Clinical Trials Register

Summary
EudraCT Number:	2018-001735-49
Sponsor's Protocol Code Number:	CTU/2015/174
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-01-22
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-001735-49

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

RIvaroxaban for Stroke patients with AntiPhospholipid Syndrome

A.3.2

Name or abbreviated title of the trial where available

RIvaroxaban for Stroke patients with AntiPhospholipid Syndrome

A.4.1

Sponsor's protocol code number

CTU/2015/174

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03684564

A.5.4

Other Identifiers

Name:

Sponsor Number

Number:

CTU/2015/174

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University College London
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Versus Arthritis (formerly Arthritis Research UK)
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Comprehensive Clinical Trials Unit at UCL
B.5.2	Functional name of contact point	Jade Dyer
B.5.3	Address:
B.5.3.1	Street Address	CCTU at UCL, Institute of Clinical Trials & Methodology
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC1V 6LJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02079074674
B.5.6	E-mail	risaps@ucl.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rivaroxaban
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rivaroxaban
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rivaroxaban
D.3.9.3	Other descriptive name	Trade Name Xarelto
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Warfarin Sodium
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Warfarin Sodium
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Warfarin sodium
D.3.9.1	CAS number	81-81-2
D.3.9.4	EV Substance Code	AS3
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with stroke or other ischaemic brain injury who have antiphospholipid syndrome (APS), with or without systemic lupus erythematosus (SLE)

E.1.1.1

Medical condition in easily understood language

Patients with APS (an immune system disorder causing blood clots), with/without lupus, with ischaemic stroke (occurring when blood flow to an area of brain is cut off) or other ischaemic brain injury

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10002817
E.1.2	Term	Antiphospholipid syndrome
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

We hypothesise that rivaroxaban is no worse that warfarin for the prevention of recurrent ischaemic stroke (which occurs when blood flow to an area of brain is cut off) or other ischaemic brain damage in APS patients.

The RISAPS trial will compare higher intensity (higher dose) rivaroxaban versus higher intensity warfarin (current standard of care treatment) for 24 months, in APS (antiphospholipid syndrome) 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).

The primary outcome measure will be changes in the volume of brain white matter hyperintensities (WMH; small brain lesions that are a sensitive marker of ischaemic damage), as a surrogate marker of ischaemic brain damage, before the trial treatment starts and after 24 months of the trial treatment.

If rivaroxaba

E.2.2

Secondary objectives of the trial

The trial will also compare the following secondary outcomes between patients on rivaroxaban versus warfarin:

Efficacy:
- Other brain MRI scan appearances, including detailed assessment of alterations in brain structure indicative of ischaemic brain damage
- Thrombosis (blood clots), including in arteries (e.g. stroke) or in veins, death; and change in cognitive (thinking) function based on assessment at trial visits

Safety
- All bleeding events: major, clinically relevant or minor
- Serious Adverse Events (SAE) other than major bleeding
- Brain microbleeds (tiny brain bleeds, visible on MRI brain scans), will be assessed as a surrogate marker of bleeding risk

Health Economics:
- The cost of the two treatment groups using quality of life questionnaires and health economics

Anticoagulation (blood thinning) intensity:
- Rivaroxaban blood levels will be measure in patients on rivaroxaban
- In patients on warfarin, the percentage of time that the patient is within the target INR r

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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.
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 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.
NB: patients weighing <50kg or >120kg may be included in RISAPS on a case by case basis, following assessment by the Investigator (PI) and consultation with the Chief Investigator (CI)/delegate before enrolment.

E.4

Principal exclusion criteria

Exclusion Criteria
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 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
a. Systemic azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole)
b. 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.

E.5 End points

E.5.1

Primary end point(s)

The primary objective of RISAPS is 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.

The primary outcome measure is the rate of change in brain WMH volume between baseline and 24 months follow up, assessed on MRI, a surrogate marker of ischaemic damage.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary end point will be analysed after the last patient recruited has undergone their last trial visit and 24 month MRI.

E.5.2

Secondary end point(s)

A. Efficacy
1. Neuroradiological markers
i) Mean diffusivity and fractional anisotropy as a measure of microstructural white matter damage derived from diffusion tensor imaging (DTI)
ii) Changes in total brain volume, white matter volume and grey matter volume on T1w volumetric images
iii) Brain infarcts
a) cortical or subcortical
b) assessment of volume
iv) Cerebral venous occlusions
2. Clinical
i) Vascular events
a) Ischaemic stroke or TIA
b) Occlusive arterial events in other sites including systemic embolism
c) Cerebral venous thrombosis
d) Venous thromboembolism in other sites
e) Microvascular thrombosis
f) Superficial venous thrombosis
ii) Death
iii) Composite clinical outcomes
a) A composite of all thrombotic events: arterial, venous microvascular; and death
b) Major adverse cardiac and cerebrovascular events (MACCE)
iv) The rate of change in cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA)
B. Safety
1. Bleeding: All bleeding events: major, clinically relevant or minor
2. Serious adverse events other than major bleeding
3. Cerebral microbleeds (CMB) assessed with susceptibility-weighted imaging (SWI) as a surrogate marker of bleeding risk.
C. Health Economics
1. Quality of life (QoL) will be assessed using EQ-5D-5L
2. Mean incremental cost per quality adjusted life year (QALY)
D. Anticoagulation intensity
1. Rivaroxaban
i) Rivaroxaban anti-Xa levels
2. Warfarin
i) Time in target therapeutic range (TTR)
ii) Amidolytic factor X as a lupus anticoagulant independent assessment of warfarin anticoagulant effect
E. Exploratory Outcomes
1. Rivaroxaban pharmacokinetic (PK) modelling
2. Cerebral blood flow (CBF) derived from MR perfusion imaging using an arterial spin labelling (ASL) technique

E.5.2.1

Timepoint(s) of evaluation of this end point

The secondary endpoints will be analysed after the last patient recruited has had their final follow-up visit.

Unless an interim analysis of safety endpoints is requested by the IDMC following any concerns regarding participant safety.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of trial will be defined as the date when all outstanding data queries have been resolved following the last participant’s last visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1