Rivaroxaban for stroke patients with antiphospholipid syndrome

Phase 2

• Conditions: Stroke patients with antiphospholipid syndrome with or without systemic lupus erythematosus; Circulatory System

• Registration Number: ISRCTN10280992
• Lead Sponsor: niversity College London

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-04-25
• Last Update Posted: 19 December 2023
• Study Completion: 2025-02-02

Recruitment & Eligibility

• Status: Ongoing
• Sex: All
• Target Recruitment: 43

Inclusion Criteria

Current inclusion criteria as of 28/11/2022:
1. Patients must be confirmed as having persistent antiphospholipid antibodies (aPL), defined as: positivity of one or more aPL, i.e. lupus anticoagulant, IgG and/or IgM anticardiolipin and/or anti beta 2 glycoprotein I antibodies at >40 GPL or MPL units or > the 99th centile of normal, on two or more occasions, at least 12 weeks apart.
2. One or more of: a) Ischaemic stroke; b) transient ischaemic attack (TIA) with evidence of either acute or chronic ischaemic injury on brain magnetic resonance imaging (MRI) (including diffusion-weighted magnetic resonance imaging (DWI) lesion(s), previous cortical or subcortical infarction(s), or white matter hyperintensities) and diagnosed by a clinician with expertise in stroke; c) brain infarcts (territorial or subcortical) or white matter hyperintensities (WMH) of presumed vascular origin on brain MRI, with or without cognitive impairment; and an expert clinical opinion that anticoagulation is a reasonable treatment option (with the aim of preventing ischaemic brain injury).
3. Patients must weigh = 50kg and = 135kg
4. Women must be on adequate contraception, barrier or hormonal, unless postmenopausal or sterilised

_____
Previous inclusion criteria as of 19/07/2021:
1. Patients must be confirmed as having persistent antiphospholipid antibodies (aPL), defined as: positivity of one or more aPL, i.e. lupus anticoagulant, IgG and/or IgM anticardiolipin and/or antibeta 2 glycoprotein I antibodies at > 40 GPL or MPL units or > the 99th centile of normal, on two or more occasions at least 12 weeks apart.
2. One or more of: a) Ischaemic stroke; b) transient ischaemic attack (TIA) with evidence of either acute or chronic ischaemic injury on brain MRI (including diffusion-weighted magnetic resonance imaging (DWI) lesion(s), previous cortical or subcortical infarction(s), or white matter
hyperintensities) and diagnosed by a clinician with expertise in stroke; c) brain infarcts (territorial or subcortical) or white matter hyperintensities (WMH) of presumed vascular origin on brain MRI, with or without cognitive impairment; and an expert clinical opinion that anticoagulation is a reasonable treatment option (with the aim of preventing ischaemic brain injury).
3. Women must be on adequate contraception, barrier or hormonal, unless postmenopausal or sterilised.

_____
Previous inclusion criteria:
1. Patients must be confirmed as having persistent antiphospholipid antibodies (aPL), defined as: positivity of one or more aPL, i.e. lupus anticoagulant, IgG and/or IgM anticardiolipin and/or anti beta 2 glycoprotein I antibodies at >40 GPL or MPL units or > the 99th centile of normal, on at least two consecutive occasions at least 12 weeks apart. Criteria for the laboratory diagnosis of aPL are detailed in Appendix 3 of the Protocol.
2. One or more of: a) ischaemic stroke; b) transient ischaemic attack (TIA) with evidence of either acute or chronic ischaemic injury on brain MRI (including DWI lesion(s), previous cortical or subcortical infarction(s), or white matter hyperintensities (WMH)) and diagnosed by a clinician with expertise in stroke; c) brain infarcts (territorial or subcortical) or WMH of presumed vascular origin on brain MRI, with or without cognitive impairment; and an expert clinical opinion that anticoagulation is a reasonable treatment option (with the aim of preventing ischaemic brain injury).
3. Women must be on adequate contraception, barrier or hormo

Exclusion Criteria

Current exclusion criteria as of 28/11/2022:
1. Patients who are triple positive for antiphospholipid antibodies (presence of lupus anticoagulant, IgG and/or IgM anticardiolipin and anti beta 2 glycoprotein I antibodies at >40 GPL or MPL units or > the 99th centile of normal*. (*patients who have previously been triple aPL-positive and have single or double aPL positivity on at least 2 occasions over at least 6 months, including once within 1 month prior to randomisation, can be recruited to the trial)
2. Pregnant or lactating women
3. Severe renal impairment with creatinine clearance < 30 mL/min (i.e. 29 mL/min or less)
4. Liver function tests ALT > 3 x ULN
5. Cirrhotic patients with Child Pugh B or C
6. Thrombocytopenia (platelets < 75 x 109/L)
7. Non-adherence on warfarin (based on clinical assessment)
8. Patients taking strong inhibitors of both CYP3A4 and P-gp pathways such as
8.1. Systemic azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole)
8.2. Patients on human immunodeficiency virus (HIV) protease inhibitors (e.g. ritonavir)
9. Patients on strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine,
phenobarbital or St. John's Wort)
10. Patients on dronedarone
11. Patients on levetiracetam, sodium valproate/valproic acid, oxcarbazepine or topiramate
12. Patients less than 18 years of age
13. Refusal to consent to the site informing General Practitioner (GP) and Healthcare
Professional responsible for anticoagulation care of the participant.
14. Contraindications to MRI (e.g. cardiac pacemaker, severe claustrophobia, inability to lie
flat: patients who do not meet local safety rules for MRI).
15. Patients at high risk of bleeding and not suitable for anticoagulation therapy.
16. Previous known allergy or intolerance to warfarin or rivaroxaban.
17. Women planning to become pregnant within the 2-year follow-up period.
18. Patients with known galactose intolerance, total lactase deficiency or galactose
malabsorption.
19. Patients who have had active cancer (excluding non-melanoma skin cancers) within the
last 2 years
20. Any other reason that the PI or delegate considers would make the patient unsuitable to
enter RISAPS

_____
Previous exclusion criteria as of 19/07/2021:
1. Pregnant or lactating women
2. Severe renal impairment with creatinine clearance <30 mL/min (i.e. 29 mL/min or less)
3. Liver function tests ALT >3 x ULN
4. Cirrhotic patients with Child Pugh B or C
5. Thrombocytopenia (platelets <75 x 10^9/L)
6. Non-adherence on warfarin (based on clinical assessment)
7. Patients taking strong inhibitors of both CYP3A4 and P-gp pathways such as
a. Systemic azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole)
b. Patients on human immunodeficiency virus (HIV) protease inhibitors (e.g. ritonavir)
8. Patients on strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort)
9. Patients on dronedarone
10. Patients less than 18 years of age
11. Refusal to consent to the site informing General Practitioner and Healthcare Professional responsible for anticoagulation care of the participant
12. Contraindications to MRI (e.g. cardiac pacemaker, severe claustrophobia, inability to lie flat: patients who do not meet local safety rules for MRI).
13. Patients at high risk of bleeding and not suitable for anticoagulation therapy.
14. Previous known allergy or intolerance to warfarin or rivaroxaban.
15. Women planning to become pre

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Current primary outcome measure as of 19/07/2021: <br><br>To compare the efficacy of high-intensity oral rivaroxaban (15mg twice daily) vs high-intensity warfarin, target INR 3.5 (range 3.0-4.0), in patients with APS with or without SLE who have had a stroke or other ischaemic brain manifestations.<br>The comparison of efficacy will be based on the rate of change in brain white matter hyperintensity (WMH) volume on MRI, a surrogate marker of ischaemic damage, between baseline and 24 months follow up.<br><br>_____<br><br>Previous primary outcome measure:<br><br>Efficacy based on the rate of change in brain white matter hyperintensity (WMH) volume on MRI, a surrogate marker of ischaemic damage, between baseline and 24 months follow-up.