Friday, 1 December 2017

Clinical trial destroys another good idea

McKee JB, Cottriall CL, Elston J, Epps S, Evangelou N, Gerry S, Kennard C, Kong Y, Koelewyn A, Kueker W, Leite MI, Palace J, Craner M.
Mult Scler. 2017 Nov 1:1352458517742979.


Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC).


To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON).


A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18-55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo ( , NCT 01802489).


Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx ( p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo ( p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer.


Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.
                                     Data from Brain Seq

Amiloride is blocker of ASICS1 channel. This is a neuronal voltage-insensitive sodium channel activated by extracellular protons permeable to Na+, however ASIC1 also shows low Ca2+permeability. It was shown to be neuroprotective in animal models so of we go and do a trial and as we can see as occurred here...the trial fails and animals studies take a beating, like so many other studies.

However I have been arguing that animal studies are not always the problem. I am sorry to say clinicians conspire to mess things up. Sorry but it bursts my bubbles too.

In this study people who had optic neuritis had a month to get on drug. But this is too late as the damage has been done. The damage is done within a few days as we showed in animals, which led to a positive trial when people were recruited and put on treatment within 1-2 weeks as shown in

Raftopoulos, R, Hickman, SJ, Toosy, A. Phenytoin for neuroprotection in patients with acute optic neuritis: A randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 259–269

However, this has chucked away our animal data as this trial was not followed up to change practice such that people with optic neuritis get treated with phenytoin. However I think the amiloride has another problem as it made the nerve transmission slower suggesting that it block remyelination.

It is interesting that oligodendrocyte presusor cells have loads of ion channels on them and this includes ASIC1 (ACCN2) and this drops once cells produce myelin. See the picture. So is this chnnel involved in myelination


  1. So, take home message is leave it too late (for optic neuritis anyway) and it won't work. Similar to our mouse work way back when.
    Well done all.

  2. Thanks for posting MD. This is another very sad failure for another potential neuroprotective agent.


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