Clinical Trials

The UK is very poorly prepared to move forward on developing clinical trials and testing new treatments in children and adults with major disabling neuromuscular diseases. Significant molecular advances have now created opportunities to test new therapies in patients, or in preclinical models but no systems are in place in the UK to facilitate this process. There is no systematic trials culture for patients with disabling neuromuscular disease and the advent of new therapeutic possibilities support the view that the UK must now move to a “trials ready” position. The MRC Centre aims to work with partners to advance clinical trials in neuromuscular disease in the UK. The clinical services linked to the MRC Centre in the partner NHS institutions are unparalleled in having excellent clinical and molecular characterisation of patients with neuromuscular disorders, thanks to the NCG molecular genetic and protein biochemistry centres.
We believe that the main current obstacles currently hindering delivery of clinical trials and which will be addressed by the MRC Centre include;

1. Lack of infrastructure including issues of trial design, regulatory support and biostatistical support.

2. Lack of agreed methodology for monitoring disease progression and treatment outcomes.

3. Lack of large-scale natural history studies for many neuromuscular diseases.

4. Lack of nation-wide patient databases with precise diagnostic criteria.

5. Lack of a specific training programme for clinical scientists in neuromuscular disease.

Aims: To overcome the current obstacles to facilitate a shift to a clinical trials culture in the UK for patients with disabling neuromuscular diseases.

Strategy: The joint London Newcastle centre will specifically address each of these obstacles by establishing core activities in clinical trials and in education and training. The centre has an unrivalled resource of carefully characterized patients who are available for studies across the full spectrum of disabling neuromuscular diseases. We already jointly provide Department of Health funded national services for limb girdle muscular dystrophy, congenital muscular dystrophy, muscle channelopathies and mitochondrial diseases (NCG centres).

At present there are state of the art clinical trials facilities available in London [recent UCL CRF Wellcome Trust funded facility] and Newcastle, although these are not geared towards the specific issues relevant for neuromuscular patients. The clinical trials core group [with the support of Dr Elaine McColl-trial design and biostatistics and the trials coordinators] will address the obstacles outlined above and ensure that appropriate support in clinical trials is available to the neuromuscular centre. The plan of work of the clinical trials core group is likely to result in a sustainable, durable expansion of clinical trials enabling us to take full advantage of these facilities.

CURRENT NATURAL HISTORY STUDIES AND CLINICAL TRIALS

1. A natural history study of ion channel non-dystrophic myotonia. UK PI: Hanna, Funded: NIH [USA] 2006-2008

2. A natural history study of Andersen’s syndrome channelopathy. UK PI: Hanna. Funded: NIH [USA] 2006-2008

3. RCT trial of Acetazolamide vs Dichlorphenamide in Periodic Paralysis. UK PI: Hanna. Funded: NIH [USA] 2007-2009

4. EN 101 (Monarsen) treatment for myasthenia gravis. NHNN PI: Hanna. Funded: Ester Neurosciences.

5. RCT of vitamin C therapy in Charcot-Marie Tooth Neuropathy. PI: Reilly. Funded: MDC 2006-2009

6. RCT of Methotrexate trial in chronic inflammatory neuropathy. NHNN PI: Reilly. Funded: GBS/CIDP Foundation International 2006-2008

7. Influence of IV Lidnocaine on peripheral nerve excitability parameters in neuropathic pain. PI: Koltzenburg. Funded: UCLH 2006-2007

8. Phase I-II Antisense oligonucleotide induced exon skipping in DMD after intramuscular injection of antisense oligonucleotides. PIs: Muntoni, Morgan, Straub, Bushby. Funded: DoH 2005-2009

9. Phase II Antisense oligonucleotide induced exon skipping in DMD. PIs: Muntoni, Morgan, Straub, Bushby. Funded: MRC 2006-2008

10. Muscular Dystrophy Heart Protection Study. Trial of early intervention with ACE inhibitors and beta blockade to prevent cardiomyopathy. PIs: Bushby, Muntoni. Funded: BHF 2008-2011

11. Myostatin antibodies MYO-29 in the treatment of muscular dystrophy. A double blind phase I/II study. UK PI: Bushby. Funded: Wyeth-USA 2005-2007

12. Steroid therapy in DMD. PI: Bushby. Funded: NIH [USA] trial planning grant

13. PTC124 read-through stop codons in DMD (and other conditions). PIs: Bushby, Muntoni, Straub. Funding: PTC

14. Idebenone trial in Friedreich’s ataxia. PI: Chinnery. Funded: Santhera

15. SRT501 in MELAS. PI: Chinnery. Funded SIRTRIS Pharmaceuticals

16. Idebebone in Leber hereditary optic neuropathy. PI: Chinnery. Funded: Senthera

17. MRI in Duchenne Muscular Dystrophy. PI: Straub. Funded: MRC