Have we got it wrong when it comes to progressive MS trials? #MSBlog #MSResearch
“This is a reposting; I originally discussed this publication 21 November 2011. The interpretation of this paper has become more important after comments in relation to a post yesterday on the ‘10 year course of MS‘.”
“What this study shows is that when a cohort of PPMSers who were in a trial of interferon were followed up 5 years later it was clear that PPMSer who had been treated with IFNbeta for 2-years had clearly done better than PPMSers on placebo. This means that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression over the next 2 years was primed by inflammation two years ago; this is why the study was negative. Therefore suppressing inflammation today will have not impact of 2-3 years as this damage has already occurred. In other words we need to take into account a lag from treatment to response. If this is the case we have yet to learn the lesson almost all SPMS and PPMS trials are running for 2-3 years without a lag phase analysis built into the design of the study. Why has this occurred? I am not sure; one reason is that it is very expensive to do 5 year trials. I remain convinced that inflammation plays a role in progressive MS and that we need to suppress it in addition to using neuroprotective agents to try and prevent loss of those axons and neurons that are destined to die from previous inflammation.”
“Is the lag concept as presented here understandable to you? I have drawn a hypothetical picture to model this delayed effect.”
CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.
“This is a reposting; I originally discussed this publication 21 November 2011. The interpretation of this paper has become more important after comments in relation to a post yesterday on the ‘10 year course of MS‘.”
“What this study shows is that when a cohort of PPMSers who were in a trial of interferon were followed up 5 years later it was clear that PPMSer who had been treated with IFNbeta for 2-years had clearly done better than PPMSers on placebo. This means that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression over the next 2 years was primed by inflammation two years ago; this is why the study was negative. Therefore suppressing inflammation today will have not impact of 2-3 years as this damage has already occurred. In other words we need to take into account a lag from treatment to response. If this is the case we have yet to learn the lesson almost all SPMS and PPMS trials are running for 2-3 years without a lag phase analysis built into the design of the study. Why has this occurred? I am not sure; one reason is that it is very expensive to do 5 year trials. I remain convinced that inflammation plays a role in progressive MS and that we need to suppress it in addition to using neuroprotective agents to try and prevent loss of those axons and neurons that are destined to die from previous inflammation.”
“Is the lag concept as presented here understandable to you? I have drawn a hypothetical picture to model this delayed effect.”
OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of PPMS.
MAIN OUTCOME MEASURES: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 MSers, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 MSers, respectively.
EDSS = Expanded Disability Status Scale
MSFC = MS Functional Composite ( a composite 3 tests the PASAT, 9-hole peg test and the timed 25-ft walk)
9-Hole Peg Test = test of upper limb function
Word List Generation Test = cognitive task
9-Hole Peg Test = test of upper limb function
Word List Generation Test = cognitive task
RESULTS: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (p=0.02) and Word List Generation Test (p<0.001) scores, and MRI measures in the normal-appearing white matter were significantly better. During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain volume (p=0.004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (p =0.004).
CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.
“This is good and bad news for MSers with PPMS. It suggest that we have missed a trick and been approaching PPMS trials incorrectly. If this study had been continued for longer than 2 years and extended to 5 years maybe there would have been a clear difference between interferon-beta and placebo. This trial suggests that PPMS may respond to interferon-beta; it is a pity that these results come so late in the life-cycle of the interferon preparations; Pharma is unlikely to spend the necessary resource on a 5-year study.”
Can anything be done to carry out the necessary trials? Can this learning be applied to trials currently running? It is almost criminal not to 'do' anything with this knowledge, and help slow the rate of progression for people with progressive MS! It's good news in that it shows there may be something that can help progressive MS.
It also indicates that (a) inflammation is part of the problem in PP/SPMS alsoand (b) Treatments in progressive MS may not be 100% effective and may not flat line your disease, but it may (slow) change the slope of worsening.Individually you may not be able to notice benefit as you may feel you are getting worse, however collectively by studying a lot of people the accumulation of this worsening may be slowed. So if you are one of the brave pioneers in clinical trials this needs to be borne in mind as benefit can still be had even if you feel it it is not working completely.
Prof G et al, I almost consider you the David Cameron of MS research in that you these statements of yours make me think you're totally no in touch with the suffering of us people, yet claim to have the answers.I was put on mitoxantrone very early in my PPMS diagnosis. At that time I was able to walk without aids, but six years later I am almost housebound. I need crutches or a walking frame at all times and continue to get worse. The aggressive and effective DMTs you advocate are not as brilliant as you make out. I am even struggling to type this comment because the progression has spread to my fingers. If mitoxantrone had had an impact on my PPMS then it ought to have kicked in by now but it has not.If you want evidence then stop consulting dubious statistical papers and start talking to those of us suffering from the disease.
Anon 1:46; I think you're misinterpreting Prof. G's comments. If you look at the graph you progress only at a slower rate. In other words if you did not have the mitoxantrone you would have become housebound earlier than 6 years. That is the depressing thing about progressive MS; slower progression is still progression. How are we going to know if the drug is working or not?
I honestly feel that my rate of decline has been constant even with the intervention of mitoxantrone. The drug seriously did not work for me.Progressive MS sufferers need remyelination therapies in conjunction with other medicines. It is our only real hope.
We need to know what drives progression, demyelination is no doubt part of the problem, but i suspect you need more that remyelination.
We have been waiting for years for the scientists to discover why we get this disease, as well a why some get PPMS and others RRMS. Not until that is known, can anyone be sure these drugs work. It is so distressing for patients to be given false hope. The drugs companies and it's shareholders are making money out of misery. Professor MacDonald said to me at diagnosis, do not believe anything you read in the papers or on television. I have stuck to this principle for years. Headlines such as 2 Litres of Coke a day cured my MS went straight over my head. I'm afraid this is beginning to apply to most drugs on offer too.
Anon 2:38 if you have progressive MS the reality is there are no drugs on offer.
there are if you are on a trial
You can only be on a trial is you meet certain criteria.
Yes this is true but each trial has different criteria. By having such criteria it removes noise from the system that would be there if entry was unrestricted, with the aim of more quickly seening a positive signal
"Prof G et al, I almost consider you the David Cameron of MS research….."Well, we've had plenty of insults but that has to be the all-time worst š
Look on the bright side of things; David Cameron's ratings are currently higher than Ed Miliband's and Nick Clegg's. I remain to be convinced that the analogy to a politician is very helpful or accurate; maybe it is an obtuse reference to being a spin doctor. If anything this blog does the opposite, which is why I read it religiously.
Yes, but look at Cameron's competition and tell me a time when a politician had it so easy? He can practically fax in his election win in 2015 because neither Labour or the Liberals can get their act together.The Tories have managed to get such fascist policies thorough the Commons in a collision partnership that I dread to think how bad it'll get for us ill folk when they acquire outright power. We'll have had it!
DOES THIS COMMENT MAKE ME NICK CLEGG?………….DID I SAY THIS BLOG WILL ALWAYS BE FREE……
You can't be Nick Clegg, as you have a spine, dodgy as it is at the moment!
Must share something with the PM…his spine has ruined his Deer hunting……Bambi must be happy.