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

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

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.

Study Overview

• Status: Completed
• Conditions: Antiphospholipid Syndrome
• Intervention / Treatment: Drug: Hydroxychloroquine

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Greece
  • Attiki
    • Athens, Attiki, Greece, 11527
      • Laikon General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: Plaquenil; Antimalarials
No Intervention: Standard care; 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?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antiphospholipid antibody titer variation	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.	3 years

Collaborators and Investigators

• Sponsor: National and Kapodistrian University of Athens
• Investigators: Principal Investigator: Maria G Tektonidou, MD PhD, National and Kapodistrian University of Athens

Study record dates

Study Major Dates

• Study Start: January 15, 2013
• Primary Completion (Actual): October 1, 2019
• Study Completion (Actual): October 16, 2019

Study Registration Dates

• First Submitted: October 21, 2019
• First Submitted That Met QC Criteria: November 3, 2019
• First Posted (Actual): November 6, 2019

Study Record Updates

• Last Update Posted (Actual): November 6, 2019
• Last Update Submitted That Met QC Criteria: November 3, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: antimalarials; hydroxychloroquine; antiphospholipid syndrome; antiphospholipid antibody titers; thrombosis prevention
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Autoimmune Diseases; Disease; Embolism and Thrombosis; Syndrome; Thrombosis; Antiphospholipid Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Hydroxychloroquine; Antimalarials
• Other Study ID Numbers: SC668/10062016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD 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.

• IPD Sharing Time Frame: Data will become available 6 months following publication of results, and will remain accessible for 2 years
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No