Ruxolitinib versus hydroxycarbamide or interferon as first-line therapy in high-risk polcythemia vera
| ISRCTN | ISRCTN12885480 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12885480 |
| EudraCT/CTIS number | 2018-001908-11 |
| ClinicalTrials.gov number | NCT04116502 |
| Secondary identifying numbers | RG_16-148; CPMS: 39201 |
- Submission date
- 20/08/2019
- Registration date
- 28/08/2019
- Last edited
- 08/04/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English Summary
Contact information
Scientific
Guys and St Thomas NHS Foundation Trust
London
SE1 9RT
United Kingdom
| Phone | +44 (0)207 188 2742 |
|---|---|
| Claire.Harrison@gstt.nhs.uk |
Study information
| Study design | Phase III randomised-controlled multi-centre international open-label trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment, Efficacy |
| 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) |
| Study 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(s) | 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 |
| 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 |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | 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 study start date | 16/08/2019 |
| Overall study end date | 30/09/2029 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 586; UK Sample Size: 293 |
| Participant inclusion criteria | Current participant inclusion criteria as of 09/05/2023: 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 10(9)/l AND at least ONE of the following: 3.1. Aged >60 years 3.2. Prior thrombosis or major haemorrhage related to disease 3.3. Platelet count >1000 x 10(9)/l at any time after diagnosis 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 _____ Previous 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 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 10(9)/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 ml/min 15. Unable to give informed consent |
| Recruitment start date | 30/09/2019 |
| Recruitment end date | 30/09/2024 |
Locations
Countries of recruitment
- England
- France
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Great Maze Pond
London
SE1 9RT
United Kingdom
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Canterbury
CT1 3NG
United Kingdom
Worthing
BN11 2DH
United Kingdom
Chichester
PO19 6SE
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Newport
NP20 2UB
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
London Road
Reading
RG1 5AN
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Gloucester
GL1 3NN
United Kingdom
Charter Way
Turner Road
Colchester
CO4 5JL
United Kingdom
Huddersfield
HD3 3EA
United Kingdom
Godfrey Road
Salterhebble
Halifax
HX3 0PW
United Kingdom
Castle Road
Cottingham
HU16 5JQ
United Kingdom
Warwick
CV34 5BW
United Kingdom
Edinburgh
Lothian
EH4 2XU
United Kingdom
Livingston
Lothian
EH54 6PP
United Kingdom
Inverness
IV2 3UJ
United Kingdom
London
NW1 2BU
United Kingdom
Stoke-on-trent
ST4 6QG
United Kingdom
Leicester
LE1 5WW
United Kingdom
Arrowe Park Road
Wirral
CH49 5PE
United Kingdom
Tooting
London
SW17 0QT
United Kingdom
Bordesley Green
Birmingham
B9 5SS
United Kingdom
Sutton Coldfield
B75 7RR
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Truro
TR1 3LJ
United Kingdom
Blackpool
FY3 8NR
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Cliftonville
Northampton
NN1 5BD
United Kingdom
Wexham
Slough
SL2 4HL
United Kingdom
Sponsor information
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)121 414 3792 |
|---|---|
| mithridate@trials.bham.ac.uk | |
| Website | http://www.birmingham.ac.uk/ |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Novartis AG, Novartis International AG
- Location
- Switzerland
No information available
Results and Publications
| Intention to publish date | 30/09/2029 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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 plan | 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). |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 26/07/2023 | No | No |
Editorial Notes
08/04/2024: ClinicalTrials.gov number added.
10/05/2023: School of Cancer Sciences, University of Birmingham, University Hospitals of Leicester NHS Trust, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Manchester University NHS Foundation Trust, Cambridge University Hospitals NHS Foundation Trust, Oxford University Hospitals NHS Foundation Trust, East Suffolk and North Essex NHS Foundation Trust, NHS Lothian, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Wirral University Teaching Hospital NHS Foundation Trust, Leeds Teaching Hospitals NHS Trust, University Hospital Southampton NHS Foundation Trust, Belfast Health & Social Care Trust, Nottingham University Hospitals NHS Trust, London North West University Healthcare NHS Trust, Taunton and Somerset NHS Foundation Trust, Western Sussex Hospitals NHS Foundation Trust, University College London Hospitals NHS Foundation Trust, Public Health Wales NHS Trust, United Lincolnshire Hospitals NHS Trust, NHS Hammersmith and Fulham CCG, Aneurin Bevan University LHB, University Hospitals Birmingham NHS Foundation Trust, Norfolk and Norwich University Hospitals NHS Foundation Trust, Sherwood Forest Hospitals NHS Foundation Trust, NHS Grampian, Wye Valley NHS Trust, University Hospitals Bristol NHS Foundation Trust, Royal United Hospitals Bath NHS Foundation Trust, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Devon and Exeter NHS Foundation Trust, Hull and East Yorkshire Hospitals NHS Trust, South Warwickshire NHS Foundation Trust, NHS Highland, Gloucestershire Hospitals NHS Foundation Trust, Guy's and St Thomas' NHS Foundation Trust and Blackpool Teaching Hospitals NHS Foundation Trust have been removed from the the trial participating centres and Guy's Hospital, Churchill Hospital, Nottingham City Hospital, Addenbrooke's Hospital, Royal Bournemouth Hospital, Kent and Canterbury Hospital, Worthing Hospital, St Richard's Hospital, University Hospital of Wales, Royal Gwent Hospital, Royal Devon and Exeter Hospital, Royal Berkshire Hospital, Sunderland Royal Hospital, Aberdeen Royal Infirmary, Gloucestershire Royal Hospital, Colchester General Hospital, Huddersfield Royal Infirmary, Calderdale Royal Hospital, Castle Hill Hospital, Warwick Hospital, Western General Hospital, St John's Hospital, Raigmore Hospital, University College Hospital, Royal Stoke University Hospital, Leicester Royal Infirmary, Arrowe Park Hospital, St George's Hospital, Birmingham Heartlands Hospital, Good Hope Hospital, Freeman Hospital, Royal Cornwall Hospital, Blackpool Victoria Hospital, Southampton General Hospital, Northampton General Hospital and Wexham Park Hospital have been added.
09/05/2023: The participant inclusion criteria have been changed.
30/12/2021: Cancer Research UK plain English summary link added to plain English summary field.
27/08/2021: Recruitment for this study is no longer paused as of 18/09/2020.
20/04/2020: Due to current public health guidance, recruitment for this study has been paused.
08/11/2019: Internal review.
27/08/2019: Trial's existence confirmed by the NIHR.
