REPAIR-MDS: Repurposed Drugs to Improve Haematological Responses in Myelodysplastic Syndromes

Sponsor

Prof. Janet Dunn (Other)

Overall Status

Recruiting

CT.gov ID

NCT04997811

Collaborator

Blood Cancer UK (Other), Dudley Group NHS Foundation Trust (Other), University of Birmingham (Other), University of Manchester (Other), King's College Hospital NHS Trust (Other)

120

Enrollment

Locations

Arms

42.3

Anticipated Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Over 7,000 people in the UK are living with Myelodysplastic Syndromes (MDS). Approximately 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 acute myeloid leukaemia (AML) an even more aggressive blood cancer. The general outlook for AML is poor, but when AML arises from MDS it is worse.

REPAIR-MDS seeks to repurpose existing drugs in order to dramatically improve the outlook, health and quality of life of people with MDS. The trial treatments aim to improve the production of healthy functioning blood and immune cells that will fight against infections and boost the immune system's action against the MDS clone.

REPAIR-MDS design is a is a multicentre open label phase 2 randomised controlled trial which will compare VBaP (sodium valproate, bezafibrate, medroxyprogesterone) with danazol in patients who have received either Erythropoiesis Stimulating Agents (ESAs) and lost response, not responded to ESAs or are deemed unlikely to respond to ESAs.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes (MDS)	Drug: Sodium Valproate, Bezafibrate, Medroxyprogesterone Drug: Danazol	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Evaluation of Haematological Improvement in Patients With Low-risk MDS by Comparing VBaP With Danazol in Patients Who Have Either Received Erythropoiesis Stimulating Agents (ESA) and Lost Response, Not Responded to ESA or Are Deemed Unlikely to Respond to ESA

Actual Study Start Date :

Dec 21, 2021

Anticipated Primary Completion Date :

Jan 31, 2025

Anticipated Study Completion Date :

Jun 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VBaP Combination of sodium valproate, bezafibrate, medroxyprogesterone	Drug: Sodium Valproate, Bezafibrate, Medroxyprogesterone Sodium Valproate 200mg bd, increasing to 500mg bd after 2 weeks. Bezafibrate 200mg tds, then from Week 4 increasing fortnightly in 200mg increments to 400mg tds. Medroxyprogesterone 400mg bd
Experimental: Danzol Single agent	Drug: Danazol Danazol 1 x 200mg capsules tds, (starting 1 x 200mg od)

Arm

Intervention/Treatment

Experimental: VBaP

Combination of sodium valproate, bezafibrate, medroxyprogesterone

Drug: Sodium Valproate, Bezafibrate, Medroxyprogesterone

Sodium Valproate 200mg bd, increasing to 500mg bd after 2 weeks. Bezafibrate 200mg tds, then from Week 4 increasing fortnightly in 200mg increments to 400mg tds. Medroxyprogesterone 400mg bd

Experimental: Danzol

Single agent

Drug: Danazol

Danazol 1 x 200mg capsules tds, (starting 1 x 200mg od)

Outcome Measures

Primary Outcome Measures

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. [12 months]
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 IWG 2018 haematology response criteria in patients with MDS.

Secondary Outcome Measures

Reduced burden of red cell and/or platelet transfusion in each arm and in the trial overall, as per the IWG 2018 response criteria. [12 months]
Changes in transfusion requirements will be assessed in each participant by comparison with their individual 16-week lead-in baseline as determined by the IWG 2018 haematology response criteria in patients with MDS.
Duration of haematological response [12 months]
Clinically meaningful haematological responses that persist for 16 weeks or longer.
Reported improved Health Related Quality of Life scores in each arm and in the trial overall. [12 months]
The four Health Related Quality of Life questions measure 1) self-perceived health (excellent, very good, good, fair, or poor), (2) number of days out of the past 30 that physical health was not good, (3) number of days out of the past 30 that mental health was not good, and (4) number of days out of the past 30 that usual activities were limited by poor physical or mental health of life scores will be evaluated using established protocols.
Overall survival [Through study completion, an average of 1 year]
Overall survival at close of trial will be reported separately for each trial arm

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Provision of written informed consent
Age ≥ 18 years and able to give informed consent
Diagnosis of Myelodysplastic Syndrome with an IPSS-R score of less than or equal to 3.51
Haematological parameters:
Mean haemoglobin < 100 g/l over 16 weeks (pre transfusion) OR
Mean platelets < 100 x 109/l over 16 weeks + evidence of bleeding (assessed using the ISTH Bleeding Assessment Tool) OR
Mean neutrophils < 1.0 x 109/l over 16 weeks + history of infection (the requirement for antimicrobial therapy and hospital admissions associated with infection)
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 guidelines2,3
ECOG performance status 0-3
Expected survival > 12months

Exclusion Criteria:

Abnormal liver function (if patient has Gilbert's syndrome, then abnormal direct Bilirubin is an exclusion)
Cockcroft Gault CrCl < 20ml/min
Current systemic treatment for low risk MDS
History of Allogeneic Bone Marrow Transplant
History of having received ESAs and/or G-CSF in the past 16 weeks
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, please see section 1.4 Statin use)
Currently receiving fibrate medications
Currently receiving sodium valproate, carbamazepine or phenytoin for treatment of epilepsy
Prior cytotoxic chemotherapy for AML/MDS
Concurrent active malignancy requiring treatment
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).
Currently receiving Vitamin K-Antagonist Anticoagulation (though patients receiving DOACs (direct oral anticoagulants) can be included)
History of Venous Thrombo-Embolism (VTE)
Cardiac Failure NYHA Class III or IV
Women of childbearing potential, pregnant or lactating
The physician or patient consider VBaP or danazol to be inappropriate for the patient
Known HIV
Abnormal CK level
Presence of isolated del 5q
Acute Porphyria
Contraindications to any of the trial medications or known hypersensitivity to any of the investigational products (see Appendix C for contraindications)
Previous randomisation in the REPAIR-MDS trial
Participation in a clinical trial of an investigational medicinal product in the last 90 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Russells Hall Hospital	Dudley	England	United Kingdom	DY1 2HQ
2	University College London Hospitals NHS Foundation Trust	London	England	United Kingdom	NW1 2PG
3	King's College Hospital NHS Foundation Trust	London	England	United Kingdom	SE5 9RS
4	Colchester General Hospital	Colchester	Essex	United Kingdom	CO4 5JL
5	East Kent Hospitals University Foundation Trust	Canterbury	Kent	United Kingdom	CT1 3NG
6	Grampian Health Board	Aberdeen	Scotland	United Kingdom	AB15 6RE
7	Hull University Teaching Hospitals	Hull		United Kingdom	HU3 2JZ
8	Royal Gwent Hospital, Aneurin Bevan University Health Board	Newport		United Kingdom	NP18 3XQ