Tuesday, May 30, 2006

The Stuttering Brain Roadshow

This blog is going on a roadshow. Here are the different cities:

June 1st to June 3th: Pisa (Italy)
June 4th: Frankfurt (Germany)
June 5th to June 7th: New York (USA)
June 8th to June 11th: Boston (USA)

If you wanne meet up, let me know!!! :-)

P.S. I am going to a wedding in Italy, and fly to NY for a consultancy job, and Boston to meet several people.

Saturday, May 27, 2006

Were you a stuttering guinea pig?

If you have participated in the Pagoclone trials, I (and I am sure the other readers) would like to hear from you. Either leave a comment or send me an email. I can make the report anonymous on request.

Ideally the report should tell us about:
1. yourself and your stuttering before the trials,
2. about the procedures and your contacts with the trial managers,
3. about your experiences during the trial and comments by others on your speech.
4. whether you would continue on Pagoclone.

It is important that you only report what you have experienced and comments by others. If you also want to share your interpretation of your experiences, it is crucial that you clearly separate them from your experiences. For example: Instead of "I was more fluent while on Pagoclone", "I took the pills and soon after I felt that I spoke more fluent, but did not ask my wife or others for independent feedback. I am fairly confident that I took Pagoclone and not a placebo, because I felt differently and was less anxious. I also think that I truely became more fluent. So I associate my experience of greater fluency to Pagoclone."

Friday, May 26, 2006

Probing Pagoclone EXPRESS

I was told that a manuscript of the Pagoclone study will soon be published with more details, which will also allow a discussion on effect sizes. So we need to wait a bit. In the mean time...

I looked at the press release a bit more, here are my thoughts:


“Indevus has completed what we believe is the largest pharmaceutical trial ever conducted for stuttering and the results are very exciting,” stated Glenn L. Cooper, M.D., chairman, president and chief executive officer of Indevus. “Our results today show that stuttering, a condition with no approved pharmacological treatment, is potentially treatable with Pagoclone. This study was designed as an exploratory trial to follow up on a limited number of observations of the effect of Pagoclone on stuttering during previous anxiety trials. The design of the EXPRESS trial enabled us to evaluate the condition from several clinical perspectives and we believe this provides us with a strong foundation to develop a clinical plan for further development.”
He says a lot without saying anything... He could be French or a politician... :-)


Gerald A. Maguire, M.D., associate professor, department of psychiatry, University of California, Irvine School of Medicine, stated, “Being a person who stutters and a physician who researches and treats stuttering, I am very excited about the results of this trial. As an investigator on this study, I saw first hand the positive impact pagoclone can have on the lives of patients. Consistent with the results of the entire study sample, more than half of my pagoclone treated patients had a clinically meaningful decrease in the severity of their stuttering. Although there is no cure for stuttering, pagoclone holds significant promise as a well-tolerated, effective and viable treatment for the millions of Americans who stutter.”

Jerry Maguire's statement is more revealing. My interpretation of his statement (which MIGHT BE COMPLETELY WRONG!) is the following: He is mostly excited about the trials, because it is the first large scale study that has been done and the drug shows more effects than any other drug but he is not excited because Pagoclone is a cure. And, not all stutterers benefit from Pagoclone, and those who do reduce their stuttering noticeably but do not eliminate it.



8-week, placebo controlled, double-blind, multi-center trial with an open label extension. There were a total of 132 patients randomized in the trial.

They have followed standard procedure.


EXPRESS (the name of the study) used the following measures:

Frequency and Duration Subscale of the Stuttering Severity Instrument Version 3 (SSI-3)
the Stuttering Severity Scale (SEV)
the Subjective Screening of Stuttering (SSS) Severity Subscore
the Clinician Global Impression-Improvement (CGI-I)
the Liebowitz Social Anxiety Scale (LSAS)
the Speech Naturalness Scale (SNS)


They claim that the measures ( SSI-3, SEV, and SSS) are validated stuttering measures.
My question:
What do they mean by "validated"? Have they done a battery of statistical checks to see how consistent the measure is? My experience is that the stuttering measures taken at week 0 are NOT normally distributed, and there are some significant outliers, i.e. some stutterers are extremely disfluent or fluent. A massive improvement of 1-2 extreme stutterers give statistical significant results for the whole group.


For all measures except SEV, the distributions of measured values for the control group and the placebo group were statistically significantly different at p-values ranging from 0.007 to .08; (typically p=0.05 is regarded as "worth noting" as only 1:20 is the result of a statistical fluctuation, and p=0.01 is considered "reliable").
My question:
1) What happens if you give the medication to normal people? I would guess that their CGI-I and LSAS would improve, too?
2) I want to see the effect size, i.e. I want to know how big the effect is.
3) Is the effect only for some people or all people?


The SEV measure is rated by clinicians from "no stuttering" to "extremely severe". They write: "The on-treatment effect of patients receiving pagoclone demonstrated a numerically superior rating versus patients treated with placebo (p=.18)."
My question:
The p-value is quite high, p=.18, which means that there is a 20% probability that the effect does not exist and is due to statistical fluctuation (i.e. chance).


On SSS, they write "The SSS Severity Subscore, measured at week 2, week 4 and week 8, is a validated, patient-rated assessment of stuttering that takes into account specific speaking situations that have taken place over the prior week. Pagoclone produced a statistically significant reduction at week 2 (p=.004) and week 4 (p=.05) and a trend for significant improvement at week 8 (p=.08) as compared to placebo."
My question:
What is interesting is that the p-values go up with time, from p=0.004, to p=0.05 to p=0.08. This makes me a bit suspicious that they experience a high / placebo effect which decreases with time. Listening at the reports from patients, they pretty well all know whether they are on Pagoclone or not, even though it is blind. So they might experience a high in their subjective assessment of fluency. This possibility can be eliminated by 4-months data.

Thursday, May 25, 2006

Before I take Pagoclone

... I would set myself 10 criteria that the medication needs to satisfy. Here are they plus my arguments.

1) The drug has been commercially available for 3-5 years without major negative news and gossip. I want to see whether Pagoclone survives the reality test away from random control trials with well-briefed doctors and especially-selected patients. The commercial use must not necessarily be for stuttering.

2) I convinced myself that the effect size is large. Taking any medication is about balancing risks, and I am only willing to take the risks on (known and unknown long-term) side effects if the effect of Pagoclone is significant (not just a bit more fluent) and lasting.

3) I convinced myself that the effect is not just due to what Pagoclone has been designed for anti-anxiety. It is possible that the positive effect claimed is due to the anti-anxiety effect. Effectively, patients know that they are on Pagoclone, because they become more relaxed. And then the placebo effect also sets in, and together greater fluency is achieved. Also, I rarely experience anxiety, and I am wondering what the drug would do to me mentally. Am I going to turn into a wild inhibited animal? :-)

4) I convinced myself that a scientific study of long-term user of Pagoclone has shown minimal and reversible side effects. My stuttering does affect my life and reduces my potential in certain situations, but I do not think I would trade more fluency with weight gain, headaches, or other effect lightly.

5) The FDA has made a positive statement on side effects and for use to treat stammering. But I would still be hesitant. I spent a lot of efforts to understand stuttering, and the issues are damm complex. So I cannot see how the generalist FDA would understand the issue better, on the contrary. So I would not trust them on what they have to say about its use for treating stuttering, but most certainly on their statements regarding side effects.

6) Neurologists or other related experts not linked in any way to Indevus recommend its use. Stuttering is potentially a multi-million market, and a lot of recognition for the involved researchers / doctors. Also, Indevus has spent a lot of money on these trials. This is just a precaution, and a best practise in any risk management. Wishful thinking and money are always a very strong motivator to twist and spin. Always ask outsiders for a second opinion.

7) Neurologists or other related experts who STUTTER themselves use Pagoclone to treat their own stuttering!!!! :-) This would be strong evidence that Pagoclone is effective and safe. They are professionals and know the realities, and are able to make a much better judgement call than myself.

8) The hype and discussions on Pagoclone are over. Currently, we are in a hype period. News came out, and many journalists are picking it up. They are no experts, and need to simplify issues for the reader. So expect white and black comments rather than greyish. Such comments will be taken on, and this will lead to strong clear-cut opinions being formed. So it is always best to wait for things to cool down until everyone is bored about it!!

9) I have personally spoken to 2-3 people who took / are taking Pagoclone. Scientific studies are crucial, but talking to actual people is a very insightful reality check.

10) Pagoclone does not delay or inhibit ejaculation. Indevus wants to sell Pagoclone to treat men with pre-ejaculation. Then the question arise whether normal man are also impacted? If so and in a significant way, I would need to think hard about this one.

Wednesday, May 24, 2006

Results from Pagoclone!!! Why no effect size??

My secret agents (The JellyFishKiller and The Junkie) are telling me that Indevus has made public the results of the Phase II trial of Pagoclone. I have been talking about Pagoclone extensively: for example here.

I had a quick look at their press release, but find it hard to interpret. I am extremely puzzled that they only talk about statistical significant difference (which measures whether control and treatment groups are different) rather than effect size (which measures how big the difference is in terms of statistical significance). This leaves me speculating that there are problems with the effect size: either it is not very high (i.e. lower than 0.2) or it is methodically difficult to compute. Another option is that they are simply not aware of the relevance of effect size, but that would be very strange for a multi-million company. God knows... So I need to know more about the trials before making a more definite judgement. However, on the social anxiety side, they seem to be most confident of a significant effect. Also, there are several mostly positive reports from participants of the trial.

The following except is taken from the Indevus website on May 24th. I could not link to this document. And you should look for it on the website.

INDEVUS ANNOUNCES PROMISING PHASE II DATA FOR PAGOCLONE IN STUTTERING

Compound Achieves Multiple Primary and Secondary Endpoints and is Well-Tolerated

LEXINGTON, MA, May 24, 2006 – Indevus Pharmaceuticals, Inc. (NASDAQ: IDEV) today announced top line results from the Company’s Phase II clinical trial for pagoclone in persistent developmental stuttering. Results from the trial show that pagoclone produces a statistically significant benefit in multiple primary and secondary endpoints compared to placebo. Additionally, pagoclone produced either numerically superior improvement or trends for significant improvement on virtually all other primary and secondary endpoints when compared to placebo. Pagoclone was also shown to be well tolerated and not associated with any serious adverse events.

The Phase II trial, known as the EXPRESS study, was an 8-week, placebo controlled, double-blind, multi-center trial with an open label extension. There were a total of 132 patients randomized in the trial. Eighty-eight patients received escalating doses of pagoclone from 0.3 mg to 0.6 mg per day. Forty-four patients received placebo. Seventy-nine percent of the patient population was male which is reflective of the gender distribution of this disorder.

As a result of the promising outcome of this study, the Company plans to meet with the FDA in an End of Phase II meeting to discuss the findings and its plans for further clinical development.

“Indevus has completed what we believe is the largest pharmaceutical trial ever conducted for stuttering and the results are very exciting,” stated Glenn L. Cooper, M.D., chairman, president and chief executive officer of Indevus. “Our results today show that stuttering, a condition with no approved pharmacological treatment, is potentially treatable with pagoclone. This study was designed as an exploratory trial to follow up on a limited number of observations of the effect of pagoclone on stuttering during previous anxiety trials. The design of the EXPRESS trial enabled us to evaluate the condition from several clinical perspectives and we believe this provides us with a strong foundation to develop a clinical plan for further development.”

Gerald A. Maguire, M.D., associate professor, department of psychiatry, University of California, Irvine School of Medicine, stated, “Being a person who stutters and a physician who researches and treats stuttering, I am very excited about the results of this trial. As an investigator on this study, I saw first hand the positive impact pagoclone can have on the lives of patients. Consistent with the results of the entire study sample, more than half of my pagoclone treated patients had a clinically meaningful decrease in the severity of their stuttering. Although there is no cure for stuttering, pagoclone holds significant promise as a well-tolerated, effective and viable treatment for the millions of Americans who stutter.”

The primary endpoints evaluated in the double-blind, phase of the study were the Frequency and Duration Subscale of the Stuttering Severity Instrument Version 3 (SSI-3), the Stuttering Severity Scale (SEV) and the Subjective Screening of Stuttering (SSS) Severity Subscore. Given that this was an exploratory study, pre-specified analyses utilized 1-tailed tests of significance.

The SSI-3 is a validated measure of stuttering. During study visits at week 4 and week 8, patients were videotaped while engaged in both a conversational and reading task. The videotapes were analyzed and scored at a central laboratory. Raters were blinded with regard to treatment and visit. The frequency and duration subscales were calculated by measuring the proportion of syllables stuttered compared to syllables spoken and the length of time of each stuttering block or event. The variability of stuttering naturally tends to wax and wane over time. Accordingly, two data points were collected prior to treatment and two data points were collected while on treatment at week 4 and week 8 to determine the on-treatment effect of pagoclone. The on-treatment effect of pagoclone was shown to produce a statistically significant reduction in the frequency and duration of stuttering as measured by the SSI-3 scale when compared to placebo (p=.02).

The SEV, measured at week 2, week 4 and week 8, is a validated measure of stuttering. The SEV is a 9-point, clinician rated severity scale anchored by “no stuttering” and “extremely severe stuttering”. The on-treatment effect of patients receiving pagoclone demonstrated a numerically superior rating versus patients treated with placebo (p=.18).

The SSS Severity Subscore, measured at week 2, week 4 and week 8, is a validated, patient-rated assessment of stuttering that takes into account specific speaking situations that have taken place over the prior week. Pagoclone produced a statistically significant reduction at week 2 (p=.004) and week 4 (p=.05) and a trend for significant improvement at week 8 (p=.08) as compared to placebo.

The secondary endpoints evaluated in the study included the Clinician Global Impression-Improvement (CGI-I), the Liebowitz Social Anxiety Scale (LSAS) and the Speech Naturalness Scale (SNS).

The CGI-I, measured at week 2, week 4 and week 8, is a 7-point, validated and widely accepted clinician-rated measure of improvement as compared to baseline, considering all sources of available clinical information about the patient. For analysis of the improvement in the severity of stuttering, patients were categorized as having either “improved” versus “no change or worsened”. Pagoclone produced numerically superior improvement at week 2 (p=.20) and statistically significant improvement at week 4 (p=.007) and at week 8 (p=.02) as compared to placebo. At week 8, 55% of pagoclone treated patients were improved compared to 36% of placebo treated patients.

The LSAS, measured at week 4 and week 8, is a validated measure of social anxiety symptoms. Stuttering is often co-morbid with symptoms of social anxiety which can be a disabling consequence of stuttering. Although patients with primary anxiety disorders were excluded from participating in the trial, pagoclone produced a trend for significant improvement in social anxiety symptoms (total LSAS score) compared to placebo at week 4 (p=.09) and week 8 (p=.07). On a subscale comprised of the elements of the LSAS that evaluate anxiety-provoking speaking situations, pagoclone produced statistically significant improvement at both week 4 (p=.02) and week 8 (p=.02).

Pagoclone was shown to be safe and well-tolerated. There were no serious adverse events associated with pagoclone. The most commonly reported side effects associated with pagoclone were headache (12.5% for pagoclone and 6.8% for placebo) and fatigue (8% for pagoclone and 0% for placebo). As with all prior trials for pagoclone, reports of somnolence and sedation were similar between pagoclone and placebo. Additionally, pagoclone exerted its clinical effect on patients without disrupting the naturalness of their speech as assessed by the SNS, a validated 9-point scale.

Approximately 90% of patients continued into the open-label phase of the study in which all patients receive pagoclone. Early results of the open-label phase indicate that patients initially randomized to pagoclone have continued to show improvement in their stuttering and those initially randomized to placebo, and now receiving pagoclone, are exhibiting improvement in their condition.

Pagoclone is a novel, non-benzodiazepine, GABA-A selective receptor modulator. It is part of a new chemical class of agents and lacks many of the common benzodiazepine side effects such as sedation and withdrawal. The precise mechanism of action is unknown however, GABA is believed to be an important neurotransmitter in the brain that may be disrupted in people who stutter. Pagoclone enhances the activity in GABA circuits in the brain and thus may help restore more normal function in speech areas of the brain.

Tuesday, May 23, 2006

Not much happening

I am out of ideas for posts!!! :-)

Behind the scenes, I have been organising a research plenary for the BSA conference: more soon.

Then I will be in New York from June 5th to June 7th, and then in Boston until Friday June 10th. I hope to meet up with Prof Shell, who wrote a book on stuttering, and with someone else from the New York self-help group. Should be fun...

Wednesday, May 17, 2006

Sex or fluency?

Recently I spoke about Pagaclone and how Indevus has registered the drug to reduce pre-ejaculation: see here.

But what is the effect on normal men? If Pagaclone delays ejaculation in pre-ejaculating men, then should not every men experience a shift in his typical ejaculation time. So normal men should have trouble to ejaculate, and man having trouble to ejaculate find it impossible.

So most stutterers might become more fluent, but experience problems with ejaculating / having an orgasm! So what is your choice? And, to the women, you rather have him stutter or ... ?

Of course, for stuttering pre-ejaculators the drug is absolute heaven: you become a fluent and a well-tuned sex god! :-)

Tuesday, May 16, 2006

Hardware vs Software problem?

Hardware is what has a clear physical manifestation: the brain cells, nerves, their general functions, and the functional organisation of a brain. Software is what is stored in the hardware and "runs" the hardware like: learned and innate behaviour, psychological processes, social issues. There is no clear transition between what is hardware and software.

Is PDS a hardware or a software problem?

1. The question contains a logical fallacy, as the question implies an either/or answer.

2. Do people who stutter have the same hardware, but only faulty software?

3. Do people who stutter have defective/suboptimal hardware?

4. If answer to 3) is yes, can a updated software correct the hardware weakness?

5. Do people who stutter start out with the same hardware, but their software gets corrupted and slowly but surely their hardware works suboptimal and then the hardware is part of the problem. For example, your car works fine, you drive like a maniac, car engine is misused, I drive the car, car doesn't drive very well?

6. Is there a continuum from 0% hardware problem and 100% software problem to 100% hardware and 0% software?

7. Is 0% hardware problem and 100% software problem not more likely that 100% hardware and 0% software? As I pointed out a hardware problem nearly always leads to software problems.

8. If there is a software problem, does it lead to permanent hardware problems?

9. Do people whether they say stuttering is a hardware or a software problem only reflect on their own stuttering and experience?

Thursday, May 04, 2006

Epitaph Competition

My thinking is very much no-ideas-barred. I have been surfing the net, and found this list of epitaphs. So naturally I have been thinking about what epitaph I should put on my grave... Here are some ideas... looking forward to feedback!!

Top Five Epitaphs for Stutterers:

1. Here rests T--tt--- forget it.

2. Finally no more stuttering.

3. Here rests TT--- me who has the same first name as the one 2 gravestones to the left and the same family name as the one 3 gravestones behind mine

4. Here r--es-- ehh lays Tom Weidig.

5. Sorry I still dont maintain eye contact.

Any more suggestions... :-)


P.S.
Here is my favourite one that I found on the Internet.

Here lies George Johnson
Hanged by mistake, 1882
He was right
We was wrong
But we strung him up
And now he's gone

Monday, May 01, 2006

Hardware vs Software

I have been thinking about what it means that PDS is a psychological or a physical problem. Here are some thoughts:

1) If PDS has a physical cause, an additional psychological component (which may in turn aggravate the condition) very likely must emerge. For example, you are in a wheelchair, you also suffer psychologically. You have a big scar in your face, you also suffer psychologically, e.g. avoid people.

2) But if stuttering is purely psychological in origin, there are no obvious physical consequences.

3) In reality, stuttering even if psychological has a physical manifestation. The brain needs to store the memory, has learned new behaviour, and creates fears against change. The key question is whether this physical imprint on the brain is strong and not easily reversible (you engrave a epitaph on a gravestone) or weak and easily reversible (you store information on a floppy disk or black/whiteboard).

To better understand the dynamics, I am using the analogy between hardware and software. More soon...