New Million-dollar Trial for <b>Multiple Sclerosis</b> Drug - Health Hub from <b>...</b>

Cleveland Clinic has been selected as the primary investigator in a $11.3 million nationwide study funded primarily by the National Institutes of Health to conduct a trial of the oral drug ibudilast for progressive multiple sclerosis (MS) patients.

The Phase 2 study will enroll patients at 28 clinical sites across the U.S. The trial is designed to evaluate the safety, tolerability and efficacy of ibudilast, which will be given twice daily to patients with progressive MS. This is a placebo-controlled trial with the goal of recruiting over 250 patients.

Potential treatment for patients with progressive MS

“Currently, progressive MS patients do not have any treatments that will alter their long-term disease course, and it is essential we conduct trials to try to identify an effective treatment,” said Robert Fox, M.D., M.S., FAAN, Principal Investigator of the trial and Staff Neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic. “This trial will not only study a potential treatment for progressive MS, but will further the knowledge of the best methodologies for evaluating therapies. This will lead to researchers being able to create shorter, more effective trials and getting therapies to patients faster.”

Evaluate safety and tolerability using brain parenchymal fraction (BPF)

The primary goal of the study is to evaluate the activity of ibudilast versus placebo at 96 weeks as measured by magnetic resonance imaging (MRI) analysis for whole brain atrophy using brain parenchymal fraction (BPF). The secondary goal is to evaluate the safety and tolerability of ibudilast (100 mg/day) versus placebo administered orally in subjects with progressive multiple sclerosis. A variety of secondary outcomes will evaluate additional advanced imaging measures and will utilize imaging and biomedical engineering expertise at Cleveland Clinic.

Working together to leverage strengths

The clinical trial will be conducted by the NeuroNEXT Network, representing that group’s largest collaborative effort to date.

The NeuroNEXT Network was created to conduct studies of treatments for neurological diseases through large partnerships and collaborations, leveraging the strengths of multiple organizations in the private, public, and non-profit sectors. The network is designed to expand the capability of The National Institute of Neurological Disorders and Stroke (NINDS) to test promising new therapies, increase the efficiency of clinical trials before embarking on larger studies, and respond quickly as new opportunities arise to test promising treatments for people with neurological disorders.

The clinical coordinating center for this trial is Massachusetts General Hospital, and the data coordinating center is the University of Iowa.  Dr. Fox and his colleagues at Cleveland Clinic will collaborate with co-investigators at 28 additional academic medical centers in the NeuroNEXT network. The National Multiple Sclerosis Society provides patient advocate input and trial enrollment awareness and has provided additional funding to increase patient access to the trial and increase patient safety.  

The trial is expected to require approximately three years for enrollment, treatment, and data analyses. The drug is already approved in Japan for asthma.

More information

Multiple Sclerosis Treatment Guide

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THC In Cannabis Does Not Slow <b>Multiple Sclerosis</b> Progression

The main active constituent of cannabis – tetrahydrocannabinol or THC – has not shown to be effective in slowing the course of progressive multiple sclerosis (MS).

The CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) study was carried out by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry,the Medical Research Council Clinical Trials Unit and University College London and is the first large, non-commercial clinical study of THC for MS progression.

CUPID enrolled 498 people with MS from 27 centers around the UK and has taken eight years to complete. People with progressive MS were randomized to receive either THC capsules or identical placebo capsules for three years, and were carefully followed to see how their MS changed over this period. The two main outcomes of the trial were a disability scale administered by neurologists (the Expanded Disability Status Scale), and a patient report scale of the impact of MS on people with the condition (the Multiple Sclerosis Impact Scale 29).

The patients were randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate).

Overall the study found no evidence to support an effect of THC on MS progression in either of the main outcomes. However, there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of enrollment but, as the benefit was only found in a small group of people rather than the whole population, further studies will be needed to assess the robustness of this finding. 

One of the other findings of the trial was that MS in the study population as a whole progressed slowly, more slowly than expected. This makes it more challenging to find a treatment effect when the aim of the treatment is to slow progression.

As well as evaluating the potential neuroprotective effects and safety of THC over the long-term, one of the aims of the CUPID study was to improve the way that clinical trial research is done, by exploring newer methods of measuring MS and using the latest statistical methods to make the most of every piece of information collected. This analysis continued for several months and has provided important information about conducting further large scale clinical trials in MS.

Professor John Zajicek, Professor of Clinical Neuroscience at Plymouth University Peninsula Schools of Medicine and Dentistry, said, “To put this study into context: current treatments for MS are limited, either being targeted at the immune system in the early stages of the disease or aimed at easing specific symptoms such as muscle spasms, fatigue or bladder problems. At present there is no treatment available to slow MS when it becomes progressive. Progression of MS is thought to be due to death of nerve cells, and researchers around the world are desperately searching for treatments that may be ‘neuroprotective’. Laboratory experiments have suggested that certain cannabis derivatives may be neuroprotective.”

He added: “Overall our research has not supported laboratory based findings and shown that, although there is a suggestion of benefit to those at the lower end of the disability scale when they joined CUPID, there is little evidence to suggest that THC has a long term impact on the slowing of progressive MS.”

Funded by the Medical Research Council (MRC), the Multiple Sclerosis Society and the Multiple Sclerosis Trust, and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership. 

Citation: Prof John Zajicek PhD, Susan Ball MSc, Prof David Wright PhD, Jane Vickery MSc, Prof Andrew Nunn MSc, Prof David Miller FMedSci,Mayam Gomez Cano PhD, David McManus MSc,Sharukh Mallik MSc, Prof Jeremy Hobart PhD, on behalf of the CUPID investigator group, ‘Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial’, The Lancet Neurology – 13 July 2013  DOI: 10.1016/S1474-4422(13)70159-5

<b>Multiple Sclerosis</b> Research: Young MSers have more relapses

L.A. Benson, B.C. Healy, M.P. Gorman, N.F. Baruch, T. Gholipour, A. Musallam, T. Chitnis Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Rel Dis July [Epub]
Objective To compare relapse rates in pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (AOMS) over the first 6-years of disease.
Methods Patients with relapsing-remitting disease onset were identified from the Partners Pediatric MS Center, Massachusetts General Hospital and Partners MS Center, Brigham and Women’s Hospital. 84 POMS and 258 AOMS patients were included. Annualized relapse rates (ARR) for each individual year from year 1 to year 6, after first attack were compared using Poisson regression, as was expanded disability status scale (EDSS) score at the visit closest to each year interval.
Results ARR was significantly higher in POMS compared to AOMS at individual years (except year 4), and was not significantly affected by adjustment for gender, race and proportion of time on treatment. Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ. ARR in years 1–5 did not impact year 5 disability measured by EDSS in POMS.
Conclusions Our findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by EDSS early in POMS. This data may be useful when designing clinical trials for POMS.

Highlights
•ARR was significantly higher in pediatric onset compared to adult onset MS in years 1–6.
•Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ.
•At first attack children were more likely to be polysymptomatic and/or encephalopathic.
•Children were more likely to have optic nerve, cerebrum and/or multiple site attack localization

Young Msers have more relapses compared to adult onset MS yet they only accumulate the same amount of disability. This suggests either the relapses are not influencing the progression or that younger Msers have a much greater reparative capacity. This maybe why people who develop MS at an older age are more likely to progress. Of course their are exceptions. It is certainly true in animals that the capacity to repair decreases with age. Is cell senility (age of cell) a central problem in neurological conditions 

<b>Multiple Sclerosis</b> Research: Female Sex Hormones

BACKGROUND Sex-related differences in the severity of multiple sclerosis (MS) could be influenced by the sex hormones.

MATERIALS AND METHODS:This cohort (historical) study evaluated the sex hormone levels during menstrual cycle and their correlation with disease severity in MS.

RESULT: Patients with MS had significantly lower testosterone, dehydroepiandrosterone sulfate and prolactin levels than controls in the follicular and luteal phase but lower oestrogen (estradiol) levels only in the follicular phase. A positive correlation coefficient between follicle stimulating hormone and disease severity, and a reverse correlation with estradiol were found.

CONCLUSION: The hormone-related modulation of disease severity supports the suggestion that sex hormones play a role in MS disease.

It is well known that sex hormones can have an influence on many outcomes in biology. These relationships are however complex.

<b>Multiple Sclerosis</b> Research: Interleukin 17 and Beta Interferon

In multiple sclerosis, type I interferon (IFN) is considered immune-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. This is in contrast to most other autoimmune disorders, because type I IFN contributes to the pathologies. Even within the relapsing-remitting multiple sclerosis (RRMS) population, 30-50% of MS patients are non-responsive to this treatment, and it consistently worsens neuromyelitis optica, a disease similar to RRMS. In this article, we discuss the recent advances in the field of autoimmunity and introduce the theory explain how type I IFNs can be pro-inflammatory in disease that is predominantly driven by a Th17 response and are therapeutic when disease is predominantly Th1.

Potential mechanisms of how type IFN exacerbates autoimmune diseases

Autoimmune diseases initiated with the IL-23/Th17 response secrete high levels of IL-17A and IL-17F. IL-17A and IL-17F initiate granulocyte infiltration to the site of inflammation as well as orchestrate germinal center formation and B-cell maturation in lymphoid tissues. Endogenously expressed or therapeutically administered IFN-β could exacerbate Th17 diseases by directly stimulating granulocytes to release tissue destructive proteases and cytokines or by elevating BAFF to enhance the production of autoreactive antibodies and memory B-cells. Type I IFN also upregulates IL-22 receptor on skin epithelial cells in psoriatic skin and BBB endothelium in NMO. IL-22 can contribute to inflammation by promoting the release of defensins and breaking down tight junctions at the BBB.

Potential mechanisms on how type I IFN protects in RRMS

Autoimmune diseases initiated by Th1 cells have high levels of IFN-γ that drive lymphocytic and macrophage infiltration in to sites of inflammation. IFN-γ upregulates IL-7 expression in lymphoid tissue stromal cells during T-cell differentiation and provides signals to expand and maintain the Th1 population. IFN-β treatment synergizes with both IFN-γ and IL-7 to attenuate inflammation by upregulating the anti-inflammatory cytokines, IL-27 and IL-10, and decrease chemokine production from macrophages/microglial cells. Type I IFN also induces BAFF expression. BAFF then could directly or indirectly induce the differentiation of IL-10-producing regulatory B cells.

BACKGROUND:Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis o fmultiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-β (IFN-β) therapy.

OBJECTIVES:The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titres and binding antibodies (BAbs) to IFN-β, as well as to find a correlation between IL-17A serum levels and other features of MS patients.

METHODS:Our prospective study included 72 inactive relapsing-remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-β and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml.

RESULTS:Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration.

CONCLUSIONS:RRMS patients with high serum IL-17A levels do not respond well to IFN-β therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.

Objective To investigate the relationship between the efficacy of interferon beta-1b (INF-β-1b) on relapsing-remitting multiple sclerosis (RRMS) and the Th17 cells in peripheral blood. 

Methods Eleven RRMS patients were enrolled and treated with 250 μg INF-β-1b for 6 months. Expanded disability status scale (EDSS) scrore and T2 lesion number on MRI were examined both at baseline and at the end of the study. Flow cytometry was used to detect the number of Th17 cells in peripheral blood before the treatment. 

Results Acoording to the EDSS scores, the 11 cases of RRMS were divided into two groups: the effective group and the ineffective group.The EDSS scores and the number of lesions on T2-weighted MRI were not different significantly between the two groups (P>0.05) before the treatment. But after the treatment, compared with the ineffective group, the EDSS scores and the number of lesions on T2-weighted MRI decreased significantly in the effective group (P<0.05). Compared with the effective group, the number of Th17 cells in the ineffective group increased significantly (P<0.01) before treatment. 

Conclusion Th17-mediated RRMS is nonresponsive to IFN-β-1b treatment.

Ramgolam VS, Sha Y, Jin J, Zhang X, Markovic-Plese S. IFN-beta inhibits human Th17 cell differentiation. J Immunol. 2009  15; 183: 5418-27

Immunology is not just black and white, it all depends on context

<b>Multiple Sclerosis</b> Research: Catch nerve damage before it is too <b>...</b>

In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed ‘focal axonal degeneration’ (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.

In the the other post they counted axon swellings as a marker of damage, this study suggests that some of the swollen axons will break up and die but some are not destined to die and recover. We know this happens in MS. Using magnetic resonance spectroscopy in MS, it was found that N acetyl aspartate (NAA) disappears. This was found to be concentrated in nerves and it was thought that it was a measure of nerve loss which it is, but in some cases the loss of NAA was reversible, so it it has similarities with the mice. In this study they found that the mitochondria, which are the power houses of nerves are affected early. If a nerve looses its energy supply then it is vulnerable to damage, but there is a window of opportunity to stop this energy loss and if you do then the nerves may not die, this can be done with anti-inflammatories that are active in the brain These can target reactive oxygen species (Hydrogen peroxide) or target the cells that make them.

This is the target for some of the therapies currently in trial for progressive MS, we can think of more 

<b>Multiple Sclerosis</b> Research: Damage occurs early in MS

Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP‐positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP‐positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so‐called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP‐positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8‐positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon‐protective treatment should start as early as possible and include strategies preventing T cell/macrophage‐mediated axon destruction and leading to remyelination of axons.

Amyloid precursor protein (APP) is shuttled down the nerve from the head to the feet, if there is a break the APP goes down the nerve then accumulates at the cut and makes a bleb. You can count the blebs. 

Bruce Trapps group did this and found 11,000 in the active lesion and < 1 in health nerve areas. This was mentioned on the brain shred post by ProfG. This says that damage is associated with the amount of active inflammation, block this and you block the nerve damage. This current post says the same thing, that nerve damage correlates with the amount and duration of inflammation. They findmore active damage early on and less later in disease. This is what we would expect because inflammatory disease is more active early in disease. This we know from MRI where gadolinium enhancing lesions are more common early in disease. This study also shows that the amount of damage correlates with the amount of inflammation. This is associated with T cells and microglia. Therefore it makes sense to think the anti-inflammatory approach within the CNS is a way to go. Target this aspect and block it and then let’s see if it stops nerve transections. The doubting minnnies will say they are clearing up the damage. Let’s see. 

They show that this damage occurs early so lets start treating this early. That is what we are trying with some of the optic neuritis trials. Protecting the nerves from the effects of inflammation, put this on top of stopping the inflammatory cells getting into the brain and you get a double whammy. This is what we are doing with the PROXIMUS trial. My gut feeling is that this early activity takes out the vulnerable nerve pools leaving the more sturdy nerves and these are damaged more slowly. Let’s see what the trials bring.