usual treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of thrombotic events in each arm after 24 months of treatment | The number of thrombotic events will be compared in the two arms of the study. The events which will be considered are deep venous thrombosis, superficial venous thrombosis, lung embolism, stroke, myocardial infarction as assessed by at least one diagnostic tests such as: doppler echography, lung scintigraphy, lung CT scan, cerebral CT scan, cerebral MRI, myocardial scintigraphy, coronarography. | 24 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE | The number of participants with treatment-related adverse events as assessed by CTCAE will be compared in the two arms of the study | 24 month | 
| Number of hospitalizations days related to thrombotic event | The number of hospitalizations days, related to thrombotic event in each arm after 24 months of treatment | 24 month | 
| Number of work incapacity days related to thrombotic event | The number of work incapacity days, related to thrombotic event in each arm after 24 months of treatment | 24 month | 
| The specific biological markers of thrombosis in APS such as type and number of antiphospholipid antibodies, complement, antinuclear antibodies, thrombocytosis | The specific biological markers of thrombosis in APS such as type and number of antiphospholipid antibodies, complement, antinuclear antibodies, thrombocytosis in each arm | 24 month | 
| Assess compliance to VKA | The different recorded values of blood INR all along the study | 24 month | 
| Assess Assess compliance to HCQ | The values of blood Hydroxychloroquine measured at the end of the 24 months of treatment | 24 month | 
| The vascular arterial rigidity measured by doppler echography | The vascular arterial rigidity measured by doppler echography will be compared between the two arms of the study at inclusion in the study and after 24 months of treatment | 24 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antiphospholipid syndrome, thrombosis, hydroxychloroquine