The current first-line treatments of MS in children use different forms of beta-interferon or glatiramer acetate. However, close to 40% of pediatric patients with MS discontinue treatment due to intolerance, toxicity, persisting relapses or non-adherence (especially because the medications are delivered through injections). This supports the need for new therapeutic options.
Until very recently there have been no randomized clinical trials or long-term safety studies in pediatric MS. Treatment has mainly been based on small observational studies, as well as clinician experience. Pediatric studies for new agents are now required by the FDA and EMA, as well as other regulatory authorities, which have necessitated the consideration of clinical trials of MS treatments in children and teens affected by this disease. Several new therapies have shown efficacy and are presently available for adults with MS. Some of these molecules can be used orally, which is very appealing for use in children.
The IPMSSG has concluded that trials must be specifically tailored for children before generalizing the use of these new molecules because:
– It is not enough to know that a molecule is efficient in adults to conclude that it will be the same in children at any age and at the same dose.
– It is not enough to know that a molecule is well tolerated in adults to conclude it will have no toxicity in children on, for example, growth, puberty, fertility etc.
There are several important benefits of conducting safe and well-monitored clinical trials in children with MS including obtaining clear safety, efficacy and dosing information. In addition, well-conducted trials may be required for national or regional regulatory approval, which will enhance access to treatments in many world regions. However, global participation as well as general agreement over design, safety parameters and efficacy outcomes is critical to ensure successful completion of studies is needed.
A trial consists of a comparison between two treatments: the old one (or sometimes a placebo) and the new medication, usually worldwide. For each of the participating children, the treatment will be randomly chosen between the two that are being evaluated. Neither the child, the family, nor the investigators are aware of the actual treatment received by a given child. The primary end point of the comparison is to demonstrate that the new treatment is more effective than the previous one, or than placebo. It is judged either on the number of relapses per year or on the time to reach the first relapse. Other secondary end-points are usually on brain MRI aspects, especially the count of new plaques. In children, it is also highly important to evaluate the effect of treatments on preserving cognitive ability, since this is often affected in children with MS. Moreover, pharmacokinetic and pharmacodynamics studies are associated to insure that the chosen dose (that depends on age and weigh) is adapted. A very careful evaluation of safety and long-term effects and side effects are needed in any pediatric MS clinical trial.
The IPMSSG has published two consensus papers related to clinical trials in children with MS:
- Chitnis T, Tenembaum S, Banwell B, Krupp L, Pohl D, Rostasy K, Yeh EA, Bykova O, Wassmer E, Tardieu M, Kornberg A, Ghezzi A; International Pediatric MS Study Group. Evaluation of new and existing therapeutics for pediatric MS. Multiple Sclerosis. 2012 Jan;18(1):116-27. Epub 2011 Dec 6. PMID: 22146610.
This paper summarizes the current treatment practice and available data on treatment efficacy in pediatric MS (as of 2011), and summarizes the views of 50 IPMSSG members on the need for well-conducted clinical trials in pediatric MS.
- Chitnis T, Tardieu M, Amato MP, Banwell B, Bar-Or A, Ghezzi A, Kornberg A, Krupp L, Pohl D, Rostasy K, Tenembaum S, Waubant E, Wassimer E. International Pediatric MS Study Group Clinical Trials Summit: meeting Report. 2013 Mar 19;80(12):1161-8. PMID: 23509048; PMCID: PMC3662305.
This paper is a summary of a meeting that took place in Washington DC in January 2012 between members of the IPMSSG, regulatory agency representatives (FDA, EMA and Health Canada), pharmaceutical company representatives and patient groups. It outlines consensus guidelines from this meeting on the conduct of clinical trials in children with MS.
Who can participate in a trial?
Most trials will require the inclusion of close to 200 children with a proportion of them being less than 12. Trials usually include children with a diagnosis of MS between the age of 10 and 17 if they had at least one relapse in the past year or two relapses in the past two years.
Given the number of children to include and considering that MS in children is a rare disease, international cooperation is mandatory to succeed.
Each trial selects participating sites in different countries. If you want to include a patient or if you are a patient and want to volunteer, you have to liaise to the main reference center in your country (or part of country) to know where the closest participating center is located.
The participation in a trial is free of charge and usually travelling and other expenses related to the trial are reimbursed. The participation in a trial does require commitments from the child and his/her parents: visits, brain MRI and blood tests are slightly more frequent than for a usual follow-up. Conversely, patients participating in a trial receive a lot of attention and will benefit early of new treatments.
Are there on-going trials?
As of early 2014 several trials are ongoing with oral drugs.
Current Clinical Trials:
- Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis
- Adherence in Pediatric Multiple Sclerosis
- Safety and Efficacy in Pediatric MS Patients Prescribed Tysabri
- Safety and Efficacy of Fingolimod in Pediatric Patients with Multiple Sclerosis
- PK and PD Study of Natalizumab in Pediatric Subjects with RRMS
- Efficacy, Safety and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS)
- Safety and Efficacy of Fingolimod in Pediatric Patients with Multiple Sclerosis (PARADIGMS)
Are they only trials for drugs acting on relapses?
Presently yes. However trials could be also performed in future with drugs protecting the brain’s cells or helping with their repair. Trials can also be launched on specific questions (for example – helping with bladder function or, helping with motor or cognitive rehabilitation).