Clinical Trials

Background: Autologous hematopoietic stem cell transplantation (HSCT) is a promising therapy in MS, but data from randomized clinical trials (RCTs) are limited. Haukeland University Hospital (HUH) is the national centre for such MS-therapy in Norway, and is currently conducting a multicentre, international randomized clinical trial to evaluate the efficacy and safety of autologous HSCT compared to standard high-efficacy therapies in MS.

This is a multidisciplinary, international treatment trial, involving the Department of Haematology (Dr. Anne Kristine Lehmann), the Department of Transfusion Medicine and Immunology (Professor Einar Kristoffersen) and the Department of Neurology (Professor Øivind Torkildsen and Professor Lars Bø) in close collaboration with coordinating centres in all Norwegian health regions and international study sites in Sweden (Uppsala and Gothenburg), Denmark (Copenhagen) and the Netherlands (Amsterdam).

The objectives are to investigate efficacy and safety of HSCT in highly active multiple sclerosis compared to standard high-efficacy therapies, and to establish sufficient evidence to support routine use of HSCT in MS.

Design: This is a randomized controlled trial comparing the efficacy and safety of HSCT (n=50) compared to standard high-efficacy therapies (n=50) in highly active multiple sclerosis with breakthrough disease activity.

The primary endpoint of the study is the difference of HSCT versus comparator in the proportion of patients with no evidence of disease activity (NEDA) after 2 years (96 weeks) in the main study, and further after 5 years (240 weeks) in the extension study.

Status: Until now, 85 patients have been enrolled in the study, and enrolment will continue until the target of 100 patients is reached. Patients from all health regions in Norway are screened and randomized at the University Hospital of North Norway (Tromsø), St. Olav’s Hospital (Trondheim), Akershus University Hospital (Lørenskog), and Haukeland University Hospital (Bergen). Norwegian patients randomized for HSCT are treated at HUH, and those for standard high-efficacy MS-therapy are treated at their local hospitals. Blood sampling, imaging and clinical scoring of the Norwegian patients are performed at HUH.

Participating Centres

Norway

• Haukeland University Hospital, Bergen
• Akershus University Hospital, Lørenskog
• St. Olav’s University Hospital, Trondheim
• University Hospital of North Norway, Tromsø

Sweden

• Sahlgrenska University Hospital, Gothenburg
• Uppsala University Hospital, Uppsala

Denmark

• Copenhagen University Hospital, Rigshospitalet

The Netherlands

• Amsterdam UMC, Amsterdam

Lead Investigator: Lars Bø

Background: B-cell depletion therapies (rituximab, ocrelizumab, ofatumumab) are proven highly effective in MS. A Norwegian health technology assessment (HTA) indicate similar treatment effects from rituximab and ocrelizumab – but clearly state that more data, preferably from a randomized double-blinded clinical trial, is needed.

Rituximab has been used for the treatment of rheumatological diseases and haematological cancers since 1998, and due to patency expiration, costs only a fraction of ocrelizumab. If rituximab proves similar effects as ocrelizumab, it may therefore reduce the annual cost for MS-therapy by several hundred million NOK in Norway alone and give MS-patients access to highly effective treatment at an earlier timepoint. In this study, the MS Node therefore aims to compare the efficacy and safety of rituximab to ocrelizumab for treatment of newly diagnosed treatment naïve patients with relapsing-remitting MS.

The objective of this a randomized double-blinded non-inferiority study is to evaluate whether rituximab has comparably efficacy and safety as ocrelizumab in the treatment of newly diagnosed patients with multiple sclerosis.

Design: This is a randomized, double-blinded, controlled non-inferiority trial comparing the efficacy and safety of rituximab (n=125) to ocrelizumab (n=83) in newly diagnosed relapsing-remitting MS patients.

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).

Status: The first patient was recruited at Haukeland University Hospital in early November 2020 and the study was fully included in November 2022, with 214 patients participating. Altogether, 12 hospitals in Norway and Sweden have recruited patients in the study and participate in the follow-up.

Participating Centres

Norway

• Haukeland University Hospital, Bergen
• Oslo University Hospital, Oslo
• Akershus University Hospital, Lørenskog
• Stavanger University Hospital, Stavanger
• University Hospital of North Norway, Tromsø
• Nordland Hospital, Bodø
• Namsos Hospital, Namsos
• Molde Hospital, Molde
• Sørlandet Hospital, Kristiansand
• Telemark Hospital, Skien
• Vestre Viken Hospital, Drammen

Sweden

• Karolinska Institutet, Stockholm

Lead Investigator: Øivind Torkildsen

Background: 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 to reverse neurological disability. Mesenchymal stem cells (MSCs) have the potential to induce neuronal repair through multiple neuroregenerative mechanisms, including remyelination, immunomodulation and stimulation of endogenous cerebral stem cells. In this study, the group aims to investigate the regenerative potential of stem cell treatment with MSCs in MS and to increase the understanding of the underlying mechanisms of action.

The objective of this pilot project is to study whether intrathecal treatment with autologous bone marrow derived MSCs is feasible, safe and promotes neural repair in patients with progressive MS.

Design: This is a randomized placebo-controlled cross-over pilot trial comparing the efficacy and safety of autologous bone marrow derived MSCs (n=9) compared to placebo (n=9) in progressive multiple sclerosis patients.

The primary endpoint of the study is the difference in the change of composite score (CEP) of three neurophysiological measures (somatosensory evoked potentials (SEP), visual evoked potentials (VEP) and motor evoked potentials (MEP)) from baseline between MSC treatment versus placebo.

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, Germany, and coordinating centres in all Norwegian health regions, including Akershus University Hospital (Lørenskog), St. Olav’s Hospital (Trondheim), and the University Hospital of North Norway (Tromsø).

Status: The first patient was included at Haukeland University Hospital in August 2021 and currently 13 patients have been enrolled in the study.

Participating Centres

Norway

• Haukeland University Hospital, Bergen
• Akershus University Hospital, Lørenskog
• St. Olav’s University Hospital, Trondheim
• University Hospital of North Norway, Tromsø

Germany

• University Hospital in Ulm

Lead Investigator: Christopher Kvistad. Study director: Lars Bø

Background: 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 the disease course in progressive multiple sclerosis (PMS). This mitochondrial dysfunction is suggested 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 bioenergetics conversion and signalling in human cells.

The objective is to study whether oral supplementation with nicotinamide riboside (NR) as add-on to standard care, reduces disability progression in PMS.

Design: This is a randomized double-blinded study where 300 patients with progressive MS receive oral 500 mg oral nicotinamide riboside (NR) (n=150) or placebo (n=150) 30 months. The patients will attend nine visits that include clinical scorings, imaging, blood sampling, questionnaires, and patient reported outcomes.

The primary endpoint is the proportion of patients with 6 months confirmed disability progression, either by worsening of Expanded Disability Status Scale (EDSS), Nine-Hole-Peg-Test (9-HPT) or Timed 25 Foot Walking (T25FW) after two years of therapy.

Status: The protocol is approved by the Regional Committees for Medical and Health Research Ethics, Western Norway, and clarified by the Norwegian Medicines Agency. Nicotinamide riboside (NR) and placebo capsules will be supplied free of cost by Elysium Health, New York, USA. Estimated study start is Q2 2023.

Participating Centres

• Haukeland University Hospital, Bergen
• Stavanger University Hospital, Stavanger
• Haugesund Hospital Trust, Haugesund
• Førde Hospital Trust, Førde

Other study centres in Norway are to be decided.

Lead Investigator: Kjell-Morten Myhr

Background: Previous studies have concluded that vaccination in general is safe for MS-patients. Vaccination is not a risk factor for developing MS, and do not represent a risk for further disease activity or disease progression. Nevertheless, live vaccines are not recommended for patients that receive disease-modifying therapies.

Vaccination response and immunity is another challenge related to vaccination of MS-patients receiving disease-modifying therapies. These medications have immunomodulatory or immuno-suppressive effects and may therefore influence the immune response to various vaccines. Although limited data are available, our MS group has previously shown that interferon-beta therapies do not influence the vaccination response, while glatiramer acetate, natalizumab, fingolimod, and especially mitoxanthrone, may influence the efficacy of vaccination. Other studies have shown that rituximab, ocrelizumab, alemtuzumab and teriflunomide, but not dimethyl fumarate, seem to reduce vaccine responses. Based on these limited data on vaccine response in MS patients receiving disease-modifying therapies, and the current challenge of COVID-19 vaccination, the MS group aimed to perform a study on efficacy and safety of COVID-19 vaccines in MS-patients.

The objective is to evaluate the efficacy and safety of COVID-19 vaccines in MS-patients with and without disease-modifying therapies, compared to healthy population controls not receiving immunotherapy.

Design: This is a prospective observational trial evaluating vaccination responses of COVID-19 vaccines in MS-patients receiving different disease-modifying therapies.

Primary endpoint: Humoral vaccine response to COVID-19 vaccine.

This is a collaborative project, chaired by Professor Rebecca Cox at the Influenza Centre at the University of Bergen. Other participants include researchers at Oslo University Hospital, University of Oslo, and Sørlandet Hospital Trust, as well as the Norwegian MS Registry. Coordinating investigator for the MS-arm of the study is Øivind Torkildsen, and the project will be included in the thesis of PhD Candidate Dr. Hilde Marie Torgauten.

Status: Patients have been recruited for participation at Haukeland University Hospital, Oslo University Hospital and Sørlandet Hospital Trust, as well as through the Norwegian MS Registry.

Results so far have shown that rituximab and fingolimod reduce the humoral vaccination response to COVID-19 vaccines, and that booster vaccines improve this vaccine response.1,2 Further studies on cellular immune responses will be conducted.

Participating Centres

•  Haukeland University Hospital, Bergen
•  Oslo University Hospital, Oslo
•  Sørlandet Hospital Trust, Kristiansand

Lead Investigator: Øivind Torkildsen

Background: B-cell depletion therapy is highly effective in relapsing-remitting MS. Rituximab seems to have comparable efficacy and safety profile to ocrelizumab, but data on optimal dosing is limited and largely based on various off-label regimes. The most frequent used dosing regimen in Norway is a single starting dose of 1000 mg infusion, followed by 500 mg infusions every six months for an undefined time. The therapy seems safe, and limited side effects are reported, where neutropenia, lymphopenia, hypogammaglobulinemia and infections are the most frequent adverse events. Real world experience indicates that B-cells may be depleted for a longer period of time, even for at least 12 months, and longer dosing intervals than 6 months (e.g., due to intercurrent illness or pregnancy planning) seems safe. Based on these observations, the MS research group aims to investigate whether an extended dosing interval from 6 to 12 months is safe in relapsing-remitting MS.

The group aims to enrol clinical stable patients who have received a standard dose of rituximab in six months intervals for at least two years. The patients will be randomized for further therapy with the same dose (500 mg) at either 6 months or 12 months intervals, and followed by frequent monitoring, by clinical, MRI and blood biomarker measurements, such as serum neurofilament, B-cell counts, rituximab serum concentration and anti-drug antibodies.

The objectives of the study are to evaluate whether the efficacy of extended dosing of rituximab is similar to the standard six months interval, and whether the frequency of neutropenia, hypogammaglobulinemia and infections are reduced.

Design: This is a randomized controlled open label trial comparing the efficacy and safety of standard interval dosing (SID – of six months; n=100) to extended interval dosing (EID – of twelve months; n=100) of rituximab in relapsing-remitting MS patients.

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

Status: This study has been postponed, mainly due to the COVID-19 pandemic. The study protocol will be finalized and prepared for submission to the Regional Committees for Medical and Health Research Ethics Western Norway, and the Norwegian Medicines Agency during Q2-2023. Estimated study start is Q3 2023.

Participating Centres

• Haukeland University Hospital, Bergen

Other study centres in Norway are to be decided.

Lead Investigator: Øivind Torkildsen

Background: The treatment of pain and spasticity in multiple sclerosis (MS) is often challenging due to suboptimal effects, and reasonable goals are often to alleviate and not eliminate the symptoms. This may lead to despairing patients, often trying alternative treatment strategies. In this context, several MS-patients have tried a new treatment method shown to reduce lower extremity pain by improved blood circulation in the lower extremities. A pressure chamber (FlowOx) sealed around the patient’s legs just below the knee, applies a negative pressure and atmospheric pressure cycles. The treatment is currently approved and used for selected patients with arterial insufficiency caused by intermittent claudication or diabetes-related leg ulcers. A recent pilot study showed significant relief of pain and spasticity with consequent improvement in functional levels in 10 MS patients.

The objective is to evaluate the clinical effects of treatment with – 40 mm Hg intermittent negative pressure applied by FlowOx2.0 on spasticity caused by multiple sclerosis (MS).

Design: This is a randomized double-blinded study where 60 patients with spasticity due to MS will receive 40 Hg intermittent negative pressure applied by FlowOx2.0 (n=30 active treatment) or 10 Hg intermittent negative pressure applied by FlowOx2.0 (n=30 placebo treatment) for four weeks, followed by an open label extension period of a total of 6 months.

The primary endpoint is the change in self-reported spasticity using Numeric Rating Scale (NRS) after 4 weeks.

Status: The Ethical Committees and the National Medicines Agencies in Sweden and Denmark have approved the protocol. The approval is pending in Norway. Patients are currently enrolled in Sweden. Estimated study start in Denmark and Norway is Q2 2023.

Participating Centres

• Haukeland University Hospital, Bergen
• NeuroCentrum, Stockholm, Sweden
• Department of Neurology, Motala Hospital, Motala, Sweden
• Department of Clinical Medicine - The Department of Neurology, Aarhus University Hospital, Denmark

Lead Investigator: Kjell-Morten Myhr

Background: Novel insights from the MS research group indicate that infection with the Epstein-Barr Virus (EBV) is the leading cause of MS. As EBV infection is persistent for life, the virus could act as a trigger or driver of MS-disease activity. If results from a clinical trial could confirm that targeting EBV reduces MS-disease activity, it would result in a paradigmatic change in our understanding of MS and the management of the disease. In collaboration with researchers at Harvard University, Boston, USA, we have identified a highly interesting candidate drug targeting EBV, not yet tested in MS patients. This trial could lead to a new paradigm in MS therapy, as it will test a drug that may target the underlying cause of the disease.

The objective of this study is to investigate the efficacy and safety of tenofovir alafenamide (TAF) on Epstein-Barr virus infection in patients with relapsing-remitting multiple sclerosis (RRMS).

Design: This is a randomized double-blinded, placebo-controlled trial comparing the efficacy and safety of two doses of Tenofovir alafenamide fumarate (TAF) (n= 16) to placebo (n=8) on EBV viral infection as add on therapy in stable RRMS patients receiving natalizumab therapy.

The primary endpoint is safety and tolerability of the drug and change in EBV shedding in saliva after 6 months of treatment.

Status: Funding is established for the trial, from a research grant from the Norwegian MS Society and the Helse Vest Regional Health Authorities, and the protocol for the trial is finalized for submission to the ethical committee. A pilot testing of methods to evaluate EBV shedding in saliva has been conducted, with positive results. The protocol will be submitted for evaluation by regulatory authorities by Q1 2023 and estimated start of patient recruitment is Q3 2023.

Lead Investigator: Øivind Torkildsen