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Clinical Trials

June 2011 Update: Clinical trials supported by the MRC Centre

Clinical 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, Alexion Pharmaceuticals, GlaxoSmithKline.

MRC Centre CTIMPs Set-up Phase trials

TAPP: THERAPEUTIC TRIAL OF POTASSIUM AND ACETAZOLAMIDE IN ANDERSEN-TAWIL SYNDROME

Status: Set-up Phase
Sponsor: University College London (UCL)
Funder: National Institutes of Health (NIH – USA)
PI: Prof Hanna Recruitment target: 12

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 or Gisela Barreto, Trials Coordinator at Gisela.barreto@uclh.nhs.uk.

DMD HEART PROTECTION TRIAL

Full-Title: A double-blind randomised multi-centre, placebo-controlled trial of combined ACE-inhibitor and beta-blocker therapy in preventing the development of cardiomyopathy in genetically characterised males with DMD without echo-detectable left ventricular dysfunction.

Status: Set-up phase
Sponsor: Newcastle NHS Foundation
Planned start date: 2011
Funder: British Heart Foundation
PI: Prof. Muntoni
Recruitment target: 140

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 characterised 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 randomised, placebo-controlled Phase III trial of combined ACEinhibitor 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 randomised. For more information about the study please contact the trial coordinator on 020 7905 2639.

MRC Centre CTIMPs Open Trials

Phase II, multicenter, randomized, adaptive, double-blind, placebo controlled Study to assess Safety and Efficacy of Olesoxime (TRO19622) in 3-25 year old Spinal Muscular Atrophy (SMA) patients

Status: Open
Sponsor: TROPHOS
Funder: Association Francaise contre les Myopathies
PIs: Francesco Muntoni, Hanns Lochmuller, Helen Roper
Recruitment target (UK): 30 (recruitment due for completion by 31st July 2011)

The UCL Institute of Child Health and Great Ormond Street Hospital for Children (London), Birmingham Heartlands Hospital, and Newcastle upon Tyne Hospitals Royal Victoria Infirmary have been invited to collaborate in this phase II clinical trial in non-ambulant patients with SMA II and III with a documented homozygous absence of SMN1 exon 7 and/or deletion and mutation on the other allele. This is a multicentre, double-blind, randomized, placebo-controlled study in patients with SMA type 2 or non-ambulant type 3. The study will be conducted in multiple centres across Europe and will be sponsored by Trophos (a biopharmaceutical company based in France) and funded by AFM (Association francaise contre les myopathies). The aim is to assess efficacy, futility, safety and tolerability of a new drug called olesoxime. This is a neuroprotective drug that acts by interacting with protein components of the mitochondrial permeability transition pore (mPTP), preventing the release of apoptotic factors and in turn neuronic death. Olesoxime has displayed an excellent safety profile and has been well tolerated in phase I clinical trials in healthy subjects. For each participant, this phase II study will involve a 4 week screening period followed by a 24 month (104 week) treatment period. Following screening procedures and confirmation of eligibility, subjects will be randomised to receive either olesoxime or placebo in a 2:1 ratio. Olesoxime (or matched placebo) will be taken daily with evening meal as a liquid formulation at a dose of 10mg/kg. 150 subjects in total will be recruited, with a target of 30 patients in the UK. Recruitment is planned to be completed in 6 months. It is possible a dose adjustment may be made once 45 patients across Europe have been received study drug for 3 months based on a review by a designated independent Data Monitoring Committee. The patients to be recruited should be at least 3 years of age but younger than 26 years at the time of enrolment, with the age of onset of symptomsto be at 3 years of age or younger. They should not be taking any medication intended for the treatment of SMA within 30 days prior to being enrolled on the study. Eligible patients can be taking oral salbutamol as long as this has been commenced at least six months prior to enrolment on the study and remains at a stable dose during the study period. Participation in another investigational drug or therapy study within 3 months of enrolment is an exclusion criterion, as well as a hypersensitivity to sesame oil and use of medications that could interfere with olesoxime absorption (including cholesteramine, fibrates, fish-oils, niacin, phytosterols and ezetimibe).

Please click here to view inclusion/exclusion criteria and visit schedule for the trial.

Further information about this study can be obtained from the Clinical Trials Coordinator on 020 7905 2639.

HYP HOP: DICHLORPHENAMIDE vs. PLACEBO FOR PERIODIC PARALYSIS

Full Title: Double-blind, placebo-controlled, parallel group, phase III study comparing dichlorphenamide vs. placebo for the treatment of periodic paralysis

Status: Open to Recruitment
Sponsor: University Rochester
Funder: National Institutes of Health (NIH - USA)
PI: Prof. Hanna
Patients recruited:12; target 40

This is a phase III trial into Periodic Paralysis. 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, Hypokalemic periodic paralysis). The 9-week studies will investigate the prevention of attacks of weakness and it will be followed by 1-year extensions without placebo to compare the long term effects of DCP 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 or Gisela Barreto, Trials Coordinator at Gisela.barreto@uclh.nhs.uk.

THERAPEUTIC TRIAL OF MEXILETINE IN NON-DYSTROPHIC MYOTONIA Full Title: A Phase II Randomised, Double-Blind, Placebo controlled, Cross-Over Study to Investigate the Efficacy of Mexiletine in Patients with Non-Dystrophic Myotonia

Status: Open to Recruitment
Sponsor: University College London (UCL)
Funder: Food and Drug Administration (FDA – USA)
PI: Prof. Hanna
Patients recruited: 15; target 15

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 total duration nine weeks. Fifteen participants have been enrolled in the UK at the MRC Centre. For information on the status of recruitment please contact Dr. Dipa Raja Rayan at d.rajarayan@ion.ucl.ac.uk or Gisela Barreto, Trials Coordinator at Gisela.barreto@uclh.nhs.uk

ARIMOCLOMOL FOR SPORADIC INCLUSION BODY MYOSITIS (IBM)

Full Title: A Randomised, Double-blinded, Placebo-controlled Pilot Study Assessing the Safety and Tolerability of Arimoclomol in Adult Patients with Sporadic Inclusion Body Myositis

Status: Open to Recruitment
Sponsor: University College London (UCL)
Funder: Arthritis Research UK and Myositis Support Group
PI: Prof. Hanna
Patients recruited: 11; target 12

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. Pedro Machado at p.machado@ion.ucl.ac.uk or Gisela Barreto, Trials Coordinator at Gisela.barreto@uclh.nhs.uk.

GSK/Prosensa clinical trial in DMD boys with study drug GSK2402968 (PRO051)

Full Title: 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 dystrophy

Status: Ongoing
Sponsor: GlaxoSmithKline
Funder: GlaxoSmithKline
PIs: Volker Straub, Francesco Muntoni
Patients recruited: 8; target (UK) 8

A multicentre trial with this study drug is recruiting DMD boys in UK at the Great Ormond Street Hospital(GOSH), London and at the Royal Victoria Infirmary, Newcastle. It is a Phase lla, double blind, exploratory, parallel clinical trial to assess the optimal dose of GSK2402968 for safety, tolerability and efficacy, in ambulant patients with DMD. This study is designed to explore efficacy and safety of GSK2402968 given as a continuous regimen and an intermittent regimen over 24 and 48 weeks.

Objective(s)

Primary objective:

• To assess the efficacy of 2 different dosing regimens of subcutaneous

GSK2402968 administered over 24 weeks in ambulant subjects with DMD.

Secondary objectives:

• To assess the safety and tolerability of 2 different dosing regimens of

subcutaneous GSK2402968 administered over 48 weeks in ambulant subjects with DMD.

• To assess the PK of 2 different dosing regimens of subcutaneous GSK2402968 administered over 48 weeks in ambulant subjects with DMD.

• To assess long term efficacy of 2 different dosing regimens of subcutaneous

GSK2402968 administered over 48 weeks in ambulant subjects with DMD.

Study Design

The study aims to randomise 54 subjects. There will be 2 parallel cohorts. Each cohort will include 16 subjects on GSK2402968 and 8 subjects on matched placebo (2:1 ratio). Further information about this study can be obtained from the MRC Centre Clinical Trials Coordinator on 020 7905 2639.

Investigation of the ability of Otelixizumab to inhibit in vitro antigen-specific T cell responses from Myasthenia Gravis patients

Status: Open to Recruitment
Sponsor/Funder: GlaxoSmithKline
PI: Prof Kullmann
Patients recruited: 11; target 40

Myasthenia Gravis (MG) is the best understood autoimnune disease (a disease in which the immune system attacks some part of the body). This attack is directed by various parts of the immune system.

There is a continued search for newer drugs that will be of benefit in the treatment of MG. There is a continued search for newer drugs that will be of benefit in the treatment of MG. Otelixizumab has been identified as a possible treatment for MG. However before clinical trials can be considered additional information is needed to determine how it interacts with the immune system of patients with MG.

In this study adult patients with MG will be invited to provide blood samples (50 ml) for research purposes. Blood collected from patients will be used for Tcell assay and autoantibody assay development. Patients may be asked to provide a repeat blood sample (additional 50ml) after 46 months following the initial collection to see if T cell activation changes over time. Up to 40 participants will be enrolled in the UK. The study is being sponsored by GlaxoSmithKline group of companies.

For information on recruitment contact Natalie James (natalie.James@uclh.nhs.uk).

THERAPEUTIC TRIAL OF LITHIUM CARBONATE IN MND/ALS (LiCALS)

Full title: A double-blind, randomised, placebo controlled trial of lithium carbonate in patients with amyotrophic lateral sclerosis.

Status: Ongoing (closed to recruitment)
Sponsor: University College London Hospitals NHS Foundation Trust
Start date: June 2009
Funder: Motor Neurone Disease Association, and NIHR UCL
PI: Dr Richard Orrell
Patients recruited: 22, target: open-ended

Recent research suggested that lithium carbonate may be effective in lowing the progression of MND/ALS. Lithium may protect motor neurons through a range of mechanisms, including improving the transport of proteins along the motor neuron, improving the transport of mitochondria, and activating cell survival factors. In one study, lithium prolonged survival in a mouse model of MND/ALS. This is a multi-centre UK study, involving 215 patients with MND/ALS, taking lithium or placebo, for 18 months. The trial is designed to assess the safety, efficacy and tolerability of lithium in combination with riluzole as a treatment for MND/ALS. Assessments include survival, symptoms, quality of life, and function. Participants are randomised to take lithium or placebo, the level of lithium in the blood is monitored, and the dose of lithium (and placebo) adjusted as needed.

LiCALS Open Label Extension

Full title: LiCALS open label extension trial of lithium carbonate in amytrophic lateral sclerosis.

Status: Recruiting
Sponsor: University College London Hospitals NHS Foundation Trust
Start date: March 2011
Funder: Motor Neurone Disease Association, and NIHR UCL
PI: Dr Richard Orrell
Patients recruited: 3 of 8 recruited

This is an open label extension study for those who have completed the randomised double blind trial of lithium carbonate in ALS. The objective is to obtain further evidence of the safety of lithium carbonate in doses achieving levels of 0.4-0.8 mmol/l.

GSK1223249 in MND/ALS (the Nogo-A study)

Full title: A Phase I, multi-center, randomized, placebo-controlled, double-blind, single and repeat dose escalation of a drug to treat ALS.

Status: Recruiting
Sponsor: Royal Free Hampstead NHS Trust
Start date: September 2010
Funder: GlaxoSmithKline UCL
PI: Dr Richard Orrell
Patients recruited: 2, target: 2

GSK 1223249 is a new drug developed by GlaxoSmithKline, that targets a protein called Neurite Outgrowth Inhibitor (Nogo-A), which impairs neurone regeneration. There is evidence of increased Nogo-A, which impairs neuron regeneration, in muscle of people with MND/ALS. By blocking the effect of Nogo-A, GSK1223249 may be an effective treatment for the disease. GSK1223249 delays symptom onset and prolongs survival in a mouse model of MND/ALS. The trial will provide safety and tolerability information, together with biomarker and functional information. This may leader to further trials to assess effectiveness. The study includes an infusion of the drug (or placebo), with a muscle biopsy taken before and following the infusion, together with other monitoring assessments. For further information please contact Dr Richard Orrell (r.orrell@ucl.ac.uk)

BIOMARKER STUDIES IN MND/ALS

Full title: Characterisation of a panel of disease biomarkers in peripheral blood from individuals with motor neuron disease

Sponsor: University College London Hospitals NHS Foundation Trust
Start date: May 2009
Funder: Motor Neurone Disease Association UCL
PI: Dr Richard Orrell

Motor neuron disease (MND) is an adult-onset neurodegenerative diseases and one of the commonest neuromuscular disorders. The speed of progression of MND varies among individuals and the condition can develop with different clinical manifestations. Currently, there are no blood tests that could help us to predict the speed of progression of the disease and the likely clinical manifestations (e.g. predominant involvement of speech and swallowing or of the limb muscles). We are testing specific disease biomarkers in the blood. To assess change over time, a blood sample is taken every 3 months. The sample has to be carefully processed as soon as it is taken to preserve the quality of the blood contents. We are studying a range of blood constituents including proteins, DNA and RNA. From some participants we also collect samples of cerebrospinal fluid. If repeated samples are not possible, a single sample of blood for DNA studies is also helpful. We also examine samples from participants without MND/ALS, and individuals with similar but unrelated neuromuscular conditions. Parallel studies of biomarkers in an animal model of ALS are informing our choice of biomarkers. The study is in collaboration with Queen Mary University of London, and other participating centres.

MRC Centre CTIMPs Completed Trials

RANDOMISED DOUBLE-BLIND PLACEBO CONTROLLED TRIAL OF LONG-TERM ASCORBIC ACID TREATMENT IN CHARCOT-MARIE-TOOTH DISEASE TYPE 1A

Status: Completed
Sponsor: University College London
Funder: Muscular Dystrophy Campaign (MDC)
PI: Professor Mary Reilly
Patients recruited: 50

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, randomised, double-blind, placebo-controlled study aiming to evaluate the efficacy of AA treatment in CMT1A.

The study is now complete. Fifty participants were enrolled in the UK site at the MRC Centre for Neuromuscular Diseases. Paper in press.

A PHASE IIb EFFICACY AND SAFETY STUDY OF PTC124 IN SUBJECTS WITH NONSENSE MUTATION-MEDIATED DUCHENNE AND BECKER MUSCULAR DYSTROPHY

Status: Completed
Sponsor: PTC Therapeutics
Funder: PTC Therapeutics
PIs: Professor Francesco Muntoni, Professor Kate Bushby
Patients recruited: 11

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 approximately 10 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, randomised, 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 are to be followed for a period of 12 months. At the completion of the blinded treatment, all compliant participants were eligible to receive open-label PTC124 in a separate extension study.

(Ataluren is now the non-proprietary generic name for PTC124).

This work has been completed.

The preliminary findings from the Ataluren Study 007 did not show significant muscle improvement in the patients who participated in the study. The study was therefore discontinued. An update on this study was presented at the International Congress on Neuromuscular Diseases, Naples, Italy, 17-22 July 2010 by Professor Kate Bushby. Details of this presentation is available on www.ptcbio.com Briefly, analysis showed that, on average, patients treated with low-dose ataluren experienced better outcomes on measures of efficacy than patients treated with high-dose ataluren or placebo - this phenomenon is not unique for ataluren and has been observed with other drugs for other diseases. Further analysis of efficacy data is ongoing.

ANTISENSE OLIGONUCLEOTIDE INDUCED EXON SKIPPING IN DUCHENNE MUSCULAR DYSTROPHY

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.

RESTORING DYSTROPHIN EXPRESSION IN DUCHENNE MUSCULAR DYSTROPHY: A PHASE I/II CLINICAL TRIAL USING AVI-4658

Status: completed
Sponsor: Imperial College London
Funder: Department of Health (DoH)
PI: Professor Francesco Muntoni
Patients recruited: 8

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].

This work has been completed and outcome data published in the journal Lancet Neurology (Volume 8, Issue 10, Pages 918 - 928, October 2009)

DOSE-RANGING STUDY OF AVI-4658 TO INDUCE DYSTROPHIN EXPRESSION IN SELECTED DUCHENNE MUSCULAR DYSTROPHY (DMD) PATIENTS – (Systemic study)

Status: Closed to recruitment
Sponsor: AVI Biopharma
Funder: Medical Research Council (MRC) and AVI Biopharma
PI: Prof. Muntoni
Patients recruited: 19

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 was conducted in London and Newcastle.

A total of 19 subject (12 at GOSH and 7 at RVI, Newcastle) were recruited and final data is being analysed for submission to regulatory authorities in Europe and the USA. Outcome data were presented at the World Muscle Society, 12-16 October 2010 in Japan and a manuscript has been submitted.

ECULIZUMAB FOR MYASTHENIA GRAVIS

Full Title: A Randomised, Double-Blind, Placebo-controlled, Cross-over, Multicenter Study of Eculizumab in Patients with Generalised Myasthenia Gravis (GMG) who have Moderate to Severe Muscle Weakness Despite Treatment with Immunosupressants

Status: Closed
Sponsor/Funder: Alexion Pharmaceuticals, Inc.
PI: Prof. Dimitri Kullmann

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. 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 signaling 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.

Patients 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 jspillane@ion.ucl.ac.uk or Natalie James at Natalie.James@uclh.nhs.uk.

Natural History – Longitudinal Studies

Set-up Phase

OUTCOME MEASURES IN SMA TYPE II AND II

Status: Recruitment to commence shortly
Funder: SMA Europe
PI: Prof Muntoni

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 across Europe 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 with SMA II and III.

Further information can be obtained from the Trials Coordinator or Research Physiotherapist on 020 7905 2639.

Open Trials

ANDERSEN-TAWIL SYNDROME: GENOTYPE AND PHENOTYPE CORRELATION AND LONGITUDINAL STUDY

Status: Open to recruitment
Sponsor: University College London
Funder: National Institutes of Health (NIH – USA)
PI: Prof. Hanna
Patients recruited: 11

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 characterised 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.

Eleven patients have been enrolled so far 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.

EPISODIC ATAXIA SYNDROME: GENOTYPE-PHENOTYPE CORRELATION AND LONGITUDINAL STUDY

Status: Recruiting
Sponsor: University College London
Funder: National Institutes of Health (NIH – USA)
PI: Prof. Hanna
Patients recruited: 36

Episodic Ataxia Syndrome is a rare, genetic disease that causes recurrent episodes of dizziness and incoordination.

The majority of cases are likely caused by an inherent genetic mutation. However in some patients the mutation is unidentifiable. The purpose of this study is to collect prospective standardized data from subjects to better define the clinical phenotype of the EAs and to establish clinically relevant endpoints for use in therapeutic trials.

The study will also :

- Fully characterize the clinical spectra and the natural history of genetically defined EA.

- Systematically investigate phenotypic differences between EA subjects harboring KCNA1/CACNA1A mutations and those that do not.

This proposal involves a multi-center cross-sectional data collection analysis as well as a prospective longitudinal study. Since EA is a chronic disease whose course is measured in years rather than months, the subjects will be followed longitudinally at a yearly interval for a period of two years.

For information about the study please contact Tracey Graves at tracey.graves@btinternet.com.

CMT: A NATURAL HISTORY STUDY

Full Title: Charcot-Marie-Tooth Disease and related disorders: A Natural History Study

Status: Open to Recruitment
Sponsor: University College London Hospitals
Funder: National Institutes of Health (NIH – USA)
PI: Dr Reilly/Prof Muntoni
Patients recruited: 72; target (UK) >50

Charcot-Marie-Tooth Disease (CMT) and related disorders (distal hereditary motor neuropathy (dHMN) and hereditary sensory and autonomic neuropathy (HSAN)) are a clinically and genetically heterogenous group of disorders affecting approximately 1 in 2500 people.

People with this condition present with upper and lower limb weakness, wasting and sensory loss as a result of degeneration of the long peripheral nerves supplying the distal muscles. Despite the clinical similarities among patients with CMT the group is genetically heterogeneous. Advances have been made in identifying the genes that cause CMT and the molecular organisation of the peripheral nervous system (PNS) nevertheless the optimal management and treatment of the different variants of this disorder is not known and moreover natural history data is lacking for most forms of inherited neuropathies.

This is a 5 year study that will be conducted by four centres in United States and two centres in the UK (National Hospital for Neurology and Neurosurgery and Great Ormond Street Hospital). The aim of the project is to fully characterise the features of different types of CMT and the longitudinal progression of the disease. The data will also be used to establish clinical relevant endpoints for use in therapeutic trials. The identification and genetic characterisation of patients will facilitate the recruitment of participants for future therapeutic trials. Ultimately the information gained with this study will lead to the improvement in the treatment and management of CMT.

The study is also seeking to establish an appropriate paediatric impairment scoring method for CMT and establish a database for the inherited neuropathies. The study will include both adult and paediatric patients. Evaluations will consist of a neurological history and examination, nerve conduction velocity (NCV) study and in some selected cases skin biopsy.

This is a NIH funded study. At least fifty patients will be enrolled at the National Hospital for Neurology and Great Ormond Street Hospital.

For more information about the study please contact Dr. Matilde Laura at m.laura@ion.ucl.ac.uk.

MITOCHONDRIAL DISEASE COHORT

Status: Open to Recruitment
Sponsor: The University of Newcastle Upon Tyne
Funder: MRC
PI: Dr Robert McFarland
Patients recruited: 456; target 1500

The current project proposes to develop a cohort of UK patients with mitochondrial diseases. The details are to be stored in a database that will enable clinicians to gain adequate information for future clinical trials.

Mitochondrial diseases present a huge challenge to patients and doctors because no effective treatment is available. The extremely diverse phenotypic presentation of mitochondrial disease has previously limited cohort development.

The cohort will comprise symptomatic adults and children, in whom a mitochondrial disease phenotype and (where possible) genotype, have been confirmed. Asymptomatic individuals who have requested genotyping and proved positive will also be included. Genotyping is important because the same mitochondrial phenotype may be caused by several distinct mutations in either the mitochondrial or nuclear genomes. Phenotype will be characterized in all individuals (symptomatic and asymptomatic) on the basis of clinical history, clinical examination and detailed investigation.

Two centres will receive referrals (Newcastle University and University College London Hospitals). The database will physically be stored at Newcastle University and it will have a dedicated, electronic secure server.

The project anticipates collecting details on 1500 patients in total.

For information on the status of recruitment please contact Dr. Robert Pitceathly (London) r.pitceathly@ion.ucl.ac.uk or Geoff Bell (Newcastle) geoff.bell@nuth.nhs.uk.

THE NATURAL HISTORY OF INCLUSION BODY MYOSITIS (IBM Net)

Status: Open to Recruitment
Sponsor: University College Hospitals
Funder: MDC
PI: Dr Matt Parton/Mike Hanna
Patients recruited: 52; target 64

Inclusion body myositis (IBM) is probably the commonest muscle disease beginning in those aged over 50.  It leads to progressive disability with, classically, a characteristic pattern of muscle involvement. However it is poorly understood: its cause is unknown, there is no conclusive diagnostic test and it has no treatment.  Furthermore, information on the pattern and prognosis of IBM is more based on anecdote from clinical experience, rather than firm fact. The largest published series of data on the natural history of the illness followed only eleven patients for six months.

The current project seeks to better characterise IBM by gathering clinical data from as many cases as possible.

Serial standardised assessment (annually for five years) will chart disease progression and so both expand and strengthen knowledge of the natural history of the illness. Furthermore, establishment of a cohort of reliably-defined cases will build a valuable resource that could potentially form the starting-point for future studies. 

For information on the status of recruitment please contact Dr. Pedro Machado at p.machado@ion.ucl.ac.uk

PERIPHERAL NEUROPATHY OUTCOME MEASURES STANDARDISATION STUDY (PERINOMS)

Status: Open
Sponsor: Erasmus Medical Center
PI: Dr Michael Lunn
Patients recruited: 110 (NHNN 4); overall target 120

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.

Closed Trials

NON-DYSTROPHIC MYOTONIAS: GENOTYPE AND PHENOTYPE CORRELATION AND LONGITUDINAL STUDIES

Status: Closed to recruitment
Sponsor: University College London
Funder: National Institutes of Health (NIH – USA)
PI: Prof. Hanna
Patients recruited: 20

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. Emma Matthews at d.rajarayan@ion.ucl.ac.uk.

Exercise Studies

Set-up Phase
None

Open Trials

EXERCISE TRAINING IN PATIENTS WITH MITOCHONDRIAL DISEASE: ASSESSING THE BENEFITS

Status: Recruiting
Sponsor: University Newcastle
Funder: Muscular Dystrophy Campaign (MDC)
PI: Prof Turnbull

Collaboration site MRC Centre London (Hanna)
Patients recruited: 6 Newcastle, 1 London

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:

To confirm that endurance training in patients with mitochondrial abnormalities improves quality of life, exercise tolerance and oxidative capacity.

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 or Dr Robert Pitceathly at r.pitceathly@ion.ucl.ac.uk.

CARDIAC ADAPTATIONS TO EXERCISE IN MITOCHONDRIAL DISEASE

Status: Recruiting
Sponsor: Newcastle upon Tyne Hospitals NHS Foundation Trust
Funder: MRC
PI: Prof D M Turnbull/Dr MI Trenell
Patients recruited: 9; target 24

Twenty four people with mitochondrial disease will take part in the study. Participants will undergo cardiac, cognitive and movement examination and then they will be randomised into two groups. They will receive either; exercise counselling and support (n = 12) or continue standard care (n = 12) over a 16 week period. At the end of the 16 week period baseline measures will be repeated. Participants to be studied will have biopsy proven mitochondrial disease (age 18−60 years; BMI 20−35 kg/m2; and do not take part in regular exercise). Subjects with heart disease that would produce an adverse response to exercise will be excluded. Subjects with significant kidney disease or in vivo ferrous material will be excluded also as these are contra-indications to the use of gadolinium-based contrast agents and magnetic resonance imaging respectively. Magnetic resonance and echocardiographic evaluation of cardiac function as well as movement and cognitive function will be assessed at baseline and at 16 weeks. A progressive exercise test will be undertaken at baseline to establish maximal aerobic capacity and evaluate for an adverse response to exercise.

The patient exercise group will be matched with a control group of individuals without known mitochondrial disease who will undergo the same evaluation and training regime (n = 12).

In total, the study will require each participant to attend the research facility for three visits for metabolic examination. The exercise groups will be requested to attend 48 exercise sessions over 16 weeks.

For information about recruitment contact Geoff Bell at geoff.bell@nuth.nhs.uk.

PHYSICAL ACTIVITY AND INCLUSION BODY MYOSITIS

Status: Recruiting
Sponsor: Newcastle upon Tyne Hospitals NHS Foundation Trust
Funder: MRC
PI: Dr M Trenell
Collaborating site MRC Centre London
Recruitment: 500 recruits expected, across 5 disease sites (all not open yet), stroke arm has 36 recruited, 100 expected

The aim of this study is to collect data on day to day physical activity levels and metabolic control in individuals with chronic disease.

DESIGN: Participants will be identified from chronic disease clinics by the following lead clinicians: Stroke-Prof Gary Ford, Neuromuscular disorders-Prof Kate Bushby, Metabolic disorders-Prof Roy Taylor, fatigue-Prof Julia Newton and Ageing-Prof Julia Newton. An equal sample of male and female participants will be used in the study which will be up to 100 patients in each disease group.

METHODOLOGY: Step 1: Relevant practitioners will highlight possible candidates for the study. Step 2: Visit 1: At the start of the study participants will either be asked to attend Newcastle University’s Campus for Ageing and Vitality (Newcastle General Hospital), or if they are an inpatient will be visited on the ward.  Participants will be provided with an information sheet about the study. They will be given the opportunity to talk with the team and ask questions. Once fully informed, participants will provide signed informed consent.

Participants will be asked to fill in a disease screening questionnaire at the start of the process. The height and weight of the participants will be recorded and this information will be entered into the physical activity monitors. Instructions will be provided as to how to use the monitors. A resting blood sample may also be taken at this point. This will be analysed for glucose, insulin, lipid profile and liver function.

Step 3: Participants will wear the arm monitors for five days including one weekend day.

Step 4: Visit 2: At the end of the five day period participants will attend the research centre again or attend a pre-arranged session either at their home work place or on the ward to return the activity monitor. Here they will complete a brief physical activity questionnaire and two brief fatigue questionnaires. Data from the physical activity monitor will be fed into a computer. Each participant will be provided with a printout of their weekly activity levels and given the opportunity to discuss their results.

For information about recruitment contact Geoff Bell at geoff.bell@nuth.nhs.uk.

EXERCISE AND SARCOPENIA

Status: Recruiting
Sponsor: Newcastle upon Tyne Hospitals NHS Foundation Trust
Funder: MRC
PI: Prof DM Turnbull
Collaborating site MRC Centre London
Patients recruited: 0; target: 36

Sarcopenia, which is a complex multifactor process, has significant implications on quality of life, performance of daily activities, maintenance of independence and on projected healthcare costs.

Studies show that low physical activity correlates with poor mitochondrial function. Conversely, exercise correlates with better mitochondrial function, clinical improvement and improved perceived quality of life. Endurance training has been proven to be safe and efficacious in mitochondrial disease which may provide a model for the aging process albeit in an accelerated form with biochemical, histological and genetic changes seen in aged muscle also found in various mitochondrial conditions.

Aims:

1.To assess the rate and extent of motor unit loss in the eighth decade of life- cross-sectional (time 0) and longitudinal analysis (end of study)2.To correlate the extent of motor unit loss with histological correlates and the development of sarcopenia3  To assess the impact of exercise on the rate and extent of motor neuron loss

4.To observe whether endurance training initiated in late middle age prevents loss of muscle strength and mass in senescence

5.To assess the impact of neuronal loss on the inability to retain gains made in muscle strength following training after the 7th decade of life

6.To characterise effects of exercise upon neural activity, muscle oxidative capacity and mitochondrial and satellite cell plasticity with age.

Method:

Thirty six (36) female participants, matched for body mass index who do not take regular exercise will be invited to participate: 40- 45 years (12), 60-65 years (12) and 80- 85 years (12). Inclusion criteria will be capacity to undertake cycling exercise and ability to give informed consent. Exclusion criteria will be co-existing active coronary artery disease or steroid therapy.

These patients will be recruited via the media and social support groups. All expenses (travel, accommodation and meals) will be paid for from the research grant.

The study will take place over 24 weeks. Participants will attend the study centre for 7 visits in total. The study will include 2 main visits at the beginning and end of the study. Each main visit will last 3 days. There will also be 5 one day visits.

For information about recruitment contact Geoff Bell at geoff.bell@nuth.nhs.uk.

Closed Trials

STRENGTHENING HIP MUSCLES TO IMPROVE WALKING DISTANCE IN PEOPLE WITH CHARCOT- MARIE-TOOTH DISEASE

Status: Completed
Sponsor: University College London Hospitals
Funder: Muscular Dystrophy Campaign (MDC)
PI: Dr. Reilly
Patients recruited: 32

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, randomised 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 include 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.

Imaging Studies

Set-Up Phase

None

Open Trials

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
Sponsor: University College London Hospitals
Funder: MRC
PI: Prof T Yousry/Dr J Thornton
Patients recruited: 52; target 80

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) and 40 patients with genetically confirmed Charcot Marie Tooth Disease (CMT). 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 characterise 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.

MRI IN FKRP-RELATED LGMD2I

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.

Status: Open to recruitment
Sponsor: Newcastle NHS Trust
Funder: MRC
PI - Prof V Straub

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.