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Highlights from the
2009 Huntington Study Group Meetings
LaVonne Goodman, MD
The annual Huntington Study Group (HSG) meeting took place in Baltimore, Maryland, November 19 and 20, 2009. The meeting included training sessions for clinical trial professionals, updates on ongoing clinical studies and trials, and education sessions. Following the annual HSG meeting, the HSG Symposium and Clinical Trial Workshop took place. For report of these latter two events see Marsha Miller's excellent review.
What follows in this article are highlights from the educational sessions preceding the symposium where the major focus was on human clinical studies and trials.
Clinical Trial Recruitment
Dr. Ira Shoulson, chairman of the HSG Executive Committee set the agenda for the meetings by challenging members to find better ways to bring more participants to Huntington clinical trials. He pointed out that recruitment is slow for the more than 1200 new participants that are needed (as of early November) to fill trials that are now ongoing:
Total # required
# Still Needed
These numbers suggest that only 6% of the estimated 10,000 Huntington disease (HD) individuals most likely to fit criteria of available trials (early to moderate stage disease) are participating in clinical trials. Dr. Shoulson pointed out that about 50% of those now in trials have come from observational studies including COHORT, PREDICT and PHAROS, and he announced that steps are already underway to extend and simplify entrance into COHORT as a means of identifying more potential participants for clinical trials.
He also recommended creation of new clinical trial programs designed to:
- Mobilize and train family members to disperse information to their local groups
- Educate Huntington family members about clinical trials through local and national patient groups
- Identify and reduce barriers to clinical trial participation: (fewer visits at more convenient times, more testing centers, in home telephonic or web evaluations, more financial compensation for travel and time lost from work)
- Improve efficiency in clinical trial performance at testing centers
Shari Kinel, JD, who is the executive director of HSG announced the establishment of a new working group to focus on ways to address recruiting problems and to improve communication and collaboration among Huntington organizations.
HSG Site Readiness
Joe Guiliano and Tae Kim from CHDI, with the assistance of Dr. Vickie Wheelock from the University of California Davis, conducted a workshop with the objective of accelerating study start up times -- the time from the site receiving first clinical trial materials to enrollment of the first participant. This is important because delay at the start of the clinical trial process carries through and multiplies the time it takes to complete a trial. Recruitment delays also add significant costs to doing the trial.
Using the example of a clinical trial that took place at 35 HSG investigational sites, they showed that times varied widely in each stage among the sites, but on average the study start-up time was 230 days (7.5 months). This was broken down into:
1) Obtaining local IRB (ethics) approval - 93 days
2) Subcontract (legal) agreement - 142 days
(Steps 1 and 2 are concurrent.)
3) Enrollment of first participant (following local IRB and legal contract approval) - 93 days
Those at the workshop identified problem areas at their own site, and learned from the value stream mapping analysis technique and experience of others how their site inefficiencies could be addressed and improved. The goal this year is to decrease start up time by 1/3 .
Dr Solomon Snyder from Johns Hopkins University presented an update on his laboratory's research on Rhes protein. He reviewed the work reported in the journal Science, June 2009 on Rhes, a small protein that occurs in high levels in the striatum, the brain location where the greatest damage in Huntington's occurs. Scientists from the Snyder lab showed that Rhes protein combines with mutant huntingtin protein much more than normal huntingtin protein -- in a manner that starts a cascade of HD cell damage. Using molecular techniques, they further illustrated that decreasing the level of Rhes protein reduced the level of damage in cell models of Huntington's.
At present Dr. Snyder's lab is extending this work to HD mouse models that are engineered to have very low or no Rhes protein. If these double mutant mice have decreased brain damage, it would give much stronger evidence that Rhes is an important part of HD.
And important for Huntington families, if mouse studies confirm the earlier cell model results, Rhes protein will be an important drug target -- because it is involved in a very early step in the HD process. While only time will tell how difficult it will be to design a drug that targets Rhes, Snyder's laboratory has begun work on methods to screen drugs for the Rhes protein target, and has initiated negotiations with pharmaceutical companies.
Subramaniam S, Sixt KM, Barrow R, Snyder SH.
Science. 2009 Jun 5;324(5932):1327-30.
Tetrabenazine in Clinical Practice
Dr. Joseph Jankovic from Baylor College of Medicine in Houston, Texas presented information on the use of tetrabenazine (Xenazine) in clinical practice. He and the group at Baylor have the greatest experience in the world with large numbers of patients with HD who have received this drug over a span of more than 3 decades.
Highlights of his presentation included:
- A review of the history of tetrabenazine, initially in Europe and subsequently at Baylor and other centers in the U.S. that culminated in FDA approval in August of 2008 for the treatment of chorea associated with HD.
- A review of findings including clinical studies of tetrabenazine at Baylor (Jan. 2007, Movement Disorders) and TETRA-HD, the pivotal placebo-controlled, HSG trial for this drug (Feb. 2006, Neurology). This study showed a significant reduction in chorea score in the group of patients treated with tetrabenazine as compared to placebo.
- A review of a Baylor study that shows duration of drug action (as measured by improvement in chorea) for a single dose of tetrabenazine is about 5 hours. This suggests that for most patients dosing may be best at 3 times per day (Jan. 2007 Movement Disorders).
- A "before and after" video presentation of a woman with HD who had been on tetrabenazine with benefit for several years. In the first video - while on tetrabenazine she had mild to moderate chorea and was able to walk. The second video was taken after stopping the drug as part of a tetrabenazine withdrawal study, which showed dramatic worsening of chorea and loss of her ability to walk. The third video was taken after she had resumed tetrabenazine, with marked improvement in chorea and motor function, regaining her ability to walk - at the same level prior to discontinuing the drug.
- Information about tetrabenazine and tardive dyskinesia. This symptom is a known serious side effect of Haldol and other antipsychotic drugs that are sometimes used to treat chorea. Dr. Jankovic pointed out that tetrabenazine does not cause this side effect - in fact it is effective treatment for tardive dyskinesia.
- A review of the side effects of tetrabenazine. Dr. Jankovic stressed the need to vigilantly check for side effects that can include drowsiness, slowness of movement, restlessness, depression, and - most serious - thoughts of suicide. In Dr. Jankovic's experience, decreasing the dose of tetrabenazine can usually control these side effects.
Kenney C, Hunter C, Jankovic J.
Mov Disord. 2007 Jan 15;22(2):193-7.
Huntington Study Group.
Neurology. 2006 Feb 14;66(3):366-72.
Kenney C, Hunter C, Davidson A, Jankovic J.
Mov Disord. 2007 Jan;22(1):10-3.
Dr Jankovic suggests the following for further information about tetrabenazine and treatment of chorea in HD:
Kenney C, Jankovic J.
Expert Rev Neurother. 2006 Jan;6(1):7-17. Review.
Frank S, Ondo W, Fahn S, Hunter C, Oakes D, Plumb S, Marshall F, Shoulson I, Eberly S, Walker F, Factor S, Hunt V, Shinaman A, Jankovic J.
Clin Neuropharmacol. 2008 May-Jun;31(3):127-33.
Kenney C, Jankovic J.
Expert Rev Neurother. 2006 Jan;6(1):7-17. Review.
Lancet Neurol. 2009 Sep;8(9):844-56. Review.
For a review of Saturday's Huntington's Disease Clinical Research Forum click here.