Saturday, 26 September 2015

Primary Progressive MS, who should be in trials?

Following on from yesterdays post by PostG

Ziemssen T, Rauer S, Stadelmann C, Henze T, Koehler J, Penner IK, Lang M, Poehlau D, Baier-Ebert M, Schieb H, Meuth S. Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review. PLoS One. 2015 Sep 22;10(9):e0138243.
BACKGROUND:So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population.
OBJECTIVE:The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator.
METHODS:A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared.
RESULTS:Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately.
CONCLUSION: Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

So for "meta analysis of the week" we have this paper which looks at trials in PPMS. As it is open access you can all have a read. So out of the 50 fifty or so trials only 4 were put under scrutiny. There was the suggestion that there may be problems in the trials and that yet again the old faithfull EDSS may not be the best endpoint to have.

One does not have to be a rocket scientist to come to the conclusion that there needs to be better outcomes than EDSS.

Why do the regulators and neuros persist with these measures to be the gold standards on what trial success is based. It is clear that the EDSS is not a scale that is linear and if you load up your trials with people with a certain EDSS, then this may change so slowly that your trials have to be years longer than anyone is going to want to wait to know if the drug such the patent life will be long gone and there will be no interest in going the study in the first place. 

We need to find functional systems that progress at a reasonable rate to measure within a trial and we need to start a study when there is still enough neural circuitry left so that a change can be seen. Is the 9 hole peg test and walking outcomes the answer?

We know that imaging such as atrophy measures is missing a lot of nerve loss and is subject to all sorts of artifacts too.

I have not done a meta-analysis but based on my reading it would seem to me that if we persist in T cell immunotherapies in PPMS or SPMS for that matter then they are unlikely to succeed properly.
However, I think people with gadolinium lesion active, relapsing PPMS will respond to these treatments, but progression will not.

As recruitment has finished, I will make a prediction that the ASCEND trial (in SPMS) with Natalizumab will fail and the PPMS trial with anti-CD20 will fail also, except for benefit in the subset above. I could extend this to a few more drugs too. 

I don't know the answer and ProfG may have a different view/ knowledge, as he must have done to allow some of his patients to enter the trials. He is an optimist and if you are not willing to fail, you can never succeed and you can do nothing or try what is available.

I hope I am proved wrong, as some of the mutterings I have heard from the pharma grapevine,and maybe the rate of progression will slow because I am sure that new lesions are forming in all MSers.

However, if I am not, then we need to wake up and smell the roses and try different approaches and stop this endless procession of demoralizing failures. 

Some companies are trying their drugs in PPMS/SPMS because of the unmet need and because they can still do placebo-control trials rather than do a non-inferiority trial against a current drug. This is because they would have to purchase the comparator drug to do a head to head trial. Easy for a company with a low hanging fruit comparator but you would have to shell out about an extra $50,000,000-$100,000 to buy the drug for say 500 people if you don't already have a drug in the market place.  However, think of the millions some companies are flushing down the toilet by doing a trial that has no/little hope of success. In my opinion it is happening as I write.

We will soon know the answers. 


  1. What a pity cell cultures can't be used, as with many cosmetics tests nowadays. Culture a brain in a petri dish, induce neurodegradation (I'm sure that's simple), apply the neuroprotective agent to be tested, and then take slices of the brain to examine. Well, they grew an ear on a mouse, didn't they?

    1. Cultures can be used but they fail to address issues such as pharmacokinetics and toxicology


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