Antiphospholipid Syndrome, Thrombotic Antiphospholipid Syndrome, Thrombosis
Conditions
Keywords
antiphospholipid antibodies, vitamin K antagonists, PROBE design, non-inferiority trial, recurrent thrombosis
Brief summary
This is an open-label, non-inferiority, randomized controlled trial with two parallel arms (experimental and control), following a PROBE (Prospective Randomized Open, Blinded Endpoint) design. The study evaluates whether anticoagulation cessation is non-inferior to anticoagulation maintenance regarding the risk of recurrent thrombosis after antiphospholipid antibodies (aPL) loss in patients with thrombotic antiphospholipid syndrome (APS). Currently, the cornerstone of APS treatment is long-term anticoagulation by vitamin K antagonists (VKAs), which expose patients to the risk of bleeding and have a negative impact on health-related quality of life due to the need for frequent International Normalized Ratio (INR) monitoring. No clinical trial in the existing literature has evaluated anticoagulant cessation after aPL loss. The primary endpoint is the first recurrent thrombotic event during follow-up.
Detailed description
The most frequent clinical manifestations of antiphospholipid syndrome (APS) are thrombotic events. The specificities of antiphospholipid antibodies (aPL), their isotypes, and the presence of multiple aPL autoantibodies have been associated with different risk profiles regarding thrombotic manifestations, while the risk of thrombotic events after disappearance of aPL appears to decrease. Currently, no clinical trial in the existing literature has evaluated anticoagulant cessation after aPL loss. At the randomisation visit, demographic, medical, and biological characteristics are collected and the 36-Item Short Form Health Survey (SF-36) questionnaire is completed. Follow-up visits are scheduled every 3 months for the first 6 months (M3, M6), then every 6 months for a minimum of 18 months and a maximum of 42 months (M12 through M48). In the experimental arm, International Normalized Ratio (INR) testing is performed at baseline then discontinued; in the control arm, INR is monitored at baseline, at each protocol visit, in case of recurrent thrombotic event, and as clinically indicated. Serum and plasma samples are collected at baseline, at each follow-up visit, and in case of recurrent thrombotic event, for centralized aPL antibody measurement and biocollection. The study was designed to demonstrate non-inferiority based on a 2-year outcome rate of 20% in the anticoagulant cessation group and 17% in the anticoagulation maintenance group. A total of 234 patients is required to reject the non-inferiority null hypothesis with 80% power, a one-sided type I error rate of 2.5%, and a non-inferiority margin of 10%. The primary endpoint will be analyzed in both intention-to-treat (ITT, primary analysis) and per-protocol (PP) populations. Between-group comparisons will use an appropriate statistical model (e.g., logistic regression, linear models, or Cox proportional hazards models), with treatment effect estimated together with its two-sided 95% confidence interval. Sensitivity analyses will be conducted to assess the robustness of the primary results, and missing data will be handled according to prespecified methods.
Interventions
Continuation of vitamin K antagonist therapy (fluindione, warfarin, or acenocoumarol), administered orally and dosed to obtain an International Normalized Ratio (INR) between 2 and 3, for a minimum of 24 months (up to 48 months depending on time of enrollment)
OTHERAnticoagulant Therapy Discontinuation
Discontinuation of vitamin K antagonist therapy at the randomisation visit. No anticoagulant treatment is administered during follow-up unless a recurrent thrombotic event occurs
Sponsors
Assistance Publique - Hôpitaux de Paris
Direction Générale de l'Offre de Soin (DGOS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
The trial follows a PROBE (Prospective Randomized Open, Blinded Endpoint) design: treatment allocation is open-label (neither patients nor investigators are blinded to the assigned arm), but the assessment of the primary endpoint follows blinded evaluation procedures to limit detection bias
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults ≥ 18 years old 2. Signed written consent form 3. Primary or secondary thrombotic APS according to 2023 ACR/EULAR classification criteria 4. aPL antibodies loss of LA, aCL, and aβ2GPI antibodies - defined as a normalised level (\< 99th percentile) - in at least two consecutive measurements with at least 12 months between each measurement including one negative measurement within the 3 months preceding inclusion 5. Long term (\>12 months) VKAs therapy
Exclusion criteria
1. History of severe venous thrombosis. Severe venous thrombosis including massive pulmonary embolism; chronic thromboembolic pulmonary hypertension; hepatic, mesenteric, renal and/or cerebral venous thrombosis 2. History of arterial thrombosis 3. History of recurrent venous thrombosis while receiving VKAs 4. History of catastrophic antiphospholipid syndrome (CAPS) 5. Triple aPL positivity 6. Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 for each VKAs medicinal product 7. Malignant hypertension 8. Severe hepatic impairment 9. Active malignancy 10. Presence of a mechanical heart valve or any other medical condition requiring anticoagulation with a VKA 11. Pregnancy or breastfeeding 12. Subject deprived of freedom, subject under a legal protective measure 13. No affiliation to any health insurance system 14. Enrolment to another interventional study (clinical trial on medicinal product, medical device and interventional research involving human participants not concerning health product)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Recurrent Of Thrombotic Event | Up to 48 months | Occurrence of a first recurrent thrombotic event during follow-up, in patients randomised to anticoagulation cessation compared to anticoagulation maintenance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Health-Related Quality of Life | At baseline and at each follow-up visit, up to 48 months | Change in health-related quality of life assessed using the 36-Item Short Form Health Survey (SF-36), a patient-reported outcome questionnaire comprising 8 subscales, each scored from 0 to 100. Higher scores indicate better health-related quality of life. |
| Major Bleeding Events | Up to 48 months | Number of major bleeding events during follow-up, with and without anticoagulant therapy. Major bleeding is defined as: a) fatal bleeding; and/or b) bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome; and/or c) bleeding causing a fall in hemoglobin level of 2 g/dL or more, or leading to transfusion |
| All-Cause Mortality | Up to 48 months | All-causes mortality rate during follow-up, compared between the anticoagulation cessation and anticoagulation maintenance arms. |
| Risk Factors Associated With Recurrent Thrombosis | Up to 48 months | Baseline and clinical characteristics (age, gender, obesity, surgeries, trauma, immobilization, infection, malignancy, pregnancy, contraceptive agents, primary/secondary APS status, aPL profile, aPL reappearance) analyzed in relation to the occurrence of recurrent thrombosis after anticoagulation cessation. |
| Incidence of aPL Reappearance | Up to 48 months | Incidence of aPL reappearance during follow-up, in patients with and without anticoagulant therapy after aPL loss. Reappearance is defined as a normalised level (\>99th percentile) of LA, aCL, or aβ2GPI antibodies in at least one measurement during follow-up. |
Countries
France
Contacts
CONTACTKARIM SACRE, MD
CONTACTARTHUR MAGEAU, MD
STUDY_CHAIRKARIM SACRE, MD
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Bichat, Department of Internal Medicine
Outcome results
None listed