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| Name | Class |
|---|---|
| University of Oslo | OTHER |
| Sykehuset Ostfold | OTHER |
| Sykehuset Telemark | OTHER_GOV |
| Vestre Viken Hospital Trust |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rituximab | Active Comparator | Biosimilar rituximab concentrate for solution for infusion |
|
| Cladribine | Active Comparator | Mavenclad oral cladribine tablets |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Biological | Biosimilar rituximab concentrate for solution for infusion |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Week 12-96 |
| Measure | Description | Time Frame |
|---|---|---|
| T2 lesions after 48 weeks | Number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 48 | Week 12-48 |
| Annual clinical relapse rate (ARR) | Annual clinical relapse rate (ARR) at 24, 48 and 96 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| MRI from baseline | Number of new or enlarging cerebral MRI T2 lesions from week -6 to week 12, 48 and 96 | Week -6 - 96 |
| No evidence of disease activity (NEDA 3) | 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hanne Flistad Harbo, MD, PhD | Oslo University Hospital | Study Chair |
| Gro Owren Nygaard, MD, PhD | Oslo University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Neurology - Drammen, Vestre Viken HF | Drammen | Buskerud | 3004 | Norway | ||
| Department of Neurology - Lillehammer, SI Lillehammer |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| D017338 | Cladribine |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| OTHER |
| Sorlandet Hospital HF | OTHER_GOV |
| Helse Stavanger HF | OTHER_GOV |
| Sykehuset Innlandet HF | OTHER |
| Sykehuset i Vestfold HF | OTHER |
| University Hospital of North Norway | OTHER |
| St. Olavs Hospital | OTHER |
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.
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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.
| Cladribine |
| Drug |
Mavenclad oral cladribine tablets |
|
|
| Week -2 to 96 |
| Relapse-free patients | Proportion of relapse-free patients at 24, 48 and 96 weeks | Week -2 to 96 |
| Disability progression | Proportion of patients with 24 weeks confirmed disability progression (24-CDP) on EDSS at 48 and 96 weeks | Week -2 to 96 |
| 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. | Week -2 to 96 |
| Week -2 - 96 |
| MRI contrast enhancing lesions | Number of new or persisting contrast enhancing (CE) MRI T1 lesions at 12, 48 and 96 weeks compared to previous scan | Week 12-96 |
| Patient reported outcome measures (PROMS) concerning work capacity | 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. | Week -2 - 96 |
| Patient reported outcome measures (PROMS) of fatigue | 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. | Week -2 - 96 |
| Patient reported outcome measures (PROMS) of anxiety and depression | 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. | Week -2 - 96 |
| Patient reported outcome measures (PROMS) of Health related quality of life | 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. | Week -2 - 96 |
| Patient reported outcome measures (PROMS) of treatment satisfaction | 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. | Week -2 - 96 |
| Treatment adherence | Proportion of patients not receiving treatment per protocol at week 48 and 96 | Week 48-96 |
| Safety endpoints blood sample: Occurrence of leukopenia indicated from blood samples | 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 | Week 0-96 |
| Safety endpoints blood sample: Occurrence of lymphopenia indicated from blood samples | 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 | Week 0-96 |
| Safety endpoints blood sample: Occurrence of thrombocytopenia indicated from blood samples | 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 | Week 0-96 |
| Safety endpoints blood sample: Occurrence of anemia indicated from blood samples | 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 | Week 0-96 |
| Safety endpoints adverse events | 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 | Week 0-96 |
| Blood sample neurofilament | Concentration of blood serum levels of neurofilament (NfL) at week -1, 51 and 96 weeks in the two treatment Groups are compared. | Week -1 - 96 |
| Blood sample glial fibrillary acidic protein | 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. | Week -1 - 96 |
| Blood sample immunization antibodies for pneumococcus | Specific antibody titers for pneumococcus at week -2, 8, 51 and 96 are compared in the treatment Groups after immunization | Week -2 - 96 |
| Blood sample rituximab | Levels of rituximab in serum at week 8, 51 and 96 is related to MRI, relapse rate and EDSS in the rituximab treatment group | Week -2 - 96 |
| Blood sample rituximab antibody | 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 | Week -2 - 96 |
| T2 lesion volume | T2 lesion volume at 12, 48 and 96 weeks are compared between the treatment groups | Week 12-96 |
| Brain volumes | Brain volumes at 12, 48 and 96 weeks are compared between the treatment groups | Week 12-96 |
| Advanced MRI analysis machine learning | Estimation of "Brain Age" at 12, 48 and 96 weeks Results of MRI analyses with and without AI and/or machine learning | Week 12-96 |
| Health economic analysis | Direct and indirect treatment costs (medication, out-patient clinic visits, hospitalizations related to treatment), working status) and health related quality of life (EQ5D) | -2 - 96 |
| Lillehammer |
| Oppland |
| 2629 |
| Norway |
| Department of Neurology, Stavanger universitetssykehus | Stavanger | Rogaland | 4068 | Norway |
| Department of Neurology - Førde, Helse Førde HF | Førde | Sogn Og Fjordane | 6807 | Norway |
| Department of Neurology - Skien, Sykehuset Telemark | Skien | Telemark | 3710 | Norway |
| Department of Neurology - Tromsø, University Hospital of North Norway | Tromsø | Troms | 9038 | Norway |
| Department of Neurology - Kristiansand, Sørlandet sykehus HF | Kristiansand | Vest-Agder | 4604 | Norway |
| Department of Neurology - Tønsberg, Sykehuset i Vestfold HF | Tønsberg | Vestfold | 3103 | Norway |
| Department of Neurology, Oslo University Hospital | Oslo | 0424 | Norway |
| St. Olavs Hospital, Trondheim University Hospital | Trondheim | 7006 | Norway |
| Department of Neurology - Kalnes, Sykehuset Østfold HF | Sarpsborg | Østfold fylke | 1714 | Norway |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D015762 | 2-Chloroadenosine |
| D000241 | Adenosine |
| D011684 | Purine Nucleosides |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D003839 | Deoxyadenosines |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |