Condition category
Circulatory System
Date applied
26/03/2019
Date assigned
25/04/2019
Last edited
25/04/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
The RISAPS trial follows on from the RAPS (Rivaroxaban in Antiphospholipid Syndrome) study that showed that rivaroxaban offers an 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, requiring frequent (usually weekly) blood tests to monitor the effect of the warfarin, which is inconvenient for patients and affects their quality of life. The RISAPS trial will compare higher intensity (higher dose) rivaroxaban versus higher intensity warfarin (current standard of care treatment) for 24 months, in APS patients, with or without lupus, requiring higher intensity 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 with other drugs. If rivaroxaban is no worse than warfarin for anticoagulation of APS patients with stroke, 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 damage and improve patients' quality of life. The more predictable blood thinning effect of rivaroxaban may also be associated with a lower risk of bleeding and thrombosis than in patients on warfarin.

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?
1. University College London Hospitals NHS Foundation Trust (UK)
2. Guys and St Thomas’ NHS Foundation Trust (UK)
3. Hammersmith Hospital Imperial Health Care NHS Trust (UK)
4. Barts Health NHS Trust (UK)
5. Kings College Hospital Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
March 2019 to July 2022

Who is funding the study?
Versus Arthritis (formerly known as Arthritis Research UK)

Who is the main contact?
Prof. Hannah Cohen

Trial website

https://www.ucl.ac.uk/comprehensive-clinical-trials-unit/

Contact information

Type

Public

Primary contact

Ms Jade Dyer

ORCID ID

Contact details

CCTU at UCL
Institute of Clinical Trials & Methodology
90 High Holborn 2nd floor
London
WC1v 6LJ
United Kingdom
+44 (0)2079074674
jade.dyer@ucl.ac.uk

Additional identifiers

EudraCT number

2018-001735-49

ClinicalTrials.gov number

NCT03684564

Protocol/serial number

CTU/2015/1974

Study information

Scientific title

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

Acronym

RISAPS

Study 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

Approval pending, London Dulwich Ethics committee, REC ref: 19/LO/0201

Study design

Phase II/III randomised controlled open-label non-inferiority clinical trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a copy of the participant information sheet.

Condition

Stroke patients with antiphospholipid syndrome with or without systemic lupus erythematosus

Intervention

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/III

Drug names

Warfarin, rivaroxaban

Primary outcome measure

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.

Secondary outcome measures

1. Efficacy
1.1. Neuroradiological markers
1.1.1. Mean diffusivity and fractional anisotropy as a measure of microstructural white matter damage derived from diffusion tensor imaging (DTI)
1.1.2 Changes in total brain volume, white matter volume and grey matter volume on T1w volumetric images
1.1.3. Brain infarcts
1.2. Cortical or subcortical
1.3. Assessment of volume
1.4. Cerebral venous occlusions
All neurological secondary outcomes will be assessed using data from the MRI scans and additional information from the cognitive function assessment using the MoCA and the Queens Square assessment tool kit. MRIs will carried out at baseline and 24 months. Assessment tools will be administered at baseline, day 42, 6, 12, 18 & 24 month clinic visits.

2. Clinical
2.1. Vascular events
2.1.1. Ischaemic stroke or TIA
2.1.2. Occlusive arterial events in other sites including systemic embolism
2.1.3. Cerebral venous thrombosis
2.1.4. Venous thromboembolism in other sites
2.1.5. Microvascular thrombosis
2.1.6. Superficial venous thrombosis
2.2. Death
2.3. Composite clinical outcomes
2.3.1. A composite of all thrombotic events: arterial, venous microvascular; and death
2.3.2. Major adverse cardiac and cerebrovascular events (MACCE)
2.4. The rate of change in cognitive function assessed using the Montreal Cognitive Assessment (MoCA)

3. Safety
3.1. Bleeding: all bleeding events: major, clinically relevant or minor
3.2. Serious adverse events other than major bleeding
3.3. Cerebral microbleeds (CMB) assessed with susceptibility weighted imaging (SWI) as a surrogate marker of bleeding risk

For clinical and safety outcomes, this data will be collected on case report forms at clinical visits, and on a participant diary card only for recording minor events, such as a minor bleed. Any major of clinically significant events will be reported as per standard UK safety reporting timelines for Serious Adverse Events. So when 24 hours of the site becoming aware. Adverse events will also be recorded at study visits or when reported to the site by the participant. These type of events will be recorded on specific reporting forms. A summary of the number of type of these events will be done monthly by the team and reported to our independent data monitoring committee every 6 months or before if an event is deemed serious enough.

4. Health economics - resource use collected from the participant self-report and medical records at baseline and then at 6, 12, 18 & 24 month follow-up visits
4.1. Quality of life (QoL) assessed using EQ-5D-5L self-completed by participants
4.2. Health and social care resource use assessed using trial follow-up visit case report forms (CRFs)
4.3. Mean incremental cost per quality-adjusted life year (QALY)

5. Anticoagulation intensity
5.1. Rivaroxaban
5.1.1. Rivaroxaban anti-Xa levels
5.2. Warfarin
5.2.1. Time in target therapeutic range (TTR)
5.2.2. Amidolytic factor X as a lupus anticoagulant independent assessment of warfarin anticoagulant effect

6. Exploratory outcomes
6.1. Rivaroxaban pharmacokinetic (PK) modelling
6.2. Cerebral blood flow (CBF) derived from MR perfusion imaging using an arterial spin labelling (ASL) technique
Exploratory outcomes use data from blood samples collected at each follow-up visit and from the MRI images

Overall trial start date

01/03/2019

Overall trial end date

01/07/2022

Reason abandoned (if study stopped)

Eligibility

Participant 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.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

140

Participant 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

Recruitment start date

01/05/2019

Recruitment end date

01/07/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom

Trial participating centre

Guys and St Thomas’ NHS Foundation Trust
St Thomas' Hospital Westminster Bridge Road Lambeth
London
SE1 7EH
United Kingdom

Trial participating centre

Hammersmith Hospital Imperial Health Care NHS Trust
150 Du Cane Rd White City
London
W12 0HS
United Kingdom

Trial participating centre

Barts Health NHS Trust
Haematology Non-Malignant Clinical Research Royal London Hospital Pathology & Pharmacy Building Research Office 4th Floor 80 Newark Street
London
E1 2ES
United Kingdom

Trial participating centre

Kings College Hospital Foundation Trust
Denmark Hill Brixton
London
SE5 9RS
United Kingdom

Sponsor information

Organisation

University College London

Sponsor details

CCTU at UCL
Institute of Clinical Trials & Methodology
90 High Holborn 2nd floor
London
WC1V 6LJ
United Kingdom
+44 (0)2079074674
risaps@ucl.ac.uk

Sponsor type

University/education

Website

https://www.ucl.ac.uk/comprehensive-clinical-trials-unit/

Funders

Funder type

Charity

Funder name

Versus Arthritis

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

The trial protocol will be made available for public access throughout the trial period. The results of the trial will be disseminated regardless of the direction of effect. The publication of results will comply with the UCL and UCL CCTU Publication Policies and will include submission to open access journals.

IPD sharing statement
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.

Intention to publish date

01/07/2023

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

27/03/2019: Trial's existence confirmed by funder and REC.