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

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.

Study Overview

• Status: Unknown
• Conditions: Primary Antiphospholipid Syndrome
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France, 49000
    • University Hospital Angers

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Hydroxychloroquine; All patients randomised in this arm will receive hydroxychloroquine with their usual treatment, which is antivitamin K anticoagulants	Drug: Hydroxychloroquine; 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; Other Names: HCQ
PLACEBO_COMPARATOR: Placebo; All patients randomised in this arm will receive a placebo with their usual treatment, which is antivitamin K anticoagulants	Drug: Placebo; The patients will receive placebo with their usual treatment

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Angers
• Investigators: Principal Investigator: Cristina Belizna, MD, PhD, University Hospital, Angers

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): August 15, 2018
• Primary Completion (ANTICIPATED): August 15, 2022
• Study Completion (ANTICIPATED): October 15, 2022

Study Registration Dates

• First Submitted: April 27, 2018
• First Submitted That Met QC Criteria: May 28, 2018
• First Posted (ACTUAL): May 30, 2018

Study Record Updates

• Last Update Posted (ACTUAL): May 30, 2018
• Last Update Submitted That Met QC Criteria: May 28, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: hydroxychloroquine; thrombosis; antiphospholipid syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease; Syndrome; Antiphospholipid Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 2017-004416-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No