Powering trials for childhood MS

Childhood MS. Do we need placebo-controlled trials? #MSBlog #MSResearch

“As you know MS is relatively rare in children. Therefore it is not feasible to do large phase 3 clinical trials to show that a DMT is effective in children as we do in adults. What we tend to do is extrapolate the results of adult trials to children. This is not correct. Children may respond or not respond to a DMT for a whole lot of reasons. Legislation has been enacted in both the US and EU that forces pharma companies to do clinical trials in the paediatric population within a certain number of years of them being granted a license for an adult indication. This is good and bad. Good in that it forces us to get data on a specific DMT in children. Bad in that the regulators often want a placebo-controlled data to show that drug is working. Is this ethical when we know how damaging untreated MS can be and we already know that this drug is effective in the adult population? Would you let your child be randomised into a placebo-controlled trial, and run the risk of them being allocated placebo or dummy drug, when the drug in question has already been shown to be effective in adult-MS?”

Epub: Verhey et al. Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials. Neurology. 2013 Aug 21.

OBJECTIVE: To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints.

METHODS: Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting model of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters.

RESULTS: Assuming a 50% reduction in new T2 lesions over 6 months, 90 MSers/arm are required, whereas 165 MSers/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (ϑ), sample sizes range from 70 MSers/arm (using ARR) to 105 MSers/arm (TTFR) for a 50% reduction in relapses, and 230 MSers/arm (ARR) to 365 MSers/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative ϑ, 2-year trials using ARR require 45 MSers/arm (60 MSers/arm for TTFR) for a 50% reduction in relapses and 145 MSers/arm (200 MSers/arm for TTFR) for a 30% reduction.

CONCLUSION: Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration.

Other posts on childhood MS:
12 Apr 2013
BACKGROUND: Obesity in late adolescence has been associated with an increased risk of multiple sclerosis (MS); however, it is not known if body size in childhood is associated with MS risk. METHODS: Using a prospective 
27 Mar 2013
“This report is timely can confirms the MS communities commitment to children with MS and the need to get DMTs approved for treating childhood MS. Hopefully, parents of children with MS will find this initiative a move in the 
05 Feb 2013
Langer Gould A, Brara SM, Beaber BE, Koebnick C: (epub) Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome Neurology 2013. OBJECTIVE:To determine whether childhood obesity is a 
29 Jan 2013
#MSBlog: Childhood and adult MS looks the same on MRI. Are you surprised? Donohue et al. No Regional Gray Matter Atrophy Differences between Pediatric- and Adult-Onset Relapsing-Remitting Multiple Sclerosis.
30 Jun 2012
Research: childhood-onset vs. adult-onset MS. Epub: Pichler et al. Differences and similarities in the evolution of morphologic brain abnormalities between paediatric and adult-onset multiple sclerosis. Mult Scler. 2012 Jun 19.
14 Mar 2012
Objective:To investigate the association between childhood trauma and multiple sclerosis (MS) by comparing histories of child abuse and neglect between patients with MS and adults from the general population in a 
26 May 2013
“No surprises here; the profile of interferon-beta in childhood-onset MS appears similar to that in adults. I wonder what the new generation drugs will be like, in particular the more efficacious ones. Will they prevent the 
23 Jan 2013
I did not have a particularly ‘sterile’ childhood, spent a lot of time at the stables and generally outside, certainly nothing like the overkill you hear of theses days. However, even my experience was probably fairly sterile 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Prof. G surely it should be about safety, rather than whether or not it works in children? Why not simply a safety register or sorts?

    • I agree; but as a scientist, and not a doctor, I can understand why you need class one evidence. But as a doctor I have a problem randomising someone to a placebo when we have a drug that works in adults. At least they don't need two phase 3 trials. But why do they need a clinical outcome when MRI is a pretty good surrogate for relapses.

  • No, I would not have risked my child getting placebo instead of a drug that is known to work in adults.

    But something needs to be done about getting the DMTs officially approved for children. Some neurologists still say things like: 'First do no harm', we don't know if this is safe, …

  • On the do no harm front, can we do better than playing the odds as we see them now? By this I mean, it appears MS does a lot of damage in the first couple of years. Can we use a projected risk analysis matrix both for treatment and not treating? I suspect many parents will look at the matrixes and choose treatment. Regardless, I am not sure the do nothing is doing no harm, but I am on the opposite side of many with my opinion. In my eyes, being able to help and choosing not to do so is not much better than being the cause. For me, it comes down to which is riskier, and which has a potential risk for a positive outcome. Not all risks are negative.

    As to would I enroll my kid, I would in large part because if we can stop the damage from happening, the plasticity of a child's brain may allow it to recover some functionality lost from the flare leading to the diagnosis. If a young child can regain some function following a hemispherectomy, could it not regain some function from areas once cut off from the nervous system? I know as Tysabri has worked thus far for me, I've regained functionality. Could I have gotten more back if I was younger?

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