Year of the Rat


Happy new Year. It is the year of the Rat in the Chinese Calendar

I predict that we will be doing some appropriate things things this year, but hopefully we will not be working with the furry kind (big teeth and hairy tail), but I am sure we will meet a few of the human kind.

Indeed “Someone will be calling me a dirty rat by the end of the year”. But it won’t be James Gagney, if you need a clue. I would say it should have happened by now.

I am sure somone will comment that my hair is a a bit ratty. I know some of you like to hurl some abuse , maybe after the comment above

Who will we rat-on to show a bit of skullduggery? …..I shoud have been a reporter.

Most importantly ratification is going to be become a new verb and a new invention. Hopefully it will confirm an idea.

You will have to stay tuned and focussed, so you can work out what I’m talking about.

This is not about hiding bad news, but today, ProfG and Sir Jeremy were involved in what turns out to be the MS-not so SMART trial.

I will take abit of the blame, but not much. So what went wrong?

Some science boffins did a meta-analysis hunting for a group of MS drugs to test and put them into a trial and no effect was seen with the three horses selected. In the interim of the trial, riluzole and fluoxetine had failed in other trials, so the writing was on the wall. Fluoxetine, which is also know as Prozac was a late entry after being pipped to the post for a drug that showed some promis, but was done in Americae. The good thing it has created a platform of neuros throughout the country working together. Why waste time let’s go again!

We have MS STAT2 on the go and MND-SMART is about to start. This is a trial abit like MS-SMART but in motor neurone disease. If they get a hit I suspect it will be of benefit. However, riluzole is one of the few drugs available for MND and it failed in this trial. Riluzole is a dirty drug that stops nerves firing and so it is not going to be tolerated very well by people with MS. Secondly MS-SMART took no notice of MS biology and they were monotherapy trials. I would argue, that until you blow out the inflammatory fire with decent DMT it is more difficult to see much effect and is perhaps on reason why effects ibudilast and statins are not great.

So where next? The drawing board, MS-SMART2 and if we do go down this road what should be tried and how should we do it. Because if we fail again, we will be called more than just a bunch of rats

Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial.

Chataway J, De Angelis F, Connick P, Parker RA, Plantone D, Doshi A, John N, Stutters J, MacManus D, Prados Carrasco F, Barkhof F, Ourselin S, Braisher M, Ross M, Cranswick G, Pavitt SH, Giovannoni G, Gandini Wheeler-Kingshott CA, Hawkins C, Sharrack B, Bastow R, Weir CJ, Stallard N, Chandran S; MS-SMART Investigators.Lancet Neurol. 2020 Jan 22. pii: S1474-4422(19)30485-5. doi: 10.1016/S1474-4422(19)30485-5. [Epub ahead of print]

BACKGROUND:Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.

METHODS:We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with, NCT01910259.

FINDINGS: Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.

INTERPRETATION:The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.

FUNDING:Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

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