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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04695080
Other study ID # 258909
Secondary ID 2018-005038-39
Status Recruiting
Phase Phase 2/Phase 3
First received
Last updated
Start date June 25, 2021
Est. completion date December 31, 2027

Study information

Verified date June 2024
Source Queen Mary University of London
Contact Klaus Schmierer, PhD, FRCP
Phone +44 (0)20 7882 6246
Email k.schmierer@qmul.ac.uk
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

MS is a chronic inflammatory and degenerative disease of the central nervous system (CNS) affecting more than 120,000 people in the UK.and 2.5 million people worldwide. Without disease modifying treatment (DMT),the majority of people with MS (pwMS) will develop significant disability within 10 years of onset, and 50% will require wheelchair assistance within 20 years. convenient, highly effective and CNS penetrant DMT for patients with relapsing multiple sclerosis (pwRMS) administered in short (8-10 days/year over 2 years) treatment courses. It effectively depletes B cells, particularly Memory B cells, a likely key mechanism of disease control in MS. Cladribine is the investigational product in this study as it not currently used to treat patients with an EDSS of 6.5 - 8.5. This is a multi-centre, randomised double-blind placebo-controlled phase IIb to test cladribine tablets (MAVENCLAD®) (3.5mg/kg over 24 months) for safety, efficacy, and cost effectiveness, and to advance mechanistic understanding of its action in people with advanced MS (pwAMS).


Recruitment information / eligibility

Status Recruiting
Enrollment 200
Est. completion date December 31, 2027
Est. primary completion date October 31, 2024
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion criteria: 1. pwAMS aged 18+ years with an EDSS of 6.5-8.5 (inclusive) 2. History of bowel cancer screening for men, and women and cervical and breast cancer screening for women as per NHS recommended guidelines https://www.nhs.uk/conditions/nhs-screening/. 3. Ability to complete the 9HPT with at least one upper limb within 180 seconds. The average score of both attempts for each hand should be used to assess eligibility. 4. Confirmation of MS diagnosis according to the McDonald Criteria (2017) Thompson et al. 2018). 5. In the judgement of the investigator, evidence of deterioration of upper limb function during the 2 years running up to the screening date. Exclusion Criteria 1. Participants with known hypersensitivity to Cladribine of any grade (as per CTCAE grading system) should be excluded 2. Any uncontrolled diabetes, arterial hypertension and hypercholesterolaemia as determined by PI or delegated sub-investigator 3. A history of stroke, deep vein or sinus venous thrombosis (including pulmonary embolus) and/or myocardial infarction 4. Moderate to severe renal impairment (creatinine clearance <60 ml/min) 5. Moderate to severe hepatic impairment (Child-Pugh score >6) 6. Significant comorbidity, e.g. cardiac failure, renal failure, malignancy, or other health condition that in the view of the PI or delegated sub-investigator precludes participation. Patients who, following discussion with their cancer treatment team, are deemed to be cured from malignancy, may be eligible to participate as per the clinical judgement of the local PI. 7. Pregnancy including planning to father a child or breastfeeding 8. Body weight less <40kg 9. Unwillingness to use effective contraception throughout the trial period until at least six months after the last administration of IMP. This is not applicable for post-menopausal women 10. Acute infection (uncontrolled) 11. Infection with Human Immunodeficiency Virus 1 and/or 2 12. Active chronic infection (Syphilis, Tuberculosis, Hepatitis). Patients with active TB will be excluded. However, patients who have a positive IGRA, Elispot or Quantiferon test, but exhibit no symptoms for TB and evidence of a normal Chest X Ray, can be included in the study as per judgement of the local PI and after clarification with the CI. 13. Precancerous condition 14. Total lymphocyte count <1.0*109/L 15. Seronegativity for varicella zoster virus. Potential participants who are IgG negative may undergo vaccination, and can be screened again once full course has been completed. Seronegativity for all of the following: measles, mumps, rubella. Potential participants who are IgG negative for all 3 viruses, may undergo vaccination and can be screened again once full course has been completed. 16. Relapse within six months before screening 17. Inability to complete an MRI (contraindications for MRI, including but not limited to, MRI-non-compatible pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, severe anxiety or claustrophobia etc.) or contraindication to Gd administration. 18. Treatment with steroids due to MS relapse/progression within three months of screening. pwAMS who fall in this category may undergo a further screening visit once the three months' window has expired and may be included if no steroid treatment has been administered in the intervening period. 19. Treatment with any interferon-beta, glatiramer acetate, teriflunomide or dimethyl-fumarate within three months before screening. 20. Treatment with natalizumab, fingolimod, siponimod, ponesimod, ozanimod (or other Sphingosine-1-phosphate receptor modulators) within three months of screening. 21. Treatment with azathioprine, methotrexate, or cyclosporine within six months before screening. 22. pwAMS treated with teriflunomide will need to undergo accelerated elimination of the compound before being considered (Research and Case Medical Research 2019). 23. Treatment with haematopoietic stem cell transplantation (HSCT), mitoxantrone, cyclophosphamide, cladribine, alemtuzumab or another B cell depleting compound, such as rituximab, ocrelizumab, ublitiuximab, ofatumumab, or biosimilars, unless the participant concerned has a memory B cell level of =20% of the CD19+ population in the peripheral blood. Such a level would normally not be expected earlier than a minimum of six months after the last drug administration. Participants who underwent such treatment will therefore have to be tested for their CD19+/CD27+ memory B cell level at screening. 24. Treatment with fampridine: If they are already on treatment for at least six months, participants should continue throughout the trial. However, starting continuous fampridine treatment after signing the consent sheet will lead to exclusion from treatment with IMP/placebo. 25. Concurrent participation or previous participation within the last 6 months in another clinical trial of an IMP or medical device. 26. Unable to swallow tablets

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Cladribine (MAVENCLAD®)
Cladribine (MAVENCLAD®) 3.5mg/kg, administered as weight-adjusted 10mg tablets in two treatment courses (12 months apart) lasting 8- 10 days each. Cladribine (MAVENCLAD®) 10mg available in blister packs of 1 tablet, 4 tablets and 6 tablets.
Placebo
Placebo administered as weight adjusted tablets in two treatment courses (12 months apart) lasting 8-10 days each. Placebo 10mg available in blister packs of 1 tablet, 4 tablets and 6 tablets.

Locations

Country Name City State
United Kingdom Queens University Belfast (Belfast Health and Social Care Trust) Belfast
United Kingdom University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham Birmingham
United Kingdom Cardiff University Hospital Cardiff
United Kingdom University Hospitals of Coventry and Warwickshire NHS Trust Coventry
United Kingdom Anne Rowling Clinic, University of Edinburgh Edinburgh
United Kingdom Queen Elizabeth University Hospital Glasgow Glasgow
United Kingdom University Hospital Hairmyres, NHS Lanarkshire Glasgow
United Kingdom Leeds Teaching Hospitals NHS Trust Leeds
United Kingdom Walton Centre NHS Trust Liverpool
United Kingdom Lewisham and Greenwich NHS Trust London
United Kingdom Queen's Hospital (Havering and Redbridge University Hospitals NHS Trust) London
United Kingdom Royal Free London NHS Foundation Trust London
United Kingdom Royal London Hospital London
United Kingdom St George's University Hospitals NHS Foundation Trust London
United Kingdom Luton and Dunstable Hospital Luton
United Kingdom Salford Royal Hospital NHS Trust Manchester
United Kingdom Aneurin Bevan University Health Board Newport
United Kingdom Nottingham University Hospital (Nottingham University Hospitals NHS Trust) Nottingham
United Kingdom University Hospitals Plymouth NHS Trust Plymouth
United Kingdom Sheffield Teaching Hospitals NHS Foundation Trust Sheffield
United Kingdom University Hospitals of North Midlands NHS Trust Stoke-on-Trent
United Kingdom Morriston Hospital, Swansea Swansea

Sponsors (6)

Lead Sponsor Collaborator
Queen Mary University of London Barts & The London NHS Trust, Merck Serono Limited, UK, Multiple Sclerosis Society of Great Britain & Northern Ireland, National Institute for Health Research, United Kingdom, National Multiple Sclerosis Society

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Other To determine if cladribine correlates with memory Bcell count. Memory B-Cell (total number and percentage of CD19+ cell count) and its association with upper limb function as measured using 9HPT speed. Screening, Month 12 and 24
Other To determine association between Memory B cell count and 9HPT speed. 9HPT speed Screening, Month 6, 12, 18 and 24
Other To determine association between Memory B cell count and 9HPT speed. ARAT score Screening, Month 6, 12, 18 and 24
Other To determine association between Memory B cell count, upper limb function and s-NfL level. Serum-NfL at 6 and 24 months compared to baseline. Screening, Month 12 and 24
Other To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions. (MRI) Change over 24 months of the study in cortical brain volume Screening, Month 6 and 24
Other To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions. (MRI) Change over 24 months of the study in thalamic brain volume Screening, Month 6 and 24
Other To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions. (MRI) Change over 24 months of the study in hippocampal brain volume Screening, Month 6 and 24
Other To determine effects of IMP on cortical and deep grey matter volumes, thalamic, hippocampal and ventricular volumes (VIENA) and slowly expanding (i.e. chronically active) lesions. (MRI) Change over 24 months of the study in new slowly expanding/evolving lesions (SELs) Screening, Month 6 and 24
Primary The 9-HPT peg speed (tasks/second) at 24 months To establish whether there is efficacy superiority of cladribine tablets over placebo in reducing deterioration of upper limb function in pwAMS.
To investigate whether cladribine tablets 3.5mg/kg over 24 months is an effective DMT in pwAMS as measured using the 9-hole peg test (9HPT) peg speed at 24 months.
24 months
Primary 9-HPT proportion of patients who do not deteriorate at 24 months 24 months
Secondary Change over 24 months of the study in clinical outcome measure: EDSS The proportion of the cladribine versus placebo arms with an increase of >=0.5 in EDSS score over 24 months. Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: ARAT ARAT (Upper Limb Function Test) upper limb function test score Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: ABILHAND ABILHAND score for manual ability Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: T25ftWT Lower Limb Function: The T25ftWT (Timed 25 foot walk test) will be collected in all pwAMS able to walk the required distance twice. Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: SLCVA SLCVA (Sloan low contrast letter visual acuity) score. Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: MSIS-29v2 MSIS-29v2 (Multiple Sclerosis Impact Scale) quality of life score Screening, , Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: SDMT SDMT (The Symbol Digit Modalities Test) score. Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: NFI-MS NFI-MS (Neurological Fatigue Index-Multiple Sclerosis) score. Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L Cost-utility: Patient's generic health-related quality of life, measured using the EuroQoL EQ-5D-5L and, separately, carer's generic health-related quality of life, measured using the EuroQoL EQ-5D-5L, health and social care and other costs. Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L Cost-utility: Carer's generic health-related quality of life, measured using the EuroQoL EQ-5D-5L Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L Cost-utility: health and social care and other costs. Screening, Month 6, 12, 18 and 24
Secondary Change over 24 months of the study in clinical outcome measure: WPAI-GH WPAI-GH (Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) score Baseline, Month 6, 12, 18 and 24
Secondary Safety/occurrence of adverse events Safety:
Any AEs/SAEs,
Lymphopenia (peripheral blood lymphocyte counts),
Severe infections,
Malignancies.
Pregnancies
Special situations (e.g. overdose)
Through study completion, an average of 24 months
Secondary Preventing loss of brain volume (MRI) Change over 24 months of the study in ventricular volume assessed using the VIENA technique. Screening, Month 6 and 24
Secondary Preventing loss of brain volume (MRI) Change over 24 months in brain volume assessed using the "Structural Image Evaluation, using Normalisation, of Atrophy" (SIENA) technique Screening, Month 6 and 24
Secondary Preventing loss of spinal cord cross sectional area (MRI) Change in the total cross-sectional area of spinal cord (at level C2) over 24 months Screening, Month 6 and 24
Secondary Preventing new focal demyelinating lesions and T2 burden of disease increase. (MRI) Total number of new focal demyelinating brain lesions over 24 months Screening, Month 6 and 24
Secondary Preventing new hypo-intense lesions ("black holes") on T1 weighted MRI (MRI) Total number of new hypo-intense T1 lesions over 24 months Screening, Month 6 and 24
Secondary Degree of unblinding To determine the perception of treatment allocation for both participants and trial teams at 24 months. Month 24
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