Clinical TrialsClinical trials linked to the MRC Centre and supported by different funding agencies including the Medical Research Council, Muscular Dystrophy Campaign, UK Department of Health, National Institutes of Health (USA), Food and Drug Administration (USA), AVI Biopharma and PTC Therapeutics.
Completed Trials RESTORING DYSTROPHIN EXPRESSION IN DUCHENNE
MUSCULAR DYSTROPGY: A PHASE I/II CLINICAL TRIAL USING AVI-4658 The primary scope of the trial is to assess efficacy (dystrophin production) and safety of intramuscular administered morpholino oligomer directed against exon 51 (AVI – 4658 PMO).Antisense therapy with the use of antisense oligomers has the potential to restore effectively the production of dystrophin, the defective protein, in >70% of DMD. This could result in increased life expectancy through improved muscle survival and function. Recent scientific research has demonstrated the potential of this technique to skip mutated dystrophin exons, restore the reading frame and generate functional dystrophin protein. Having demonstrated proof-of-principle in human cell culture and animal model studies, we now intend to determine efficacy and safety of this approach to induce dystrophin exon skipping in children with DMD. This study is aimed at children with Duchenne muscular dystrophy above the age of 10 years with mutations than can be rescued by the skipping of exon 51 [45-50; 47-50; 48-50; 49-50; 50; 52; 52-63]. RANDOMISED DOUBLE-BLIND PLACEBO CONTROLLED TRIAL OF LONG-TERM ASCORBIC ACID TREATMENT IN CHARCOT-MARIE-TOOTH DISEASE TYPE 1A Status: Follow-up phase (closed to recruitment) Charcot-Marie-Tooth disease 1A (CMT1A) is associated with a duplication of the peripheral myelin protein 22 (PMP22) gene. To date there is no pharmacological treatment for CMT1A patients. Treatments and therapy for CMT is restricted to symptomatic treatments such as physiotherapy and surgery for skeletal deformities. Recently, treatment with ascorbic acid (AA) has been shown to be effective for transgenic mice over-expressing PMP22, a model of the human disease. Treated animals had much less severe neuropathy as compared to untreated controls as shown by clinical and histological findings. Some clinical parameters even improved during treatment. This is a phase III prospective, multi-centre, randomized, double-blind, placebo-controlled study aiming to evaluate the efficacy of AA treatment in CMT1A. The study has been running now almost for two years and it is now in the follow-up phase. Fifty participants were enrolled in the UK site at the National Hospital for Neurology and Neurosurgery. For information about the study please contact Dr. Matilde Laura at m.laura@ion.ucl.ac.uk.
Open Trials THERAPEUTIC TRIAL OF MEXILETINE IN NON-DYSTROPHIC MYOTONIA Full Title: A Phase II Randomized, Double-Blind, Placebo controlled, Cross-Over Study to Investigate the Efficacy of Mexiletine in Patients with Non-Dystrophic Myotonia Status: Open to recruitment The non-dystrophic myotonia (NDM) is a group of rare neuromuscular disorders that causes episodes of muscle stiffness (known as myotonias) and paralysis. Predominantly the muscles of the face, hands and legs are affected. In addition to these episodes a permanent and debilitating muscle weakness can develop. The optimal treatment for these disorders is unknown. Non-dystrophic myotonias are due to abnormalities of ion channels present in skeletal muscle membranes. There is experimental evidence that drugs like mexiletine which block the abnormal function of these ion channels allow the muscle to perform normally. The study aims to test the efficacy of mexiletine in the treatment of the non-dystrophic myotonias. This proposal involves a multi-centre, double-blind, placebo-controlled cross over trial of a total duration of nine weeks. Approximately fifteen participants will be enrolled in the UK at the National Hospital for Neurology and Neurosurgery. For information on the status of recruitment please contact Dr Dipa Raja Rayan at d.rajarayan@ion.ucl.ac.uk. ECULIZUMAB FOR MYASTHENIA GRAVIS
Status:
Open to recruitment
This is a randomized, double-blind, placebo-controlled, cross-over, multicenter study to evaluate the safety and efficacy of eculizumab for the treatment of patients with myasthenia gravis. There are four stages in the study, the Screening Period, the first Treatment Period, the Wash-Out Period, and the second Treatment Period (the cross-over Treatment Period). Myasthenia gravis (MG) is an acquired autoimmune syndrome caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies to proteins involved in signalling at the neuromuscular junction (NMJ). These proteins include the nicotinic AChR or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering. Current available treatments for myasthenia gravis aim to modulate neuromuscular transmission, to inhibit the production or effects of pathogenic antibodies, or to inhibit inflammatory cytokines. There is currently no specific treatment that corrects the autoimmune defect in MG. Eculizumab is a humanized murine monoclonal antibody that blocks the activation of complement by selectively binding to C5 and preventing the enzymatic cleavage of C5 to C5a and C5b. The blockade of complement activation at this point in the cascade has been shown to prevent the proinflammatory effects of both C5a and C5b, especially the chemotaxis of inflammatory cells, and MAC (C5b-9)-mediated cell activation and lysis. Since eculizumab effectively inhibits complement, especially MAC formation, it is a potentially effective therapeutic approach for diseases such as MG in which the formation of the MAC and/or the release of C5a leads to localized destruction of the postsynaptic NMJ membrane and play a important role in the disease process. Each patient who completes the study will receive approximately 22 infusions including 11infusions of eculizumab and 11 infusions of placebo. The estimated duration of a patient’s participation is approximately 41 weeks. For more information about the study please contact Dr. Jennifer Spillane at j.spillane@ion.ucl.ac.uk. DMD HEART PROTECTION TRIAL Status:
Site Specific Approval pending Duchenne muscular dystrophy [DMD] is an X-linked recessively inherited neuromuscular disorder due to a deficiency in the expression of the protein dystrophin on the inner aspect of cell sarcolemma. Its clinical course has traditionally been characterized by progressive weakness of proximal limb-girdle muscles and calf muscle hypertrophy. Duchenne-affected individuals typically lose ambulation and become wheelchair dependent before the age of 13 and die from cardio-respiratory failure at around the age of 20 years. From the cardiology perspective, some 90% of males with DMD develop a severe, progressive form of cardiomyopathy. Twenty to 30% have evidence of left ventricular impairment on echocardiography by age 10 years. Abnormalities in left ventricular function are evident in an even larger proportion of patients at all ages when more sensitive imaging techniques, such as tissue Doppler, magnetic resonance or metabolic imaging, are deployed. Despite the severity of cardiac involvement in DMD, cardiologists have largely ignored this particular inherited form of cardiomyopathy. This is due to the fact that, because of their inability to exercise, cardiac symptoms only occur terminally in DMD patients when all cardiac reserve has been eroded. Even today in most hospitals, cardio-active drug therapy is only started in patients with DMD when overt heart failure is evident and, even then, is typically deployed tentatively for symptom control, without any expectation that it can prolong life. The objective of this trial is to determine whether the introduction of ACE-inhibitor combined with beta-blocker therapy, before the onset of echo-detectable left ventricular dysfunction, can delay the age of onset and/or slow the rate of progression of cardiomyopathy compared to placebo in males with DMD. This is a double-blind randomized, placebo-controlled Phase III trial of combined ACE inhibitor and beta-blocker therapy (perindopril and bisoprolol) over a minimum of three years and a maximum of five years. 140 participants (70 per arm) are to be enrolled and randomized. For more information about the study please contact trial coordinator Rahela Choudhury at r.choudhury@ich.ucl.ac.uk.
ARIMOCLOMOL FOR SPORADIC INCLUSION BODY MYOSITIS (IBM) Status: Open to recruitment Sporadic Inclusion Body Myositis (IBM) is the commonest acquired disease of muscle affecting people aged 50 years and over. This is a progressive and debilitating disease with both muscle weakness and wasting, characteristically of the quadriceps and finger flexors. Over time the condition can lead to severe disability, falls and swallowing impairment. Affected muscle tissue demonstrates inflammation and degeneration. Arimoclomol is a new compound which acts by enhancing a normal, inbuilt protective cell reaction to stresses. The products of this response are ‘Heat Shock Proteins (HSPs) which counteract processes that end up leading to abnormal protein deposition and to damage mediated by inflammation. This proposal involves a multi-centre, double-blind, placebo-controlled parallel study of total duration twelve weeks. This study proposal aims to assess the safety and tolerability of Arimoclomol (100 mg TDS) as compared with placebo over 4 months of treatment in patients with IBM. Recruitment will take place at the National Hospital for Neurology and Neurosurgery and twelve patients will be enrolled. For information on the status of recruitment please contact Dr Adrian Miller at a.miller@ion.ucl.ac.uk. HYP HOP: DICHLORPHENAMIDE vs. PLACEBO FOR PERIODIC PARALYSIS This is a phase III trial into Periodic Paralysis planned to start in 2010. This proposal involves a multi-centre, double-blind, placebo-controlled parallel group, nine-week studies comparing the effects of dichlorphenamide(DCP) vs placebo in patients with period paralysis (Hyper, Hypokalaemic periodic paralysis). The 9-week studies will investigate the prevention of attacks of weakness and it will be followed by 1-year double-blind extensions without placebo to compare the long term effects of DCP vs ACZ on the course of the diseases and on inter-attack weakness. Approximately 40 participants will be recruited from the United Kingdom. For information on the status of recruitment please contact Dr. James Burge at James.burge@uclh.nhs.uk.
A PHASE IIb EFFICACY AND SAFETY STUDY OF PTC124 IN SUBJECTS WITH NONSENSE MUTATION-MEDIATED DUCHENNE AND BECKER MUSCULAR DYSTROPHY Status: Ongoing (closed to recruitment) Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder affecting young boys. The condition is disabling and life-threatening. A small subset of boys are classified as having Becker muscular dystrophy (BMD), a phenotypically milder form of the dystrophic muscle disease. In approximately10 to 15% of boys with DMD and BMD the causative defect is the presence of a nonsense mutation in the dystrophin gene that truncates dystrophin protein production by introducing a premature stop codon into the dystrophin messenger ribonucleic acid (mRNA). PTC124 is a novel, orally bioavailable, small-molecule drug that promotes ribosomal read-through of mRNA containing a premature stop codon. Through this mechanism of action, PTC124 has the potential to overcome the genetic defect in boys for whom a nonsense mutation causes DMD/BMD. In vitro studies in cell lines with dystrophin nonsense mutations have shown that PTC124 can restore production of the missing dystrophin gene. This is an international, multi-centre, randomized, double-blind, placebo-controlled, dose-ranging, efficacy and safety study. The study primary aim is to evaluate the effect of PTC124 on ambulation as assessed by the distance walked during a 6-minute walk test (6MWT). The double-blind arm of the study randomised 174 participants worldwide which were followed for a period of 12 months. At the completion of the blinded treatment, eligible and compliant participants went on to receive PTC124 (Atularen) in an open-label extension study. However, this study was prematurely discontinued based on a decision made by the Data Monitoring Committee, following the analysis of 6-minute walk-test (primary endpoint) data showing no statistical difference in placebo and active treatment in the main study. Dystrophin expression data is yet to be fully analysed. (Ataluren is now the non-proprietary generic name for PTC124).
New PTC 124 in non-ambulant DMD has been suspended This initiative is led by the MDEX consortium (The MDEX consortium led by Professor Muntoni, is a multidisciplinary enterprise to promote translational research into muscular dystrophies, and is formed by the clinical groups of Professor Francesco Muntoni (UCL Institute of Child Health) and Professor Kate Bushby and Professor Volker Straub (Newcastle University), and scientists from Imperial College London (Professor Dominic Wells), UCL Institute of Child Health (Dr Jennifer Morgan), Royal Holloway University of London (Professor George Dickson and Dr Ian Graham), Oxford University (Dr Matthew Wood) and University of Western Australia (Prof Steve Wilton). In addition, the charities Muscular Dystrophy Campaign (MDC), Action Duchenne and Duchenne Family Support Group also participate in the Consortium, www.mdex.org.uk). The current two trials led by the consortium are mentioned below.
DOSE-RANGING STUDY OF AVI-4658 TO INDUCE DYSTROPHIN EXPRESSION IN SELECTED DUCHENNE MUSCULAR DYSTROPHY (DMD) PATIENTS – (Systemic study)Status: Ongoing (closed to recruitment). This is a safety study of AVI-4658 (a 30-base phosphorodiamidate Morpholino oligomer [PMO]), to skip exon 51 of the dystrophin gene in relevant subjects with DMD.This is an open-label, two-centre, dose-ranging comparative clinical study of duration twelve weeks. The objectives of the study are to assess safety and to select the optimum dose that elicits at least 10% de novo dystrophin-positive fibres and dystrophin in a sentinel muscle group after an intravenous AVI-4658 dosing regimen. A total of up to 16 subjects (ambulatory paediatric males, aged ≥5 and ≤15 years of age) will be enrolled in this study, consisting of four treatment cohorts and four subjects per cohort. It is expected that there will be four treatment arms ranging from 0.5 mg/kg to 4 mg/kg. All subjects will receive 12 weekly intravenous infusions of AVI-4658.Precedent studies have demonstrate that AVI-4658 might have therapeutic relevance in managing DMD for boys whose frame-shifted dystrophin gene lesion could be restored after excision of exon 51 if sufficient drug is translocated into the nucleus of the afflicted muscle cell. This trial is being conducted in London and Newcastle. All participants have completed treatment. Analysis of results is ongoing. For further information please contact Guru Ganeshaguru, MDEX Clinical Trials Coordinator (Dr K. Ganeshaguru k.ganeshaguru@ich.ucl.ac.uk) or Geoff Bell, Trials Coordinator (MRC centre Newcastle site) at geoff.bell@nuth.nhs.uk. CCRN 165 (NDS mito
function) A phase 2a, double blind, randomised, placebo-controlled, 28 day, two-arm, parallel group study of A0001 in patients with the A3243G mitochondrial DNA point mutation and evidence of impaired mitochondrial function. PI – Professor P.F. Chinnery, Department of Neurology, Newcastle University, and Newcastle upon Tyne Foundation Hospitals NHS Trust. The primary objective of this study is to establish proof of concept of the efficacy of A0001 in the treatment of patients with an established mitochondrial disorder using metabolic imaging, a number of functional assessments, biochemical measures and patient/clinical-rated scales. Secondary objectives of the study are to evaluate the tolerability and safety of A001 in this patient population and to establish pharmacokinetics of A0001 in this patient population. Patients will be invited to participate if they fit the inclusion criteria which briefly consists of aged 18 – 70 (male or female), confirmed carriers of the A3243G mitochondrial DNA point mutation, with one or more of the associated symptoms and are capable of performing the required tests associated with this study (MRI,MRS, 6 minute walk test). The study will recruit approximately 30 patients, which should ensure 21 (14 on treatment, 7 on placebo) evaluable patients, which will give sufficient power to detect an improvement of 50% on one of the outcome variables, the primary endpoint being improvement in the rate of ATP recovery in cardiac muscle as measured by P-MRS. Following informed consent and screening, patients will be randomized to receive 28 days of either A0001 capsules (to be taken orally) at dose level of 0.75g BID (1.5g total daily dose) or placebo. PK samples will be collected at Baseline and days 4,7,11,14,21 and 28 Safety will be evaluated by history updates, physical examinations, vital sign assessments, 12 lead ECG, routine blood lab analysis and adverse event assessments. This study is open to recruitment, for further information contact P.F.Chinnery p.f.chinnery@newcastle.ac.uk, Dr G Gorman Grainne.Gorman@newcastle.ac.uk or Mr G Bell Geoffrey.bell@ncl.ac.uk Exercise Studies STRENGTHENING HIP MUSCLES TO IMPROVE WALKING DISTANCE IN PEOPLE WITH CHARCOT- MARIE-TOOTH DISEASE Status: Closed to recruitment Charcot-Marie-Tooth (CMT) disease is a form of hereditary peripheral neuropathy. People with CMT present with weakness, wasting and sensory loss as a result of degeneration of the long peripheral nerves supplying the distal muscles. The aim of this study will be to investigate the efficacy of a 16 week home based programme of training to increase hip flexor muscle strength and walking endurance. Additional measures of gait speed, exertion, fatigue, disability and general activity will also be recorded. Baseline impairment measures will be obtained to ascertain predictors of strength gains. This study will use a single blinded, randomized cross over design to investigate if training the hip flexor muscles will strengthen the hip flexor muscle and improve walking endurance in people with all types of CMT. The trial will included people, aged between 18 and 70 years, who have been diagnosed with CMT on the basis of genetic tests (where possible), family history and neurophysiology testing. Each subject will be involved with the study for a 40 week period. For further information please contact Alex Pollard, Research Physiotherapist at a.pollard@ion.ucl.ac.uk.
EXERCISE TRAINING IN PATIENTS WITH MITOCHONDRIAL DISEASE: ASSESSING THE BENEFITS Status: Open to recruitment Mitochondrial myopathies are a very important group of muscle diseases associated with weakness, pain and fatigue. At present, treatment options are very limited. Exercise therapy has been found to have some benefit in this group of patients and we wish to explore this further in terms of both strength and endurance. The aim of this study is to demonstrate that strength exercise training is an effective approach to therapy in certain patients with mitochondrial myopathy, specifically those with sporadic mutations in mitochondrial DNA. Based on our previous research studies, we believe that such training will improve muscle strength, mitochondrial function, exercise tolerance and overall quality of life. The main objectives will be: 1) To confirm that endurance training in patients with mitochondrial abnormalities improves quality of life, exercise tolerance and oxidative capacity. 2) To determine the ability of resistance muscle strength training to improve skeletal muscle strength and oxidative capacity by incorporation of satellite cells into mature myofibres. Participants are expected to commit to an exercise training and testing over a period of 4 to 8 months. The study will include patients between the ages of 18 and 65 years who have had a previous muscle biopsy showing a defect in skeletal muscle mitochondrial DNA that is either in the form of a sporadic point mutation or single large-scale deletion. Patients who have this type of mutation and do not have any family members that are affected and have no major cardiac involvement, hypertension, pulmonary or peripheral vascular disease that may complicate findings. For information about recruitment contact Geoff Bell at geoff.bell@nuth.nhs.uk.
Open Natural History – Longitudinal Studies NON-DYSTROPHIC MYOTONIAS: GENOTYPE AND PHENOTYPE CORRELATION AND LONGITUDINAL STUDIES Status: Closed to recruitment This multi-centre project involves a prospective, cross-sectional and longitudinal natural history in non-dystrophic myotonias (NDM). The aim is to collect standardized data from NDM patients, to include clinical symptoms, exam findings, as well as the results of strength, functional, and electrophysiological testing. Genetic testing will permit precise identification of individual NDM subtype. This information will allow for the identification and implementation of appropriate endpoints in studies of potential treatments. This is a NIH funded study. Twenty patients were enrolled at the National Hospital for Neurology and Neurosurgery. For more information about the study please contact Dr Dipa Raja Rayan at d.rajarayan@ion.ucl.ac.uk.
ANDERSEN-TAWIL SYNDROME: GENOTYPE AND PHENOTYPE CORRELATION AND LONGITUDINAL STUDY Status: Open to recruitment Andersen-Tawil syndrome is a neuromuscular disorder caused by a mutation in the KCNJ2 gene which codes for the inwardly rectifying potassium channel Kir2.1. A number of different mutations in this gene have already been identified in affected individuals. This disorder is characterized by the triad of periodic paralysis, developmental abnormalities and cardiac arrhythmias. This project is a natural history trial into Andersen-Tawil Syndrome. The aim of the trial is to study the relationship between the genetic abnormalities underlying the disorder and the diverse clinical features. Eight patients have been enrolled so far at the National Hospital for Neurology and Neurosurgery. For more information about the study please contact Dr Dipa Raja Rayan at d.rajarayan@ion.ucl.ac.uk. CHARCOT-MARIE-TOOTH DISEASE AND RELATED DISORDERS: A NATURAL HISTORY STUDY Status: Open to recruitment The main aims of this study are to: Collect natural history data on CMT and related disorders Identify genetic factors that cause and modify Charcot-Marie-Tooth neuropathies. CMT is the most common inherited neurological disorders for which there are no established treatments and there is a need to fully characterise the disease and the different genetic components. Other aims are to: The success of the paediatric scoring system will be determined by whether it can reproducibly quantify disease progression in children with various types of CMT. Establish a Website Resource for the Inherited Neuropathies for patients, families and investigators. For further information, please contact Rahela Choudhury at r.choudhury@ich.ucl.ac.uk.
Planned Trials A PHASE II, DOUBLE BLIND, EXPLORATORY, PARALLEL-GROUP, PLACEBO-CONTROLLED CLINICAL STUDY TO ASSESS TWO DOSING REGIMENS OF GSK2402968 FOR EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS IN AMBULANT SUBJECTS WITH DUCHENNE MUSCULAR DYSTROPHYStatus: Set-up phase GSK2402968 has been explored at doses up to 6mg/kg subcutaneous (s.c.) weekly initially for 5 weeks in ambulant subjects with Duchenne Muscular Dystrophy (DMD). An open-label extension protocol is ongoing, and to date subjects have received GSK2402968 6mg/kg/week for at least 3 months. GSK2402968 appears to be well-tolerated, and has the potential to be efficacious based on the dystrophin expression previously observed in muscle biopsies. However, more information is needed to determine dosing regimens for optimal therapeutic safety margin in relation to efficacy. This study is designed to explore efficacy and safety of GSK2402968 given as a continuous regimen over 24 and 48 weeks. For further information please contact Rahela Choudhury, Clinical Trials Coordinator at r.choudhury@ich.ucl.ac.uk. NOTE: GSK2402968 formerly know as PRO051 TAPP: THERAPEUTIC TRIAL OF POTASSIUM AND ACETAZOLAMIDE IN ANDERSEN-TAWIL SYNDROME Status: Set-up Phase Andersen-Tawil Syndrome (ATS) is a rare form of periodic paralysis that is associated with serious heart-rhythm abnormalities. ATS is characterized by a triad of episodic muscle weakness, long-QT syndrome with potentially fatal cardiac dysrhythmias and skeletal developmental anomalies. The underlying cause of this potentially fatal condition is only partly understood and there are no established treatments. Mutations in the KCNJ2 gene encoding Kir2.1, an inward-rectifying potassium channel account for approximately 60% of ATS cases (termed ATS1), the remaining 40% are presumed to have an as yet undetermined gene lesion and are designated ATS2. ATS1 and ATS2 are phenotypically indistinguishable. The treatment of ATS has been largely anecdotal and empirical. This proposal involves a multi-centre, placebo-controlled ‘n of 1’ study design of total duration 45 weeks. The expected total enrolment for this multi-centre study is 16 participants. The aim of this study is to determine whether potassium supplements and/or acetazolamide alter the duration of muscle weakness and potentially life-threatening heart rhythm abnormalities in patients with ATS. For information on the status of recruitment please contact Dr. James Burge at James.burge@uclh.nhs.uk.
OUTCOME MEASURES IN SMA TYPE II AND III This project provides an excellent opportunity as for the first time, ten leading neuromuscular centers in Europe which have been involved in the development and validation of functional scales for SMA will collaborate to validate and cross validate measures that have been suggested to be the most suitable for multicentric trials by a large international consensus, but have not been tested in large multicentric studies yet. One hundred and thirty patients affected by type II and type III SMA will be enrolled and assessed at baseline and 6 and 12 months later. Non ambulant patients will be assessed using the modified version of the Hammersmith Motor Functional Scale while ambulant patients will be assessed using the extended module of the Hammersmith Motor Functional Scale and timed items, the 6 minute walk and a step activity monitor. All patients will also be assessed using the MFM, that covers the whole range of activities for both ambulant and non ambulant patients. All measures will undergo a process of validation including inter observer reliability. This information will be most valuable for any future trial and will make the groups involved ready to participate to future collaborative studies saving a lot of time on the preliminary aspects (validation, reliability, training) that will be fulfilled by the present study. The study will also provide natural history data for a 12 month period on patients. Please contact Rahela Choudhury, Clinical Trials Coordinator at r.choudhury@ich.ucl.ac.uk for further details.
PERIPHERAL NEUROPATHY OUTCOME MEASURES STANDARDISATION STUDY (PERINOMS)
The current study aims to expand the clinimetric knowledge on outcome measures at various levels of outcome (pathology, impairment, activity & participation limitation, and quality of life) in autoimmune polyneuropathies, particularly in GBS, CIDP, MMN, MGUSP, and autoimmune small fibre neuropathies (AI-SFN). Also, the general applicability of an autonomic symptoms scale plus some selected activity limitation scales will be examined. Outcome measures will be assessed in a cross-sectional and longitudinal group of patients at the level of: -Pathology: Intraepidermal nerve fibre (IENF) density will be assessed in patients with GBS, CIDP, MGUSP, and AI-SFN (in sarcoidosis). IENF density will be examined regarding its correlation with other outcome measures (validity), its reliability (intra-observer and inter-observer), and its responsiveness to clinical changes over time. - Impairment: comparison studies, evaluating the validity, reliability, and responsiveness will be performed between MRC sumscore versus NIS motor subset, INCAT sensory sumscore versus NIS sensory sumscore, and hand-held Vigorimeter versus Jamar dynamometer. Also, the correlation of electrophysiological studies with other impairment outcome measures will be evaluated. Finally, the scientific soundness of the modified Dutch composite autonomic symptoms scale (mdCompass) will be examined. - Activity limitation: comparison studies, evaluating the validity, reliability, and responsiveness will be performed between the ODSS and an overall neuropathy limitations scale (ONLS). Also, a newly devised weighted (based on Rasch analyses) activity and participation scale will be constructed, aiming specifically on the limitations in patients with polyneuropathy. - Quality of life: Disease-specific versus generic quality of life measures will be assessed, determining their clinimetric soundness and by comparison studies in the various polyneuropathy groups. The ultimate goal of the current study will be the presentation of a specific minimum core set of outcome measures to be used in future clinical and follow-up studies in patients with polyneuropathy, mainly those patients with autoimmune mediated polyneuropathies. The study will be performed in collaboration with several local, European, and USA neurological centres with great experience in dealing with inflammatory neurological disorders. Imaging Studies MRI in IBM and CMT Full Title: A Study of Quantitative Magnetic Resonance Imaging and the Clinical Features of Inclusion Body Myositis and Charcot Marie Tooth Disease Status: Open to recruitment Magnetic resonance imaging (MRI) is a key tool in the diagnosis and management of a number of diseases. Despite the wide use of MRI in several clinical settings, so far its role in neuromuscular disease has not been well established. The current standard for the diagnosis of neuromuscular disorders includes clinical examination, electrophysiological investigations, biopsy and genetic testing. Due to the nature of the involvement of prominent muscles and peripheral nerves in these disorders it is proposed that MRI could play a prominent role in understanding of neuromuscular disease. This study aims to investigate the use of MRI as a tool in the study of nerve and muscle diseases by focusing on two particular neuromuscular diseases, one primarily neuropathic and one principally myopathic. Two separate patient cohorts with neuromuscular disease will be recruited. Forty patients with Sporadic Inclusion Body Myositis (IBM) will be recruited and 40 patients with genetically confirmed Charcot Marie Tooth Disease (CMT) will be recruited. In addition to the two patient cohorts, two groups of healthy volunteers each of size 40 will act as comparators for the disease groups. Each of the patients enrolled in the study will undergo an MRI scanning session in which the quantitative MR techniques developed in Phase 1 with the health volunteers will be applied. In addition to the MRI scanning sessions, each patient will undergo a clinical examination to record the main clinical features of their disease status including an electrophysiological nerve conduction assessment. In the final phase of the study, a sub-group of the patients will then be followed-up at 6 month intervals for 5 years in a longitudinal natural history study of IBM and CMT that focuses on the MR methods and clinical findings that were shown to be most illuminating. Changes over time in the MRI parameters in the diseased groups and Healthy volunteers will be compared. Objectives: To detect, using quantitative magnetic resonance imaging (qMRI), the changes in the nerves and muscles of patients with inclusion body myositis or Charcot Marie Tooth disease, and to relate these changes to the measurable clinical and neurophysiological features in these diseases. This will allow the value of various qMRI techniques as markers of disease activity and progression to be tested. Secondary objectives of the study include: -The development of novel quantitative MR techniques for targeted assessment of the human neuromuscular system -To more fully characterize both the magnetic resonance imaging and clinical features of inclusion body myositis or Charcot Marie Tooth disease as compared with healthy individuals and to study the progression of these characteristics with time over a period of 5 years. For more information about the study please contact Dr. Jasper Morrow at j.morrow@ion.ucl.ac.uk.
Full-Title: A study using Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) in Patients with Limb Girdle Muscular Dystrophy 2I; an assessment of muscle damage. Re-defined in 1995, the LGMDs are face sparing, proximally predominant, progressive muscular dystrophies with elevated creatine kinase levels and dystrophic features on muscle biopsy. In the current classification system, LGMDs are divided into autosomal dominant (LGMD1) and autosomal recessive (LGMD2) disorders with a superimposed lettering system denoting the chronological order of the chromosomal linkage. Limb Girdle Muscular Dystrophy 2I (LGMD2I) is caused by a mutation in the fukutin related protein gene (FKRP)1 and manifests temporal variability. Clinically the age of onset, rate of progression and severity varies greatly between cases and even within the same family. They range from asymptomatic patients with mildly raised creatine kinase levels to those severely affected and non ambulant. The respiratory and cardiac complications, well known to occur in this type of muscular dystrophy, in 30% and 60% of patients respectively, occur independently of the general muscle weakness and also cardiac complications occur independently from respiratory compromise. Magnetic Resonance imaging (MRI) has been increasingly used in imaging in patients with neuromuscular disorders over the past 5 years. Studies have shown that whilst there is considerable overlap in muscle involvement there is also striking differences that can be of diagnostic value. In both patients with LGMD2A and LGMD2I there is a prominent pattern of involvement of the posterior thigh muscles, however in LGMD2A there is also selective involvement of the medial gastrocnemius and soleus muscles in the lower leg, which was not seen in LGMD2I. Although it is clearly demonstrated that MRI findings mirror those obtained from clinical examination, it has been reported recently that in fact MRI abnormalities can be detected in patients with neuromuscular disorders when clinical examination of particular muscle groups have been normal. MRI can therefore be useful to show early manifestations of a disease and to monitor the effect of early therapeutic interventions. Beside MRI another non-invasive technique to consider is phosphorus magnetic resonance spectroscopy (P-MRS). P-MRS studies have demonstrated several metabolic abnormalities in the skeletal muscle of patients with Duchenne Muscular Dystrophy (DMD)/ Becker Muscular Dystrophy (BMD) and in the group of autosomal recessive LGMDs, associated with sarcoglycan deficiency (LGMD2C-F) . These changes are thought to be specific for dystrophies secondary to deficits in the dystrophin-glycoprotein complex. In these patients there appears to be an increased cytosolic pH in both groups, however there is also abnormal concentrations of phosphorylated compounds (in particular, decreased phosphocreatine and increased inorganic phosphate concentrations). The study overall aim is to develop and evaluate non-invasive techniques to quantify muscle pathology and the rate of change over time in LGMD2I, which is potentially a useful tool for monitoring response to treatment and therapies. This shall be achieved by measuring static MRI over a 2 year period and comparing this to age matched adult controls including the quantitative 3-point Dixon technique for measuring fat. At the same time we will also be measuring the Pi and cytosolic pH, ATP and ADP via MRS to see whether a specific pattern of metabolic abnormality is detected in these patients. For further information about the study please contact Dr. Jasper Morrow at j.morrow@ion.ucl.ac.uk.
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NewsBritish Myology Society Annual Meeting 2011 UK Neuromuscular Translational Research Conference |
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