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

Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS) A Prospective Randomized Open-label Blinded Endpoint (PROBE) Multicenter Non-inferiority Study

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Relapsing Multiple Sclerosis
• Intervention / Treatment: Biological: Rituximab; Drug: Cladribine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 264
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Gro Owren Nygaard, MD, PhD; Phone Number: +47 91757192; Email: uxgryg@ous-hf.no
• Study Contact Backup: Name: Helle Stangeland, MSc; Phone Number: +47 90029660; Email: stahel@ous-hf.no

Study Locations

• Norway
  • Oslo, Norway, 0424
    • Recruiting
    • Department of Neurology, Oslo University Hospital
    • Contact: Gro Owren Nygaard, MD, PhD; Phone Number: +47 91757192; Email: uxgryg@ous-hf.no
    • Contact: Helle Stangeland, MSc; Phone Number: +47 90029660; Email: 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
  • Trondheim, Norway, 7006
    • Recruiting
    • St. Olavs Hospital, Trondheim University Hospital
    • Contact: Kristin Wesnes, MD; Phone Number: +47 72 57 30 00; Email: kristin.wesnes@stolav.no
  • Buskerud
    • Drammen, Buskerud, Norway, 3004
      • Not yet recruiting
      • Department of Neurology - Drammen, Vestre Viken HF
      • Contact: Cecilia Smith Simonsen, MD, PhDfell; Phone Number: +47 98673256; Email: cecsim@vestreviken.no
  • Oppland
    • Lillehammer, Oppland, Norway, 2629
      • Recruiting
      • Department of Neurology - Lillehammer, SI Lillehammer
      • Contact: Tone Hognestad, MD; Phone Number: +47 91506200; Email: Tone.Hognestad@sykehuset-innlandet.no
  • Rogaland
    • Stavanger, Rogaland, Norway, 4068
      • Recruiting
      • Department of Neurology, Stavanger universitetssykehus
      • Contact: Alok Bhan, MD; Phone Number: +47 97109768; Email: alok.bhan@sus.no
  • Sogn Og Fjordane
    • Førde, Sogn Og Fjordane, Norway, 6807
      • Not yet recruiting
      • Department of Neurology - Førde, Helse Førde HF
      • Contact: Kristin Lif Breivik, MD; Phone Number: +47 57839000; Email: kristin.lif.breivik@helse-forde.no
  • Telemark
    • Skien, Telemark, Norway, 3710
      • Recruiting
      • Department of Neurology - Skien, Sykehuset Telemark
      • Contact: Heidi Flemmen, MD, PhDfell; Phone Number: +47 35003500; Email: fleh@sthf.no
  • Troms
    • Tromsø, Troms, Norway, 9038
      • Not yet recruiting
      • Department of Neurology - Tromsø, University Hospital of North Norway
      • Contact: Margitta Kampman, MD, PhD; Phone Number: +47 77626000; Email: margitta.kampman@unn.no
  • Vest-Agder
    • Kristiansand, Vest-Agder, Norway, 4604
      • Recruiting
      • Department of Neurology - Kristiansand, Sørlandet sykehus HF
      • Contact: Åslaug Lorentzen, MD, PhD; Phone Number: +47 90610600; Email: aaslor@sshf.no
  • Vestfold
    • Tønsberg, Vestfold, Norway, 3103
      • Not yet recruiting
      • Department of Neurology - Tønsberg, Sykehuset i Vestfold HF
      • Contact: Stein Bjelland, MD; Phone Number: +47 33342000; Email: Stein.Bjelland@siv.no
      • Sub-Investigator: Kennet Idland, MD
  • Østfold
    • Sarpsborg, Østfold, Norway, 1714
      • Not yet recruiting
      • Department of Neurology - Kalnes, Sykehuset Østfold HF
      • Contact: Charlotte Natvig Olafsen, MD; Phone Number: +47 95968689; Email: charlottenatvig@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Mavenclad

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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

Other Outcome Measures

Outcome Measure	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.	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

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Vestre Viken Hospital Trust; University of Oslo; Göteborg University; University Hospital of North Norway; Helse Stavanger HF; Sorlandet Hospital HF; St. Olavs Hospital; Sykehuset Innlandet HF; Sykehuset Telemark; Helse Forde; Sykehuset Ostfold; Sykehuset i Vestfold HF
• Investigators: Study Chair: Hanne Flistad Harbo, MD, PhD, Oslo University Hospital; Principal Investigator: Gro Owren Nygaard, MD, PhD, Oslo University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2019
• Primary Completion (Anticipated): July 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: September 23, 2019
• First Submitted That Met QC Criteria: October 8, 2019
• First Posted (Actual): October 9, 2019

Study Record Updates

• Last Update Posted (Actual): May 6, 2022
• Last Update Submitted That Met QC Criteria: May 5, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: rituximab; multiple sclerosis; probe; cladribine; ms; rms
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab; Cladribine
• Other Study ID Numbers: 11383

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No