Clinical trial NCT04121403: Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS)
Official title: Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS) A Prospective Randomized Open-label Blinded Endpoint (PROBE) Multicenter Non-inferiority Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsing Multiple Sclerosis
Multiple Sclerosis
Keywords: multiple sclerosis
ms
rms
rituximab
cladribine
probe
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: University of Oslo
name: Sykehuset Ostfold
name: Sykehuset Telemark
name: Vestre Viken Hospital Trust
name: Sorlandet Hospital HF
name: Helse Stavanger HF
name: Sykehuset Innlandet HF
name: Sykehuset i Vestfold HF
name: University Hospital of North Norway
name: St. Olavs Hospital
First posted: 2019-10-09
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A prospective randomized open-label blinded endpoint (PROBE) multicenter non-inferiority study, designed to establish non-inferiority of the test treatment rituximab compared with the comparator oral cladribine for consecutively included patients with active RMS. Randomization rituximab:cladribine is 1:1.
Primary purpose: TREATMENT

Brief summary: The main aim and overall objective of the study is to assess whether rituximab is non-inferior to cladribine for the treatment of relapsing MS. Secondly, the investigators will test specific blood and MRI biomarkers that may contribute to future personalized treatment for MS patients. Furthermore, the investigators want to evaluate the health economic consequences of the two therapies.

Detailed description: Multiple sclerosis (MS) is a demyelinating and neurodegenerative inflammatory disease of the central nervous system, affecting more than 12 000 patients in Norway and more than 2.2 mill patients worldwide.

Oral cladribine is one of the first choices for highly efficient disease modulatory treatment (DMT), while Rituximab is used off-label as DMT in relapsing MS. Large observational studies indicate good tolerance and treatment effect of rituximab in MS and studies from other diseases indicate a good safety profile. However, no phase 3 studies have been performed to test whether rituximab is as efficient as established MS treatments. Formal safety data is also lacking for the treatment with rituximab in MS.

The investigators will perform a prospective randomized open-label blinded endpoint multicenter non-inferiority study. The primary objective is to test whether rituximab is non-inferior to oral cladribine in the treatment of relapsing MS. 264 MS patients aged 18-65 years with relapsing MS will be recruited from 10 centers and followed for 96 weeks. The primary endpoint is difference in new T2 lesions between the groups. Furthermore, the investigators will test novel blood sample and MRI biomarkers to provide tools for personalized MS treatments. Finally, the health economic consequences of these treatment options will be evaluated.

This study will guide clinicians and patients in the future treatment choice for MS and can potentially make a huge impact on the costs of future MS treatment.

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 65 years
* A diagnosis of relapsing MS according to the 2017 McDonald criteria
* Disease activity seen as either a clinical relapse or MRI activity during the last 12 months
* EDSS between 0 and 5.5
* Thrombocytes and leukocytes within normal range, and lymphocytes above 0.8 x10 9/L before first dose of study medication
* A) For women of childbearing potential: accepting to use adequate contraception in the trial period. If randomized to cladribine, women who use systemic hormonal contraception must accept to use additional barrier contraception during each treatment cycle and for four weeks after each treatment cycle.
* B) For men: If randomized to cladribine, accepting to use adequate contraception in the safety period of 6 months after each treatment cycle.
* Able to understand written and spoken Norwegian or English
* Able to complete treatment or follow-ups in the study (e.g. no contraindications for MRI, severe psychiatric disease, drug abuse or plans of moving)
* Signed informed consent

Exclusion Criteria:

* Any contraindication or increased risk of side-effects from rituximab or cladribine (such as ongoing acute or chronic infection, live vaccination less than 4 weeks before start of treatment or planned live vaccination, immunocompromised, previous or active malignant disease, ongoing glucocorticoid treatment or allergy against any products of the medication)
* Previous use of any of cladribine, rituximab, alemtuzumab, ocrelizumab, hematopoietic stem cell therapy (HSCT) or other immunosuppression with long lasting effects
* Fingolimod or natalizumab treatment within the last six months before inclusion
* Current pregnancy or lactation

Primary outcomes:
measure: Number of new or enlarging cerebral MRI T2 lesions
timeFrame: Week 12-96
Secondary outcomes:
measure: T2 lesions after 48 weeks
timeFrame: Week 12-48
measure: Annual clinical relapse rate (ARR)
timeFrame: Week -2 to 96
measure: Relapse-free patients
timeFrame: Week -2 to 96
measure: Disability progression
timeFrame: Week -2 to 96
measure: Change in disability
timeFrame: Week -2 to 96
Other outcomes:
measure: MRI from baseline
timeFrame: Week -6 - 96
measure: No evidence of disease activity (NEDA 3)
timeFrame: Week -2 - 96
measure: MRI contrast enhancing lesions
timeFrame: Week 12-96
measure: Patient reported outcome measures (PROMS) concerning work capacity
timeFrame: Week -2 - 96
measure: Patient reported outcome measures (PROMS) of fatigue
timeFrame: Week -2 - 96
measure: Patient reported outcome measures (PROMS) of anxiety and depression
timeFrame: Week -2 - 96
measure: Patient reported outcome measures (PROMS) of Health related quality of life
timeFrame: Week -2 - 96
measure: Patient reported outcome measures (PROMS) of treatment satisfaction
timeFrame: Week -2 - 96
measure: Treatment adherence
timeFrame: Week 48-96
measure: Safety endpoints blood sample: Occurrence of leukopenia indicated from blood samples
timeFrame: Week 0-96
measure: Safety endpoints blood sample: Occurrence of lymphopenia indicated from blood samples
timeFrame: Week 0-96
measure: Safety endpoints blood sample: Occurrence of thrombocytopenia indicated from blood samples
timeFrame: Week 0-96
measure: Safety endpoints blood sample: Occurrence of anemia indicated from blood samples
timeFrame: Week 0-96
measure: Safety endpoints adverse events
timeFrame: Week 0-96
measure: Blood sample neurofilament
timeFrame: Week -1 - 96
measure: Blood sample glial fibrillary acidic protein
timeFrame: Week -1 - 96
measure: Blood sample immunization antibodies for pneumococcus
timeFrame: Week -2 - 96
measure: Blood sample rituximab
timeFrame: Week -2 - 96
measure: Blood sample rituximab antibody
timeFrame: Week -2 - 96
measure: T2 lesion volume
timeFrame: Week 12-96
measure: Brain volumes
timeFrame: Week 12-96
measure: Advanced MRI analysis machine learning
timeFrame: Week 12-96
measure: Health economic analysis
timeFrame: -2 - 96
Locations:
city: Drammen
country: Norway
facility: Department of Neurology - Drammen, Vestre Viken HF
state: Buskerud
city: Lillehammer
country: Norway
facility: Department of Neurology - Lillehammer, SI Lillehammer
state: Oppland
city: Stavanger
country: Norway
facility: Department of Neurology, Stavanger universitetssykehus
state: Rogaland
city: Førde
country: Norway
facility: Department of Neurology - Førde, Helse Førde HF
state: Sogn Og Fjordane
city: Skien
country: Norway
facility: Department of Neurology - Skien, Sykehuset Telemark
state: Telemark
city: Tromsø
country: Norway
facility: Department of Neurology - Tromsø, University Hospital of North Norway
state: Troms
city: Kristiansand
country: Norway
facility: Department of Neurology - Kristiansand, Sørlandet sykehus HF
state: Vest-Agder
city: Tønsberg
country: Norway
facility: Department of Neurology - Tønsberg, Sykehuset i Vestfold HF
state: Vestfold
city: Oslo
country: Norway
facility: Department of Neurology, Oslo University Hospital
city: Trondheim
country: Norway
facility: St. Olavs Hospital, Trondheim University Hospital
city: Sarpsborg
country: Norway
facility: Department of Neurology - Kalnes, Sykehuset Østfold HF
state: Østfold
Study officials:
affiliation: Oslo University Hospital
name: Hanne Flistad Harbo, MD, PhD
role: STUDY_CHAIR
affiliation: Oslo University Hospital
name: Gro Owren Nygaard, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: