Rivaroxaban for stroke patients with antiphospholipid syndrome
| ISRCTN | ISRCTN10280992 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10280992 |
| ClinicalTrials.gov (NCT) | NCT03684564 |
| Clinical Trials Information System (CTIS) | 2018-001735-49 |
| Integrated Research Application System (IRAS) | 248593 |
| Protocol serial number | CTU/2015/1974, IRAS 248593 |
| Sponsor | University College London |
| Funder | Versus Arthritis |
- Submission date
- 26/03/2019
- Registration date
- 25/04/2019
- Last edited
- 03/03/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English summary of protocol
Background and study aims
The RISAPS trial follows on from the RAPS (Rivaroxaban in Antiphospholipid Syndrome) study that showed that rivaroxaban could offer a potentially effective alternative to warfarin for patients with antiphospholipid syndrome (APS) who have thrombosis (blood clots) in their veins, rather than in their arteries and require standard intensity anticoagulation (blood thinning).
Currently, APS patients who have had an ischaemic stroke (which occurs when blood flow to an area of brain is cut off) are treated with warfarin to reduce the risk of a recurrence. Warfarin tends to have a variable ‘blood thinning’ effect in patients with APS, necessitating frequent (usually weekly) INR blood tests to monitor the effect of the warfarin, which is inconvenient for patients.
The RISAPS trial will compare high intensity (high dose) rivaroxaban versus high intensity warfarin (current standard of care treatment) for 24 months, in APS patients, with or without lupus (systemic lupus erythematosus; SLE), requiring anticoagulation after experiencing a stroke, a 'mini stroke' (also known as a transient ischaemic attack) or other ischaemic brain damage (caused by blood clots in the brain arteries or smaller blood vessels).
Rivaroxaban, unlike warfarin, does not require regular blood tests, because it has a more predictable blood thinning effect. Furthermore, rivaroxaban does not interact with food or alcohol and has fewer interactions than warfarin with other drugs. If rivaroxaban is no worse than warfarin for anticoagulation of APS patients with stroke or other ischaemic brain manifestations, it could become the standard of care for the treatment of APS patients, with or without lupus, who have experienced stroke or other ischaemic brain manifestations, and improve patients' quality of life.
The European Medicines Agency recommended, in 2019, against the use of DOACs, which include rivaroxaban, in individuals with a history of thrombosis (blood clots) who have APS, especially in patients with triple positive antiphospholipid antibodies. This recommendation, which has been adopted by other regulatory authorities, refers to the current (standard intensity) doses of DOACs prescribed for long term use. Importantly, the RISAPS trial is using high intensity rivaroxaban to ‘match’ high intensity warfarin (standard of care treatment). The trial will not include individuals who have triple positive antiphospholipid antibodies (i.e., lupus anticoagulant, anticardiolipin and anti-beta 2 glycoprotein I antibodies) – such individuals may be allowed in the study, in due course, only if the Independent Data Monitoring Committee confirms that it is safe for them to take part in RISAPS and receive a high dose of rivaroxaban.
Who can participate?
Stroke patients with antiphospholipid syndrome
What does the study involve?
Participants are randomly allocated to take either rivaroxaban or warfarin for 24 months. All participants undergo a series of assessments, including an MRI brain scan, at the start and the end of the study (i.e. after 24 months) and the research teams also record all safety related events, including any thrombosis or bleeding, that occur during the trial period.
What are the possible benefits and risks of participating?
Taking part in this trial may or may not benefit participants directly. Participants may be helping to improve treatment for all APS patients in the future. After the trial results are available, we should know if rivaroxaban is as effective as warfarin for stroke patients with APS, with or without lupus.
Where is the study run from?
University College London Hospitals NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
March 2019 to February 2025
Who is funding the study?
Versus Arthritis (formerly known as Arthritis Research UK)
Who is the main contact?
RISAPS@ucl.ac.uk
Contact information
Public
CCTU at UCL
Institute of Clinical Trials & Methodology
90 High Holborn 2nd floor
London
WC1V 6LJ
United Kingdom
| Phone | +44 (0)20 76790948 |
|---|---|
| RISAPS@ucl.ac.uk |
Scientific, Principal investigator
Clinical Trial Manager
Comprehensive Clinical Trials Unit
Institute of Clinical Trials and Methodology
90 High Holborn, 2nd Floor
London
WC1V 6LJ
United Kingdom
| RISAPS@ucl.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Randomized controlled open-label non-inferiority Phase IIb proof of principle clinical trial |
| Secondary study design | Randomised controlled trial |
| Study type | Participant information sheet |
| Scientific title | Rivaroxaban versus warfarin for stroke patients with antiphospholipid syndrome, with or without SLE (RISAPS): a randomised, controlled, open-label, phase IIb, non-inferiority proof of principle trial |
| Study acronym | RISAPS |
| Study objectives | Current hypothesis as of 19/07/2021: We hypothesise high-intensity oral rivaroxaban (15mg twice daily) is non-inferior to high intensity warfarin (target international ratio [INR] 3.5 (range 3.0-4.0]) for the secondary prevention of stroke, transient ischaemic attack (TIA) or other ischaemic brain manifestations in patients with antiphospholipid syndrome (APS). These are currently unlicensed indications for rivaroxaban and other direct oral anticoagulants (DOACs). We therefore propose to establish a) non-inferiority in the efficacy of rivaroxaban compared with that of warfarin; and b) absence of safety signals. We believe that this would provide sufficient supporting data to change practice for our patients, i.e., to make rivaroxaban the standard of care for the treatment of APS patients, with or without SLE, who have stroke or other ischaemic brain manifestations. _____ Previous hypothesis: It is hypothesised that rivaroxaban is non-inferior to warfarin for the secondary prevention of ischaemic stroke or other ischaemic brain manifestations in patients with antiphospholipid syndrome (APS). These are currently unlicensed indications for rivaroxaban and other direct oral anticoagulant (DOACs). Clinically, the hypothesis is that in patients with thrombotic APS with ischaemic stroke, TIA or other ischaemic brain manifestations, the efficacy of high intensity rivaroxaban would be no worse than that of high intensity warfarin. The researchers therefore propose to establish a) non-inferiority in the efficacy of rivaroxaban compared with that of warfarin; and b) absence of safety signals. They believe that this would provide sufficient supporting data to change practice for patients, i.e. to make rivaroxaban the standard of care for the treatment of APS patients, with or without systemic lupus erythematosus (SLE), who have stroke or other ischaemic brain manifestations. |
| Ethics approval(s) | Approved 24/06/2019, London Dulwich Ethics Committee (Ground Floor, Skipton House, 80 London Road, London, SE1 6LH, UK; +44(0)20 797 22567; dulwich.rec@hra.nhs.uk), ref: 19/LO/0201 |
| Health condition(s) or problem(s) studied | Stroke patients with antiphospholipid syndrome with or without systemic lupus erythematosus |
| Intervention | Current interventions as of 05/02/2025: Phase IIb Trial, 40 patients will be randomised with a ratio of 1:1 to receive either: • Rivaroxaban 15mg twice daily orally for 24 months or • Warfarin (standard of care in the RISAPS trial) to maintain a target INR of 3.5 (range 3.0-4.0) for 24 months. _____ Previous interventions as of 19/07/2021: 140 patients will be randomised with a ratio of 1:1 to receive either: • Rivaroxaban 15mg twice daily orally for 24 months or • Warfarin (standard of care in the RISAPS trial) to maintain a target INR of 3.5 (range 3.0-4.0) for 24 months. _____ Previous interventions: Patients will be randomised to receive either: 1. Rivaroxaban 15 mg twice daily for 24 months 2. Warfarin (as per standard care for the trial sites) to maintain a target INR of 3.5 (range 3.0-4.0) for 24 months Patients will be randomised with a ratio of 1:1 WMH will be used as a surrogate marker of ischaemic damage (stroke), as there are relatively few APS stroke patients, possibly due to underdiagnosis, and recurrent stroke and other clinical cerebral events in APS patients are rare in clinical practice because of effective anticoagulation. Measurements of WMH volume have successfully been used in longitudinal studies of cerebral SVD and SLE. |
| Intervention type | Drug |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Warfarin, rivaroxaban |
| Primary outcome measure(s) |
Current primary outcome measure as of 19/07/2021: |
| Key secondary outcome measure(s) |
1. Efficacy |
| Completion date | 03/02/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | All |
| Target sample size at registration | 40 |
| Total final enrolment | 43 |
| Key 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 hormonal, unless postmenopausal or sterilised. NB: patients weighing <50 kg or >120 kg may be included in RISAPS on a case by case basis, following assessment by the Investigator and discussion with the CI/delegate before enrolment. |
| Key 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 pregnant within the 2-year follow-up period. 16. Patients with known galactose intolerance, total lactase deficiency or galactose malabsorption. 17. Any other reason that the PI considers would make the patient unsuitable to enter RISAPS. _____ Previous exclusion criteria: 1. Pregnant or lactating women 2. Severe renal impairment with creatinine clearance (Cockcroft & Gault) <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 109/L) 6. Non-adherence on warfarin (based on clinical assessment) 7. Patients taking strong inhibitors of both CYP3A4 and P-gp pathways such as: 7.1. Systemic azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole) 7.2. Patients on 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 GP and healthcare professional responsible for anticoagulation care of participation 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. Patients with known galactose intolerance, total lactase deficiency or galactose malabsorption |
| Date of first enrolment | 09/07/2021 |
| Date of final enrolment | 14/11/2022 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centres
London
NW1 2PG
United Kingdom
150 Du Cane Rd
White City
London
W12 0HS
United Kingdom
Royal London Hospital
Pathology & Pharmacy Building
Research Office
4th Floor
80 Newark Street
London
E1 2ES
United Kingdom
Brixton
London
SE5 9RS
United Kingdom
Rom Valley Way
Romford
RM7 0AG
United Kingdom
Wrythe Lane
Carshalton
SM5 1AA
United Kingdom
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Available on request |
| IPD sharing plan | Participant level data will be stored securely on UCL CCTU servers. This dataset will not be made public in its raw form to protect the participant's identities and to comply with data protection. A fully anonymised dataset will be made available to researchers on submission and review of a formal request, sent in writing to UCL CCTU and the RISAPS Trial Chief Investigator. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
| Study website | Study website | 11/11/2025 | 11/11/2025 | No | Yes |
Editorial Notes
03/03/2025: The overall study end date was changed from 02/02/2025 to 03/02/2025.
05/02/2025: The following changes were made to the trial record:
1. The contacts were changed.
2. The interventions were changed.
06/12/2023: The following changes were made to the study record:
1. The scientific title was changed from 'Rivaroxaban versus warfarin for stroke patients with antiphospholipid syndrome, with or without SLE (RISAPS): a randomised, controlled, open-label, phase II/III, non-inferiority trial' to 'Rivaroxaban versus warfarin for stroke patients with antiphospholipid syndrome, with or without SLE (RISAPS): a randomised, controlled, open-label, phase IIb, non-inferiority proof of principle trial'.
2. The study design was changed from 'Phase II/III randomised controlled open-label non-inferiority clinical trial' to 'Randomized controlled open-label non-inferiority Phase IIb proof of principle clinical trial'.
3. The study participating centres were updated to remove Guys and St Thomas’ NHS Foundation Trust, St George's University Hospitals NHS Foundation Trust and Manchester Royal Infirmary and add Epsom and St Helier University Hospitals NHS Trust.
4. The recruitment end date was changed from 24/10/2022 to 14/11/2022.
5. The overall study end date was changed from 30/11/2024 to 02/02/2025.
6. The intention to publish date was changed from 01/03/2025 to 01/08/2025.
7. The target number of participants was changed from 140 to 40.
8. Total final enrolment added.
30/11/2022: A scientific contact was added.
28/11/2022: The following changes were made to the trial record:
1. The overall end date was changed from 31/12/2023 to 30/11/2024 and the plain English summary was updated accordingly.
2. The inclusion criteria were changed.
3. The exclusion criteria were changed.
4. The recruitment end date was changed from 07/10/2022 to 24/10/2022.
19/07/2021: The following changes were made to the trial record:
1. The IRAS number was added.
2. The study hypothesis was changed.
3. The ethics committee email address was changed.
4. The overall end date was changed from 15/12/2022 to 31/12/2023.
5. The interventions were changed.
6. The primary outcome measure was changed.
7. The secondary outcome measures were changed.
8. The inclusion criteria were changed.
9. The exclusion criteria were changed.
10. The recruitment start date was changed from 15/09/2019 to 09/07/2021.
11. The recruitment end date was changed from 15/12/2020 to 07/10/2022.
12. The trial participating centre Hammersmith Hospital Imperial Health Care NHS Trust was changed to Imperial College Healthcare NHS Trust. The trial participating centres St George's University Hospitals NHS Foundation Trust, Manchester Royal Infirmary, Barking, Havering and Redbridge University Hospitals NHS Trust were added.
13. The intention to publish date was changed from 15/12/2023 to 01/03/2025.
14. The plain English summary was updated to reflect these changes.
17/04/2020: The following changes were made to the trial record:
1. Due to current public health guidance, recruitment for this study has been paused.
2. Study contact updated.
26/07/2019: The following changes were made to the trial record:
1. The ethics approval details were added.
2. Study contact updated.
3. The recruitment start date was changed from 01/05/2019 to 15/09/2019.
4. The recruitment end date was changed from 01/07/2019 to 15/12/2020.
5. The overall trial end date was changed from 01/07/2022 to 15/12/2022.
6. The intention to publish date was changed from 01/07/2023 to 15/12/2023.
27/03/2019: Trial's existence confirmed by funder and REC.
