Saturday, 11 April 2015

Multiple Sclerosis - Secondary Progressive Multi-Arm Randomisation Trial

You asked what is the MS-SMART Trial.  
We will hopefully get a post from Dr. Chataway on this

Multiple Sclerosis - Secondary Progressive Multi-Arm Randomisation Trial
MS-SMART is a trial being undertaken across the United Kingdom by a Network of UK-based Neurologists aimed at finding treatments for progressive MS. Visit the website for details (CLICK).

What will MS-SMART test?
MS-SMART will test 3 drugs (riluzole, amiloride and fluoxetine) in 440 people with SPMS. The drugs were selected from a group of medicines that are used to treat other conditions and show promising signs in the treatment of MS (in particular SPMS). Amiloride is used to treat heart disease, fluoxetine (depression) and riluzole (motor neurone disease).



It will take approximately one year to screen and recruit people into the trial. Participants will take one of the drugs OR a placebo pill (a dummy pill) for two years. No one will know which treatment they are taking while the trial in on-going. ‘Blinding’ as this is known is widely used in clinical trials and ensures the results of the trial are not subject to bias. During the trial participants will have a number of clinic assessments and Magnetic Resonance Imaging (MRI) scans.


Why is the trial for Secondary and Not Primary Progressive MS?
Whilst we think that this trial will identify treatments useful for primary progressive MS, we have had to focus on secondary progressive MS. Firstly, because there are many more people with secondary progressive MS than people with primary progressive MS and so it will be quicker to undertake the study and secondly if we added primary progressive MS, it could add to the variability in the studies, meaning that the trial would have to be larger and so much more costly.

Is the trial suitable for me?
Everyone who takes part in a clinical trial needs to meet the eligibility criteria, a defined set of rules which state who is suitable to join the trial. The eligibility criteria ensures the trial recruits people who may benefit from the treatment being tested and provides a safeguard so that people who may be at risk if they take part are not recruited.

It’s also worth thinking about the practicalities of joining the trial, for example there are several clinic visits and Magnetic Resonance Imaging (MRI) scans over a two year period.

A screening process will take place to find out if someone meets the eligibility criteria. Screening is made up of several stages. It is very detailed and some stages of the screening process take place at a clinic visit. Only once the full screening process has taken place will the medical team know whether the trial is suitable for someone and at that point invite them to participate in the MS-SMART trial.


What does the trial involve?
Tablets containing one of the drugs being tested or a dummy pill will be taken every day for 2 years. The effects of treatment will be measured by:
  • Assessments at clinic visits (approximately 8 in year 1 and approximately 2 in year 2).
  • A number of questionnaires will be completed at certain clinic visits. 
  • Blood samples will be taken at each clinic visit to monitor safety. 
  • At some centres participants may be invited to take part in additional sub-studies (participation in any of the sub-studies is optional).
  • Participants will have 3 MRIs during the trial, before treatment starts, at 6 months and at 2 years at the end of the trial. 
I've registered my details, what happens next?
A research nurse or doctor will be in touch. He or she will ask you some questions about yourself and your medical history. You may then be invited to come to the clinic for a screening visit. Screening and recruitment will take place over a one year period. Once someone is recruited they will take part in the trial for 2 years.


The eligibility criteria.Ages Eligible for Study: 25 Years to 65 Years. Genders Eligible for Study: Both

Inclusion Criteria
  • Confirmed diagnosis of SPMS at randomisation
  • Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. 
  • Progression can be evident from either an increase of at least one point in EDSS or clinical documentation of increasing disability in patients notes
  • EDSS 4.0-6.5
  • Aged 25 to 65
  • Men or Women of childbearing age must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the 3 drugs from time of consent, to 6 weeks after treatment, inclusive.
  • Females have a negative pregnancy test within 7 days prior to being enrolled (baseline visit) unless not of child bearing potential e.g. have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy or they are post-menopausal
  • Willing and able to comply with the trial protocol and have the ability to understand and complete questionnaires
  • Willing and able to give full written informed consent
  • Able to undertake MRI
Exclusion Criteria:
  • Pregnancy or breast feeding females
  • Patients unable to tolerate baseline MRI scan or scan not of adequate quality for analysis (e.g. too much movement artefact)
  • Patients fitted with pacemakers or permanent hearing aids
  • Significant organ co-morbidity (e.g. malignancy or renal or hepatic failure)
  • Routine screening blood values
  • Relapse within 3 months of baseline visit
  • Patients who have been treated with iv or oral steroids within 3 months of baseline visit (these patients can undergo future screening visits once the 3 month window has expired)
  • Commencement of Fampridine within 6 months of baseline visit
  • Use of immunosupressants (e.g. azathioprine, methotrexate, cyclosporine) or first generation disease modifying treatments (β-interferons, glatiramer) within 6 months of baseline visit
  • Use of fingolimod/fumarate/teriflunomide/laquinomod/or other experimental disease modifying treatment (including research in an investigational medicinal product) within 12 months of baseline visit
  • Use of mitoxantrone/natalizumab/alemtuzumab/daclizumab if treated within 12 months of baseline visit
  • Primary progressive MS
  • Relapsing-remitting MS
  • Known hypersensitivity to any of the active drugs for this trial
  • Use of: lithium, chlorpropamide, triamterene, spironolactone,
  • Use of potassium supplements
If you feel you may fit these criteria an are willing to enter the study, please contact your Neurologist, General Practioner or if not satisfied you will be able to self-refer via the MS-SMART enrollment website (CLICK HERE). 

The sites involved
Anne Rowling Regenerative Neurology Clinic, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom, EH16 4SA.Principal Investigator: Siddharthan Chandran

Hurstwood Park Neurosciences Centre, Brighton and Sussex University Hospitals Haywards Heath, United Kingdom, RH16 4EX. Principal Investigator: Waqar Rashid

The Walton Centre, Liverpool, United Kingdom, L9 7LJ. Principal Investigator: Carolyn Young

The National hospital for Neurology and Neurosurgery, University College London, London, United Kingdom, WC1N 3BG. Principal Investigator: Jeremy Chataway

Imperial College, London, United Kingdom, W6 8RF. Principal Investigator: Richard Nicolas

Barts and the London, London, United Kingdom, E1 1BB. Principal Investigator: Gavin Giovannoni

The Royal Victoria Infirmary, Newcastle, United Kingdom, NE1 4LP. Principal Investigator: Martin Duddy

Queens Medical Centre, Nottingham, United Kingdom, NG7 2UH. Principal Investigator: Nikolaos Evangelou

John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom, OX3 9DU. Principal Investigator: Mathew Craner

Derriford Hospital, Plymouth, United Kingdom, PL6 8DH. Principal Investigator:Jeremy Hobart

Royal Hallamshire Hospital, Sheffield, United Kingdom, S10 2JF. Principal Investigator: Basil Sharrack

University Hospital of North Staffordshire, Stoke-on-Trent, United Kingdom, ST4 7LN. Principal Investigator: Clive Hawkins

Royal Cornwall Hospital, Truro, United Kingdom, TR1 3LJ .Principal Investigator: Brendan McLean



CoI:  I have no financial interests to declare in relation to any of the treatments.

8 comments:

  1. Would have taken part, I'm not a NIMBY, but have a history of malignancy. This is how it happens Prof G, for many of us the ship has sailed.

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  2. Significant co-morbidity implies concurrent medical problems, previously treated cancer should not be an issue. It's worthwhile going ahead and finding out from the MS-SMART trial group

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    1. Thank you Doc, I'll speak to my GP.

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  3. Are peoples time and expenses paid?

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  4. If MS-SMART really that smart?
    Are their patents that are going to make pharma interested in this approach as most of these are very old drugs can you really repurpose them?

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    1. Very good question I don't know I wonder if ProfG as a collaborator or Sir Jeremy have an answer...I suspect sadly it will be we will cross that bridge when we come to it.

      As for Riluzole and MS there is WO0074676 which as filed in June 1999. Biogen who hold the patent have obviously not been interested in developing this. THe MS Smart trial will take 3-4 years to complete so will be at 2019 and the paptent will have expired unless Biogen have something up their sleeve. But should academia be doing a trial were biogen call the shots?

      Amiloride has a patent WO2008007131 filed July 2006 by the MRC. Have they kept this alive as that is 9 years of feeding a patent which is not cheap. Have they done a secret deal. Oxford have done two trials one in primary progressive, one in optic neuritis. There was signal of positivity in the first and the second will be ready in about 6 months. So if positive will they go to phase III. I doubt on any public money as they will say wait for MS SMART to finish so. Phase II finishes in 2019, Phase III will take 5-7 years to complete so we are at 2025 and then a year for regulators to get it together and we are at 2026. Patent is too old to be interesting.
      Fluoxetine and MS I didn't see a patent so the inventiveness is in public domain and so there is no patent to be filed.

      So do not get your hopes too high. However on the positive side it give SPMSers in UK access to a compound that may be neuroprotective, it tests a trial whereby 3 drugs are put against one which speeds the process up and it works out which outcomes to use for a pharma study. Because what will be happening is that Pharma will be making a new SSRI (Prozac) a new riluzole (glutamate receptor antagonist and a new acid sensing ion channel blocker. They will file patents on the new compounds and they will have some confidence that they will work. This is where it is SMART because it kick starts company interest.

      Where else is it SMART, maybe no longer having Ibudilast as an arm. Ibudilast is a phosphodiesterase 4 inhibitor that looks promising
      http://www.ncbi.nlm.nih.gov/pubmed/20200338

      Rolipram is a PDE4 inhibitor that wasn't
      http://www.ncbi.nlm.nih.gov/pubmed/19776093
      http://www.ncbi.nlm.nih.gov/pubmed/11156943
      http://www.ncbi.nlm.nih.gov/pubmed/21689500

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  5. BBC News at 6! Really hitting the big time!

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  6. The exclusion of PPMSers in this trial really lets me know where I stand.

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