Many of you already know that I was a participant in the Spheramine trial,
Phase I. There were only 6 of us - the first group to receive retinal cell
transplants (with the theory that they would produce the dopamine not being
made in our brains). We later found out that the "cells" came from the retina of a baby who only lived a day or two. Our bodies naturally produce dopamine in the retina, adrenal glands, testicles (ahem!), and of course, the brain.

My surgery was 8 years ago - and although I am far from cured, I function
pretty well (still drive - do some travel - sometimes do presentations and
do household chores (ever so slowly, but do them). But after 8 years, I
have MUCH less "off" time, and when I'm "on" I am really quite normal in
appearance (except for some dyskinesia). More on myy condition but let's get to the point.

Thus far, up to 48 months after the first 6 underwent experimental surgery
for Spheramine, the stats were holding a 44% improvement from baseline UPDRS. (See below
Long-term improvement of symptoms was demonstrated and,
importantly, significant clinical improvements were noted in
mobility - an average of 44 percent improvement from baseline
at 48 months in UPDRS motor scores.

-- Significant clinical improvements were seen in
patient-reported quality of life scores - 23 percent
improvement from baseline at 48 months

-- There were no Spheramine-related serious adverse events
reported

-- The most frequent adverse event was post-surgical headache,
which spontaneously resolved within 1-2 weeks for all
patients.

Based on the positive one-year results seen in the open-label
pilot study, Titan and its partner Bayer Schering Pharma AG initiated
a multicenter, double-blind, randomized, sham surgery-controlled study
(STEPS) to further evaluate the safety and efficacy of Spheramine.
This study completed enrollment with 71 patients last year, and
top-line efficacy results are expected to be available in third
quarter of 2008.
Source: http://www.reuters.com/article/press...008+BW20080428

So things were clicking right along for Spheramine. But as the statisticians
were reviewing the 1-year results of Phase II (and even days earlier researchers were making international presentations about how "good" this find was,) behold the sponsors put out a press release that Phase II did NOT meet its endpoints and Bayer pulls our of the study sponsorship.

What this meant was that the statistical formula predetermined to make this a valid and reliable study calculated that 70+ participants would be required in a multicenter, double-blind, randomized, sham surgery-controlled study (half having sham or "fake" surgery). However, that promising results' hope held onto up to the final hour was now being reported as showing no difference in improvement between groups. To say it another way, according to what the statistics indicated, those that DID get the transplanted cells faired no better after a year than those who THOUGHT they got the cells but DID NOT. Confused yet?

I personally know that the executives and stockholders of Titan - the original sponsors, and Schering AG & Bayer (who bought into the trial,) dropped their jaws, scratched their heads, and looked at each other and said, "Huh? No way!" So I ask you how did this happen? Why did it appear to work - and work well - better results in Phase I than DBS - how the heck did it fail in Phase II?

What I am about to suggest next is not scientifically nor statistically-based, but comes from 14+ years of living with Parkinson's, being on the front line with the Spheramine trials, and working my butt off through the Pipeline grassroots group and PDF trying to get Amgen to squeeze the good out of the earlier GDNF trials, and from knowing Carolyn personally (CERE-120 gene therapy participant) and another participant who received sham surgery in the same (neurturin)trial, Tom Intili.

We can point our finger at the antiquated UPDRS scale (and this widely used scale is being studied for revision as we speak. See below*), or blame the method of screening for trial participants, or yell "rater bias" and all of those usual things claimed, but has anybody reviewed the diversity of PD patients lately? Has anyone asked the PD patient what might be happening for these 3 major trials (GDNF, Spheramine, & CERE-120 - neurturin)?

*Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results.

Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N; Movement Disorder Society UPDRS Revision Task Force.
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. cgoetz@rush.edu

We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites.

But I say unto you that Parkinson's is highly unique from many other neurological diseases. Our day-to-day, hour-to-hour movement or on/off time can be affected by so many other things that aren't major compoents of the assessment package.

Here are some areas (in my opinion) that we need to look at as possible areas of concern when working with trial design or endpoint formulation:

1. Add a diet diary. Not everyone has a proteinor dairy product problem interferring with L-dopa absorption, but it really does make a difference in performance efficacy according to what is eaten. (Grapefruit, chese, and other foods high in tyramine are are often the culprits)

2. Educate trial volunteers about changes in medication regimens and even supplements added to their regular regime. It’s not just changes in PD drugs that can affect our outcomes, but ALL meds (I don’t think this is always clear)

3. Note that emotional swings and stressors can really alter individual trial evaluation outcomes. Just a few questions asked at each follow-up visit as to the participant’s well-being could provide important and relevant information. This doesn’t have to be something as radical as a divorce, family death or injury, but reporting on a scale daily as to the trial participants' well-being would add validity to the assessment scores.

4. As medication reductions are attempted, it is also imperative that trial participants’ emotional well-being be charted. Stopping PD meds abruptly can be devastating to volunteers, often causing severe depression (a proven fact). To a lesser degree, cutting back medications in trials like these is not always clean-cut across the board - again, it's an individualized thing. Many trials do a neuropsychological evaluation before treatment intervention or when screening participants, then never again.

5. Creation of an individualized statistical formula on PD progression – I believe this is doable. Have a statistician create a formula for each participant based on how rapidly symptom progression had been historically and compare that to current routine evaluation visits.

6. Be aware and keep records on particiants' sleep patterns. I cannot emphasize what a difference proper sleep has on most PWP's symptoms.

And that concludes my epistle. The brains of people with Parkinson's are not as predictable as an orthopedic study on kneecaps. I am anxious to read your comments.