Here is the transcript of a 2 hour long chat. Enjoy!
Tom Weidig: Thanks for having the courage to a no-questions barred interview with TheStutteringBrain! Let me start with yourself. You said that you are a person who stutters. At talks or in person, you are stuttering relatively little apart from occasional small blocks/pauses. Is my observation correct? In all situations? How about when you were younger?
Gerald Maguire: My stuttering is greatly affected by the medication I take. If I were to stop my medication, my stuttering would return to its levels that were around when I was younger. My
speech is at least 80-90% improved, depending on the day, with medication. I have been on medication since 1994.
Tom Weidig: Would you have the courage to do the test and drop your medication to see whether it is true?
Gerald Maguire: I have done such many times and my stuttering returns to his pre-treatment levels within just a few days--depending on the half-life of the medication. Also, I have tried numerous medications over the years to determine the effects particulary of each compound within myself.
Tom Weidig: Why did you choose a career as a medical doctor where you have to speak a lot? I presume u decided this before taking medication?
Gerald Maguire: I chose this career before starting medication primarily to study the brain--motivated by my own stuttering. I earned a degree in Biochemistry and a minor in Psychology in my undergraduate work to prepare for my medical school with the goal to figure out what was wrong with my brain and, if possible, to help others. My father is a psychiatrist (who stuttered as a child) and my mother is a nurse and both were (and continue to be) very supportive in not letting stuttering get the best of one.
Gerald Maguire: I should also mention that my mother stutters--in addition to her brother.
Tom Weidig: when was the first time you were thinking about using medication to reduce/eliminate stuttering?
Gerald Maguire: In 1991, my father reviewed a research in article by Dr. John Paul Brady on the psychopharmacology of stuttering. Although I had always thought about trying to investigate and help somehow with stuttering, this article gave me a foundation to base my focus. I had just graduated from medical school in June of 1991 and Dr. Brady's article was published in October--great timing!
Tom Weidig: so it kind of became your goal in life?
Gerald Maguire: Absolutely.
Tom Weidig: If I give you a magic one-pill cure for stuttering and no more medication needed in exchange for one of your fingers, would you do it?
Gerald Maguire: Could I choose the finger?
Tom Weidig: ok then...
Gerald Maguire: Considering I make my living through communication (teaching, research, clinical) as a psychiatrist and professor--I would have considered the bet before 1993. I am not a surgeon and do not rely on my fingers to carry on my profession! Now, with the right medications, I can keep all ten fingers and speak much better.
Tom Weidig: But there are some downside to taking medication for you, right? So if not a finger, how about 50% of your savings?
Gerald Maguire: Given the state of the economy in the state of California right now--I would take that bet! No seriously, freedom with spoken speech is greater than any monetary award than I can consider. I have traded speech fluency for side-effects such as weight gain and sedation--still positive trade-offs for me in my view. Now, with better treatments available, I have been able to eliminate those risks for me. I cherish my more fluent speech as it has allowed me to express my true self much more easily and allowed me to literally spread the word about stuttering and hopefully have helped some people along the way. An aspect I cherish more are the health of my wife and daughter--they are the most precious to me.
Tom Weidig: You are the director of the center for medical treatment of stuttering where you treat people pharmacologically. For how long? How many patients have you had sofar?
Gerald Maguire: The Center officially began in October 2007 with the founding donation of Mr. Granville Kirkup. We were fortunate to have you visit us during our opening event! I have been treating patients in this capacity since 1993 at the University of California, Irvine. Our patient database numbers around 350 so far.
Tom Weidig: How many are still in treatment?
Tom Weidig: I mean on medication
Gerald Maguire: The majority--we do not keep numbers on those who drop by for consultation (as they travel from great distances) and receive treatment recommendations. They then follow-up with their primary physician in their home/state country. I can provide numbers on those who stay in treatment locally within in our center and we number approximately 75% continue on the therapy. We have approximately 40% of those who originally enrolled in the first phase of the pagoclone exploratory study still on the medication going on its fifth year.
Tom Weidig: So the 75% of those at your center from the 350 is how many?
Gerald Maguire: Approximately 200 of those individuals received consultations and followed-up in their home state/country. We have approximately 115 patients still being seen in our clinic out of the approximately 150 who presented for their day-to-day care with us.
Tom Weidig: Are you willing and planning to make aggregated numbers from your center public in an article maybe? For science and the confidence of the stuttering community?
Gerald Maguire: We are collecting good outcome data and follow-up information on those enrolled in the pagoclone extension studies--we'll definitely publish these data. As for our aggregate patient population, you provide an excellent suggestion. We'll gather the data and submit it to the community as you suggest. As you know, our Center does present its data to the scientific community as evidenced by our poster presentation at Oxford Dysfluency, presentations at IFA and journal publications. I am not sure our aggregate data will be publishable,however, as the treatments involve many variables--different medications, etc. The pagoclone extension data is more easily publishable given its greater variability control.
Tom Weidig: I understand. So I guess more of a report rather than a scientific study.
Tom Weidig: How can you treat people for stuttering when in fact no compound has been officially found to clearly improve stuttering. Is that not paradoxical?
Gerald Maguire: All is a risk/benefit ratio. We have studied risperidone and olanzapine in double-blind, placebo-controlled trials showing efficacy and tolerability. Per Alm's work lends support to the dopamine hypothesis. Our brain imaging PET studies suggest dopamine antagonists may be beneficial and the recent genetics study from China further supports the work. Ultimately, we need a medication that is specifically FDA approved for stuttering--pagoclone is going down this pathway. The medications we do prescribe are FDA approved for other conditions--we understand the safety profiles well. We do have studies supporting their use in stuttering and a mechanistic understanding. We also publish our results for review in the scientific literature and do not make claims of "outcomes guaranteed" or "stuttering cured." We understand we have a long way to go but our center is thankful for our patients who share in our vision of developing better, proven treatments for stuttering.
Tom Weidig: Let me more to more general questions on pharmacology and stuttering before coming to the trials. Our good friend Per Alm suggested the following questions.
Gerald Maguire: Great!
Tom Weidig: According to his experience, what portion of stuttering persons benfit substantially from treatment with D2 antagonists, and choose to continue the treatment for long time?
Gerald Maguire: I haven't captured the long-term data formally as our grants were for the acute treatment. Our general review shows that the short-term results persist long-term. We observe an approximate 60-70% response rate which maintains long-term. The concern with long-term treatment with our older compounds, olanzapine and risperidone, is the adverse-event profile. Some patients have stopped these compounds secondary to weight gain (notably with olanzapine), sedation and sexual dysfunction (more notably with risperidone.) Many patients are no being tried on newer-generation compounds such as aripiprazole (case report only published in stuttering) and ziprasidone. We have applied for a grant to gather long-term data with these compounds but the initial reports appear promising. I know Per did not specifically ask about pagoclone here, but we have found that the initial response from this medication maintains long-term.
Tom Weidig: Experience of 3rd generation D2 antagonists, like Abilify, compared with 2nd generation? (olanzapine, etc)
Gerald Maguire: Aripiprazole is an interesting compound--it acts as a partial agonist/antagonist--I have observed it worsen stuttering in some cases and improve in others. It has a favorable side-effect profile compared to olanzapine (less weight gain, lipid elevations) but is associated with more akathisia (restlessness). We need to gather more information on this compound in stuttering before making strong conclusions.
Tom Weidig: Clinical attempts to try low dose stimulants, like in ADHD, in cases not responding to D2 antagonists?
Gerald Maguire: Interesting--we run into such with our patients with co-morbid ADHD. Stimulants which act on dopamine (unlike noradrenergic agents, atomoxetine and guanfecine) can worsen stuttering in the majority of cases. Also, I forgot to mention in a previous question, that approximately 40% of the individuals we treat at the Kirkup Center present for psychiatric conditions in addition to stuttering (e.g. ADHD, Tourette Syndrome, OCD). We have not used stimulants in individuals with just stuttering--only in those with co-morbid ADHD. We utilize the noradrenergic compounds first-line in ADHD co-morbid with stuttering.
Tom Weidig: The most frequent complaint from persons who choose to continue treatment with D2 antagonists? (side effect)
Gerald Maguire: It depends on the agent--with olanzapine: weight gain and sedation. Aripiprazole: restlessness, weight gain and insomnia. Risperidone: sexual dysfunction and weight gain. Ziprasidone: mild dyskinesias in the mouth--teeth-grinding, tongue motions.
Gerald Maguire: I should mention that not everyone experienced these side-effects, of course.
Tom Weidig: I guess it is not possible to predict outcome or side effect? So patients need to do it by trial and error, really?
Gerald Maguire: We have a good database from clinical trials to predict side-effects with olanzapine--those who are thinner and of non-Caucasian descent, have a greater risk of weight gain with this compound. Those with risk factors for diabetes (e.g. family history) should not take this agent first-line. All-in-all, the databases we have available for these compounds are from studies in schizophrenia and bipolar disorder--individuals who stutter tend to respond to lower dosages of these compounds. Many of the side-effects are dose-related--therefore, one should seek assistance from a clinician who is aware of such side-effects and has knowledge on how to properly dose these medications. Unfortunately, it is not quite as easy as pulling a bottle off a shelf and taking whatever dose!
Tom Weidig: Sorry, I mean which compound works for stuttering. Not just the side effect
Tom Weidig: I guess patients need to try out and see what works for them? or have to develop an algorithm?
Gerald Maguire: Absolutely. We are working toward personalized medicine--basing a treatment on a genetic profile or a brain imaging scan--unfortunately, we are not there yet--not in hypertension treatment nor in stuttering treatment. Some cases of oncology base treatments on tumor receptor markers--one day, we will have such and I'll rely on my stuttering colleagues, Dr. Alm, Dr. Neumann, etc., to help us get there!
Tom Weidig: Let move to Phase IIa trial. The article has finally come out and the wider public can study it. Why did it take so long? Is that not a big obstacle to real debates? In physics for example, all articles is first published online in an archive and then send to a peer-reviewing journal.
Gerald Maguire: The journals in medicine require that the article has not been published anywhere before--a poster abstract is OK, but that is it. We presented the poster abstract at the Oxford Dysfluency Conference in 2008. We submitted the article first to a "really well known top medical journal." (These are my quotes.) We wanted a huge impact. Unfortunately, after some time, the editor responded stating the article was good but stuttering was not worthy of mention in their "lofty" journal. I won't say the name to protect the innocent. Instead, we submitted to a leading psychiatric medication journal, the Journal of Clinical Psychopharmacology. After the initial review, they accepted the journal with some revision plans--including the open-label, long-term data. We then submitted back with the long-term data and the article is now published.
Tom Weidig: You had 132 subjects. The 132 where divided into 44 and 88. Why this split?
Tom Weidig: Why not 50% compound 50% control group?
Gerald Maguire: A two to one ratio of medication vs. placebo--based on the initial power analysis.
Tom Weidig: is it the same in Phase IIb?
Gerald Maguire: We used a multiple dosage range of low, medium and high dose randomization compared to placebo with approximately 3X the number of subjects. The FDA is always interested in a "minimally effective" dose and a dosage curve.
Tom Weidig: So let in Phase IIb, you have 300. So how many are on placebo?
Gerald Maguire: It should be approximately 1/4 but I haven't reviewed the final randomization as the blind has not been broken.
Gerald Maguire: We should keep in mind that the lowest dosage is likely essentially a placebo level of response as well--we'll have to see the results!
Tom Weidig: OK. Let go back to Phase IIb. Are you concerned that the control group had significantly more social anxiety?
Tom Weidig: The LSAS score of the placebo was 56 and the Pagoclone 46.
Tom Weidig: i know it is randomized but there is a difference.
Gerald Maguire: I'm reviewing the article to see if this was a statistically significant difference. I don't believe it was.
Tom Weidig: see Table 2 baseline, Total LSAS score.
Gerald Maguire: Good analysis, Tom! The LSAS was a secondary measure. The magnitude of changes were different favoring pagoclone. We must remember that the total LSAS was not developed specifically for stuttering and it is a secondary outcome measure in this study. Interesting positive effect.
Tom Weidig: Yes, but the control group had more social anxiety which has a bigger impact on the placebo effect?
Gerald Maguire: Correct--related to the randomization.
Tom Weidig: i have a question on patient selection
Tom Weidig: 232 patients were screened but only 132 taken. What were the criteria? Could there be a bias here for the general population?
Gerald Maguire: If patients had too mild or too severe of stuttering based on % of Syllables Stuttered--exclusionary. Also, those on other CNS active medications including drugs of abuse were excluded. Clinical Trial patient populations are always more selective than the general population to isolate the medication effect and to reduce variabilities. The general population will always be more varied.
Tom Weidig: So if Pagoclone is shown to be effective, it has only be shown for moderate stuttering?
Gerald Maguire: The Phase IIb study was more inclusive--including severe range--mild to severe on %SS. The very mild were excluded--too varible in detecting a direct medication effect.
Gerald Maguire: The key is that "covert stuttering" was not captured in these studies. Definitely something to consider for Phase IV--post-marketing.
Tom Weidig: I see.
Tom Weidig: Let's go some results.
Gerald Maguire: Sure!
Tom Weidig: After 8 weeks, the P groups showed a reduction of -17.4% and the control groupp a reduction of 7.9%. The difference is 10% which is not a lot and it was stat not significant. Even the absolute effect of 17.4% is not very strong. Right?
Gerald Maguire: The short-term trial was fixed dose and of limited (8 week duration.) This exploratory study is just that--it provided a significant signal which guided the larger Phase IIb study which just completed the double-blind phase. We learned from this study to follow patients for a longer period and at higher dosages to fully analyze the treatment effect.
Tom Weidig: But for me the signal was quite weak. Of course this is just the average, do you want to say something about the distribution?
Gerald Maguire: What one sees is an average effect across the group including those who did not respond and those who did respond. The key is that we have some individuals, even in this low dose, limited duration study who showed a marked reduction. I believe the key lessons learned from this study are the following: pagoclone showed a signal of efficacy leading to the large, Phase IIb study. Pagoclone appears well-tolerated without significant side-effects observed in this study. It also has a positive benefit on social anxiety. When it does work, it maintains its response long-term (vastly different than most of the behavioral treatment programs.) Pagoclone also did not impair (in fact, improves) speech naturalness. Promising data to pursue further investigation.
Tom Weidig: only 43% continued to the open label. why?
Gerald Maguire: That's 43% at one year were still in the trial. Such is actually higher than must open extension pharmacologic trials.
Tom Weidig: Yes, but if it works, wouldn't have stay on it? who decided to go on to open label? only those in the P group? so is there a correlation between reduction in stuttering after 8 weeks and willingness to participate?
Gerald Maguire: Ninety patients participated in the open-label trial with at least one assessment. Many patients want a quick fix and some dropped out. Some dropped out as the medication was not a "cure." If one did not experience a positive result early on, one was more prone to dropping out. We learned to increase the dosage in the open-label phase and to give more time for the treament effect.
Tom Weidig: but still the open label group which is a biased sample shows 40% reduction. so at the very least Pagoclone is not a miracle pills even for those who went on ti, right?
Gerald Maguire: It depends how you define miracle. Many of my patients state significant improvements in their lives owing to the medication treatment. Some may define as such but I'll leave such claims to the higher powers as to how one defines a miracle.
Tom Weidig: but u said that many were disapointed because they wanted a quick fix.
Gerald Maguire: Some were disappointed without a quick fix and some have maintained a significant response. Such is the attraction of my profession--one cannot always predict response leaving the constant search for new and better treatments.
Tom Weidig: Lets move on to current Phase IIb trial. what is the difference?
Gerald Maguire: Larger patient sample size, multiple dosages and longer duration of treatment effect. In addition, we are measuring effects on quality of life
Tom Weidig: how is the dosis determined? in the phase iib you have a higher dosis, when is the threshold reached after which there is no additional effect?
Gerald Maguire: We are analyzing such now. We know at ten times the dosage we are using, based in animal models, pagoclone may lose its partial agonist effect. Hence, we have an idea of what would be a minimal dose and what is maximal. At ten times the dosage, one may see sedation and possibly tolerance.
Tom Weidig: The trial is 24 weeks. What do you expect that the control group will show? Shouldn't the placebo go down to zero?
Gerald Maguire: I wouldn't predict down to zero but it should be significantly lower than in the 8 week study.
Tom Weidig: wouldn't you agree that at the very least the trial is an excellent way to test the measurement bias? I.e. if placebo should be very small, but if it is not, it is a measurement bias?
Gerald Maguire: We will learn a great deal about the proper metrics of stuttering in this trial--excellent conclusion, Tom.
Tom Weidig: So if the placebo is not significantly lower than in phase iia, the measurments are biased, and one should reduce all outcomes by the control group's gain?
Gerald Maguire: We must be concerned that if the medication doesn't separate from placebo that it was not due to a failed study design (and failed measurements.) If it truly fails, it should be that the medication is not useful. We are breaking new ground here and it presents a challenge to our field--how does one accurately measure the effect of change of stuttering treatment. Our studies are the best designed to do such and we have included multiple researcher to help us answer these important questions.
Tom Weidig: lets look into the future. when do you expect the results to come out?
Gerald Maguire: We are analyzing the data now. I'll wait until the study sponsors, Teva Neuroscience and Endo Pharmaceuticals, provide a release.
Tom Weidig: i thought u said the blinds are not broken yet?
Tom Weidig: so before the summer is a good estime?
Gerald Maguire: We are gathering the data now for the "lock" before the blind is broken. By the summer should be enough time if not earlier.
Gerald Maguire: We're both northern hemisphere folks for your readers!
Tom Weidig: just a last question to finish off.
Gerald Maguire: Great!
Tom Weidig: is the data of Phase IIa being make public? Or more general is there a requirement that trials need to lay open their data for others to check. I mean if one statistician messes up, e.g.?
Gerald Maguire: Beyond the manuscript, you mean? Many pharmaceutical companies post the trial results on line. I'll inquire (and you should feel free as well) with the folks at Endo pharmaceuticals regarding your request.
Tom Weidig: Yes. The article just presents aggregated data but not each subject. for example no-one can look at the distribution of outcomes.
Gerald Maguire: Good suggestion. I'll inquire for the raw data.
Tom Weidig: who is actually doing the calculation?
Tom Weidig: i would not be surprised if it is just one person who actually does it
Tom Weidig: does the fda get the data?
Gerald Maguire: Dr. Franklin and I worked with the statisticians at Indevus pharmaceuticals (now Endo). Other authors as well. I believe the FDA will have access to the entire database for these regulated studies. The trial is published and on clinicaltrials.gov
Tom Weidig: yes but not the underlying data.
Tom Weidig: Thank you!