Repurposed drugs to improve blood counts and reduce transfusions in myelodysplastic syndromes
| ISRCTN | ISRCTN15563554 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15563554 |
| EudraCT/CTIS number | 2020-005446-42 |
| IRAS number | 1003603 |
| ClinicalTrials.gov number | NCT04997811 |
| Secondary identifying numbers | CPMS 48916, IRAS 1003603 |
- Submission date
- 19/07/2021
- Registration date
- 05/08/2021
- Last edited
- 30/10/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English Summary
Background and study aims
Over 7,000 people in the UK are living with myelodysplastic syndromes (MDS). About 1,600 of these individuals (23%) die each year from their disease. MDS affects the production of blood cells by the bone marrow, causing chronic fatigue, bleeding, and recurrent infections. Many patients die because their disease transforms into the even more aggressive blood cancer: acute myeloid leukaemia (AML). The general outlook for AML is poor, but when AML arises from MDS it’s even worse. At diagnosis, MDS patients are categorised according to the likelihood of developing AML or dying very early for other reasons. This determines their treatment plan. Groups are termed low risk, intermediate risk or high risk. High-risk patients are often eligible for AML trials. However, very few trials are available for low-risk patients. Low-risk patients have a 20-35% risk of developing AML within 5 years of diagnosis. Meanwhile their quality of life is poor due to low blood counts. Most die prematurely from infections or complications related to MDS irrespective of whether they progress to AML. This study will be in low risk and some intermediate risk patients and will test the ability of already existing drugs to improve blood cell production in these patients. Currently, drugs that boost blood cell production in MDS patients are very limited and patients become resistant to such treatments or fail to respond to them at all. Consequently, the current backbone of care for low-risk MDS patients is transfusions. Donor red blood cells and platelets are used to restore the deficit in blood cells being produced by the patient’s bone marrow. These transfusions place a heavy burden on patients with frequent hospital visits and impact on their quality of life. This study aims to improve this situation. Studies performed on patient’s blood samples will also investigate key questions about how the drugs work if they are successful. The results of these important experiments will inform a better understanding of MDS and help design future trials.
Who can participate?
Patients aged 18 years and over diagnosed with lower-risk MDS, who have either not been suitable for erythropoietin injections (EPO), have not responded or stopped responding to EPO, or they have a low neutrophil and/or platelet cell count.
What does the study involve?
The study will test two new experimental treatment options, taking already existing drugs currently used for other purposes or conditions, and now using them to treat MDS. Treatment Group 1 receive sodium valproate (V), bezafibrate (Ba), and medroxyprogesterone (P). This treatment is called ‘VBaP’. Bezafibrate and medroxyprogesterone were used in an earlier trial in acute myeloid leukaemia patients. Several people responded with improved blood cell production. The research team's laboratory has shown that the addition of valproate at low doses could make BaP work better. Treatment Group 2 receive danazol. This drug has been used for many years in patients with low blood counts, but newer studies suggest it may work particularly well in MDS. The study is trying to find out if these ‘repurposed’ drugs can be used to treat MDS patients and to improve their blood counts, reduce their need for transfusions, improve their quality of life, and prolong their survival.
What are the possible benefits and risks of participating?
Taking part in this study may improve patient’s blood counts, reduce their need for transfusions and therefore reduce the frequency of their hospital visits. It may also improve their quality of life – for example, participants may feel less tired. Furthermore, the information from this study may help to improve the treatment of people with MDS in the future. The study drugs may have some side effects. Additional bone marrow samples are required at 6 months and at the end of study. Additional blood samples are twice monthly and then monthly, but the samples can be taken at the same time as regular blood tests whenever the schedule matches. Participants will be asked to complete quality of life questionnaires which may add time to their usual hospital visits, but they can choose to take these home and post them back to the Trials Unit. Participants will also be asked to complete a diary about their trial medication.
Where is the study run from?
University of Warwick Clinical Trials Unit (UK)
When is the study starting and how long is it expected to run for?
September 2020 to June 2025
Who is funding the study?
Blood Cancer UK
Who is the main contact?
Bethany Foster (trial manager)
Dr Steve Jenkins and Dr Manoj Raghavan (Clinical CIs)
repairMDS@warwick.ac.uk
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-treatment-for-low-risk-myelodysplastic-syndromes-repair-mds
Contact information
Scientific
Trial Manager
Clinical Trials Unit
Warwick Medical School
University of Warwick
Gibbet Hill
Coventry
CV4 7AL
United Kingdom
| Phone | +44 (0)2476 575 675 |
|---|---|
| repairmds@warwick.ac.uk |
Scientific
Chief Investigator
Professor of Clinical Trials & Head of Cancer Trials
Warwick Clinical Trials Unit
Warwick Medical School
Gibbet Hill Campus
University of Warwick
Coventry
CV4 7AL
United Kingdom
 ORCID ID |
0000-0001-7313-4446 |
|---|---|
| Phone | +44 (0)2476 575847 |
| j.a.dunn@warwick.ac.uk |
Scientific
Chief Investigator
Consultant Haematologist
Russells Hall Hospital
The Dudley Group NHS Foundation Trust
Pensnett Road
Dudley
DY1 2HQ
United Kingdom
| Phone | +44 (0)1384456111 |
|---|---|
| stephen.jenkins2@nhs.net |
Scientific
Co-Chief Investigator
Consultant Haematologist and Senior Lecturer
University Hospitals Birmingham
Birmingham
B15 2TH
United Kingdom
| ORCID ID |
0000-0002-5464-2602 |
|---|---|
| Phone | +44 (0)121 371 4476 |
| Manoj.Raghavan@uhb.nhs.uk |
Study information
| Study design | Multi-centre open-label randomized Phase II trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | 40181_PIS_V2.0_22Apr2021.pdf |
| Scientific title | Repurposed drugs to improve haematological responses in myelodysplastic syndromes |
| Study acronym | REPAIR-MDS |
| Study hypothesis | The repurposed drugs combinations in this trial (VBAP or danazol) can be used to treat myelodysplastic syndrome (MDS) patients in order to: (i) improve their blood counts (ii) reduce their need for transfusions (iii) improve their quality of life. |
| Ethics approval(s) | Approved 20/05/2021, East of Scotland Research Ethics Service (EoSRES, Tayside Medical Science Centre, Residency Block Level 3, George Pirie Way, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK; +44 (0)1382 383848; tay.eosres@nhs.scot), REC ref: 21/ES/0037 |
| Condition | Myelodysplastic syndromes |
| Intervention | Randomisation: Randomisation will use a minimisation algorithm adjusting for age (70 years and older or <70 years of age), Revised International Prognostic Scoring System for MDS (IPSS-R; very low, low or intermediate) and transfusion requirements (NTD, LTB, HTB). Interventions: The REPAIR-MDS Trial has two interventions/treatment groups: VBaP arm Sodium valproate tablet 500 mg BD, (starting 200 mg BD), bezafibrate standard release tablet 400 mg tds, (starting 200 mg tds) and medroxyprogesterone acetate tablet 400 mg BD VBap starting doses: Sodium valproate 200 mg bd, increasing to 500 mg bd after 2 weeks Bezafibrate 20 0mg tds, then from Week 4 increasing fortnightly in 200 mg increments to 400 mg tds Medroxyprogesterone 400 mg bd Danazol arm Danazol 1 x 200 mg capsules tds (starting 1 x 200 mg od) Danazol 200 mg od, increasing fortnightly by 200 mg increments to 200 mg tds Dose for both arms will follow a set titration according to clinical outputs/absence of adverse effects. For both arms, the minimum duration of therapy for patients to be included in the final analysis will be 12 weeks. A full treatment period will be considered 12 months of study therapy. At this point, the trial medication will stop and the patient will revert back to their usual clinical care. In both arms, the Investigational Medicinal Product (IMP) will be dispensed at each clinic visit (fortnightly during the first 3 months and then monthly). IMPs will be self-administered by the participant at home with clear instructions provided by the research team during each clinic visit. IMPs will need to be taken orally, must not be crushed and the IMPs are not available as a liquid. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Sodium valproate, bezafibrate, medroxyprogesterone acetate, danazol |
| Primary outcome measure | Haematological improvement (HI) in each arm and in the trial overall, with 25% or more of the participants having HI in each arm and overall. HI will be assessed in each participant by comparing post-randomisation FBC parameters (haemoglobin, platelet and neutrophil counts) and transfusion requirements, with their individual baseline as determined by the International Working Group (IWG) 2018 haematology response criteria in patients with MDS. Baseline assessment will be determined by the mean FBC parameters (haemoglobin, platelet and neutrophil counts) and transfusion burden (non-transfused [NTD], low transfusion burden [LTB], high transfusion burden [HTB]) during a 16-week lead-in to randomisation to either VBaP or danazol treatment; Timepoint(s): 12 months |
| Secondary outcome measures | 1. Burden of red cell and/or platelet transfusions measured by comparing mean haemoglobin, platelet and neutrophil counts in addition to transfusion requirements collected during the 16-week evaluation lead-in period to data collected 8 weeks from the start of trial treatment 2. Duration of haematological improvement (i.e. clinically meaningful response as per the IWG 2018 criteria) will be assessed in each participant by comparing post-randomisation full blood counts parameters (haemoglobin, platelet and neutrophil counts) and transfusion requirements, with their individual baseline as determined by the IWG 2018 haematology response criteria in patients with MDS. Baseline assessment will be determined by the mean full blood counts parameters (haemoglobin, platelet and neutrophil counts) and transfusion burden (NTD, LTB, HTB) during a 16-week lead-in to randomisation to either treatment arm. 3. Quality of life measured using patient-reported health-related quality of life (QoL) scores (EQ5D-5L, EORTC-QlQ-C30, HM-PRO and QOL-E) at time of randomisation (baseline), 12 weeks post-randomisation, 24 weeks post-randomisation & 12 months post-randomisation 4. Overall survival assessed using Kaplan Meier curves at 12 months post-randomisation 5. Health resource use measured utilising data collected via the Clinical Report Forms in respect to clinic attendances, admissions, blood transfusion episodes and trial drug and through the use of patient diaries collected at randomisation, 12 weeks, 24 weeks and 12 months post-randomisation |
| Overall study start date | 01/09/2020 |
| Overall study end date | 06/06/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 120; UK Sample Size: 120 |
| Participant inclusion criteria | Current participant inclusion criteria as of 14/06/2023: 1. Provision of written informed consent 2. Age ≥ 18 years and able to give informed consent 3. Diagnosis of myelodysplastic syndrome with an IPSS-R score of less than or equal to 3.5 4. Haematological parameters: 4.1. Mean haemoglobin < 100 g/l over 16 weeks (pre-transfusion) OR 4.2. Mean platelets < 100 x 109/L over 16 weeks + evidence of bleeding (assessed using the ISTH Bleeding Assessment Tool) OR 4.3. Mean neutrophils < 1.0 x 109/L over 16 weeks + history of infection (the requirement for antimicrobial therapy and hospital admissions associated with infection) 5. No response to erythroid stimulating agents (ESAs) OR have ceased to respond to ESAs OR are Predicated not to Respond to ESAs by current UK guidelines (NB Patients with thrombocytopenia and/or neutropenia, without anaemia, are eligible as they are predicated not to respond). 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-3 7. Expected survival > 12 months Previous participant inclusion criteria: 1. Provision of written informed consent 2. Age ≥18 years and able to give informed consent 3. Diagnosis of myelodysplastic syndrome with an IPSS-R score of less than or equal to 3.51 4. Haematological parameters: 4.1. Mean haemoglobin <100 g/l over 16 weeks (pre-transfusion) OR 4.2. Mean platelets <100 x 10e9/l over 16 weeks + evidence of bleeding (assessed using the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool) OR 4.3. Mean neutrophils <1.0 x 10e9/l over 16 weeks + history of infection (the requirement for antimicrobial therapy and hospital admissions associated with infection) 5. No response to erythroid stimulating agents (ESAs) OR have ceased to respond to ESAs OR are predicated not to respond to ESAs by current UK guidelines 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-3 7. Expected survival >12 months |
| Participant exclusion criteria | Current participant exclusion criteria as of 14/06/2023: 1. Abnormal liver function (if the patient has Gilbert’s syndrome, then abnormal direct bilirubin is an exclusion) 2. Cockcroft Gault CrCl < 20 ml/min 3. Current systemic treatment for low-risk MDS 4. History of allogeneic bone marrow transplant 5. History of having received ESAs and/or G-CSF in the past 16 weeks 6. Currently receiving statin medication for secondary prophylaxis of cardiovascular disease, cerebrovascular, or peripheral vascular disease (Please note patients receiving statin medication for primary prophylaxis of cardiovascular disease – i.e. the patient has no prior history of ischaemic heart disease or cerebrovascular disease - can still be entered 7. Currently receiving fibrate medications 8. Currently receiving sodium valproate, carbamazepine or phenytoin for the treatment of epilepsy 9. Prior cytotoxic chemotherapy or hypomethylating agents for AML/MDS (e.g. azacitidine) 10. Concurrent active malignancy requiring treatment 11. History of any androgen-dependent tumour (patients with prostate cancer are excluded when a biopsy-proven diagnosis of prostate cancer has been made OR their PSA is known to be elevated OR they are on active treatment for prostate cancer, including hormonal therapy). 12. Currently receiving vitamin K antagonist anticoagulation (though patients receiving direct oral anticoagulants (DOACs) can be included) 13. History of venous thromboembolism (VTE) 14. Cardiac failure NYHA Class III or IV 15. Women of childbearing potential, pregnant or lactating 16. The physician or patient considers VBaP or danazol to be inappropriate for the patient 17. Known HIV 18. Abnormally high CK level 19. Presence of isolated del 5q 20. Acute porphyria 21. Contraindications to any of the trial medications or known hypersensitivity to any of the investigational products 22. Previous randomisation in the REPAIR-MDS trial 23. Participation in a clinical trial of an investigational medicinal product in the last 16 weeks Previous participant exclusion criteria: 1. Abnormal liver function (if the patient has Gilbert’s syndrome, then abnormal direct bilirubin is an exclusion) 2. Cockcroft Gault CrCl < 20 ml/min 3. Current systemic treatment for low-risk MDS 4. History of allogeneic bone marrow transplant 5. History of having received ESAs and/or G-CSF in the past 16 weeks 6. Currently receiving statin medication for secondary prophylaxis of cardiovascular disease or cerebrovascular disease (Please note patients receiving statin medication for primary prophylaxis of cardiovascular disease – i.e. the patient has no prior history of ischaemic heart disease nor cerebrovascular disease - can still be entered) 7. Currently receiving fibrate medications 8. Currently receiving sodium valproate, carbamazepine or phenytoin for treatment of epilepsy 9. Prior cytotoxic chemotherapy for AML/MDS 10. Concurrent active malignancy requiring treatment 11. History of any androgen-dependent tumour (patients with prostate cancer are excluded when a biopsy-proven diagnosis of prostate cancer has been made OR their PSA is known to be elevated OR they are on active treatment for prostate cancer, including hormonal therapy). 12. Currently receiving vitamin K antagonist anticoagulation (though patients receiving direct oral anticoagulants (DOACs) can be included) 13. History of venous thromboembolism (VTE) 14. Cardiac failure NYHA Class III or IV 15. Women of childbearing potential, pregnant or lactating 16. The physician or patient consider VBaP or danazol to be inappropriate for the patient 17. Known HIV 18. Abnormal CK level 19. Presence of isolated del 5q 20. Acute porphyria 21. Contraindications to any of the trial medications or known hypersensitivity to any of the investigational products 22. Previous randomisation in the REPAIR-MDS trial 23. Participation in a clinical trial of an investigational medicinal product in the last 90 days |
| Recruitment start date | 21/12/2021 |
| Recruitment end date | 30/06/2024 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Pensnett Road
Dudley
DY1 2HQ
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Edgbaston
Birmingham
B15 2GW
United Kingdom
Colchester
CO4 5JL
United Kingdom
Heath Park Way
Cardiff
CF14 4XW
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Broomhall
Sheffield
S10 2JF
United Kingdom
Harehills
Leeds
LS9 7TF
United Kingdom
Truro
TR1 3LJ
United Kingdom
London
SE1 9RS
United Kingdom
London
SE5 9RS
United Kingdom
Northampton
NN1 5BD
United Kingdom
London
WC1H 8NJ
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
Canterbury
CT1 3NG
United Kingdom
Wythenshawe
Manchester
M23 9LT
United Kingdom
Basingstoke
RG24 9NA
United Kingdom
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Heath Town
Wolverhampton
WV10 0QP
United Kingdom
Dorchester
DT1 2JY
United Kingdom
Stoke-on-Trent
ST4 6QG
United Kingdom
Cottingham
HU16 5JQ
United Kingdom
Blackpool
FY3 8NR
United Kingdom
Reading
RG1 5AN
United Kingdom
Worcester
WR5 1DD
United Kingdom
Worcester
WR5 1DD
United Kingdom
Broomfield
Chelmsford
CM1 7ET
United Kingdom
Leicester
LE1 5WW
United Kingdom
Winchester
SO22 5DG
United Kingdom
Sponsor information
University/education
Research and Impact Services & Head of Research Governance
University House
Kirby Corner Road
Coventry
CV4 8UW
England
United Kingdom
| Phone | +44 (0)2476 575733 |
|---|---|
| sponsorship@warwick.ac.uk | |
| Website | http://www2.warwick.ac.uk/ |
"ROR" |
https://ror.org/01a77tt86 |
Hospital/treatment centre
Research & Development
1st Floor North Wing
Russells Hall Hospital
Dudley
DY1 2HQ
England
United Kingdom
| Phone | +44 (0)1384 456111 |
|---|---|
| jeffneilson@nhs.net | |
| Website | http://dudleygroup.nhs.uk/ |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 06/06/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Protocol v3.0 to be made available after the next amendment. Results will be disseminated via scientific publications and the trial website so they can be accessed by participants, healthcare professionals, the public and other relevant groups. |
| IPD sharing plan | The datasets generated and/or analysed during the current study are/will be available upon request from the Repair MDS Trial Management Group (TMG) via repairmds@warwick.ac.uk. Summary data including baseline characteristics and outcome data will become available after the primary publication and the data will be available for up to 5 years from the end of the study. The data will be shared with any researchers for whom the scope and purpose of the data sharing are agreed upon by the TMG. All participants have agreed to use of data for research, no identifiable data will be released, and patients will have a unique trial number assigned. There are no ethical or legal restrictions. The researchers encourage data sharing, and all reasonable requests will be reviewed favourably. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 2.0 | 22/04/2021 | 04/08/2021 | No | Yes |
| HRA research summary | 26/07/2023 | No | No |
Additional files
Editorial Notes
30/10/2023: Cancer Research UK plain English summary link added to plain English summary field.
14/06/2023: The following changes were made to the trial record:
1. The study website was added.
2. The participant inclusion criteria have been changed.
3. The participant exclusion criteria have been changed.
4. The recruitment end date was changed from 31/08/2024 to 30/06/2024.
5. The trial participating centres "Royal Devon and Exeter Hospital", "Queen Elizabeth Hospital Kings Lynn", "The County Hospital", "Northwick Park Hospital" and "Queen Alexandra Hospital" have been removed.
6. The trial participating centres "Worcestershire Royal Hospital", "Broomfield Hospital", "Leicester Royal Infirmary" and "Royal Hampshire County Hospital (rhch)" have been added.
22/04/2022: The trial participating centre “Queen's Hospital” has been removed and the trial participating centre “Queen Elizabeth Hospital” has been updated to "University Hospitals Birmingham NHS Foundation Trust".
07/02/2022: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/09/2021 to 21/12/2021.
2. The recruitment end date was changed from 28/02/2024 to 31/08/2024.
3. The ClinicalTrials.gov number was added.
19/07/2021: Trial's existence confirmed by the NIHR.
