Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS) (NOR-MS)
Primary Purpose
Relapsing Multiple Sclerosis, Multiple Sclerosis
Status
Recruiting
Phase
Phase 3
Locations
Norway
Study Type
Interventional
Intervention
Rituximab
Cladribine
Sponsored by
About this trial
This is an interventional treatment trial for Relapsing Multiple Sclerosis focused on measuring multiple sclerosis, ms, rms, rituximab, cladribine, probe
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
Sites / Locations
- Department of Neurology - Drammen, Vestre Viken HF
- Department of Neurology - Lillehammer, SI LillehammerRecruiting
- Department of Neurology, Stavanger universitetssykehusRecruiting
- Department of Neurology - Førde, Helse Førde HF
- Department of Neurology - Skien, Sykehuset TelemarkRecruiting
- Department of Neurology - Tromsø, University Hospital of North Norway
- Department of Neurology - Kristiansand, Sørlandet sykehus HFRecruiting
- Department of Neurology - Tønsberg, Sykehuset i Vestfold HF
- Department of Neurology, Oslo University HospitalRecruiting
- St. Olavs Hospital, Trondheim University HospitalRecruiting
- Department of Neurology - Kalnes, Sykehuset Østfold HF
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Rituximab
Cladribine
Arm Description
Biosimilar rituximab concentrate for solution for infusion
Mavenclad oral cladribine tablets
Outcomes
Primary Outcome Measures
Number of new or enlarging cerebral MRI T2 lesions
The primary outcome is the number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 96
Secondary Outcome Measures
T2 lesions after 48 weeks
Number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 48
Annual clinical relapse rate (ARR)
Annual clinical relapse rate (ARR) at 24, 48 and 96 weeks
Relapse-free patients
Proportion of relapse-free patients at 24, 48 and 96 weeks
Disability progression
Proportion of patients with 24 weeks confirmed disability progression (24-CDP) on EDSS at 48 and 96 weeks
Change in disability
Change in disability on the Expanded Disability Status Scale (EDSS) from week -2 to 48 and 96 weeks. Disability progression is defined as an increase in EDSS of at least 1.5 points if baseline EDSS was 0, 1 point with baseline EDSS 0.5-4.5 and 0.5 point with baseline EDSS 5-5.5. EDSS is a scale from 0-10 measuring neurological disability.
Full Information
NCT ID
NCT04121403
First Posted
September 23, 2019
Last Updated
May 5, 2022
Sponsor
Oslo University Hospital
Collaborators
University of Oslo, Göteborg University, Sykehuset Ostfold, Sykehuset Telemark, Vestre Viken Hospital Trust, Sorlandet Hospital HF, Helse Stavanger HF, Sykehuset Innlandet HF, Sykehuset i Vestfold HF, Helse Forde, University Hospital of North Norway, St. Olavs Hospital
1. Study Identification
Unique Protocol Identification Number
NCT04121403
Brief Title
Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS)
Acronym
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
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 16, 2019 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Oslo University Hospital
Collaborators
University of Oslo, Göteborg University, Sykehuset Ostfold, Sykehuset Telemark, Vestre Viken Hospital Trust, Sorlandet Hospital HF, Helse Stavanger HF, Sykehuset Innlandet HF, Sykehuset i Vestfold HF, Helse Forde, University Hospital of North Norway, St. Olavs Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing Multiple Sclerosis, Multiple Sclerosis
Keywords
multiple sclerosis, ms, rms, rituximab, cladribine, probe
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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.
Masking
Outcomes Assessor
Masking Description
Two independent blinded radiologists assess the primary endpoint, New or enlarging T2 lesions. The blinding is asserted by transfer of deidentified MRIs to a Research server, from where the assessment is performed, so that the radiologists know only the ID, not the treatment allocation of the patients from whom the assess MRIs.
Allocation
Randomized
Enrollment
264 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Rituximab
Arm Type
Active Comparator
Arm Description
Biosimilar rituximab concentrate for solution for infusion
Arm Title
Cladribine
Arm Type
Active Comparator
Arm Description
Mavenclad oral cladribine tablets
Intervention Type
Biological
Intervention Name(s)
Rituximab
Intervention Description
Biosimilar rituximab concentrate for solution for infusion
Intervention Type
Drug
Intervention Name(s)
Cladribine
Other Intervention Name(s)
Mavenclad
Intervention Description
Mavenclad oral cladribine tablets
Primary Outcome Measure Information:
Title
Number of new or enlarging cerebral MRI T2 lesions
Description
The primary outcome is the number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 96
Time Frame
Week 12-96
Secondary Outcome Measure Information:
Title
T2 lesions after 48 weeks
Description
Number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 48
Time Frame
Week 12-48
Title
Annual clinical relapse rate (ARR)
Description
Annual clinical relapse rate (ARR) at 24, 48 and 96 weeks
Time Frame
Week -2 to 96
Title
Relapse-free patients
Description
Proportion of relapse-free patients at 24, 48 and 96 weeks
Time Frame
Week -2 to 96
Title
Disability progression
Description
Proportion of patients with 24 weeks confirmed disability progression (24-CDP) on EDSS at 48 and 96 weeks
Time Frame
Week -2 to 96
Title
Change in disability
Description
Change in disability on the Expanded Disability Status Scale (EDSS) from week -2 to 48 and 96 weeks. Disability progression is defined as an increase in EDSS of at least 1.5 points if baseline EDSS was 0, 1 point with baseline EDSS 0.5-4.5 and 0.5 point with baseline EDSS 5-5.5. EDSS is a scale from 0-10 measuring neurological disability.
Time Frame
Week -2 to 96
Other Pre-specified Outcome Measures:
Title
MRI from baseline
Description
Number of new or enlarging cerebral MRI T2 lesions from week -6 to week 12, 48 and 96
Time Frame
Week -6 - 96
Title
No evidence of disease activity (NEDA 3)
Description
NEDA 3 (no evidence of disease activity) defined as no new or enlarging T2 lesions, no clinical relapse and no confirmed disability progression on EDSS from before treatment in week -2 to 48 and 96 weeks. Rate of NEDA in the two treatment groups are compared.
Time Frame
Week -2 - 96
Title
MRI contrast enhancing lesions
Description
Number of new or persisting contrast enhancing (CE) MRI T1 lesions at 12, 48 and 96 weeks compared to previous scan
Time Frame
Week 12-96
Title
Patient reported outcome measures (PROMS) concerning work capacity
Description
Patient self-evaluation with PROMS at week
-2, 48 and 96 using questions about work capacity. The numerical values of the respones to the questions concerning adherence to work (percentage in full time work) in the two treatment groups are compared.
Time Frame
Week -2 - 96
Title
Patient reported outcome measures (PROMS) of fatigue
Description
Patient self-evaluation with PROMS at week
-2, 48 and 96 using questions about fatigue, the Fatigue Scale for Motor and Cognitive Functions (FSMC). The FSMC includes a Likert-type 5-point scale (ranging from 'does not apply at all' to 'applies completely') and produces a score between 1 and 5 for each scored question. Thus minimum value is 20 (no fatigue at all) and maximum value is 100 (severest grade of fatigue).The numerical values of the scores of the questionnaire in the two treatment groups are compared.
Time Frame
Week -2 - 96
Title
Patient reported outcome measures (PROMS) of anxiety and depression
Description
Patient self-evaluation with PROMS at week
-2, 48 and 96 using questions concerning anxiety and depression, Hospital Anxiety and Depression Scale (HADS). Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression.Thus minimum value is 0 (no anxiety or depression at all) and maximum value is 21 (severest grade of anxiety or depression).The numerical values of the scores of the questionnaire in the two treatment groups are compared.
Time Frame
Week -2 - 96
Title
Patient reported outcome measures (PROMS) of Health related quality of life
Description
Patient self-evaluation with PROMS at week
-2, 48 and 96 using questions concerning Health Related Quality of Life using the questionnaire EuroQol 5 Dimension scale (EQ5D). The respondents are asked to choose one of five statements which best describes their health status. Rated level can be coded as a number between 1-5, which indicates having no problems for 1, having slight problems for 2, having moderate problems for 3, having severe problems for 4, and having extreme problems for 5.The numerical values of the scores of the questionnaires in the two treatment groups are compared.
Time Frame
Week -2 - 96
Title
Patient reported outcome measures (PROMS) of treatment satisfaction
Description
Patient self-evaluation with PROMS at week 48 and 96 using questions concerning treatment satisfaction, measured with the Treatment Satisfaction Questionnaire for Medicine (TSQM 1.4). The TSQM consists of fourteen questions distributed across four domains: effectiveness, side effects, convenience and global satisfaction. The score ranges from 0 to 100 in each domain and, the higher the score, the greater the patient satisfaction with medication. The numerical values of the scores of the questionnaires in the two treatment groups are compared.
Time Frame
Week -2 - 96
Title
Treatment adherence
Description
Proportion of patients not receiving treatment per protocol at week 48 and 96
Time Frame
Week 48-96
Title
Safety endpoints blood sample: Occurrence of leukopenia indicated from blood samples
Description
Occurrence of leukopenia grade 1 or 2 (mild), 3 or 4 (severe), according to World Health Organization (WH) using indicated from blood samples between first treatment at week 0 and end of study at week 96
Time Frame
Week 0-96
Title
Safety endpoints blood sample: Occurrence of lymphopenia indicated from blood samples
Description
Occurrence of lymphopenia grade 1 or 2 (mild), 3 or 4 (severe), according to World Health Organization (WH) using indicated from blood samples between first treatment at week 0 and end of study at week 96
Time Frame
Week 0-96
Title
Safety endpoints blood sample: Occurrence of thrombocytopenia indicated from blood samples
Description
Occurrence of thrombocytopenia grade 1 or 2 (mild), 3 or 4 (severe), according to World Health Organization (WH) using indicated from blood samples between first treatment at week 0 and end of study at week 96
Time Frame
Week 0-96
Title
Safety endpoints blood sample: Occurrence of anemia indicated from blood samples
Description
Occurrence of anemia grade 1 or 2 (mild), 3 or 4 (severe), according to World Health Organization (WH) using indicated from blood samples between first treatment at week 0 and end of study at week 96
Time Frame
Week 0-96
Title
Safety endpoints adverse events
Description
Adverse events (AE), serious adverse events (SAE) and suspected unexpected serious adverse reactions (SUSAR) reported between first treatment at week 0 and end of study at week 96
Time Frame
Week 0-96
Title
Blood sample neurofilament
Description
Concentration of blood serum levels of neurofilament (NfL) at week -1, 51 and 96 weeks in the two treatment Groups are compared.
Time Frame
Week -1 - 96
Title
Blood sample glial fibrillary acidic protein
Description
Concentration of blood serum levels of glial fibrillary acidic protein (GFAP) at week -1, 51 and 96 weeks in the two treatment Groups are compared.
Time Frame
Week -1 - 96
Title
Blood sample immunization antibodies for pneumococcus
Description
Specific antibody titers for pneumococcus at week -2, 8, 51 and 96 are compared in the treatment Groups after immunization
Time Frame
Week -2 - 96
Title
Blood sample rituximab
Description
Levels of rituximab in serum at week 8, 51 and 96 is related to MRI, relapse rate and EDSS in the rituximab treatment group
Time Frame
Week -2 - 96
Title
Blood sample rituximab antibody
Description
Specific antibody titers at week 8, 51 and 96 of rituximab antibodies are correlated With rituximab concentration, MRI, EDSS and relapse rate in the rituximab treatment group
Time Frame
Week -2 - 96
Title
T2 lesion volume
Description
T2 lesion volume at 12, 48 and 96 weeks are compared between the treatment groups
Time Frame
Week 12-96
Title
Brain volumes
Description
Brain volumes at 12, 48 and 96 weeks are compared between the treatment groups
Time Frame
Week 12-96
Title
Advanced MRI analysis machine learning
Description
Estimation of "Brain Age" at 12, 48 and 96 weeks Results of MRI analyses with and without AI and/or machine learning
Time Frame
Week 12-96
Title
Health economic analysis
Description
Direct and indirect treatment costs (medication, out-patient clinic visits, hospitalizations related to treatment), working status) and health related quality of life (EQ5D)
Time Frame
-2 - 96
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gro Owren Nygaard, MD, PhD
Phone
91757192
Ext
+47
Email
uxgryg@ous-hf.no
First Name & Middle Initial & Last Name or Official Title & Degree
Helle Stangeland, MSc
Phone
90029660
Ext
+47
Email
stahel@ous-hf.no
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hanne Flistad Harbo, MD, PhD
Organizational Affiliation
Oslo University Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Gro Owren Nygaard, MD, PhD
Organizational Affiliation
Oslo University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Neurology - Drammen, Vestre Viken HF
City
Drammen
State/Province
Buskerud
ZIP/Postal Code
3004
Country
Norway
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cecilia Smith Simonsen, MD, PhDfell
Phone
98673256
Ext
+47
Email
cecsim@vestreviken.no
Facility Name
Department of Neurology - Lillehammer, SI Lillehammer
City
Lillehammer
State/Province
Oppland
ZIP/Postal Code
2629
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tone Hognestad, MD
Phone
91506200
Ext
+47
Email
Tone.Hognestad@sykehuset-innlandet.no
Facility Name
Department of Neurology, Stavanger universitetssykehus
City
Stavanger
State/Province
Rogaland
ZIP/Postal Code
4068
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alok Bhan, MD
Phone
97109768
Ext
+47
Email
alok.bhan@sus.no
Facility Name
Department of Neurology - Førde, Helse Førde HF
City
Førde
State/Province
Sogn Og Fjordane
ZIP/Postal Code
6807
Country
Norway
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristin Lif Breivik, MD
Phone
57839000
Ext
+47
Email
kristin.lif.breivik@helse-forde.no
Facility Name
Department of Neurology - Skien, Sykehuset Telemark
City
Skien
State/Province
Telemark
ZIP/Postal Code
3710
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Heidi Flemmen, MD, PhDfell
Phone
35003500
Ext
+47
Email
fleh@sthf.no
Facility Name
Department of Neurology - Tromsø, University Hospital of North Norway
City
Tromsø
State/Province
Troms
ZIP/Postal Code
9038
Country
Norway
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Margitta Kampman, MD, PhD
Phone
77626000
Ext
+47
Email
margitta.kampman@unn.no
Facility Name
Department of Neurology - Kristiansand, Sørlandet sykehus HF
City
Kristiansand
State/Province
Vest-Agder
ZIP/Postal Code
4604
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Åslaug Lorentzen, MD, PhD
Phone
90610600
Ext
+47
Email
aaslor@sshf.no
Facility Name
Department of Neurology - Tønsberg, Sykehuset i Vestfold HF
City
Tønsberg
State/Province
Vestfold
ZIP/Postal Code
3103
Country
Norway
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stein Bjelland, MD
Phone
33342000
Ext
+47
Email
Stein.Bjelland@siv.no
First Name & Middle Initial & Last Name & Degree
Kennet Idland, MD
Facility Name
Department of Neurology, Oslo University Hospital
City
Oslo
ZIP/Postal Code
0424
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gro Owren Nygaard, MD, PhD
Phone
91757192
Ext
+47
Email
uxgryg@ous-hf.no
First Name & Middle Initial & Last Name & Degree
Helle Stangeland, MSc
Phone
90029660
Ext
+47
Email
stahel@ous-hf.no
First Name & Middle Initial & Last Name & Degree
Einar August Høgestøl, MD, PhDfell
First Name & Middle Initial & Last Name & Degree
Elisabeth Gulowsen Celius, MD, dr med
First Name & Middle Initial & Last Name & Degree
Pål Berg-Hansen, MD, PhD
First Name & Middle Initial & Last Name & Degree
Hiba Bashari, MD
First Name & Middle Initial & Last Name & Degree
Iselin Marie Wedding, MD, PhD
Facility Name
St. Olavs Hospital, Trondheim University Hospital
City
Trondheim
ZIP/Postal Code
7006
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristin Wesnes, MD
Phone
72 57 30 00
Ext
+47
Email
kristin.wesnes@stolav.no
Facility Name
Department of Neurology - Kalnes, Sykehuset Østfold HF
City
Sarpsborg
State/Province
Østfold
ZIP/Postal Code
1714
Country
Norway
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charlotte Natvig Olafsen, MD
Phone
95968689
Ext
+47
Email
charlottenatvig@hotmail.com
12. IPD Sharing Statement
Learn more about this trial
Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS)
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