Hydroxychloroquine for Thrombosis Prevention and Antiphospholipid Antibody Reduction in Primary Antiphospholipid Syndrome

Study Overview
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Brief Summary
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This is an interventional drug study designed as a pilot for a randomized clinical trial, aimed at assessing the effect of hydroxychloroquine on the incidence rate of thrombosis in patients with primary antiphospholipid syndrome as the main outcome, as well as the safety of hydroxychloroquine administration in this population. In addition, the effect of hydroxychloroquine on antiphospholipid antibody titers will be assessed.

Detailed Description
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Patients with primary antiphospholipid syndrome (either thrombotic or obstetric) on regular follow-up at our outpatient rheumatology department and being treated with standard care (systemic anticoagulants and/or antiplatelet agents), are randomized to receive either hydroxychloroquine plus standard care, or standard care alone, on a 1:1 ratio using block size 2 randomization, after exclusion of patients with contraindications to hydroxychloroquine or prior hydroxychloroquine use within 12 months of consideration for enrollment. Patients are monitored clinically every 3 months and the development of thrombosis and/or adverse effects attributable to hydroxychloroquine is recorded. Antiphospholipid antibody titers (anti-cardiolipin immunoglobulin G (IgG)/Immunoglobulin M (IgM) and anti-beta2-glycoprotein I IgG/IgM isotypes) are measured semi-annually. Intention-to-treat survival analysis is applied for assessing the effect of hydroxychloroquine on the incidence of thrombosis. Longitudinal mixed linear models are applied for assessing the effect of hydroxychloroquine on longitudinal titers of antiphospholipid antibodies.

Official Title
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Effect of Hydroxychloroquine on Thrombosis Prevention and Antiphospholipid Antibody Levels in Patients With Primary Antiphospholipid Syndrome: An Pilot Randomized Prospective Study.

Conditions
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Antiphospholipid Syndrome

Intervention / Treatment
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* Drug: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients diagnosed with primary antiphospholipid syndrome (PAPS) [updated Sapporo criteria: Miyakis et al, J Thromb Haemost. 2006 Feb;4(2):295-306. PubMed 16420554] Exclusion Criteria: ≥4 American College of Rheumatology (ACR) classification criteria for Systemic Lupus Erythematosus (SLE) ACR classification criteria for other systemic autoimmune disorders active malignancy treatment with Hydroxychloroquine (HCQ) in the previous 12 months history of serious adverse events or contraindication to HCQ including a history of HCQ allergy, HCQ eye toxicity, or glucose-6-phosphate dehydrogenase deficiency, uncontrolled seizure disorder, liver enzyme elevation >2-fold the upper normal limit, and creatinine clearance <30ml/min

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1 intervention arm (Hydroxychloroquine plus standard care), 1 control arm (standard care) Patients randomized 1:1 using block size 2 randomization
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine<br>Patients with primary antiphospholipid syndrome started on hydroxychloroquine while continuing standard care (vitamin K antagonists or direct oral anticoagulants, and/or antiplatelet agents, depending on primary APS subgroup) | Drug: Hydroxychloroquine<br>* Hydroxychloroquine 200 mg daily for patients weighing < 60 kg, hydroxychloroquine 400 mg daily for patients weighing >= 60 kg<br>* Other names: Plaquenil;|
| No Intervention: Standard care<br>Patients with primary antiphospholipid syndrome continuing standard care only (vitamin K antagonists or direct oral anticoagulants, and/or antiplatelet agents | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incident acute thrombosis in the venous or arterial circulation | incident acute arterial thrombosis (myocardial infarction, stroke, transient ischemic attack, occlusion of the peripheral limb and neck, splanchnic, or retinal arteries) or venous thrombosis (pulmonary embolism, deep vein thrombosis, splanchnic vein thrombosis, retinal vein occlusion) confirmed by appropriate imaging studies (doppler ultrasonography, computed tomography pulmonary angiogram, conventional angiography, magnetic resonance angiography, ventilation/perfusion lung scintigraphy) | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hydroxychloroquine-related safety outcomes | Retinal toxicity by ocular examination, visual field testing and optical coherence tomography yearly and upon reporting visual symptoms Toxic myopathy: new onset motor strength <=4/5, myalgia and creatine kinase elevation Liver toxicity: liver enzyme elevations >3x of upper limit of normal (ULN), or serum total bilirubin >2x ULN, with no cholestasis Metabolism disorders (hypoglycemia, weight decrease) by quarterly body weight and blood glucose testing Bone marrow suppression: drop in hemoglobin to < 10 mg/dl, white blood cells < 3700/μL, platelets < 150,000/μL according to a hematologist Cardiac complications (conduction defects, QT prolongation, cardiomyopathy) screened by interview, physical examination, and semi-annual electrocardiogram Seizures screened by interview and confirmed by electrocardiogram Gastrointestinal upset, allergic reactions, skin reactions by interview and physical exam | 3 years | 
| Anticoagulation treatment-related safety outcomes | Major bleeding, defined as fatal bleeding, or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin level of 2 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells. Minor bleeding defined as clinically evident bleeding not fulfilling the definition of major bleeding | 3 years | 
| General safety outcomes | Hospitalization for any cause Death of any cause APS-related death (based on death certificate records) | 3 years | 

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