Multiple sclerosis (MS)

International Coordinating Investigator: Lars Bø

A randomized clinical trial for comparing autologous hematopoietic stem cell transplantation (HSCT) versus alemtuzumab in MS (The RAM-MS study https://helse-bergen.no/ram-ms)
HSCT is a promising therapy in MS, but limited data from randomized clinical trials (RCTs) are available. A Norwegian health technology assessment (HTA) confirmed this challenge, and concluded that further studies are needed (https://nyemetoder.no/metoder/autolog-stamcelletransplantasjon/). Haukeland University Hospital has been the national centre for such MS-therapy in Norway, and are currently organizing a multicentre, international randomized clinical trial to evaluate the efficacy and safety of autologous HSCT compared to standard high-efficacy therapies in MS (https://clinicaltrials.gov/ & NCT03477500). The trial is multidisciplinary and involves a close collaboration between the department of haematology (investigators Anne Kristine Lehmann and Aymen Ahmed), department of transfusion medicine and immunology (investigator Einar Kristoffersen) and the department of neurology (investigator Øivind Torkildsen).

The objective is to study whether HSCT is a safe and effective therapy in highly active multiple sclerosis compared to standard high-efficacy therapies, and to establish sufficient evidence to support routine use of HSCT in MS.
The primary endpoint of the study is the proportion of patients with no evidence of disease activity (NEDA) after 2 year (96 weeks) and further after 5 year (240 weeks).

Currently, about 45 patients have been enrolled in the study, and during the next years, more patients will be included to a maximum of n=100. Patients from all over Norway are included for screening and randomization at Haukeland University Hospital (HUS). Patients randomized for HSCT are treated at HUS, and those for standard highly active MS-therapy are treated at their local hospitals. Blood sampling, imaging and clinical scoring of the Norwegian patients are performed at HUS. The patients are primarily followed for two years and further for another 3 years in the extension phase of a total of 5 years. Patients are also recruited at centres in Sweden, Denmark and The Netherlands.

Newsletter (Norwgian)

News 01
News 02
Newsletter 1
Newsletter 2
Newsletter 3
Newsletter 4
Newsletter 5
Newsletter 6
Newsletter 7
Newsletter 8
Newsletter 9
Newsletter 10
Newsletter 11
Newsletter 12
Newsletter 14
Newsletter 15
Newsletter 17

Principal Investigator: Øivind Torkildsen

The Ocrelizumab VErsus Rituximab off-Label at the Onset of Relapsing MS Disease; The OVERLORD-MS study;

B cell depletion therapies (rituximab, ocrelizumab, ofatumumab) are proven highly effective in MS. A very recent Norwegian health technology assessment (HTA) indicates similar treatment effects from rituximab and ocrelizumab – but clearly, state that more data, preferably from a RCT is needed (https://nyemetoder.no/Documents/Rapporter/disease-modifying-treatments-for-relapsing- remitting-multiple-sclerosis-including-rituximab-hta-rapport-2019.pdf/). Rituximab has been used for the treatment of rheumatologically diseases and haematological cancers since 1998, and due to patency expire, costs only a fraction of ocrelizumab. If rituximab proves to have similar effects as ocrelizumab, it may therefore substantially reduce the annual cost for MS-therapy, and give MS-patients access to highly effective treatment at an earlier time point. In this study, we therefore aim to compare the efficacy and safety of rituximab to ocrelizumab for early treatment in MS.

The objectives of this non-inferiority study are to evaluate if rituximab has comparably efficacy and safety as ocrelizumab in the treatment of newly diagnosed patients with MS.
The primary endpoint of the study is the proportion of patients free of new T2 magnetic resonance imaging (MRI) lesions between month 6 and month 24 (two years).

The study (https://clinicaltrials.gov/ & NCT04578639 is approved by the Regional Committees for Medical and Health Research Ethics Western Norway, and the Norwegian Medicines Agency. The first patient will be included in late October 2020 at Haukeland University Hospital.

Newsletter 1 (Norwegian)
Newsletter 2 (Norwegian)
Newsletter 3 (Norwegian)
Newsletter 4 (Norwegian)
Newsletter 5 (Norwegian)
Newsletter 6 (Norwegian)
Newsletter 7 (Norwegian)
Newsletter 8 (Norwegian)
Newsletter 9 (Norwegian)
Newsletter 10 (Norwegian)
Newsletter 11 (Norwegian)
Newsletter 12 (Norwegian)
Newsletter 13 (Norwegian)
Newsletter 14 (Norwegian)
Newsletter 15 (Norwegian)
Newsletter 16 (Norwegian)
Newsletter 17 (Norwegian)
Newsletter 18 (Norwegian)

Coordinating Investigator: Lars Bø

Study of Mesenchymal Autologous stem cells as Regenerative Treatment for Multiple Sclerosis (SMART-MS).

There is currently no effective treatment available to promote repair of damage to the central nervous system (CNS), caused by multiple sclerosis (MS), and thereby reverse neurological disability. Mesenchymal stem cells (MSCs) have the potential to induce neuronal repair through multiple neuro-regenerative mechanisms, including remyelination, immunomodulation and stimulation of endogenous cerebral stem cells. In this study, we aim to investigate the potential of regenerative stem cell treatment with MSCs in MS and to increase the understanding of the underlying mechanisms of action.

The objectives of this study are to assess if treatment with autologous bone marrow derived MSCs is feasible, safe and promotes neural repair in patients with progressive MS.

The study is performed as a collaboration between Haukeland University Hospital, the Tissue Engineering Group at the University of Bergen, the University Hospital in Ulm, Akershus University Hospital in Lørenskog, St Olav’s Hospital, in Trondheim, and the University Hospital of North Norway, Tromsø

Currently, the study is under evaluation by the Regional Committees for Medical and Health Research Ethics Western Norway, and the Norwegian Medicines Agency. Estimated study start; Q1-2, 2021.

Principal investigator: Kjell-Morten Myhr

Evidence suggests that mitochondrial dysfunction occurs in the brain of patients with MS, and may play a particularly important role in the neurodegenerative processes underlying progressive multiple sclerosis (PMS). This mitochondrial dysfunction is predicted to compromise neuronal metabolism and survival, including ATP deficiency and decreased rate of mitochondrial NADH oxidation, leading to depletion of neuronal NAD, one of the most essential molecules for bioenergetic conversion and signalling in human cells. We propose that increase of neuronal NAD levels may improve mitochondrial function and rescue neuronal dysfunction and death in PMS. We therefore aim to investigate if oral nicotinamide riboside (NR), a NAD precursor, can improve neuronal NAD deficiency and mitochondrial dysfunction in patients with PMS.

The objectives are to study if oral nicotinamide riboside (NR) reduce disability progression in PMS, and thus is a novel therapy for this devastating MS disease course.

Currently, the study protocol is under preparation for submission to the Regional Committee for Medical and Health Research Ethics Western Norway, and the Norwegian Medicines Agency Q-1, 2020, and estimated study start; Q2-3, 2021.

Principal Investigator: Øivind Torkildsen

B-cell depletion therapies are highly effective in relapsing-remitting MS (RRMS). Rituximab seems to have a similar efficacy and safety profile to ocrelizumab, but data on optimal dosing is limited and largely based on various off-label regimens. The most commonly used dosing regimen in Norway is a single starting dose of 1000 mg intravenous infusion, followed by maintenance doses of 500 mg every 6 months indefinitely. Rituximab is well tolerated and the frequency of reported side effects is low, but infections, neutropenia and hypogammaglobinaemia occur in some patients and can be associated with serious adverse events or therapy discontinuation. Real world data indicate that B-cells may be depleted for a longer period than the current dosing interval, possibly up to 12 months or more, and prolonged dose intervals (i.e. postponed doses due to intercurrent illness or pregnancy planning) seems safe.

Based on these observations, we aim to investigate if extended dosing intervals from 6 to 12 months is safe and effective in RRMS. We plan to enrol clinical stable patients that have received a standard dose of rituximab at 6 months intervals for 1-3 years. Patients will be randomized into maintenance therapy (rituximab 500 mg) groups of either 6 month or 12 month dosing intervals. Participants will be closely monitored by clinical evaluation (including standardized scoring), magnetic resonance imaging (MRI) and immune cell phenotyping, including CD19 and CD27 B-cell monitoring.

The objectives of the trial are to evaluate efficacy of extended dosing (12 months) interval of rituximab versus todays’ standard (6 months)  interval, and to compare safety in the two dosing regimens including frequency of neutropenia, hypogammaglobinaemia and infections. We will also evaluate and compare vaccine response in the two dosing regimens.

The primary endpoint of the study is the proportion of patients with no evidence of disease activity (NEDA) after 2 years.

Currently, the study protocol is under preparation for submission to the Regional Committees for Medical and Health Research Ethics Western Norway, and the Norwegian Medicines Agency autumn 2020. Estimated study start; Q1, 2021

Principal Investigator: Stig Wergeland

MS-SEQ – elucidating the genetic susceptibility of multiple sclerosis by whole exome sequencing

The cause of multiple sclerosis (MS) is unknown, but there is strong evidence for involvement of both genetic and environmental factors. There is a clear heritability in MS, but the genes and variants involved are largely unknown. GWAS studies have provided some insight by identifying genetic markers (> 200) associated with a modified risk for MS. These have generally small effects and mark loci rather that specific genes. Therefore, the genes and biological pathways involved remain largely unmapped. To overcome this limitation, we aim to sequence the complete coding genome (exome) of a large cohort of patients and controls and apply sensitive analyses methods to understand the role of common and rare genetic variation in MS. Unlike GWAS studies, our design will allow the direct identification of genes and molecular pathways involved in the disease and therefor help identify novel therapeutic targets. We therefore aim to map the entire coding genome (exome) of 2500 MS patients and 3500 controls to elucidate the heritability of MS

The objectives are to identify novel genetic risks of MS and possible biomarkers for diagnosis and disease progression, and further exploit the obtained insight of disease mechanisms to identify novel therapeutic targets.

DNA samples from about 2500 MS patients in the Norwegian MS Registry and about 3000 controls, mainly from the HUSK-study (https://husk-en.w.uib.no/) will be analysed by whole exome sequencing and data will be available for analyses from Q4 2020. We will then analyse the data for possible novel genetic risks of MS or possible biomarkers for diagnosis and disease progression, and further exploit the obtained insight of disease mechanisms to identify possible novel therapeutic targets.

Currently, the study is approved by to the Regional Committee for Medical and Health Research Ethics Western Norway, and contract for collaboration with HUSK and the exome sequencing providers is finalized.

SUPPORT ________________________________________________________________

Participating Centres

• The Norwegian MS Registry
• Haukeland University Hospital
• University of Bergen

Funding

• The Norwegian MS Registry
• The Research Council of Norway, Neuro-SysMed
• Haukeland University Hospital
• University of Bergen