This study is a randomized multicentre, multinational, treatment interventional study of RRMS patients with breakthrough inflammatory disease activity in spite of ongoing standard immunomodulatory medication. The study has two treatment arms; arm A: HSCT (hematopoietic stem cell transplantation) and arm B: alemtuzumab, cladribine or ocrelizumab. A pre-planned 3-year follow-up extension period will be performed depending on future funding. The aim of the study is to assess the effectiveness and side effects of a new treatment intervention in RRMS; HSCT, and, thereby, the value of HSCT in clinical practice. Data from recently published patient series indicate that HSCT may have a significantly higher treatment effect than currently registered RRMS immunomodulatory treatments. This study will determine the relative role of HSCT versus alemtuzumab, cladribine or ocrelizumab.
This is a randomized study of autologous HSCT using a low intensity, non-ablative conditioning regimen with cyclophosphamide and ATG versus treatment with the currently presumed best available immunomodulatory medication (alemtuzumab, cladribine or ocrelizumab) in RRMS patients with significant inflammatory disease activity in spite of ongoing immunomodulatory MS treatment. Significant disease activity is defined as having one or more clinically reported multiple sclerosis (MS) relapse(s), AND 1 or more T1 Gd-enhanced lesion(s), OR three or more new or enlarging T2 lesions on magnetic resonance imaging (MRI) over the last year while being treated on immunomodulatory medication by standard national guidelines. The relapse(s) must have occurred 3 or more months after the onset of an immunomodulatory treatment, as immunomodulatory treatment in MS may reach full effect after 3 months or more. Both the knowledge of the treatment effect of registered immunomodulatory therapies for RRMS, and the number of treatments approved for RRMS by the European Medicines Agency (EMA) are rapidly increasing. During the study period, there may thus appear new supplementing information on other MS immunomodulatory treatments that favour the use of a new comparator (replacing or supplementing the comparators). This will be evaluated by the PMC if applicable during the study period and the planned extension period. If the treatment efficacy obtained by HSCT is better than the currently most efficacious standard, immunomodulatory treatment in randomized treatment trials, HSCT will likely be approved as a part of the standard treatment recommendations for a significant proportion of RRMS patients. A randomized study regarding with statistical power to evaluate the clinical outcome of autologous HSCT compared to a standard immunomodulatory treatment in MS has not yet been published. Except for Sweden, HSCT is currently not registered as a part of standard MS treatment in the public health services of Europe. The HSCT regimen for the study will be identical to the regimen used in similar patient populations in Sweden, Norway and Denmark. Alemtuzumab, cladribine or ocrelizumab have been chosen as the primary comparators, because they are the immunomodulatory medication currently authorised by the EMA for treatment of RRMS with the most favourable therapeutic effects. In a meta-analysis of immunomodulatory treatment effects in RRMS, thse medications had the most eminent reduction of annualized relapse rate and 3 month confirmed disability progression. In this study, a health economic evaluation will be included. Accordingly, the proposed study should provide a robust basis for future official decisions regarding the role of HSCT in RRMS treatment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
100
Hematopoetic stem cell transplantation
Alemtuzumab (Lemtrada)
Cladribine (Mavenclad)
Ocrelizumab (Ocrevus)
Rigshospitalet
Copenhagen, Denmark
VUmc
Amsterdam, Netherlands
Haukeland University Hospital
Bergen, Norway
Akershus University Hospital
Oslo, Norway
University Hospital of North Norway
Tromsø, Norway
St. Olav's University Hospital
Trondheim, Norway
Sahlgrenska University Hospital
Gothenburg, Sweden
Akademiska sjukhuset
Uppsala, Sweden
Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol).
A protocol-defined disease activity event is the occurrence of at least one of the following: * A new T1 Gd-enhanced lesion on MRI of the brain and spinal cord * A new T2 hyperintense lesion on MRI of brain and spinal cord * A protocol-defined MS relapse (see below) * 24 week confirmed disability progression based on increases in Expanded Disability Status Scale (EDSS)
Time frame: 2 year (96 week) period with a 5 year (240 week) planned extension
NEDA-4
Proportion of patients with no evidence of disease activity, including atrophy (NEDA 4), as per protocol defined disease activity events (as defined in section 2.2) plus atrophy (measured yearly atrophy above threshold of 0, 4 %)
Time frame: 2 year (96 week) period
Pre-planned study extension:
Proportion of patients who have NEDA 4
Time frame: 5 year (240 week) period.
Time to first protocol-defined disease activity event
Time to first sign of new disease activity, as measured as new relapses, EDSS-progression, MRI-activity or brain atrophy
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Change in Expanded Disability Status scale (EDSS) from baseline (Visit 4.1) to Weeks 96 and 240
EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Change was calculated by subtracting retreatment baseline (annual visit prior to the retreatment start date) value from EDSS scores at specified time points.
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
The proportion of patients who, at Week 96, have protocol-defined Confirmed Disability Improvement (CDI) , confirmed stable EDSS or Confirmed Disability Progression (CDP) compared to baseline
Disability progression, as measured with EDSS. EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Change was calculated by subtracting retreatment baseline (annual visit prior to the retreatment start date) value from EDSS scores at specified time points.
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Annualized rate of protocol-defined relapses during 96 weeks
ARR
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Time to onset of first protocol-defined relapse
Time to first relapse
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Change in MRI T2-weighted hyperintense lesion volume from baseline to weeks 96 (and 240)
Change in T2-weighted hyperintense lesion volume
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Change in MRI T1-weighted hypointense lesion volume from baseline to weeks 96 (and 240)
Change in MRI T1-weighted hypointense lesion volume
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Change in brain volume from baseline to week 96 (and week 240)
Change in brain volume
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Time to detection of a new MRI T2 lesion
Time to New MRI T2-lesion
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Total number of MRI T1-weighted Gd-enhanced lesions
Number of Gd-lesions
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Proportion of patients free from T1 Gd-enhancing lesions
Proportion of patients free from T1 Gd-enhancing lesions
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Change in Nine-hole-peg test (9-HPT) score from baseline to week 96 (and 240)
The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Change in Timed 25 Foot Walk (T25FW) score from baseline to week 48, 96 (and 240)
The T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. The score for the T25FW is the average of the 2 completed trials. The 95% CI of the percentage is based on normal approximation.
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to week 96 (and 240)
BICAMS is a composite cognitive assessment tool comprising of the three components : Symbol Digit Modalities Test (SDMT) , California Verbal Learning Test-II (CVLT-II) and Brief visuospatial memory test- Revised (BVMT-R)
Time frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
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