Results from an RSRT funded clinical trial testing the drug copaxone (glatiramer acetate) in 10 children with Rett Syndrome were recently published by Dr. Sasha Djukic, director of the Tri State Rett Syndrome Center in the Bronx, in the journal Pediatric Neurology. Copaxone, an injectable drug used for multiple sclerosis, boosts levels of an important molecule in the brain called Brain Derived Neurotrophic Factor (BDNF). BDNF levels have been reported to be low in Rett mice, hence the interest in this particular drug.
It took significant thought to design this trial to have maximum efficacy. One key decision to be made was whether the trial would be a small open label one (meaning all patients get the drug) or whether a larger placebo-controlled trial should be done right from the get go. While the gold standard for trials is placebo-controlled, there is a hefty price to pay both financially and on the Rett community as a whole in terms of the number of patients required. Conducting large placebo-controlled trials for every drug that might have efficacy in Rett is likely to drain the patient population, clinics, financial resources, time, bandwidth, etc.
After reflection and due diligence the decision was made by Dr. Djukic and her advisors to conduct a small open label trial. The idea being that the trial would simply probe whether copaxone might be efficacious and if so, whether the beneficial effects were sufficient to warrant performing a larger more definitive trial.
Copaxone was administered via injection to 10 patients between the ages of 10-21 for 6 months. The primary endpoint for the trial was gait velocity. This outcome measure was chosen because of its relative stability over short periods of time and the fact it can be objectively assessed. Secondary endpoints included respiratory function (breath holds and oxygen desaturation index), cognitive function (measures of attention and memory), quality of life scale, and EEG.
Gait Velocity: Improvements in 7 patients (2 patients showed major improvements in their ability to walk). 6 of the 7 patients stayed on copaxone for 1 year after the trial ended. Gait was tested again after a year and the improvements were still evident.
Respiratory Function: Breathholds improved in 5, worsened in 1 and remained unchanged in the others. Oxygen desaturation did not change with treatment.
Cognition: 7 patients completed the testing. Memory scores for faces improved in all, but not for patterns. 5 of 7 had improvements in recognition.
EEG: Marked decreases were observed in all 4 subjects that had epileptiform discharges at baseline.
The results from this small trial are encouraging, and 6 of 10 families felt the improvements were large enough that they continued to administer daily injections of copaxone after the study ended. Nevertheless, researchers know that the likelihood of placebo effect is high in any open label clinical trial. In other words, it is possible that the improvements resulted from participation in the trial, not from treatment with copaxone.
Although it is reasonable to argue that any meaningful improvement is worthwhile, even if the improvement results from a placebo effect, copaxone has the potential to produce side effects. Families need to be able to balance the likelihood of benefit versus the potential for adverse effects of copaxone before initiating chronic treatment with this drug.
The traditional next step to definitively assess efficacy would be to perform a trial where individuals are randomly assigned to receive either copaxone or placebo injections. Families and treating physicians would not know whether individual trial participants were receiving copaxone or placebo, and all efficacy assessments would therefore be ‘blinded’ to treatment. Although definitive, this type of traditional study design is not efficient and we estimate that it would require enrollment of 200 subjects in a trial where half would receive placebo injections for up to 6 months. This estimate is based upon the medium effect size actually observed in the open label pilot study. Note that a medium effect size is “visible to the naked eye of a careful observer”. Much larger studies are required to identify smaller, yet clinically meaningful, beneficial effects.
RSRT deems these findings supportive of continued rigorous research. However, rather than immediately funding a traditional placebo-controlled efficacy trial, we are exploring alternative study designs while simultaneously developing better efficacy measures (see the Outcomes Measures and Biomarkers Development Consortium). We are optimistic that improved measures will allow definitive efficacy assessments in a much smaller study. At that time, we will also evaluate copaxone in the broader context of all other potential trials that could be initiated.
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