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.

10 comments:

Lloyd said...

Hi Tom,

I'd throw in my hat for the effect being hard to measure. Many people are reporting positive results and greater quality of life but I suspect it is hard to quantify specific "increased fluency" results. I know it has been so in my case.

I can definitely tell you that I hope they'll continue to allow me access to Pagoclone as it has had a positive effect for me.

BTW - Shoot me an e-mail.

Best,
Lloyd

Michael said...

Hi Tom - second try,
nice to see that you try to go to the bottom of stuttering. I assume what you will find there :) ... but better you figure it out yourself. One crucial questions came to my mind: How will one measure a quality with quantitive means?
I found the following paragraph quite suitable to describe the whole problem ...
"Sri Aurobindo quotes the ancient Vedanta to the effect that when a phenomena exhibits several degrees of quality, its inherent nature should be judged by the highest expression of the characteristics it exhibits, not by the lowest. According to this principle, when matter and material energy give rise to living systems and mental consciousness, we must re-examine our conception of the inherent qualities of matter to recognize the involved principles of life and consciousness as inherent attributes of matter (and indeed more fundamental attributes than atomic structure or quantum mechanics), rather than ignoring the entire higher range of human emotional, mental, artistic and spiritual experience or trying to reduce life and consciousness to artifacts of mechanical, physical systems."
taken from http://www.motherservice.org/Essays/Issues%20Relating%20to%20Science.htm

Anyway, you may already know what I am trying to say - the only place to find the secret behind stuttering lies within ourselves.

All the best, yours Michael.

Anonymous said...

Tom:

Enjoy reading your posts. I was involved with the 8-week trial and am now along for the one-year follow-up. I too have trouble quantifying the affect. In my more rational moments I have to say that there is an overall positive affect. Then I'll get the screws put to me, have a dysfluency, and vow to myself that this is snakeoil. I think a mild to moderate positive affect is a more reasonable description, less so in stressful situations. I also flatly reject any suggestion of side effects. I feel fine. Few things in life are simple. One wonders whether such a drug coupled with speech therapy will eventually be recommended?


Greg

Anonymous said...

Can anybody tell me where to buy Pagoclone? I am 47 years old and have stutterd all of my life and i would love to try this. My email is ralphedwards@sbcglobal.net Thank you

jamster said...

Hi everyone,

I just came across this blog and I was so happy to see that there were so many people that I can relate to out there!!..I have had a stutter all my life and dont know what to do about it, i am to embaressed to go to a speech therapist...What is this "pagoclone?" and where can i get it from? I would love totry it?...if anyone has any good advice for me on how to obtain then please do let me know....

thank you

benjaminhewins@hotmail.co.uk

jamster said...

Hi everyone,

I just came across this blog and I was so happy to see that there were so many people that I can relate to out there!!..I have had a stutter all my life and dont know what to do about it, i am to embaressed to go to a speech therapist...What is this "pagoclone?" and where can i get it from? I would love totry it?...if anyone has any good advice for me on how to obtain then please do let me know....

thank you

benjaminhewins@hotmail.co.uk

Omar Khan said...

Assuming Phase III went through and all trial statistics were acceptable enough to release the product to the public, would one need a prescription to get it and also when would be the earliest release date?

Anonymous said...

The pagoclone phase III study won't be until January or February 2009, unfortunately. I understand it's going to be a larger study, this time. And if all goes well, it probably won't be on the market until late 2010 or early 2011, if not later. That's how long it takes for these things to get improved. Or at least that's my understanding. Sounds promising, though!

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Pascal said...

If any one has any idea as to where in the world i could buy the drug Pegaclone it would be much appreciated, i am a stammerer from childhood and would like to see if that drug has any positive effects on the speech.
thanks a lot