Through the participants , investigators, ceregene company, [i heard the cere120 employees are mostly laid off], researchers, readers, caregivers, consumers, medical doctors for anywhere on our body....lol...can we create the story? It seems a practical way to discuss everything that is on our minds about all clinical trials with all of those involved in the cere 120 trial. The Cere 120 Reality story....everyone swears an oath to tell the truth.

This always happens; you think you've done [and had!] enough...today this idea just focused even tho others are at their own story versions quite possibly...this idea isn't original, but doing it here would be. Let's write the story. I'm starting with Carolyn. who so many of you know. I'm inviting Dr. Michael Rogan to be the MJFF observer, who is welcome to join in at anytime [I've already begged and explained enough about why I think we should communicate. ]

This kind of story you can't make up as well as the real story will be, please join us Dr. Rogan. I don't think we knew what we wanted to talk about; in spite of all the pleading and the need to have it include many disciplines. This is an ideal topic and an example of many issues on our minds .

Carolyn is ..[carolyn who are you? type it on your thread please].....she can write out how much personal info that she wants to reveal on her own post, but i will introduce her from a patient consumer and advocate viewpoint.

I have known Carolyn for quite a few years now. She is a great Internet correspondent; is not afraid of emotion, very informed and knowledgeable. She is one of the pipeliners who find and supply information; it's like our food supply in importance to us. I think I consume more information than food most days. She will correct any of my mistakes, but every attempt to be accurate will be made from this end. It will soon become apparent how little has been revealed to us, especially by those who know more...., and we think this clinical trial can be the best teachable moment in our struggles to be a part of the solution.

As you will learn about, Carolyn had a fall, which has been labeled a seizure, while in recovery from the trial's gene therapy. From brain swelling, as Carolyn called it, she was in a - would rather she label it - but it seemed semi-lucid state - for about a week, with memory lapses and many yes/no responses. Carolyn reported that she couldn't stop an activity, like brushing her teeth; she didn't know how to initiate the end of the task. Carolyn recovered; maybe she can discuss it in more depth.

Questions- I'll post and then try to categorize, each time I add another post. Some of these are freshly thought, I just talked to Carolyn on the phone. She isn't afraid. Off the cuff, first post:

Someone speak up nicely if we post something confidential, please, I will try not to.

1. seemed fast and unexpected - did the last participant just meet his year in Oct.? Then the "results" announced a month later?

2. what else will you publish and how soon?

3. Many of us have been stewing about the differences in substance between phase I and phase II in the reports. Phase I being reported in percentages of improvement, with a follow up article saying they continued to improve. Phase II was discontinued with a statement saying the placebo and treated were the same.

4. Who are the responders? Who felt better? Any patterns spotted?

paula
kindly reply

Thanks Carolyn for sharing your experiences in the CERE120 clinical trial. It might not necessarily be a bad thing that Ceregene annnouned its preliminary results so quickly. I read somewhere that if the results were good,the company was planning to move on to phase III as quickly as possible . But of course they were expecting different results. Hoping they will be further analyzing and releasing the data -- they might also find new information that could have an impact on the other gene therapy trials.

To start, my trial coordinator wrote in an email to me that "both groups (sham and treated) showed the same improvement. They compared the "off" scores at 12 months to the pre-op scores so this would have been individual scores. I would imagine more info. would be forthcoming.”

Personally, I have a hard time with this statement, as do a few other patients.

I wonder if gene therapy has more to do with the PD and the individuals brain, and maybe the surgeon. What I mean by "with the PD" is that we all are so different...some slow to progress, some significantly disabled within a few short years of dx, some with dyskinesia, some with dystonia, some with neither of the latter two.

Is is possible that gene therapy might only be a good therapy for some, while not recommended for others. Without further study and investigation, we will never know.

To "correct" some of what Paula stated above: I had my surgery on June 18,2007. I was transferred from the ICU to regular neuro on the morning of the 19th. Upon arrival to the regular neuro floor I requested a visit to the bathroom. While there I collapsed to the floor. After "taking too long" in the bathroom the nursing person decided to check on me and found me on the floor. I requested a copy of the safety report and as of this date I do not have the copy, but I will begin to pursue it more vigorously. I was told I had a seizure...not uncommon after brain surgery...and was put on anti-seizure medication. I should have gone home on the 19th, but due to this unexpected seizure I stayed until June 28th.

A safety report is the document that is filed with a government agency detailing what happened during a given incident involving a trial patient. In my case this document would tell me that an MRI was preformed to confirm the seizure, etc. I do know that my facial swelling was very bad and I am told my seizure was due to brain swelling. (The swelling would have been caused by the surgical invasion into my brain during the insertion of the therapy. Of course, neither my trial investigator nor I every spoke of this as a possible reason for the swelling. Why? Because of this was a blinded trial. I have just guessed all these months.)

I do not remember ANYTHING from the morning of the 18th until I woke up in on the Rehab floor June 25th...I lost a whole week. Those days were an ordeal for my oldest daughter, who had to deal with home care setup, etc. I could not have a conversation of any kind...just yes or no. As Paula explained above. I would start to brush my teeth, but I couldn't figure out HOW to stop brushing. My daughter had to take the brush out of my hand. This also happened with bathing. I would begin, but I didn't know how to stop bathing, turn off the water and dry myself. Suffice it to say, it was a very scarey time for my family. I was clueless, so it was not scarey for me.

On July 3rd, both my daughter's took me back to Philadelphia to see the neurosurgeon out of great concern. I was still only able to say Yes or No to anything I was asked.

I checked back into the hospital on July 3rd. I think I can home again on July 21st, but I am not confident this is the right date. I do know I was in the hospital for a month, combining both hospitalizations. This second inpatient included I was on the regular neuro floor. Those that called me on the phone will attest to how difficult it was for me to have a conversation, but as the days passed, this skill improved. By the time of my final discharge I was able to think and act normally.

I have had not problems since that last discharge on July 21st. I did spent three months on anti-seizure meds and no driving as a precaution.

Would I do it all again...yes, I would do it all again.

As we exhausted what seemed like all roads to challenge Amgen's GDNF halt, we heard about neurturin. "Word on the street" was that although neurturin was in the GDNF family, the results were not as striking. [pre-clinical research]

Later, it became a matter of who you talked to. And that's one of the purposes of clinical trials. To determine efficacy.

The cere 120 trial was actually determining much more than efficacy of neuturin. It's experimental gene therapy delivery as well.

Seems like a lot to prove. I'm glad the risks were taken and extend deep gratitude to all involved. This isn't another GDNF, at least I don't think it is. The only efficacy reports I have learned about is through word of mouth. Carolyn and one other's [rumored] capability of going off meds. And a post from Tom, who thought he improved but discovered he was on the placebo. Dottie, who is on this forum reported she was on the placebo and always thought so.

I wasn't that interested in phase III until one participant told me she went off her meds. Then I decided to go for it...a spark that soon fizzled with the announcement that only says there was no difference between placebo and treated.

All comments welcome.....trial participants I would love to hear from you.

paula

My "surgery" was June25th - a week after Carolyns' She had already fallen so my s-i-l and I went to the hospital on the 24th to see how she was doing. My participation in this trial was a nonevent after her experience.

Approximately every three months I was evaluated and lab work was done.

When there was no improvenment leading up to the 6 month evaluation
I knew i was on thhe placebo list.

I'll try to answer any questions.

Doottie

Thanks Dottie,

I wish it had done something you could feel. If rumors about a phase III possibility are true, and should that occur, are you entitled to get the actual treatment?

I really appreciate your honesty and thanks for taking the time.

paula

-------------

Received this through Pipeline email and copying here with Perry Cohen's permission. The placebo effect is a troublesome factor to deal with and appears to be interfering with treatments that can work.

They haven't given up on cere 120. Phase III still on the table.

Perry's email exchanges:


I talked with Ray Bartus today who indicated that Ceregene thinks they now know how to design a successful clinical trial for PD and they want to get back to the FDA with a new design to start another trial in mid 2009. He mentioned they were doing something with the dosing and were going to educate patients to have no expectations and use strict rules to minimize the placebo effects, and he wanted our help with this. I told him that he may be undermining some of the benefits of the treatment by reducing positive interaction effects between the placebo benefits and the treatment (the logic of this interction effect is that by restoring some of the function of dopamine neurons the body can more consistently sustain the 'placebo' benefits from hope and positive expectations which would allow greater activity and further reinforce benefits). He pointed out that FDA requires placbo controls which I know is true in practice, even though the FDA Law does not require a placebo. He wants me to reassure people in the community that Ceregene is not giving up. I indicated that we would do whatever we could do to make the study a success. I also said that he can request that FDA patient consultant participate in the meeting.

I also talked with Dave Banks about the FDA requirement for placebo, which he confirmed is ranked well above the 10 commandments and the Koran in absolute authority at FDA. He said he would work with us to present a case for alternative designs. He is also now aware of the Ceregene meeting and will work on getting patient consultants assigned.

end of email.

So we have a trial being designed that must follow certain regs and in doing so the numbers won't show success? Throwing lower expectations into the mix.....will that work? I'm sure glad they are still trying!

What to do with this natural response of self healing? The link between emotion and dopamine production is truly complex.
paula

Paula,

Thanks for taking steps to expand the discussion that we have been addressing as a group among Pipeline Project members. It is a question that is critical to us all, especially because of the continuing series of "failed" clinical trials, which upon further scrutiny appear not to be failure of the treatments, but failures of the studies and failures of the methodologies and standards for evaluation to account for the full and varied scope of the disease in real life situations. I hope this forum will bring together the 1st hand views of PWP who volunteer for studies of new therapies with the views of scientists and regulators and industry sponsors of clinical trials to better recognize the strengths and weaknesses current methods to accommodate the needs of PWP to determine our own risk -benefit calculations in patient centered health care systems.

Perry

Read this in wikipedia[for what it's worth to you] and wondered if training participants to not expect anything could result in this phenomenon:

Main article: Nocebo
In the opposite effect, a patient who disbelieves in a treatment may experience a worsening of symptoms. This effect, now called by analogy the "nocebo effect" (Latin nocebo = "I will harm") can be measured in the same way as the placebo effect, e.g., when members of a control group receiving an inert substance report a worsening of symptoms. The recipients of the inert substance may nullify the placebo effect intended by simply having a negative attitude towards the effectiveness of the substance prescribed, which often leads to a nocebo effect, which is not caused by the substance, but due to other factors, such as the patient's mentality towards his or her ability to get well, or even purely coincidental worsening of symptoms.[8]

http://en.wikipedia.org/wiki/Placebo...Placebo_effect

http://en.wikipedia.org/wiki/Nocebo

paula

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.