ChariotMS - Cladribine to Halt Deterioration in People With Advanced Multiple Sclerosis

• Sponsor: Queen Mary University of London (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04695080
• Collaborator: National Institute for Health Research, United Kingdom (Other), Merck Serono Limited, UK (Industry), Multiple Sclerosis Society of Great Britain & Northern Ireland (Other), National Multiple Sclerosis Society USA (Other), Barts & The London NHS Trust (Other)
• Enrollment: 200
• Locations: 19
• Arms: 2
• Anticipated Duration (Months): 36.3
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Advanced Multiple Sclerosis; Progressive Multiple Sclerosis	Drug: Cladribine (MAVENCLAD®); Drug: Placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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?
• Actual Study Start Date: Jun 25, 2021
• Anticipated Primary Completion Date: Jul 4, 2024
• Anticipated Study Completion Date: Jul 4, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Cladribine (MAVENCLAD®)	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 Comparator: Placebo	Drug: 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.

Outcome Measures

Primary Outcome Measures

1. The 9-HPT peg speed (tasks/second) at 24 months [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.

2. 9-HPT proportion of patients who do not deteriorate at 24 months [24 months]

Secondary Outcome Measures

1. Change over 24 months of the study in clinical outcome measure: EDSS [Screening, Month 6, 12, 18 and 24]

   The proportion of the cladribine versus placebo arms with an increase of >=0.5 in EDSS score over 24 months.

2. Change over 24 months of the study in clinical outcome measure: ARAT [Screening, Month 6, 12, 18 and 24]

   ARAT (Upper Limb Function Test) upper limb function test score

3. Change over 24 months of the study in clinical outcome measure: ABILHAND [Screening, Month 6, 12, 18 and 24]

   ABILHAND score for manual ability

4. Change over 24 months of the study in clinical outcome measure: T25ftWT [Screening, Month 6, 12, 18 and 24]

   Lower Limb Function: The T25ftWT (Timed 25 foot walk test) will be collected in all pwAMS able to walk the required distance twice.

5. Change over 24 months of the study in clinical outcome measure: SLCVA [Screening, Month 6, 12, 18 and 24]

   SLCVA (Sloan low contrast letter visual acuity) score.

6. Change over 24 months of the study in clinical outcome measure: MSIS-29v2 [Screening, , Month 6, 12, 18 and 24]

   MSIS-29v2 (Multiple Sclerosis Impact Scale) quality of life score

7. Change over 24 months of the study in clinical outcome measure: SDMT [Screening, Month 6, 12, 18 and 24]

   SDMT (The Symbol Digit Modalities Test) score.

8. Change over 24 months of the study in clinical outcome measure: NFI-MS [Screening, Month 6, 12, 18 and 24]

   NFI-MS (Neurological Fatigue Index-Multiple Sclerosis) score.

9. Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L [Screening, Month 6, 12, 18 and 24]

   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.

10. Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L [Screening, Month 6, 12, 18 and 24]

    Cost-utility: Carer's generic health-related quality of life, measured using the EuroQoL EQ-5D-5L

11. Change over 24 months of the study in clinical outcome measure: EuroQoL EQ-5D-5L [Screening, Month 6, 12, 18 and 24]

    Cost-utility: health and social care and other costs.

12. Change over 24 months of the study in clinical outcome measure: WPAI-GH [Baseline, Month 6, 12, 18 and 24]

    WPAI-GH (Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) score

13. Safety/occurrence of adverse events [Through study completion, an average of 24 months]

    Safety: Any AEs/SAEs, Lymphopenia (peripheral blood lymphocyte counts), Severe infections, Malignancies. Pregnancies Special situations (e.g. overdose)

14. Preventing loss of brain volume [Screening, Month 6 and 24]

    (MRI) Change over 24 months of the study in ventricular volume assessed using the VIENA technique.

15. Preventing loss of brain volume [Screening, Month 6 and 24]

    (MRI) Change over 24 months in brain volume assessed using the "Structural Image Evaluation, using Normalisation, of Atrophy" (SIENA) technique

16. Preventing loss of spinal cord cross sectional area [Screening, Month 6 and 24]

    (MRI) Change in the total cross-sectional area of spinal cord (at level C2) over 24 months

17. Preventing new focal demyelinating lesions and T2 burden of disease increase. [Screening, Month 6 and 24]

    (MRI) Total number of new focal demyelinating brain lesions over 24 months

18. Preventing new hypo-intense lesions ("black holes") on T1 weighted MRI [Screening, Month 6 and 24]

    (MRI) Total number of new hypo-intense T1 lesions over 24 months

19. Degree of unblinding [Month 24]

    To determine the perception of treatment allocation for both participants and trial teams at 24 months.

Other Outcome Measures

1. To determine if cladribine correlates with memory Bcell count. [Screening, Month 12 and 24]

   Memory B-Cell (total number and percentage of CD19+ cell count) and its association with upper limb function as measured using 9HPT speed.

2. To determine association between Memory B cell count and 9HPT speed. [Screening, Month 6, 12, 18 and 24]

   9HPT speed

3. To determine association between Memory B cell count and 9HPT speed. [Screening, Month 6, 12, 18 and 24]

   ARAT score

4. To determine association between Memory B cell count, upper limb function and s-NfL level. [Screening, Month 12 and 24]

   Serum-NfL at 6 and 24 months compared to baseline.

5. 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. [Screening, Month 6 and 24]

   (MRI) Change over 24 months of the study in cortical brain volume

6. 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. [Screening, Month 6 and 24]

   (MRI) Change over 24 months of the study in thalamic brain volume

7. 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. [Screening, Month 6 and 24]

   (MRI) Change over 24 months of the study in hippocampal brain volume

8. 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. [Screening, Month 6 and 24]

   (MRI) Change over 24 months of the study in new slowly expanding/evolving lesions (SELs)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 either 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.

1. 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 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

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

11. Infection with Human Immunodeficiency Virus 1 and/or 2

12. Active chronic infection (Syphilis, Tuberculosis, Hepatitis)

13. Precancerous condition or previous diagnosis of cancer

14. Total lymphocyte count <1.0*109/mL

15. Seronegativity for varicella zoster IgG, rubella, measles, mumps. Potential participants who fall in this category 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.

1. Treatment with any interferon-beta, glatiramer acetate, teriflunomide or dimethyl-fumarate within three months before screening.

2. Treatment with natalizumab, fingolimod, siponimod, ponesimod, ozanimod (or other Sphingosine-1-phosphate receptor modulators) within three months of screening.

3. Treatment with azathioprine, methotrexate, or cyclosporine within six months before screening.

4. pwAMS treated with teriflunomide will need to undergo accelerated elimination of the compound before being considered (Research and Case Medical Research 2019).

5. 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.

6. 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.

7. Concurrent participation or previous participation within the last 6 months in another clinical trial of an IMP or medical device.

8. Unable to swallow tablets

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Queens University Belfast (Belfast Health and Social Care Trust)	Belfast		United Kingdom	BT12 6BA
2	University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham	Birmingham		United Kingdom	B15 2TH
3	Cardiff University Hospital	Cardiff		United Kingdom	CF14 4XW
4	Anne Rowling Clinic, University of Edinburgh	Edinburgh		United Kingdom	EH16 4SB
5	Queen Elizabeth University Hospital Glasgow	Glasgow		United Kingdom	G51 4TF
6	University Hospital Hairmyres, NHS Lanarkshire	Glasgow		United Kingdom	G75 8RG
7	Leeds Teaching Hospitals NHS Trust	Leeds		United Kingdom	LS1 3EX
8	Walton Centre NHS Trust	Liverpool		United Kingdom	L9 7LJ
9	Royal London Hospital	London		United Kingdom	E1 1FR
10	Royal Free London NHS Foundation Trust	London		United Kingdom	NW3 2QG
11	Queen's Hospital (Havering and Redbridge University Hospitals NHS Trust)	London		United Kingdom	RM7 0AG
12	St George's University Hospitals NHS Foundation Trust	London		United Kingdom	SW17 0RE
13	Luton and Dunstable Hospital	Luton		United Kingdom	LU4 0DZ
14	Salford Royal Hospital NHS Trust	Manchester		United Kingdom	M6 8HD
15	Nottingham University Hospital (Nottingham University Hospitals NHS Trust)	Nottingham		United Kingdom	NG7 2UH
16	University Hospitals Plymouth NHS Trust	Plymouth		United Kingdom	PL6 8DH
17	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield		United Kingdom	S10 2JF
18	University Hospital Southampton NHS Foundation Trust	Southampton		United Kingdom	SO16 6YD
19	Morriston Hospital, Swansea	Swansea		United Kingdom	SA6 6NL

Sponsors and Collaborators

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

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Queen Mary University of London
• ClinicalTrials.gov Identifier: NCT04695080
• Other Study ID Numbers: 258909; 2018-005038-39
• First Posted: Jan 5, 2021
• Last Update Posted: Jun 10, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Queen Mary University of London: 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)
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Cladribine

Study Results

No Results Posted as of Jun 10, 2022