Condition category
Cancer
Date applied
20/08/2019
Date assigned
28/08/2019
Last edited
28/08/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Scientific

Primary contact

Prof Claire Harrison

ORCID ID

Contact details

Guys and St Thomas NHS Foundation Trust
London
SE1 9RT
United Kingdom
+44 (0)207 188 2742
Claire.Harrison@gstt.nhs.uk

Additional identifiers

EudraCT number

2018-001908-11

ClinicalTrials.gov number

Protocol/serial number

RG_16-148; CPMS: 39201

Study information

Scientific title

A phase III, randomised, open-label, Multicenter International Trial comparing ruxolitinib with either HydRoxycarbamIDe or interferon Alpha as first-line ThErapy for high-risk polycythemia vera (MITHRIDATE)

Acronym

MITHRIDATE

Study hypothesis

To compare the time to the combined incidence of; major thrombosis, major haemorrhage, death or transformation to MDS, AML or post-PV (PPV) MF in high-risk PV patients randomised to ruxolitinib versus standard care.

Ethics approval

Approved 16/08/2019, London-Fulham Research Ethics Committee (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; Tel: +44 (0)207 104 8235; Email: nrescommittee.london-fulham@nhs.net), REC ref: 19/LO/0951

Study design

Phase III randomised-controlled multi-centre international open-label trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Polycythaemia vera

Intervention

The interventions are Arm A: Ruxolitinib and Arm B: Best Available Therapy (Hydroxycarbamide OR Interferon Alpha, any formulation permitted), which will be selected by the Investigator prior to randomisation. Randomisation will be in a 1:1 ratio and will be performed using a bespoke computer randomisation system developed by the Cancer Research UK Clinical Trials Unit (CRCTU) employing a stratified minimisation method.
Patients will be stratified by:
1. Country of Origin: UK, France
2. Elected standard of care therapy: IFN, HC
3. Age: <60, ≥ 60
4. Prior thrombosis: No, Yes
5. Length of time from diagnosis: <5: ≥5 years
6. Cardiovascular risk factors, (including the following: arterial hypertension, diabetes, dyslipidemia, tobacco use, obesity): No, Yes

Randomisation will be in a 1:1 ratio AND There will be no cross-over either between arm A and B or between therapies on Arm B.

Arm A: Ruxolitinib – starting dose of 10 mg adjusted in line with the summary product of characteristics throughout for treatment period of 3 years
Arm B: Best Available Therapy (Hydroxycarbamide OR interferon alpha (any formulation permitted)) – treatment for 3 years, dosage is in line with the summary product of characteristics

Patients will be required to attend for study visits to monitor their disease, as they would do whilst following standard care. In addition, patients will be asked to consent to complete quality of life questionnaires every few months and have an additional bone marrow biopsy and an ultrasound scan at 3 years.

Intervention type

Drug

Phase

Phase III

Drug names

Ruxolitinib, hydroxycarbamide, interferon alpha (any formulation permitted)

Primary outcome measure

Event Free Survival (EFS): defined as the time from randomisation to the date of the first event including;
1. Major thrombosis
2. Major haemorrhage
3. Death
4. Transformation to MDS, AML or PPV-MF
Patients who do not experience an event during the trial will be censored at their date last seen

Secondary outcome measures

1. Major thrombosis (both combined and split into venous and arterial)
2. Major haemorrhage
3. Transformation to PPV-MF
4. Transformation to AML and/or MDS
5. Complete haematological response (CHR) as defined by ELN response criteria at 1 year
6. Symptom burden/(QALY) quality of life years gained
7. Health economics including cost-utility and cost-effectiveness analyses
8. Peripheral blood JAK2 V617F allele burden according to ELN response criteria
9. Rates of discontinuation
10. Adverse events
11. Spleen response in patients with splenomegaly at baseline
12. Time free from venesection
13. Rate of second malignancies
14. Change in QRisk score

Overall trial start date

16/08/2019

Overall trial end date

30/09/2029

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Patient 18 years of age or over
2. Diagnosis of PV meeting WHO criteria within past 10 years
3. Meets criteria of high risk* PV, defined as WBC > 11 x 109/l* AND at least ONE of the following:
3.1. Age > 60 years
3.2. Prior thrombosis or major haemorrhage related to disease
3.3. Platelet count > 1000 x 109/l*
3.4. Diagnosed < 10 years
3.5. Received treatment for < 5 years)
4. Patients may have received antiplatelet agents and venesection
5. Patients may have received ONE or less cytoreductive therapy for less than 5 years (BUT they should not be resistant or intolerant to that
therapy)
6. Able to provide written informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 586; UK Sample Size: 293

Participant exclusion criteria

1. Diagnosis of PV > 10 years previously
2. Absence of JAK-2 mutation
3. Patients with any contraindications to any of the investigational medical products
4. Treatment with >1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 5 years OR resistance/intolerance to that therapy
5. Active infection including hepatitis B, hepatitis C, Tuberculosis
6. Pregnant or lactating patients (Women of childbearing potential must have a negative urine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry)
7. Patients and partners of childbearing potential not prepared to adopt highly effective contraception measures (if sexually active) whilst on treatment and for at least 6 months after completion of study medication
8. ECOG Performance Status Score ≥ 3
9. Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstable angina, recent (within the last 6 months) myocardial infarction or acute coronary syndrome or any clinically significant cardiac disease > NYHA (New York Heart Association) Class II
10. Patients who have transformed to myelofibrosis
11. Previous treatment with ruxolitinib
12. Previous (within the last 12 months) or current platelet count <100 x 109/L or neutrophil count < 1 x 109/L not due to therapy
13. Inadequate liver function as defined by ALT/AST >2.0 x ULN
14. Inadequate renal function as defined by eGFR < 30 mls/min
15. Unable to give informed consent

Recruitment start date

30/09/2019

Recruitment end date

30/09/2024

Locations

Countries of recruitment

France, United Kingdom

Trial participating centre

School of Cancer Sciences
University of Birmingham Edgbaston
Birmingham
B15 2TT
United Kingdom

Trial participating centre

University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
Royal Bournemouth General Hospital Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Trial participating centre

Manchester University NHS Foundation Trust
Cobbett House Oxford Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Oxford University Hospitals NHS Foundation Trust
John Radcliffe Hospital Headley Way Headington
Oxford
OX3 9DU
United Kingdom

Trial participating centre

East Suffolk and North Essex NHS Foundation Trust
Colchester District General Ho Turner Road
Colchester
CO4 5JL
United Kingdom

Trial participating centre

NHS Lothian
Waverley Gate 2-4 Waterloo Place
Edinburgh
EH1 3EG
United Kingdom

Trial participating centre

The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital Freeman Road High Heaton
Newcastle Upon-Tyne
NE7 7DN
United Kingdom

Trial participating centre

Wirral University Teaching Hospital NHS Foundation Trust
Arrowe Park Hospital Arrowe Park Road
Upton
CH49 5PE
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
St. James's University Hospital Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

University Hospital Southampton NHS Foundation Trust
Mailpoint 18 Southampton General Hospital Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Belfast Health & Social Care Trust
Trust Headquarters A Floor - Belfast City Hospital Lisburn Road
Belfast
BT9 7AB
United Kingdom

Trial participating centre

Nottingham University Hospitals NHS Trust
Trust Headquarters Queens Medical Centre Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

London North West University Healthcare NHS Trust
Northwick Park Hospital Watford Road
Harrow
HA1 3UJ
United Kingdom

Trial participating centre

Taunton and Somerset NHS Foundation Trust
Musgrove Park Hospital
Taunton
TA1 5DA
United Kingdom

Trial participating centre

Western Sussex Hospitals NHS Foundation Trust
Worthing Hospital Lyndhurst Road
Worthing
BN11 2DH
United Kingdom

Trial participating centre

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

Trial participating centre

Public Health Wales NHS Trust
Number 2 Capital Quarter Tyndall Street
Cardiff
CF10 4BZ
United Kingdom

Trial participating centre

United Lincolnshire Hospitals NHS Trust
Lincoln County Hospital Greetwell Road
Lincoln
LN2 4AX
United Kingdom

Trial participating centre

NHS Hammersmith and Fulham CCG
15 Marylebone Road
London
NW1 5JD
United Kingdom

Trial participating centre

Aneurin Bevan University LHB
Headquarters - St Cadoc's Hospital Lodge Road Caerleon
Newport
NP18 3XQ
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551 Queen Elizabeth Medical Centre Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Norfolk and Norwich University Hospitals NHS Foundation Trust
Colney Lane Colney
Norwich
NR4 7UY
United Kingdom

Trial participating centre

Sherwood Forest Hospitals NHS Foundation Trust
Mansfield Road
Sutton-in-Ashfield
NG17 4JL
United Kingdom

Trial participating centre

NHS Grampian
Summerfield House 2 Eday Road
Aberdeen
AB15 6RE
United Kingdom

Trial participating centre

Wye Valley NHS Trust
County Hospital Union Walk
Hereford
HR1 2ER
United Kingdom

Trial participating centre

University Hospitals Bristol NHS Foundation Trust
Marlborough Street
Bristol
BS1 3NU
United Kingdom

Trial participating centre

Royal United Hospitals Bath NHS Foundation Trust
Combe Park
Bath
BA1 3NG
United Kingdom

Trial participating centre

Sheffield Teaching Hospitals NHS Foundation Trust
Northern General Hospital Herries Road
Sheffield
S5 7AU
United Kingdom

Trial participating centre

Royal Devon and Exeter NHS Foundation Trust
Royal Devon & Exeter Hospital Barrack Road
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Hull and East Yorkshire Hospitals NHS Trust
Hull Royal Infirmary Anlaby Road
Hull
HU3 2JZ
United Kingdom

Trial participating centre

South Warwickshire NHS Foundation Trust
Warwick Hospital Lakin Road
Warwick
CV34 5BW
United Kingdom

Trial participating centre

NHS Highland
Reay House 17 Old Edinburgh Road
Inverness
IV2 3HG
United Kingdom

Trial participating centre

Gloucestershire Hospitals NHS Foundation Trust
Trust HQ Alexandra House
Cheltenham
GL53 7AN
United Kingdom

Trial participating centre

Guy's and St Thomas' NHS Foundation Trust
Trust Offices Guy's Hospital Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

Blackpool Teaching Hospitals NHS Foundation Trust
Victoria Hospital Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Sponsor information

Organisation

University of Birmingham

Sponsor details

Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 3792
mithridate@trials.bham.ac.uk

Sponsor type

University/education

Website

http://www.birmingham.ac.uk/

Funders

Funder type

Industry

Funder name

Novartis

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)

Location

Switzerland

Funder name

MPN Voice

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

There will be a trial website (currently under construction so URL unavailable ) that will include the protocol, patient documents etc. for sites to download.
Results of this trial will be submitted for publication in a peer-reviewed journal. The manuscript will be prepared by TMG and authorship will be determined by mutual agreement.
Any secondary publications and presentations prepared by Investigators must be reviewed by the TMG. Manuscripts must be submitted to the TMG in a timely fashion and in advance of being submitted for publication, to allow time for review and resolution of any outstanding issues. Authors must acknowledge that the trial was performed with the support of the University of Birmingham.
Intellectual property rights will be addressed in the corresponding contracts between Sponsor and national coordinating centres/sites.
Individual countries will be allowed to publish their efficacy results, however, the publication of efficacy results from the pooled analysis will take precedence over efficacy result publications of individual countries, unless the TMG decides otherwise.

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Claire Harrison (Claire.Harrison@gstt.nhs.uk).

Intention to publish date

30/09/2029

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

27/08/2019: Trial's existence confirmed by the NIHR.