Monday, September 27, 2010

Ingham critical of Phase IIa design

Roger Ingham, professor at Santa Barbara, has written a reply to the Phase IIa trials on Pagoclone. He has been critical of the procedures, and some of these have been considered for the Phase IIb. I have also expressed my concerns about the study, and said that a larger better controlled trial needs to be done. (Unfortunately I cannot find the post on my blog!) The non-published Phase IIb trial has now kind of confirmed my suspicion that the effect is not significant, except possibly for a subgroup. But we have no official data, so I can only speculate.
I often hear people say that Jerry is a hero and so on. No doubt he is heroically trying to find medication for stuttering, and he understands us and stuttering better than his medical colleagues but he is not a perfect scientist and must be open to criticism. Here is the reply.
Maguire et al’s.1 recent report on a clinical trial evaluating the effect of pagoclone on stuttering concluded that “pagoclone may have potential as a pharmacological treatment of stuttering” (p. 48, 2010).  This conclusion was qualified by some comments on the limitations of their study, but there are many that were not mentioned and that raise serious doubts about clinical value of their findings.
Maguire et al. report effects of pagoclone on experimental (n = 88) and placebo (n = 44) groups of adults who stutter who participated in a multi-site double-blind treatment followed by a 1-year open-label extension in patients who stutter. They report a 40% reduction in stuttering frequency as measured by the SSI-32 – an instrument that has questionable reliability and validity3, in part because it assesses only 200 syllables of speech, all of it generated within the clinic rather than in ecologically valid beyond-clinic environments.4   That limitation is actually
recognized by Maguire et al. (p. 48). What is unrecognized, however, is that there is absolutely no evidence that the level of reported improvement exceeded the level of variability in their subjects’ speech performance (experimental or placebo group) prior to treatment.  Failure to collect such data totally ignores the notorious variability of stuttering over time as well as over speaking situations.  J.Ingham and Riley5 have illustrated that this is the case in children, but it is also the case in adults who stutter6,7.  In fact, one reason why a recent review8 of pharmacological treatments of stuttering concluded that there was no evidence that these treatments produce clinically meaningful effects is because literally no study reported that at follow-up their subjects achieved even a minimum 50% reduction in stuttering.  Maguire et al. rather conspicuously ignored the fact that their findings also failed to reach this very liberal criterion.  They also failed to acknowledge that numerous behavioral treatments of stuttering achieve improvements in speech performance that are closer to 90% or better than is the case with pagoclone8,9 – and without the risk of side effects that customarily accompany drug treatments.  Thus even if the finding of a 40% reduction in stuttering could be trusted, that is at best a weak therapeutic effect – and one that the authors also fail to acknowledge.  However, that issue is really moot because after 8 weeks of medication there was no significant difference between the level of stuttering in the placebo and pagoclone groups, and there was no control group comparison for the larger group treated for 12 months.
Another reason for this author’s concerns about clinical value of the Maguire et al. findings is familiarity with the way data were collected at one of the sites.  The individual collecting the data at that site was completely untrained in stuttering measurement.  Yet that individual was required to provide judgments of speech performance that were never assessed for independent observer reliability.  The authors acknowledge that many of these oversights are being corrected in another trial with the drug being conducted on a larger population.  But if there is essentially no evidence that this drug is significantly more effective than a placebo beyond 4 weeks then there is little justification for subjecting an even larger cohort of adult stutterers to this treatment.
The origins of pagoclone being considered as a possible treatment for stuttering reside in earlier drug trials of pagoclone’s value in treating anxiety.  It was observed that two individuals who were in those trials were speakers who stuttered and who reported that their fluency was improved by this drug10.  Surely a more clinically meaningful investigation of the effects of this drug should have started by a thorough investigation of these individuals to establish the validity and magnitude of their reported improvements?  Other individuals among the 1000 in the anxiety trial may also have stuttered (likely because of the 1% prevalence of this disorder4).  A more clinically meaningful investigation of this drug might have begun with a series of single subject experimental trials on stuttering speakers.  This could have been used to systematically document the drug’s efficacy using appropriate repeated measurements across trials in which placebo conditions can be introduced (and withdrawn) and measures can be made in appropriate speaking conditions.  Similar methods have been used to establish the efficacy of many stuttering treatments, including drug treatments (e.g., investigations of haloperidol11). 
In short, trials such as those conducted by Maguire et al contribute little to the treatment of this disorder.  And the news that pagoclone trials with children have been contemplated12 - given the availability of effective therapies for children who stutter9 - should be greeted with concern by clinicians who might consider encouraging parents to permit their children to participate in these trials.
References.
1. Maguire G, Franklin D, Vatakis NG, Morgenshtern E, Denko T, Yaruss JS, Spotts C, Davis L, Davis A, Fox P, Soni P, Blomgren M, Silverman A, Riley G. Exploratory randomized clinical study of pagoclone in persistent developmental stuttering: the EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study. J Clin Psychopharm. 2010; 30: 48-56.
2. Riley G. Stuttering Severity Instrument 3rd Edition (SSI-3). Austin, TX: Pro-Ed; 1994.
3. Lewis KE. Do SSI-3 scores adequately reflect observations of stuttering behaviors? Am J Speech-Lang Path. 1995; 4: 46–55.
4. Bloodstein O, Ratner NB. A Handbook on Stuttering. 6th ed. New York: Thompson: 2008.
5. Ingham JC, Riley G. Guidelines for documentation of treatment efficacy for young children who stutter. J Speech Lang Hear Res. 1998; 41; 753-770.
6. Ingham RJ, Kilgo M, Ingham JC, Moglia R, Belknap H, Sanchez T. Evaluation of a stuttering treatment based on reduction of short phonation intervals. J Speech Lang Hear Res. 2001; 44: 1229-1244.
7. Martin RR, Haroldson SK. Contingent self-stimulation for stuttering. J Speech Hear Dis. 1982; 47: 407-413.
8. Bothe AK, Davidow JH, Bramlett RE, Franic DM, Ingham RJ. Stuttering treatment research, 1970 – 2005: II. Systematic review incorporating trial quality assessment of pharmacological approaches. Am J Speech-Lang Path. 2006; 15: 342-352.
9. Bothe AK, Davidow JH, Bramlett RE, Ingham RJ. Stuttering treatment research, 1970 – 2005: I. Systematic review incorporating trial quality assessment of behavioral, cognitive, and related approaches. Am J Speech-Lang Path. 2006; 15: 321-341.
10. UPI.com (2005, December 31). Failed anxiety drug may help stuttering. http://www.upi.com/Business_News/2005/12/31/Failed-anxiety-drug-may-help-stuttering/UPI-54741136072891/ Accessed January 24, 2010,
11. Ingham RJ. Stuttering and behavior therapy: Current status and experimental foundations. San Diego: College-Hill Press. 1984.
12. Free Library (2006, September 26). Indevus announces clinical and regulatory plans for pagoclone. http://www.thefreelibrary.com/Indevus+Announces+Clinical+and+Regulatory+Plans+for+Pagoclone-a0154329952 Accessed January 24, 2010

7 comments:

Konstantin said...

"They also failed to acknowledge that numerous behavioral treatments of stuttering achieve improvements in speech performance that are closer to 90% or better..."

Wow, it is surprising that stuttering is still a great problem for so many people when there are *numerous* treatments achieving an improvement of over 90%! I guess SpeechEasy also falls into this category?

Anonymous said...

Is that called the Hawthorne Effect?

Tom Weidig said...

@Konstantin:

I am also skeptical about this statement. I would be interested to see the long-term data.

Olivier said...

What Maguire replied to this ?

Ora said...

Maguire's response to this reply from Ingham was published in the same issue of the journal (October 2010).

(See http://journals.lww.com/psychopharmacology/pages/default.aspx, then click on "Current Issue: October 2010 . . . ", then "Table of Contents Online" then "Letters to the Editors", and look toward the bottom of that page.)

Tom - It would be helpful to your readers if you could get a copy of Maguire's response and print it for us. It doesn't seem fair for you to print Ingham's criticism in full, and not to print Maguire's response.

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Tom Weidig said...

@Ora: I will publish the response today or tomorrow. I am not sure it is unfair after all Maguire et al have written a whole article to present their arguments!