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

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ClinicalTrials.gov Identifier: NCT04153201
Recruitment Status : Completed
First Posted : November 6, 2019
Last Update Posted : November 6, 2019
Sponsor:
Information provided by (Responsible Party):
Maria Tektonidou, National and Kapodistrian University of Athens

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Antiphospholipid Syndrome Drug: Hydroxychloroquine Not Applicable

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Prevention
Official Title: Effect of Hydroxychloroquine on Thrombosis Prevention and Antiphospholipid Antibody Levels in Patients With Primary Antiphospholipid Syndrome: An Pilot Randomized Prospective Study.
Study Start Date : January 15, 2013
Actual Primary Completion Date : October 1, 2019
Actual Study Completion Date : October 16, 2019


Arm Intervention/treatment
Experimental: Hydroxychloroquine
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
Hydroxychloroquine 200 mg daily for patients weighing < 60 kg, hydroxychloroquine 400 mg daily for patients weighing >= 60 kg
Other Names:
  • Antimalarials
  • Plaquenil

No Intervention: Standard care
Patients with primary antiphospholipid syndrome continuing standard care only (vitamin K antagonists or direct oral anticoagulants, and/or antiplatelet agents



Primary Outcome Measures :
  1. Incident acute thrombosis in the venous or arterial circulation [ Time Frame: 3 years ]
    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)


Secondary Outcome Measures :
  1. Hydroxychloroquine-related safety outcomes [ Time Frame: 3 years ]
    • 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

  2. Anticoagulation treatment-related safety outcomes [ Time Frame: 3 years ]
    • 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. General safety outcomes [ Time Frame: 3 years ]
    • Hospitalization for any cause
    • Death of any cause
    • APS-related death (based on death certificate records)


Other Outcome Measures:
  1. Antiphospholipid antibody titer variation [ Time Frame: 3 years ]
    Anticardiolipin IgG antibody titers, anti-cardiolipin IgM antibody titers, anti-beta2-glycoprotein I IgG antibody titers, antibeta2-glycoprotein I IgM antibody titers measured every 6 months.



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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:

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:

  1. ≥4 American College of Rheumatology (ACR) classification criteria for Systemic Lupus Erythematosus (SLE)
  2. ACR classification criteria for other systemic autoimmune disorders
  3. active malignancy
  4. treatment with Hydroxychloroquine (HCQ) in the previous 12 months
  5. 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

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): NCT04153201


Locations
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Greece
Laikon General Hospital
Athens, Attiki, Greece, 11527
Sponsors and Collaborators
National and Kapodistrian University of Athens
Investigators
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Principal Investigator: Maria G Tektonidou, MD PhD National and Kapodistrian University of Athens
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Responsible Party: Maria Tektonidou, Associate Professor of Rheumatology, National and Kapodistrian University of Athens
ClinicalTrials.gov Identifier: NCT04153201    
Other Study ID Numbers: SC668/10062016
First Posted: November 6, 2019    Key Record Dates
Last Update Posted: November 6, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Following publication of results in a medical journal, we are considering sharing data on longitudinal apl titers, demographic information, time to first thrombotic event, adverse events with hydroxychloroquine.

General data protection rule (GDPR) of the European Union special requirements may apply.

Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Analytic Code
Time Frame: Data will become available 6 months following publication of results, and will remain accessible for 2 years
Access Criteria: Individual patient data will be provided to researchers in order to perform relevant meta-analyses, after review and approval of the meta-analysis protocol. Potential publications of our results with the same data should be cited if sharing our data results in new publications.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Maria Tektonidou, National and Kapodistrian University of Athens:
antiphospholipid antibody titers
thrombosis prevention
hydroxychloroquine
antimalarials
antiphospholipid syndrome
Additional relevant MeSH terms:
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Thrombosis
Antiphospholipid Syndrome
Syndrome
Disease
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Autoimmune Diseases
Immune System Diseases
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents