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Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS) (NOR-MS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04121403
Recruitment Status : Recruiting
First Posted : October 9, 2019
Last Update Posted : October 15, 2019
Sponsor:
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
Information provided by (Responsible Party):
Gro Owren Nygaard, Oslo University Hospital

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.

Condition or disease Intervention/treatment Phase
Relapsing Multiple Sclerosis Multiple Sclerosis Biological: Rituximab Drug: Cladribine Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 264 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Single (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.
Primary Purpose: Treatment
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
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Rituximab
Biosimilar rituximab concentrate for solution for infusion
Biological: Rituximab
Biosimilar rituximab concentrate for solution for infusion

Active Comparator: Cladribine
Mavenclad oral cladribine tablets
Drug: Cladribine
Mavenclad oral cladribine tablets
Other Name: Mavenclad




Primary Outcome Measures :
  1. Number of new or enlarging cerebral MRI T2 lesions [ Time Frame: Week 12-96 ]
    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 :
  1. T2 lesions after 48 weeks [ Time Frame: Week 12-48 ]
    Number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 48

  2. Annual clinical relapse rate (ARR) [ Time Frame: Week -2 to 96 ]
    Annual clinical relapse rate (ARR) at 24, 48 and 96 weeks

  3. Relapse-free patients [ Time Frame: Week -2 to 96 ]
    Proportion of relapse-free patients at 24, 48 and 96 weeks

  4. Disability progression [ Time Frame: Week -2 to 96 ]
    Proportion of patients with 24 weeks confirmed disability progression (24-CDP) on EDSS at 48 and 96 weeks

  5. Change in disability [ Time Frame: Week -2 to 96 ]
    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.


Other Outcome Measures:
  1. MRI from baseline [ Time Frame: Week -6 - 96 ]
    Number of new or enlarging cerebral MRI T2 lesions from week -6 to week 12, 48 and 96

  2. No evidence of disease activity (NEDA 3) [ Time Frame: Week -2 - 96 ]
    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.

  3. MRI contrast enhancing lesions [ Time Frame: Week 12-96 ]
    Number of new or persisting contrast enhancing (CE) MRI T1 lesions at 12, 48 and 96 weeks compared to previous scan

  4. Patient reported outcome measures (PROMS) concerning work capacity [ Time Frame: Week -2 - 96 ]

    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.


  5. Patient reported outcome measures (PROMS) of fatigue [ Time Frame: Week -2 - 96 ]

    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.


  6. Patient reported outcome measures (PROMS) of anxiety and depression [ Time Frame: Week -2 - 96 ]

    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.


  7. Patient reported outcome measures (PROMS) of Health related quality of life [ Time Frame: Week -2 - 96 ]

    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.


  8. Patient reported outcome measures (PROMS) of treatment satisfaction [ Time Frame: Week -2 - 96 ]
    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.

  9. Treatment adherence [ Time Frame: Week 48-96 ]
    Proportion of patients not receiving treatment per protocol at week 48 and 96

  10. Safety endpoints blood sample: Occurrence of leukopenia indicated from blood samples [ Time Frame: Week 0-96 ]
    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

  11. Safety endpoints blood sample: Occurrence of lymphopenia indicated from blood samples [ Time Frame: Week 0-96 ]
    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

  12. Safety endpoints blood sample: Occurrence of thrombocytopenia indicated from blood samples [ Time Frame: Week 0-96 ]
    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

  13. Safety endpoints blood sample: Occurrence of anemia indicated from blood samples [ Time Frame: Week 0-96 ]
    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

  14. Safety endpoints adverse events [ Time Frame: Week 0-96 ]
    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

  15. Blood sample neurofilament [ Time Frame: Week -1 - 96 ]
    Concentration of blood serum levels of neurofilament (NfL) at week -1, 51 and 96 weeks in the two treatment Groups are compared.

  16. Blood sample glial fibrillary acidic protein [ Time Frame: Week -1 - 96 ]
    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.

  17. Blood sample immunization antibodies for pneumococcus [ Time Frame: Week -2 - 96 ]
    Specific antibody titers for pneumococcus at week -2, 8, 51 and 96 are compared in the treatment Groups after immunization

  18. Blood sample rituximab [ Time Frame: Week -2 - 96 ]
    Levels of rituximab in serum at week 8, 51 and 96 is related to MRI, relapse rate and EDSS in the rituximab treatment group

  19. Blood sample rituximab antibody [ Time Frame: Week -2 - 96 ]
    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

  20. T2 lesion volume [ Time Frame: Week 12-96 ]
    T2 lesion volume at 12, 48 and 96 weeks are compared between the treatment groups

  21. Brain volumes [ Time Frame: Week 12-96 ]
    Brain volumes at 12, 48 and 96 weeks are compared between the treatment groups

  22. Advanced MRI analysis machine learning [ Time Frame: Week 12-96 ]
    Estimation of "Brain Age" at 12, 48 and 96 weeks Results of MRI analyses with and without AI and/or machine learning

  23. Health economic analysis [ Time Frame: -2 - 96 ]
    Direct and indirect treatment costs (medication, out-patient clinic visits, hospitalizations related to treatment), working status) and health related quality of life (EQ5D)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Current pregnancy or lactation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04121403


Contacts
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Contact: Gro Owren Nygaard, MD, PhD 91757192 ext +47 uxgryg@ous-hf.no
Contact: Helle Stangeland, MSc 90029660 ext +47 stahel@ous-hf.no

Locations
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Norway
Department of Neurology - Drammen, Vestre Viken HF Not yet recruiting
Drammen, Buskerud, Norway, 3004
Contact: Cecilia Smith Simonsen, MD, PhDfell    98673256 ext +47    cecsim@vestreviken.no   
Department of Neurology - Lillehammer, SI Lillehammer Not yet recruiting
Lillehammer, Oppland, Norway, 2629
Contact: Tone Hognestad, MD    91506200 ext +47    Tone.Hognestad@sykehuset-innlandet.no   
Department of Neurology, Stavanger universitetssykehus Not yet recruiting
Stavanger, Rogaland, Norway, 4068
Contact: Elisabeth Farbu, MD, PhD    51518000 ext +47    elisabeth.farbu@sus.no   
Department of Neurology - Førde, Helse Førde HF Not yet recruiting
Førde, Sogn Og Fjordane, Norway, 6807
Contact: Kristin Lif Breivik, MD    57839000 ext +47    kristin.lif.breivik@helse-forde.no   
Department of Neurology - Skien, Sykehuset Telemark Not yet recruiting
Skien, Telemark, Norway, 3710
Contact: Heidi Flemmen, MD, PhDfell    35003500 ext +47    fleh@sthf.no   
Department of Neurology - Tromsø, University Hospital of North Norway Not yet recruiting
Tromsø, Troms, Norway, 9038
Contact: Margitta Kampman, MD, PhD    77626000 ext +47    margitta.kampman@unn.no   
Department of Neurology - Kristiansand, Sørlandet sykehus HF Not yet recruiting
Kristiansand, Vest-Agder, Norway, 4604
Contact: Åslaug Lorentzen, MD, PhD    90610600 ext +47    aaslor@sshf.no   
Department of Neurology - Tønsberg, Sykehuset i Vestfold HF Not yet recruiting
Tønsberg, Vestfold, Norway, 3103
Contact: Stein Bjelland, MD    33342000 ext +47    Stein.Bjelland@siv.no   
Sub-Investigator: Kennet Idland, MD         
Department of Neurology, Oslo University Hospital Recruiting
Oslo, Norway, 0424
Contact: Gro Owren Nygaard, MD, PhD    91757192 ext +47    uxgryg@ous-hf.no   
Contact: Helle Stangeland, MSc    90029660 ext +47    stahel@ous-hf.no   
Sub-Investigator: Einar August Høgestøl, MD, PhDfell         
Sub-Investigator: Elisabeth Gulowsen Celius, MD, dr med         
Sub-Investigator: Pål Berg-Hansen, MD, PhD         
Sub-Investigator: Hiba Bashari, MD         
Sub-Investigator: Iselin Marie Wedding, MD, PhD         
Department of Neurology - Kalnes, Sykehuset Østfold HF Not yet recruiting
Sarpsborg, Østfold, Norway, 1714
Contact: Charlotte Natvig Olafsen, MD    95968689 ext +47    charlottenatvig@hotmail.com   
Sponsors and Collaborators
Oslo University Hospital
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
Investigators
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Study Chair: Hanne Flistad Harbo, MD, PhD Oslo University Hospital
Principal Investigator: Gro Owren Nygaard, MD, PhD Oslo University Hospital

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Responsible Party: Gro Owren Nygaard, Gro Owren Nygaard, MD, PhD, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT04121403     History of Changes
Other Study ID Numbers: 11383
First Posted: October 9, 2019    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gro Owren Nygaard, Oslo University Hospital:
multiple sclerosis
ms
rms
rituximab
cladribine
probe
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Cladribine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immunosuppressive Agents