Clinical trial NCT04695080: ChariotMS - Cladribine to Halt Deterioration in People With Advanced Multiple Sclerosis
Official title: ChariotMS - A National (UK) Phase IIb, Multi-centre, Randomised, Double-blind, Placebo Controlled (1:1) Efficacy Trial With Cost-utility Analysis of Cladribine Tablets (3.5mg/kg Over Two Years) in People With Advanced Multiple Sclerosis. Is Cladribine Superior to Placebo in Protecting Upper Limb Function?
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Advanced Multiple Sclerosis
Progressive Multiple Sclerosis
Keywords: Multiple Sclerosis
Progressive multiple sclerosis
Advanced multiple sclerosis
Upper limb function
Cladribine
Quality of life
Cognition
Health Economics
Biomarkers
Neurofilament light chain
B cells
Lymphocytes
Magnetic Resonance Imaging (MRI)
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: National Institute for Health Research, United Kingdom
name: Merck Serono Limited, UK
name: Multiple Sclerosis Society of Great Britain & Northern Ireland
name: National Multiple Sclerosis Society
name: Barts & The London NHS Trust
First posted: 2021-01-05
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).


Eligibility criteria: 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

Primary outcomes:
measure: The 9-HPT peg speed (tasks/second) at 24 months
timeFrame: 24 months
measure: 9-HPT proportion of patients who do not deteriorate at 24 months
timeFrame: 24 months
Secondary outcomes:
measure: Change over 24 months of the study in clinical outcome measure: EDSS
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: ARAT
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: ABILHAND
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: T25ftWT
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: SLCVA
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: MSIS-29v2
timeFrame: Screening, , Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: SDMT
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: NFI-MS
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L
timeFrame: Screening, Month 6, 12, 18 and 24
measure: Change over 24 months of the study in clinical outcome measure: WPAI-GH
timeFrame: Baseline, Month 6, 12, 18 and 24
measure: Safety/occurrence of adverse events
timeFrame: Through study completion, an average of 24 months
measure: Preventing loss of brain volume
timeFrame: Screening, Month 6 and 24
measure: Preventing loss of brain volume
timeFrame: Screening, Month 6 and 24
measure: Preventing loss of spinal cord cross sectional area
timeFrame: Screening, Month 6 and 24
measure: Preventing new focal demyelinating lesions and T2 burden of disease increase.
timeFrame: Screening, Month 6 and 24
measure: Preventing new hypo-intense lesions ("black holes") on T1 weighted MRI
timeFrame: Screening, Month 6 and 24
measure: Degree of unblinding
timeFrame: Month 24
Other outcomes:
measure: To determine if cladribine correlates with memory Bcell count.
timeFrame: Screening, Month 12 and 24
measure: To determine association between Memory B cell count and 9HPT speed.
timeFrame: Screening, Month 6, 12, 18 and 24
measure: To determine association between Memory B cell count and 9HPT speed.
timeFrame: Screening, Month 6, 12, 18 and 24
measure: To determine association between Memory B cell count, upper limb function and s-NfL level.
timeFrame: Screening, Month 12 and 24
measure: 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.
timeFrame: Screening, Month 6 and 24
measure: 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.
timeFrame: Screening, Month 6 and 24
measure: 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.
timeFrame: Screening, Month 6 and 24
measure: 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.
timeFrame: Screening, Month 6 and 24
Locations:
city: Belfast
country: United Kingdom
facility: Queens University Belfast (Belfast Health and Social Care Trust)
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham
city: Cardiff
country: United Kingdom
facility: Cardiff University Hospital
city: Coventry
country: United Kingdom
facility: University Hospitals of Coventry and Warwickshire NHS Trust
city: Edinburgh
country: United Kingdom
facility: Anne Rowling Clinic, University of Edinburgh
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital Glasgow
city: Glasgow
country: United Kingdom
facility: University Hospital Hairmyres, NHS Lanarkshire
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Liverpool
country: United Kingdom
facility: Walton Centre NHS Trust
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: Queen's Hospital (Havering and Redbridge University Hospitals NHS Trust)
city: London
country: United Kingdom
facility: Lewisham and Greenwich NHS Trust
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: Luton
country: United Kingdom
facility: Luton and Dunstable Hospital
city: Manchester
country: United Kingdom
facility: Salford Royal Hospital NHS Trust
city: Newport
country: United Kingdom
facility: Aneurin Bevan University Health Board
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital (Nottingham University Hospitals NHS Trust)
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospitals of North Midlands NHS Trust
city: Swansea
country: United Kingdom
facility: Morriston Hospital, Swansea
Study officials:
References: