A phase 2b study of Cladribine to halt deterioration in people with advanced multiple sclerosis

• Register: EUCTR
• Last refreshed on: 7 December 2020
• Main ID: EUCTR2018-005038-39-GB
• Date of registration: 29/09/2020
• Prospective Registration: Yes
• Primary sponsor: Queen Mary University of London
• Public title: A phase 2b study of Cladribine to halt deterioration in people with advanced multiple sclerosis
• Scientific title: ChariotMS – A national (UK), multi-centre, randomised, double-blind, placebo-controlled (1:1) phase IIb efficacy trial with cost-utility analysis of cladribine tablets (3.5mg/kg over two years) in people with advanced multiple sclerosis (EDSS 6.5-8.5). Is cladribine superior to placebo in protecting upper limb function? - ChariotMS - Cladribine for people with advanced multiple sclerosis
• Date of first enrolment: 02/12/2020
• Target sample size: 200
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-005038-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Contacts

• Name: Klaus Schmierer
• Affiliation: Queen Mary University of London

• Name: Klaus Schmierer
• Affiliation: Queen Mary University of London

Key inclusion & exclusion 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 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. 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

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 160
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 40

Exclusion criteria:
1. Known hypersensitivity to cladribine of Grade 3 or Grade 4 severity according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system
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.
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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Advanced Multiple Sclerosis (EDSS 6.5-8.5)
MedDRA version: 20.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.0 Level: HLT Classification code 10052785 Term: Multiple sclerosis acute and progressive System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.1 Level: LLT Classification code 10078558 Term: Multiple sclerosis plaque System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 22.1 Level: LLT Classification code 10028246 Term: Multiple sclerosis aggravated System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.1 Level: LLT Classification code 10078559 Term: Multiple sclerosis brain lesion System Organ Class: 10028245 - Multiple sclerosis
MedDRA version: 21.1 Level: PT Classification code 10063401 Term: Primary progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1 Level: PT Classification code 10063401 Term: Primary progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1 Level: LLT Classification code 10064137 Term: Progression of multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1 Level: PT Classification code 10053395 Term: Progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1 Level: PT Classification code 10053395 Term: Progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1 Level: PT Classification code 10067063 Term: Progressive relapsing multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1 Level: PT Classification co

Intervention(s)

Trade Name: MAVENCLAD
Product Name: MAVENCLAD
Pharmaceutical Form: Tablet
INN or Proposed INN: Cladribine
CAS Number: 4291-63-8
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: The secondary objectives include establishing whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in:

- Protecting limb function
- Safety/occurrence of adverse events
- Blood/serum biomarkers of (i) inflammation (lymphocyte subsets) and/or (ii) neurodegeneration (serum neurofilament light chain)
- Preventing loss of brain volume
- Preventing loss of spinal cord cross sectional area
- Preventing new focal demyelinating lesions and T2 burden of disease increase.
- Preventing new hypo-intense lesions (“black holes”) on T1 weighted MRI
- Degree of unblinding

Main Objective: The primary clinical objective of the study is to establish whether there is efficacy superiority of cladribine tablets over placebo in reducing deterioration of upper limb function in pwAMS.

Primary end point(s): The primary outcome measure is the 9-hole peg test (9HPT), a simple, sensitive and established test of upper limb function, which is well accepted among pwMS. To detect a 15% treatment effect in 9HPT peg speed, adjusting for baseline, with 90% power at 5% significance and 20% drop-out we calculated a sample size of n=200 over 24 months is considered sufficient to address the primary objectives of the study.

Timepoint(s) of evaluation of this end point: The 9-HPT peg speed (tasks/second) at 24 months.

Secondary Outcome(s)

Secondary end point(s): Change over 24 months of the study in clinical outcome measures: EDSS, ARAT, T25ftWT, SLCVA and the questionnaires (including MSIS-29v2, 5NFI-MS, EuroQoL EQ-5D-5L, WPAI-GH and neurocognitive tests such as BICAMS).

- 9-HPT proportion of patients who do not deteriorate at 24 months.
- The proportion of the cladribine versus placebo arms with an increase of >=0.5 in EDSS score over 24 months.
- ARAT (Upper Limb Function Test) upper limb function test score
- ABILHAND score for manual ability
- Lower Limb Function: The T25ftWT (Timed 25 foot walk test) will be collected in all pwAMS able to walk the required distance twice.
- SLCVA (Sloan low contrast letter visual acuity) score.
- BICAMS (Brief International Cognitive Assessment for MS) score
- MSIS-29v2 (Multiple Sclerosis Impact Scale) quality of life score
- NFI-MS (Neurological Fatigue Index-Multiple Sclerosis) score.
- WPAI-GH (Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) score
- (MRI) Change over 24 months in brain volume assessed using the “Structural Image Evaluation, using Normalisation, of Atrophy” (SIENA) technique
- (MRI) Change in the total cross-sectional area of spinal cord (at level C2) over 24 months
- (MRI) Total number of new focal demyelinating brain lesions over 24 months
- (MRI) Total number of new hypo-intense T1 lesions over 24 months
- (MRI) Change over 24 months of the study in ventricular volume assessed using the VIENA technique.

Safety:
- Any AEs/SAEs,
- Lymphopenia (peripheral blood lymphocyte counts),
- Severe infections,
- Malignancies.
- Pregnancies
- Special situations (e.g. overdose)
- Cost-utility: Patient’s generic health-related quality of life, measured using the EuroQoL EQ-5D-5L and, separately, MSIS 8D, carer’s generic health-related quality of life, measured using the EuroQoL EQ-5D-5L, health and social care and other costs.
- Blinding: To determine the perception of treatment allocation for both participants and trial teams at 24 months

Timepoint(s) of evaluation of this end point: - 9-HPT proportion of patients who do not deteriorate at 24 months
- (MRI) Change over 24 months of the study in brain volume assessed using the “Structural Image Evaluation, using Normalisation, of Atrophy” (SIENA) technique
- (MRI) Change in the total cross-sectional area of spinal cord (at C2) over 24 months
- (MRI) Total number of new focal demyelinating brain lesions over 24 months
- (MRI) Total number of new hypo-intense T1 lesions over 24 months
- (MRI) Change over 24 months of the study in ventricular volume assessed using the VIENA technique.

Ethics review

Status: Approved
Approval date: 02/12/2020
Contact: