Friday, October 22, 2010

Proposal for Beyond Pagoclone Drug Trials

We have argued in previous posts that there may be several potential etiologies (causes) of stuttering--namely excessive dopaminergic activity, insufficient levels of GABA, or inadequate neurosteroid production. Moreover, these chemical imbalances in the brain may stem from a myriad of problems. For example, excessive dopaminergic activity may be due to the production of too much dopamine, or too large a density of dopamine receptors on post-synaptic neurons, or insufficient dopamine reuptake by pre-synaptic neurons. Similarly, in our discussion of GABAergic drugs we have seen that the level of GABA depends on a number of factors as well.

It is reasonable, therefore, to speculate that stutterers might fall into subgroups based on the potentially different underlying root causes of their disfluency. If this were the case, then we could not expect that all individuals would respond the same to any specific drug therapy. And this observation has implications for the testing of the impact of drugs on fluency.

Given that a number of different drugs have been identified that target different pathways leading to excessive dopaminergic activity, it is reasonable to propose that these drugs be put through clinical trials to test their efficacy on fluency. Since the drugs are currently on the market and used for other purposes, presumably their safety already has been established to the satisfaction of the relevant government agencies. Thus, phase 3 trials testing for safety may not be required for these drugs.

One difficulty with conventional trials is that they basically take all comers. Many participants may not benefit from a specific drug treatment and those who do not respond may cause the drug to fail even though a significant minority might benefit.

A new model, called "adaptive design," for drug trials has been applied to the treatment of breast cancer. It focuses on leaner faster trials involving simultaneous testing of multiple drugs that enroll patients with a higher probability of responding to a specific treatment. And, unlike conventional trials in which results are not examined until the end, data is examined as the trial progresses. What is learned in the early going determines which drugs are administered to specific trial participants later in the study.

This model can be adapted to the testing of drugs that may affect fluency. Unlike drugs for breast cancer where a cure is sought, fluency enhancing drugs are a palliative rather than a cure. Thus, it may even be possible to eliminate a standalone control group in such a design by cycling trial participants through periods where the drug being tested is replaced by a placebo and observing the effect on both fluency using standard methods and on dopaminergic activity via brain scans. In addition, given the existing theoretical understanding of the action of a drug, the classification of trial participants may be further refined according to their specific etiologies.

Finally, since the clinical trials would involve existing drugs from a number of commercial pharmaceutical companies, it would be appropriate that the trials be conducted by a government organization (such as the NIH), a clinical trials unit in the academic sector, or a contract research organization not affiliated with any pharmaceutical company. In this way, we could enhance the level of objectivity of any such study.


Anonymous said...

i found this blog through toms blog, and have found it really useful in understanding the brain, chemical, mind body connection in relation to stuttering..

thank you for all your good work, and keep up the excellent non egotistical writing style ;)

Gerald Maguire, MD said...

Thank you for writing such an informative blog.

Anonymous said...

i am happy to find it thanks for sharing it here. Nice work.

Anonymous said...

Now if we could get Dr. McGuire to shed some light on the outcomes of the pagoclone trials. I realize that he may be constrained by confidentiality agreements he might have made with the pharmaceutical company. But the dissemination of clinical results, even if negative, would add to the knowledge base regarding stuttering.

Gerald Maguire, MD said...

Endo Pharmaceuticals is still analyzing the Pagoclone IIb results and my co-investigators and I will seek publication of the data once fully analyzed. As you know, we did publish the Phase II study in the Journal of Clinical Psychopharmacology earlier this year. Also, my colleagues and I at UC Irvine will be starting a trial of asenapine for stuttering in the coming months. We have other compounds for stuttering in our pipeline development as well. Fortunately, multiple studies investigating dopamine antagonists in stuttering (e.g. haloperidol, risperidone, olanzapine) have yielded positive efficacy. Newer generation dopamine blocking agents such as asenapine and others have fewer side-effects than their predecessors and we are very excited to begin this new chapter in stuttering pharmacotherapy research.

Again, I want to thank the author of this blog for providing this forum for discussion.