Clinical research

1. SIMCOMBIN study

·Study design and patients: Patients with relapsing-remitting multiple sclerosis will be treated with interferon-beta 1a (Avonex) for 3 months and thereafter randomised to treatment with either Simvastatin 80 mg daily or placebo for at least 12 months. The patients will be examined clinically at 6 months intervals. MRI's are performed before start of treatment and after 24 months. In all, 40 centres in the Nordic countries will participate in the study.

·Outcome measures: The primary outcome measure is the time to first documented relapse. Secondary outcome measures include number of documented relapses during the first 12 months of randomisation, proportion of relapse free patients, number of new and/or enlarging lesions on T2-weighted MRI at 12 months compared with baseline.

· Timelines: Enrolment of patients was completed by March 31, 2009. End of study March 31, 2010. Report of results June 2010.

· Financial support:Per Soelberg Sørensen.

· Principal investigator: Per Soelberg Sørensen

· Study group: Ana Voldsgaard, Annette Oturai, Lars Pinborg, Morten Blinkenberg, Finn Sellebjerg, Dan Hesse, Stephan Bramow, Joan Pietraszek, Per Soelberg Sørensen

[to top]

2. Recycline study

A multicenter, double-blind, randomised, placebo controlled, parallel group trial investigating minocycline as add-on treatment to interferon-beta 1a (Rebif) for treatment of relapsing-remitting multiple sclerosis.
An investigator driven international multicenter study initiated and organised by Danish Multiple Sclerosis Research Centre.

· Objectives: The primary objective of this trial is to estimate the effect of Minocycline versus placebo as add-on treatment to interferon-beta 1a (Rebif) on the annualized relapse rate (documented relapses) up to year 2 in patients with relapsing-remitting MS.

· Study design and patients: Eligible patients, who have started treatment with interferon-beta 1a (Rebif), will after 3 months be randomised for treatment with either Minocycline 200 mg daily as add-on treatment or placebo for 2 years. Patients will be examined clinically at 3-6 months intervals. MRI will be performed in a subgroup of 120 patients before treatment and after 96 weeks. In all, 40 centres in the Nordic countries, France and Switzerland participate in the study.

· Outcome measures: The primary outcome measure is the annualized relapse rate (documented relapses) up to 2 years. Secondary endpoints include time to first relapse and in a limited number of patients the number of new or enlarging lesions on T2-weighted MRI and changes in brain volume.

· Time lines: End of patient enrolment March 31, 2010. End of study March 31, 2012. Report of results June 2012.

· Financial support: Merck Serono.

· Principal investigator: Per Soelberg Sørensen.

· Study group: Finn Sellebjerg, Karen Schreiber, Ana Voldsgaard, Annette Oturai, Morten Blinkenberg, Dan Hesse, Stephan Bramow, Vibeke Jespersen, Per Soelberg Sørensen.

[to top]

3. TRIMS A study

A safety study of treatment with trichuris suis ova in patients with relapsing-remitting MS.
An investigator driven study initiated and organised by Danish Multiple Sclerosis Research Centre.

· Objectives: The objective of the trial is to evaluate safety and practicability of treatment with trichuris suis ova in patients with relapsing-remitting MS.

· Study design and patients: In all, 10 patients with relapsing-remitting MS or secondary progressive MS with relapses, an EDSS </= 5.5 and at least 2 documented relapses in the last 24 months or one documented relapse in the last 24 months and at least one gadolinium positive lesion on baseline MRI are eligible for this study. Patients will be treated with 2.500 trichuris suis ova suspended in water every 2 weeks taken in the outpatient clinic for a duration of 12 weeks.

· Outcome measures: Standard safety parameters including adverse events, clinical laboratory test and vital signs, MRI scans and relapses.

· Timelines: Start of patient enrolment January 1, 2010. End of patient enrolment March 31, 2010. End of study September 2010. Report of results October 2010.

· Principal investigator: Ana Voldsgaard.

· Study group: Finn Sellebjerg, Ana Voldsgaard, Vibeke Jespersen, Per Soelberg Sørensen.

[to top]

4. REPAIR study

Response on interferon-alpha (Multiferon) in patients with anti-interferon-beta neutralizing antibodies.
An investigator driven study initiated and organised by Danish Multiple Sclerosis Research Centre.

· Objectives: The objective of the trial is to examine, whether MS patients who have developed neutralizing antibodies against interferon-beta can obtain a full biological response after injection of interferon-alpha (Multiferon).

· Study design and patients: In all, 10 patients who during treatment with interferon-beta have developed neutralizing antibodies and still are antibody positive without an in vivo MxA response to interferon-beta, will receive one injection of interferon-beta (homologous with the interferon-beta against which neutralizing antibodies was raised), and after 4 weeks one injection of human leukocyte interferon-alpha (Multiferon) 6 mio unit subcutanously.

· Outcome measures: The primary endpoint is the in vivo mRNA MxA response after an injection with interferon-alpha compared with the in vivo mRNA MxA response after injection of interferon-beta. Secondary outcome measures include in vivo response of other interferon-beta response markers and gene induction on affymetrix genechips.

· Timelines: Start of patient enrolment April 1, 2010. End of patient enrolment September 30, 2010. End of study December 2010. Report of results April 2011.

· Financial support: Swedish Orphan International.

· Principal investigator: Melinda Magyari.

· Study sponsor: Per Soelberg Sørensen.

· Study group: Finn Sellebjerg, Melinda Magyari, Poul Erik Hyldgaard Jensen, Vibeke Jespersen, Per Soelberg Sørensen.

[to top]

5. EPO study

Double-blind placebo controlled study to assess the effect of erytropoietin on clinical disability and brain pathology as shown by MRI in patients with progressive MS.
An investigator driven study initated and organised by Danish Multiple Sclerosis Research Centre.

· Objectives: The objective of this study is to evaluate the effect on clinical outcome measures of EPO treatment compared with placebo in patients with progressive MS.

· Study design and patients: Patients with primary progressive MS or secondary progressive MS without relapses will be treated with either erytropoietin (EPO) 48.000 IU or placebo administered weekly for 12 weeks and by weekly for 12 weeks followed by an observation period of 24 weeks.

· Outcome measures: The primary endpoint is the change from baseline to 24 weeks in a composit of maximum gate distance, 9-hole-peg-test, and TRAIL-making-B comparing the placebo treated group with the EPO treated group. The secondary outcome measures include maximum gate distance, 9-hole-peg-test, TRAIL-making-B, MSFC, EDSS, MSIS, number and relapses and change in brain volume between baseline and week 24, and brain magnetization transfer ratio between baseline and week 24.

· Timelines: Start of patient enrolment December 2009. End of patient enrolment June 2010. End of study December 2010. Report of results April 2011.

· Financial support: Roche.

· Principal investigator: Karen Schreiber.

· Study sponsor: Per Soelberg Sørensen.

· Study group: Melinda Magyari, Karen Schreiber, Finn Sellebjerg, Jeppe Romme Christensen, Rikke Ratzer, Annette Oturai, Joy Mendell-Hartvig, Poul Erik Hyldgaard Jensen, Joan Pietraszek, Per Soelberg Sørensen.

[to top]

6. Study of Natalizumab treatment in progressive multiple sclerosis

An investigator driven study initiated organised by Danish Multiple Sclerosis Research Centre.

· Objectives: The objective of this study is to investigate if treatment with natalizumab in patients with progressive MS is safe, and study the effect on intrathecal inflammation.

· Study design and patients: Patients with secondary progressive or primary progressive MS with an EDSS less than 6.5 and recent progression of disability will be treated with natalizumab 300 mg i.v. every 4 weeks for 68 weeks. 12 patients with primary progressive and 12 patients with secondary progressive MS will be included.

· Outcome measures: The primary endpoint is the change in intrathecal inflammation measured by concentration of osteopontin in the cerebrospinal fluid. The secondary efficacy endpoints include EDSS, time 24 food-walking, changes of inflammatory markers in csf, gadolinium positive lesions on T1-weighted MRI, new or enlarging lesions on T2-weighted MRI, change in brain volume and magnetization transfer ratio.

· Timelines: Start of patient enrolment March 2010, end of patient enrolment February 2011. End of study April 2012. Report results: June 2012.

· Financial support: Biogen Idec.

· Principal investigator: Jeppe Romme Christensen.

· Study sponsor: Finn Sellebjerg.

· Study group: Jeppe Romme Christensen, Finn Sellebjerg, Poul Erik Hyldgaard Jensen, Per Soelberg Sørensen.

[to top]

7. NEUROIMAGING

· Neuroimaging group: Morten Blinkenberg, Henrik Mathiesen, Per Soelberg Sørensen.

PET
During the last decades, functional imaging has improved our understanding of the neurodegenerative processes in Multiple Sclerosis (MS).
Former positron emission tomography (PET) studies, carried out in Danish Multiple Sclerosis Research Center, have shown that cerebral activations in MS patients, is severely reduced as a consequence of disease progression. We have also shown that several regions of importance for cognitive function is affected by MS, and that these changes correlate with neuropsychological measures, as well as MRI lesion burden.
Our current PET studies focuses on the early relapsing remitting phase of the disease and the corresponding changes in cerebral activation. Our hypothesis is, that changes in cerebral activation is present in very early disease, and affect neural networks of importance for cognitive function. We are currently analyzing data from a cross-sectional study, and a subgroup of these patients has also been followed prospectively, and awaits further analysis.

MRI
In collaboration with Danish Research Center for Magnetic Resonance we have initiated two functional imaging studies in 2007.
We have previously shown that measurements of MR Spectroscopy (MRS) correlate with cognitive dysfunction in MS. This cohort has now been re-evaluated and analyzed for longitudinal changes in MRS and cognitive function.
Another study focuses on the pathophysiological mechanisms underlying changes in cerebral activation in MS patients.
There is increasing evidence that the severity of the clinical manifestations of MS does not result simply from the extent of tissue destruction, rather it represents a complex balance between tissue damage, tissue repair and cortical reorganization.
Functional MRI (fMRI) provides information regarding the extent and nature of brain plasticity following MS-related structural injury, with the potential to limit the clinical manifestations of the disease. Functional connectivity MRI (fcMRI) is a new method of assessing neuronal connectivity in the human brain, by mapping brain regions with synchronous, regional fluctuations in cerebral blood oxygenation. fcMRI in combination with fMRI, may therefore detect functional alterations, that lead to neurological disability in MS.
Using this approach, we describe MRI changes in cerebral activation and neural connectivity during an acute MS relapse and following treatment with i.v. methylprednisolone. Furthermore, we describe functional activation and connectivity in a cross-sectional selection of MS patients with different stages of disease.

[to top]