Cere 120 - The Story

[paula_w]

Through the participants , investigators, ceregene company, , 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 [I]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....:winky:, 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

[LindaH]

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.

[Stitcher]

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.

[paula_w]

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

[Dottie]

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

[paula_w]

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

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


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

[paula_w]

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

[Perryc]

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


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_w]

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 (http://en.wikipedia.org/wiki/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 (http://en.wikipedia.org/wiki/Nocebo_effect)" (Latin (http://en.wikipedia.org/wiki/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 (http://en.wikipedia.org/wiki/Mentality) towards his or her ability to get well, or even purely coincidental worsening of symptoms.[8] (http://en.wikipedia.org/wiki/Placebo_effect#cite_note-7)

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

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

paula

[pegleg]

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/pressRelease/idUS160471+28-Apr-2008+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.

[jeanb]

Thanks Peg and all for your posts,

Many good things to consider.

Jean

[paula_w]

Th new PD sounds a lot harder to fix than the old one that was located in the substantia nigra and just a neurological disorder. One question I've had is about the two subtypes that have been recognized for some time - those of tremor dominant and bradykinesia, rigid dominant. Some research on these two has resulted in the belief that bradykinesia and rigidity present a higher risk for dementia. Those with tremor dominance often change to rigid/bradykinesia dominance and after this happens, they are also at higher risk for dementia.

Has anyone looked at these two subtypes among the responders with Cere 120 or spheramine? Should it be a component of every trial ? perhaps it even affects the chances of having placebo effect?

in the new trial - can enough people be included to compare subtyes in at least these two categories?

These 2 subtypes we already know about. Genotypes we must wait for. One person who is experienced, has expressed to me that DNA testing isn't everything it's cracked up to be. Are we to put our hopes in waiting another 5 years for cheaper DNA testing that isn't reliable?

In the meantime, I hope the human component, the emotional component involved in this "slow death", the part that can only be relayed by pwp, is exhaustively explored for subtypes, as well as gastro-intestinal, immunological, hormonal, and other accompanying conditions' effects on trial results.

We are taking scientists word for it about the placebo effect. But we are not dealing with pd when we talk about the placebo, we are talking about tricking people, deception, trying to get past their psyches. It has nothing to do with PD in concept. We already know that emotions, stress levels, excitement, positivity, negativity affect pd symptoms and performance.

What are we looking for, for success? What can we do to help this process along?

paula

[jeanb]

Paula - excellent points

And to throw in the mix there are people like me who have both tremor and rigidity, but neither is dominant?

[LindaH]

Paula raises many important issues. One of them is that it's time to demand more facts about the role of the placebo effect in clinical trials for PD. We've been told for years it is especially strong in PWP because the expectation of treatment can increase dopamine production -- even in our dopamine starved brains and can last for a long time. Many of the phase I trials that showed promising results and then "failed" in phase II have been explained away by the placebo effect. We need more precise definition of what the placebo effects is and how long can it last. Can expecting to get better reasonably bring about the magnitude of improvements that Peggy wrote about and actually last for 2 years? 4 years? 6 years?

Or did she get better because Spheramine worked for her? just as gDNF worked for many of those trial participants in both phase I and II. Both of these treatments have been shelved. It would be difficult to find funding to reinstate the trials after being labeled as "failures." The Parkinson's community cannot afford to let that happen to CERE120 too. Ceregene should do further analysis of the data and also seek, listen to and analyze the experiences of the trial participants like Carolyn to try to determine what really failed -- the treatment or the trial design.
Dr. Michael Hutchinson, one of the trial doctors who supported reinstatement of treatment for the GDNF trial participants, often said -- if you want to know if a treatment is working -- look at the patients. It's a shame he wasn't listened to then.

For listing of recent "Failed" and terminated PD trials see:
http://pdpipeline.org/terminated_thearpy_thru2004.htm

[Stitcher]

I know everyone is intrigued by my not taking meds, but I now wish I had never uttered those words to anyone. I guess I got caught up in the moment when I was shouting from the rooftops.

I am considering returning permanently to my meds and would like it if no one would mention my stopping again. I hope this doesn't sound harsh, I don't mean for it to sound that way. I just have great fears about anyone outside the PD community discovering the fact that I ever stopped at all.

On to the topic at hand:

I feel that change needs to begin in the clinic setting, and I know this would not be an easy task to achieve.

Peggy, has great points in your reply.

Question: Why are we, as a patient group not categorized…as time passes the PWP may change category, where the PWP is at diagnosis is certainly not where the PWP would be five years later:

Categories would include: I believe Peggy called this a Statistical Formula
1) slow progression with tremor,
2) rapid progression with tremor,
3) #1 without tremor,
4) #2 without tremor,
5) with dynkinesia,
6) with dystonia,
7) with both 3 and 4.
Secondly, why are therapies not trialed/tested by these categories? And there may be other combinations I have not thought of.
I would be at #1.

So, if NTN data was analyzed using these categories, would the analytical results have been different?

Why was UPDRS the ONLY factor examined in the NTN trial? Why?

In a surgical trial, is it possible that the neurosurgeon simply by skill or by luck hit the right spot in the brain?
If this is even a possibility, why is this not examined when the data is analyzed?

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.

Regarding the above that I have quoted from Peggy's reply:
For NTN we had a diary we were required to complete for the 3-days prior to each quarterly evaluation. This diary did not address mood, illness or any other potential factor that may have had a impact on how well our meds worked or how our symptoms manifested themselves during those three days and there was no questionnaire on clinic day that inquired about illness, injury or any other potential factor that may have had a impact on how well our meds worked or how our symptoms manifested themselves over the prior three months. The diary only address when carbidopa/levodopa was taken and whether dyskinesia was present at any time as well as "on" and "off"

Matter of fact, the only clinic I have ever been too that required a “how have you been feeling” questionnaire to be completed at each visit was Univ of Maryland, but then Dr. Shulman is the PD community leader in quality of life and studies this daily.

I had forgotten this, but when I was searching for how to spell Dr. Z's last name for the who I am post below, I stumbled upon this study.

(July 18, 2007) -- (http://hscweb3.hsc.usf.edu/health/now/?p=185)
The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has awarded Robert Hauser, MD, director of the University of South Florida Parkinson’s Disease and Movement Disorders Center of Excellence, $124,996 to identify different forms of Parkinson’s disease (http://hscweb3.hsc.usf.edu/health/now/?p=185) based upon patterns of long-term outcomes in patients.

The USF study will evaluate whether it is possible to identify Parkinson’s disease subgroups based on how patients are faring seven to eight years after initial diagnosis. Some patients experience few symptoms at this stage of the disease, while others have problems with thinking and memory, motor fluctuations, mood, parkinsonism (slowness, stiffness, tremor) or autonomic function (blood pressure, urinary and bowel function).

“One of the most frustrating aspects of Parkinson’s disease — for patients, researchers and clinicians alike — is the significant variability in how the disease manifests itself from patient to patient,” said Sarah Orsay, chief executive officer of the Foundation. “The retrospective studies funded under PD Subtypes aim to analyze data already gathered on different forms of the disease. This analysis could yield valuable information with potential to improve clinicians’ ability to treat patients with existing therapies. It could also advance development of new treatments and enable better design of future clinical trials.”

The USF project will tap into two significant clinical research populations in the Parkinson’s field -- the DATATOP (http://www.ninds.nih.gov/news_and_events/press_releases/pressrelease_datatop_012093.htm) (Deprenyl (http://www.deprenyl.net/) [Selegiline] and Tocopherol Antioxidativ (http://www.deprenyl.info/parkinson%27s/deprenyl-parkinson%27s-12.htm)e [Vitamin E (Tocopherol)] Therapy of Parkinsonism) study and the CALM-PD (http://www.parkinson-study-group.org/Completed%20Clinical%20Trials.html) (Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson’s Disease) study.

How will this study be used?

The items in [] were added by me.

[Stitcher]

Paula asked who am I...I will take a stab at my assumption of what she is seeking and add the following to the post above:

I wrote the following months ago when I attended a CISCRP panel in Philadelphia



I became interested in clinical trials soon after I was diagnosed, October 24, 1994 at the University of South Florida, Tampa, Florida

The USF Movement Disorder Center, through Dr. Robert Hauser, is very involved in clinical trials.
.
I saw participation in clinical trials as a way to potentially help myself,

In the late 1990s I participated in three Parkinson’s therapy trial: Rasagline/Azilect, Tasmar, Remacemide

In 2004 I participated in a trial at the University of Rochester, NY focusing on the treatment of depression in Parkinson’s disease.

In the beginning, in Tampa, I was very naïve about participation in trial.

Dr. Hauser or Dr. Zesiewicz (Dr. Z to patients) simply asked me to participate, I read the Informed Consent…actually I skimmed it, since I didn’t understand the importance of the document.

Today I know full well the importance of the Informed Consent document and process and have spent the last two years working with other PWPs on refining this process with regard to the safety of the patient.

In late 2006 my then movement disorder specialist, Dr. Lisa Shulman, began urging me to have a DBS (deep brain stimulation) done, citing my number of years with PD and my tremor. I resisted for several months. I the Spring of 2007 I received a PDF newsletter by email that indicated the Phase II of a Ceregene trial was recruiting. The trial was surgical and was implanting gene therapy into the brain in the hope to rejuvenate the dopamine cells back into action. I did my research and discovered that Phase I had excellent results.

I join the trial and had my CERE-120 surgery done on June 18, 2007 at Pennsylvania Hospital, Philadelphia (not to be confused with the Hospital of the University of Pennsylvania.)

Even with the aftermath problems that arose post-surgery...Yes, I would do any of my prior trials, as well as my current trial again. Any brain surgery can experience this same problem.

Today I am able to live relatively normal. I drive my car. I do my own grocery shopping. I don't need any assistance of any kind. The only medical issue I have that is troublesome to me is my depression.

[paula_w]

never mind...lol...i understand and no problem.

[Stitcher]

Starting with "(July 18, 2007)," content was added to Post #16.

[paula_w]

These passed through my pipeline email:

1: Understanding the placebo effect. Part 2: underlying psychological & neurobiological processes. (http://www.ncbi.nlm.nih.gov/pubmed/18595454?ordinalpos=1&itool=Email.EmailReport.Pubmed_ReportSelector.Pubm ed_RVDocSum)Howland RH.
J Psychosoc Nurs Ment Health Serv. 2008 Jun;46(6):15-8. Review.
PMID: 18595454 [PubMed - indexed for MEDLINE] Related Articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=18595454&ordinalpos=1:)

2: Placebo response in Parkinson's disease: comparisons among 11 trials covering medical and surgical interventions. (http://www.ncbi.nlm.nih.gov/pubmed/18228568?ordinalpos=2&itool=Email.EmailReport.Pubmed_ReportSelector.Pubm ed_RVDocSum)Goetz CG, Wuu J, McDermott MP, Adler CH, Fahn S, Freed CR, Hauser RA, Olanow WC, Shoulson I, Tandon PK; Parkinson Study Group, Leurgans S.
Mov Disord. 2008 Apr 15;23(5):690-9.
PMID: 18228568 [PubMed - indexed for MEDLINE]
Related Articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=18228568&ordinalpos=2:)

[Tom819]

I would like to thank the regular contributors to this forum for their tireless dedication in the quest to find an effective treatment and ultimately, the cure. I thought the unity I felt on the old Braintalk forums was gone but its back and stronger than ever.

Although I still don't know what my stats were, I was one participant that had a very impressive placebo response. Here's why I think this happened:

Just prior to signing up to be a participant in this trial, I didn't realize how discouraged I had become about the future. There's no doubt I was very lethargic and sedentary and frankly my partner (who I love to death and couldn't live without) was become more frightened and pessimistic as I progressed.

I remember my study doctor making a dramatic statement more than once "Tom, you are the perfect candidate" having one the lowest early advanced motor scores off meds and improving by roughly 40% on meds.

I remember my son at age 10 absorbing the idea of real vs sham surgery and seeing other advanced patients in the waiting room and it broke my heart as I saw the fear in his eyes.

One of the most touching moments of my life was seeing my son's reaction when I told him Dad was accepted into the trial. I called him at his friends house and he dropped the phone ran up the street at top speed and grabbed me, hugged me and told me he loved me.

After seeing how the possibility of recovery affected my family, I wanted it to happen very badly. If Ceregene wants to minimize the placebo response, I think they need to spend more time on the psychological make up of each candidate.

Futhermore, I have no objection to the concept of sham surgeries in clinical trials as long as there is a guaranteed reward for participating. I'm not sure how this could be implemented but I know how much it hurt to watch my son cry when he heard I was in the placebo group and to realize my consolation prizes were two long scars on the top of my head and some lovely parting gifts.

Putting placebo patients through great emotional and physical trauma and taking every precaution to make the experience feel as real as possible does one thing to a clinical trial - it corrupts the results by producing an abnormally powerful placebo response.

Bottom line:

There are people right now that participated in the Spheramine and Ceregene trials who had a very significant response to receiving the real treatment and went from having advanced PD back to early stage PD. It would be shameful if the potential for these treatments never gets realized due to the design flaws that created such a powerful placebo response.

[Tom819]

The Results:

The trial did not demonstrate an appreciable difference between patients treated with CERE-120 versus those in the control group. Both groups showed an approximate 7 point improvement in the protocol-defined primary endpoint (Unified Parkinson's Disease Rating Scale- motor off score at 12 months), relative to a mean at baseline of approximately 39 points. Both groups had a substantial number of patients who demonstrated a meaningful clinical improvement from baseline. CERE-120 appeared to be safe and well tolerated.

Now I am awake (look out everyone!!!). After these results were announced, I was stunned. Ceregene is a very impressive company. They did an amazing job meeting the timelines promised and I have a tremendous amount of respect and gratitude for their desire to find an effective treatment so this is not a "sour grapes" comment. It is extremely important that everyone stop what they are doing, put their pencils down and hear this:

If Patient #1 in the real treatment group reduced their meds in a dramatic fashion and demonstrated a 7 point improvement and Patient #1 in the placebo group demonstrated the same 7 point improvement but increased their meds (which was permitted as long as the sponsor was notified in advance) how is this considered the same result? Please tell me the results were weighted in some way to account for this. If not, then a major injustice has occurred here!!!

[paula_w]

Thanks so much for joining in and your question [if i had been holding a pencil, i would have put it down!] is almost so simple it's hard to believe something like that could be overlooked. We have been puzzled by the wording of this announcement all along.

In your first post, another interesting thought:

"Putting placebo patients through great emotional and physical trauma and taking every precaution to make the experience feel as real as possible does one thing to a clinical trial - it corrupts the results by producing an abnormally powerful placebo response."

This might be especially true with sham surgery.

Talking about your son brings the story home to all of us. So many other people are stressing right along with us.

I will ask you the same question as Dottie. If they go to phase III, are you entitled to the treatment? Does the Informed Consent address this?

paula

The Results:

The trial did not demonstrate an appreciable difference between patients treated with CERE-120 versus those in the control group. Both groups showed an approximate 7 point improvement in the protocol-defined primary endpoint (Unified Parkinson's Disease Rating Scale- motor off score at 12 months), relative to a mean at baseline of approximately 39 points. Both groups had a substantial number of patients who demonstrated a meaningful clinical improvement from baseline. CERE-120 appeared to be safe and well tolerated.

Now I am awake (look out everyone!!!). After these results were announced, I was stunned. Ceregene is a very impressive company. They did an amazing job meeting the timelines promised and I have a tremendous deal of respect and gratitude for their desire to find an effective treatment so this is not a "sour grapes" comment. It is extremely important that everyone stop what they are doing, put their pencils down and hear this:

If Patient #1 in the real treatment group reduced their meds in a dramatic fashion and demonstrated a 7 point improvement and Patient #1 in the placebo group demonstrated the same 7 point improvement but increased their meds (which was permitted as long as the sponsor was notified in advance) how is this considered the same result? Please tell me the results were weighted in some way to account for this. If not, then a major injustice has occurred here!!!

[Tom819]

Thank you for asking Paula. From the consent form:

"If results confirm the continued safety and efficacy of CERE-120 following the conclusion of the trial, another study will be opened to allow subjects who received the sham surgery to receive the study drug CERE-120. Participation will be made available to all subjects deemed suitable for the surgical procedure by the subjects study neurologist and neurosurgeon."

It would be tragic if those that received the sham are not given the option of receiving the real treatment.

[LindaH]

Found on the Alzheimer's Forum dated Jan 9, 2009 under PD news (scroll down to middle of page--
"In the meantime, the JAMA study may help soften the blow from the disappointing Phase 2 trial of CERE-120, a PD gene therapy approach. Unlike DBS, which can relieve symptoms but does nothing to slow neuronal death, gene therapy strategies aim to rescue dying neurons by delivering growth factors to brain regions affected by disease. Such methods have shown some success in AD (see ARF related conference story"

"CERE-120, an adeno-associated viral vector developed by San Diego, California-based Ceregene, Inc., carries the growth factor neurturin to dopamine-producing nigral neurons that degenerate in PD. In a November news release, the company announced that CERE-120 showed no clinical benefit in a Phase 2 study of 58 patients with advanced PD. The trial did have a silver lining. “We saw no product-related side effects at all,” said Ray Bartus, the company’s chief scientific officer, in an interview with ARF.

Based on autopsy data his team has analyzed from two patients in the recent trial, he thinks the gene delivery procedure could be at fault. While it appeared that neurturin DNA was taken up at the injection site—the terminal fields of nigral neurons—the researchers saw no evidence of the target protein in nigral cell bodies. To work in advanced PD patients, Bartus said the therapy should target both terminal fields and cell bodies. Based on this working hypothesis, he hopes the company can launch a trial that includes those adjustments later this year."

http://www.alzforum.org/new/detail.asp?id=2012

This is the first i've read about this explanation. Has anyone else?

[paula_w]

Hadn't heard that Linda; the plot just thickened, but I'm not surprised. The statement for cancellation was too vague. They haven't abandoned it - they have a record for moving quickly - so does this mean we can be cautiously optimistic?

Anyone that can explain these results? It would be helpful to understand.

paula

[Tom819]

Wow Linda, great find!!! To speculate, maybe Phase III will be new and improved version with a design that minimizes the placebo effect. Hope its true.

[Dottie]

I found this in my Informed Consent:

If it is determined at the conclusion of this study that it is appropriate to provide CERE-120 to people with Parkinson's disease, those assigned to the sham surgery group may be permitted to enroll into an open-label follow-up study in which CERE-120 will be given"

The Questionnaire has this:

After the study is completed, you will be informed about which groiup (active treatment with Cere- 120 or sham surgery) you were assigned. If you were assigned to the sham surgery group, are you aware that you will
have the option to receive active treatment with CERE-120? Yes/No

I sent the coordinator the following:
" Someone asked me about the option of having the surgery - did that end with the completion of phase 2 or does it carry over to phase ?

Her reply:

"...I have not heard anything regarding a possible phase 3. I was told the last time I inquired that they were still in discussions as to what and if there
would be a next step even with the sham group".

[paula_w]

Thanks much Dottie. It's understandable that they wouldn't know yet. The open label in your informed consent is different than a phase III tho don't you think? That raises another question that maybe they are still working on.

paula

oh i thought about that more....lol....you would have to be in a follow up study I guess because you certainly don't want to end up with the placebo again!

[Tom819]

In my opionion, if Phase III becomes a reality, the fair thing to do would be to offer the sham group the real treatment in a separate open label study. If the procedure is modified, maybe we can be the group to prove the treatment is safe before it is rolled out to a larger group in Phase III. It probably won't happen that way but its a nice thought. In reality, if they would give me another crack at it and placebo was a part of it, I would sign up in a heartbeat!!!

By the way, I have no idea why anyone believes that Mirapex can cause compulsive gambling, eating and hypersexual behavior. I haven't experienced anything like that. Wait a minute!!! I'll be right back!!! I think that prostitute stole some of my gambling chips at the casino buffett!!!

[paula_w]

Tom and Dottie, I hope we soon know the changes they are making for phase III. If they can't use the changes without first testing it in a clinical trial, could they keep you out of the statistics and do it all during phase III?

I'm thinking that you couldn't be fully in phase III, because it would be open label for you. It seems logical [this is all speculation] to keep you separate but give you the newer version being used in phase III. Does this leave more to actually observe and work with? 3 groups, two blnded- one placebo and one with new treatment- and one group open label with new treatment?

But then sometimes procedures defy logic from our perspective.

hope that makes sense,
paula

[Tom819]

Paula,

I love your logical way of thinking but my concern is the expense to do the right thing for the sham group. With my luck, they will decide to have us as a seperate group
(19 real 1 sham) and guess who will get the sham? Incidentally, at my facility, 4 got the real treatment and only 1 got the sham, me!!!

I pride myself on being very perceptive and felt that the folks who knew post-surgery were behaving in kind of an awkward fashion. In fact, the surgeon literally ran away from me after making sure I was OK. A year later, he laughed and said it was his only placebo. I had misinterpreted this behavior as confirmation that I received the real treatment. Guess I over-thunk it!!!

[pegleg]

OK. I wrote so much last time that I was only going to say "thanks" to Tom's post. You put a face20on the trial participant - and that's the story we have to tell. That is why we have "human" trials - people who must cope with diseases like Parkinson's - who live its emotional ups and downs every day - otherwise we could just stop the trials at the primate (monkey) level.

There's a wonderful opportunity for us to ask an expert all of these questions first-hand on an upcoming webinar (the first I've heard of ever!) see announcement below:

Participating in Parkinson's Clinical Research: The Key to Becoming an Informed Study Volunteer

Wednesday, January 14, 2009, at 3:00 PM Eastern time

Featuring Kenneth Getz, M.B.A., author of The Gift of Participation: A Guide to Making Informed Decisions About Volunteering for a Clinical Trial

Click here to register:
http://event.netbriefings.com/event/pdtrials/Live/infvol/register.html

I think this idea of testing of subtypes of Parkinson’s is brilliant. Greg Wasson came up with theidea (I believe) andwrote about it in an OpEd on the Pipeline site:
http://pdpipeline.org/advocacy/oped_wasson_july23008.htm

I'm not a statistician, and only took a couple of statistics courses at the Master's degree level, so if I am way off course, please correct me. We have small numbers of participants in phase I trials, because they are conducted to evaluate the safety of a treatment in humans. Any improvement of participants is a plus. Any unsafe results, and the trial is halted immediately.

The Phase II level is (or should be) carefully planned, with a requirement of "testing" enough participants to show that any improvement from the treatment didn't just happen per chance. Endpoints, or outcomes, must be hypothesized and projected. The IRB (Institutional Review Board) at each research institution decides what those expected results will be. There are statistical tests that must be done after all the data is gathered and a significance level at a minimum of 0.5 must be shown for the trial to be valid. Validity means the study tests what it said it was to test. Reliability is achieved when the study can be replicated with relatively the same results when repeated.

At present there is no test to “prove” that one has PD (with Multiple sclerosis, for instance, an MRI shows demyelinating or white patches visible on the brain). With Parkinson’s, we go by symptoms and the ruling out of other disorders.

So , I pose this question:
Is it ethical to “fake” the surgery a trial? Since PD is diagnosed via observation of symptoms, why doesn’t observing whether or not there is improvement of symptoms count?

I have been searching through some old books and online about this subtypes testing. There’s some really good stuff at this site: http://www.improvingmedicalstatistics.com/

If a study did test a treatment dividing them into subtypes of PD (e.g. tremor dominant vs rigidity or balance issues dyskinesia vs no dyskinesia), we would have to be very, very careful with how those groups were divided because itsays "the validity tends to be inversely proportional to the number of subgroups which are analyzed":

Inappropriate subgroup analysis can lead to ludicrous results.

Subgroup analysis, at times, can lead to findings that are incorrect. If a subgroup analysis results in an unexpected finding in outcome that is different from a highly significant and beneficial effect for the group as a whole, the subgroup analysis is often incorrect. In fact,it is more likely that the unexpected subgroup finding that runs counter to the group finding is simply not valid.
Source: Improving Medical Statistics

Read this very easy-to-comprehend article for a better explanation.:
http://www.improvingmedicalstatistics.com/Sleight%20&%20Subgroup%20analysis%20%20%20.pdf

This same article says, “A subgroup analysis which results in variance from the overall group outcome is more likely to be true if it involves a large subgroup and there are a very limited number of pre-specified analyses.” This means the Phase II recruiting of volunteers would be even greater in number. Recruitment would be even more difficult. It isn’t like people are knocking down doors to enter a trial where half of them will have sham surgery. But the results using subtype analysis would result in some real meat to chew on – a way of treating PD that’s never been done before. I sincerely believe this could turn the treatment of PD around.

[paula_w]

Peg thanks so much for a really comprehensive and honest post. And to those pipeline members who contributed. Outstanding points and what do i know about statistics if someone doesn't write it down and explain it well?


i took out the reference i had here. it didn't seem specific enough for what we are focusing on.

paula

[paula_w]

Expectations in clinical trials were investigated in 2005 resulting in a good paper by Fabrizio Benedetti et al. Altho a few years old, it talks about expectation pathways in our minds, that could be working in a way similar to the actual treatment. He also comments about "hidden treatments", where the person doesn't know he/she received a treatment, not working as well as when the person knows he is getting it. Here are two references about this.

Ray Bartus has not responded to emails asking for more information about ceregene, so based on his first comments to Perry Cohen about "lowering trial participant expectations to reduce placebo noise", I thought these may be interesting:

http://www.sfn.org/index.cfm?pagename=news_111505c

[from ppp email - planton]: actual Benedetti study

http://dcscience.net/placebo.pdf

excerpt:

Another important point is represented by the role of expectations and subsequent
neurobiological changes in clinical trial design. In a recent double-blind study that
addressed the perceived assignment of treatment in human fetal mesencephalic
transplantation for Parkinson’s disease, it was found that the perceived assignment
of treatment (either active or placebo) had a more powerful impact on both quality of
life and motor function than did the actual treatment. In other words, which group
participants believed they belonged to was more important than the group to which
they were actually assigned (active treatment or placebo). This study raises a crucial
question about how a clinical trial should be conceived: should we consider the perceived assignment to an arm of the trial rather than the actual assignment?

---
This leaves patient consumers wide open to be told just about anything before a trial begins. This deserves an ethical discussion and if it is being considered for cere 120 phase III, patient advocates should be involved. Isn't our brain saying that it basically believes what it is told? Human nature......it's abnormal to use trickery and when does trickery become quackery?

When this trickery involves brain surgery, it may be going too far. The refinement of pump infusion seems logical, safer , controllable and reversable.

paula

[pegleg]

Interesting, paula. One may not buy into the "heal thyself" theory, but cannot deny its positive effect on both physical and emotional wellness. I want to address a sensitive subject now, and I hope the monitors can see the science in what I am about to say, and not the "religion" so that others can read it.

Growing up with the philosophy of Norman Vincent Peale (especially in his book The Power of Positive Thinking), I have to say that I am convinced with all my heart that attitude plays the most powerful role in healing. This isn't about Christianity, but it is about the mindset of Christianity (and just like with any religion, there are good and bad apples). If we feel a power within us that we can overcome something, what could be unhealthy or even unscientific about that?

I found this tidbit about Peale that I want to share:

Peale applied Christianity to everyday problems and is the person who is most responsible for bringing psychology into the professing Church, blending its principles into a message of "positive thinking." Peale said, "through prayer you ... make use of the great factor within yourself, the deep subconscious mind ... [which Jesus called] the kingdom of God within you ... Positive thinking is just another term for faith." He also wrote, "Your unconscious mind ... [has a] power that turns wishes into realities when the wishes are strong enough."

This is a whole "nutter" topic, but I sincerely believe that scientists should not be so quick to poo-poo the theory of positive thinking and its impact on healing. If it improves the well-being of a person suffering with pain and disabling symptoms, I fail to see the bad in that - and I definitely fail to see "failure" in that.

And what - do tell - could possibly be wrong with that???
Peg

[paula_w]

Nothing like a middle of the night post. We all used to be much braver. Anyway, Peg, your message is personal, which is not used by younger generations or various professionals, medical in particular, I've discovered...if I'm wrong, you know all someone has to do is explain it and set me straight.

I like to spend time learning the scriptures and get great comfort from them, and I am pretty sure i know what you mean about Norman VP. There isn't much Norman Vincent Peale around now. Currently, there is an attack mode that never seems to let up; balanced "positively" with the obsession to get wealthy and place accumulating wealth as the highest priority.

And here we are.....trying to stay positive using the only successful ways that work. Scriptures are so cool.

The entire world could use a good chill out with scripture quotes, just ignoring the source so as to avoid pcitis - and taking in the wisdom

Perhaps a thread could be started. It could be quite profound - just the verses - no preaching - particularlly as they might apply to this situation with the pd community. Competitive, fractured, don't really know the patients on the inside. It 's such an inside disease.

Ok I'll leave one here and if you want to start another thread go for it.

Hebrews 10:1

Now faith is the substance of things hoped for, the evidence of things not seen.

paula



Interesting, paula. One may not buy into the "heal thyself" theory, but cannot deny its positive effect on both physical and emotional wellness. I want to address a sensitive subject now, and I hope the monitors can see the science in what I am about to say, and not the "religion" so that others can read it.

Growing up with the philosophy of Norman Vincent Peale (especially in his book The Power of Positive Thinking), I have to say that I am convinced with all my heart that attitude plays the most powerful role in healing. This isn't about Christianity, but it is about the mindset of Christianity (and just like with any religion, there are good and bad apples). If we feel a power within us that we can overcome something, what could be unhealthy or even unscientific about that?

I found this tidbit about Peale that I want to share:

Peale applied Christianity to everyday problems and is the person who is most responsible for bringing psychology into the professing Church, blending its principles into a message of "positive thinking." Peale said, "through prayer you ... make use of the great factor within yourself, the deep subconscious mind ... [which Jesus called] the kingdom of God within you ... Positive thinking is just another term for faith." He also wrote, "Your unconscious mind ... [has a] power that turns wishes into realities when the wishes are strong enough."

This is a whole "nutter" topic, but I sincerely believe that scientists should not be so quick to poo-poo the theory of positive thinking and its impact on healing. If it improves the well-being of a person suffering with pain and disabling symptoms, I fail to see the bad in that - and I definitely fail to see "failure" in that.

And what - do tell - could possibly be wrong with that???
Peg

[pegleg]

I didnt intend to turn this very important thread around. There is a "Santuary for Spiritual Support" forum where we can share our spiritual life.
http://neurotalk.psychcentral.com/forum27.html

But I did want to show the connection between placebo/attitude/and positive thinking/spirituality. Guess we'll keep this thread "clinical."

Hope is what we all need and must have - and I believe the research people who don't see the connection are the real losers.

Peg ;)

[paula_w]

Ok this is going to sound different and it just might be a determiner [something that determines lol] who or what is real in this thread.

I 'm assuming some things just from writing this story; would anyone correct an error if they read one here? If not, I feel it's possible that some of the researchers, industry, orgs, etc., [and if reading] are still way behind in how they view patients studying current research, especially now that it is getting very sophisticated. You can't ignore how we feel about these things .....heres why:


it's not going to stop the aggressive verbal ...ness. this is science/journalism; with forums and blogs having bad reputations. We are in a very unique postion to interact with 100% innovation. And do it right.
Ok - there's a recent patent application - Dr. Gill et al for an infusion pump to be approved in the USA......includes mentioning of Amgen's gdnf. Dr, Gill stayed mostly out of the fray, always knew he could possibly need that gdnf. Dr. Clive Svendsen , I would love to hear from you about this.
Teamwork - can you all have a phase III or phase II/III of pump infused GDNF and at the same time, let's have Ceregene Phase III , along with an accompanying smaller study of supplying the phase II placebo with the real treatment. Lots to watch and learn.
Give us some choices, many of us are your next - what da?? patients, participants, consumers, patient consumers, clients, lab rats - who are we? [and what is the meaning of life...lol]
Repeating the previous one, many of us are at the point where clinical trial participation is where the hope lies. But as I said in the above post... Hebrews 10:1 says "Faith is the substance of what is hoped for...the evidence of what is unseen." Where do patients place their faith? How do the non-pwp gain the trust of the pwp and their loved ones?


One way is by interacting on an equal level with all. Doctors and medical personnel, I want to say here that I respect your position but do not always agree with what you say. I've caught doctors in mistakes, not deliberately looking for them, and usually don't correct them. The few times I have, a fancy song and dance conversation switch usually occurs, to avoid the correction.

Progress has been made in many areas buy you are still a ways off on what we can do....It's like the movie ..darn can't think of name...Tim Allen was a washed up superpower; he gets kidnapped by the gov. to train new young kids with uncontrolled superpowers. They bonded and did great things.
ok for the 689th time....can someone in the research or industry of ceregene, mjff, UK, Gill, investigators. clinicians, grad assistants.......kindly give us an update of whether we could possibly have these 3 choices in place soon? Or comment on placebo; there's an abundance of issues....really....in this thread. It behooves someone to be respectful enough to enter into this peaceful thread and enlighten us. Allow us into the research agenda plannng .....Andy Grove.....we were nice to you!..lol

I do not know how to think on a more local scale. This is where I was taken from the beginning - all things are possible.

When we were little, we used to call each other "yellow bellied chicken livers." Note how I have not done that. I 'm here in peace and will squawk if anyone is mean.

I'll attempt to clean up or organize this thread, unless somebody else wants to? ...

[Stitcher]

I attempted to address subtypes in post #15 above. Are those of you who are speaking of subtypes thinking in this way about subtypes? If not, can you be more specific about what you would consider subtypes to be.

Subtypes would include:
1) slow progression with tremor,
2) rapid progression with tremor,
3) #1 without tremor,
4) #2 without tremor,
5) with dynkinesia,
6) with dystonia,
7) with both 3 and 4.

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

On the topic of placebo I found this:

plac-, placi-, -plais
(Latin: to please, to satisfy; peace, peacefulness; calm, calmness)

http://www.wordinfo.info/words/index/info/view_unit/1682/2/?spage=8&letter=P

placate
placebo (antonym: "nocebo")

1. "I shall please".
2. In medicine, a prescription given to please a patient who, in the physician's opinion, needs no medication.
3. something of no inherent benefit that is done, or said, simply to placate or to reassure someone.
4. Something prescribed for a patient that contains no medicine, but is given for the positive psychological effect it may have because the patient believes that he or she is receiving treatment.
5. A "sugar pill" or any dummy medication or treatment; for example, in a controlled clinical trial, one group may be given a real medication while another group is given a placebo that looks just like it in order to learn if the differences observed are due to the medication or to the power of mental suggestion.
6. Etymology: from Latin placebo, "I shall please"; future indicative of placere, "to please".

The medical sense is first recorded in about 1785, "a medicine given more to please than to benefit the patient".


The placebo effect and the power of belief
"Michael Brooks, a writer of an article in New Scientist magazine, took part in a "placebo" experiment in which he was told that a computer screen would indicate whether electric shocks would be mild when a green light showed up or a red light would indicate when the shock would be "more severe".

"After about fifteen minutes, the experiment ended with what he thought were a series of "mild shocks" until he was told that the "last series of shocks" were all severe. He "felt the electric fence jolts as a series of gentle taps" on his arm until he was told that the "last series of shocks were all severe".

"He realized that he had experienced "the placebo effect" because his brain had been conditioned to anticipate low pain when he saw the green light on the computer screen for the series.

"The "placebo effect" for quite awhile has been considered to be nothing more than the "power of positive thinking" and so people believed that they were receiving good medical care even though it might have been nothing more than a sugar pill or an encouraging manner of the physician. In many cases, people started to feel better without any additional medical treatment.

"Some current research about the placebo effect indicates that it is more complicated than simply being a "positive thinking" result; however, depending on how it is done, the placebo effect can make some people feel better even when they are not really any better."

—Based on information from
"The Power of Belief" by Michael Brooks; New Scientist;
August 23, 2008; pages 36-39.

Editorial: "Patient, heal thyself"
"The placebo effect has been known since the beginnings of medicine.

"About the only medicine doctors from long ago could offer their patients was the reassurance that a medical treatment would work and it often was successful.

"It has become apparent that a patient's state of mind, awareness of his/her condition and expectations of the care she/he is about to receive can influence many outcomes of medicine from consultations with a doctor to clinical trials of a new drug.

"Apparently the usefulness of a drug, for example, depends on much more than the chemicals in a pill, and a deeper understanding of the placebo effect can turn it into a valuable tool for reducing suffering."

—Based on information from
"Patient, heal thyself", editorial; New Scientist;
August 23, 2008; page 5.

[paula_w]

Yes I saw that stitcher and didn't reply because I don't know what kinds of sub-types are possible, altho your choices sounded very logical. This is an area of interest and one that needs to be put to use, which i'm sure they are. We may have something to contribute here.

paula

[girija]

MJFF has funded atleast two researchers to study PD subtypes and disease progression. The subtypes defined in these studies are different from whats been discussed here. One of the abstracts is as follows: I hope some of the data from these studies can be reanalyzed for the features discussed here without having to do a new study. Any thoughts on how to do that?


Taken from MJFF Website http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_3.cfm?ID=298
Defining PD Subtypes Based on Patterns of Long-term Outcome

PD Subtypes 2007

The purpose of our study is to identify Parkinson’s disease subtypes based on how individuals are doing approximately seven to eight years after diagnosis. Some patients have few symptoms at this time, while others may have problems with thinking and memory, balance, mood, motor fluctuations and dyskinesia, parkinsonism (slowness, stiffness, tremor), or autonomic function (blood pressure, urinary, and bowel function). We will analyze two long-term studies (DATATOP - Deprenyl and Tocopherol Antioxidant Therapy of Parkinsonism and CALM-PD - Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson’s Disease) and attempt to identify groups of patients with similar patterns of symptoms. We will then analyze characteristics of these patients when they were first diagnosed and treated to determine if we are able to predict their pattern of symptoms seven to eight years after diagnosis.

Early identification of patients who are anticipated to develop particular patterns of symptoms may allow selection of specific therapies that will improve long-term outcome and specific subtypes of patients may be selected for entry into clinical trials designed to evaluate therapies to forestall the development of that pattern of symptoms. In addition, identification of distinct PD subtypes may aid in delineating genetic and environmental causes of PD.

Researchers

Robert A. Hauser MD, MBA
University of South Florida
Parkinson’s Disease and Movement Disorders Center

Michael P. McDermott, PhD
University of Rochester
University of Rochester

[girija]

From MJFF web site under research
http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_3.cfm?ID=298
Phenoprofiling PD

PD Subtypes 2007

Parkinson's disease is generally characterized as a movement disorder. Over the last years, however, there has been an increasing awareness that many people with PD may also suffer so-called "non-motor features," including problems with mental functioning, depression, falling asleep or staying awake, and autonomic functions (for example bladder and bowel problems). Furthermore, when patients are treated over the long term with dopaminergic drugs (e.g. levodopa) they may start to experience motor or psychiatric side effects. Although all these different features are aspects of PD, not all PD patients will have the same problems. There are differences between patients concerning the age at onset of their symptoms, the rate of disease progression, and the combination of symptoms and side-effects, suggesting the existence of subgroups. These clinical differences between patients may in turn result in different consequences on the level of disability, quality of life and required care.



Fundamental to our understanding of how one patient may differ from another is the availability of good quality measures that cover the broad spectrum of motor and nonmotor features of PD. The SCales for Outcomes in PD (SCOPA) program (www.scopa-propark.eu) was begun in 1999 to develop rating scales that measure motor and nonmotor features of PD as well as disability and global outcomes of health. In 2003, the SCOPA-PROPARK cohort study started, in which 420 patients are evaluated annually with the SCOPA scales.



The current project aims to identify groups of patients (subtypes) that share characteristics with respect to their motor and nonmotor features and their progression. Knowledge about how the expression of PD varies between patients may help our understanding of the mechanisms that underlie the development of the disease.

Researchers

Jacobus Johannes van Hilten MD, PhD
Leiden University Medical Center
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*

[pegleg]

girja (and Stitcher who gave a snip of these studies earlier) - thanks for this info. It appears (and I am not surprised) that the Fox Foundation has been on top of this subtype thing. This information has probably passed by me several times (a good reason to have flashing lights and bells and whistles attached to such studies - lol).

Such studies, however, would require the input of several people with PD who are knowledgeable enough about the disease to differentiate between categorizing symptoms common to PD and those not. And as paula has said before, NeuroTalk would be a good vehiclel for providing such information.

So, what are we waiting for?
;) Peg

PS - meant to add that Doctors Hauser and van Hilten (Netherlands) are excellent choices for these studies.

[paula_w]

Thank you MJFF and Dr. Ray Bartus, for hearing our pleas to understand these trial failures before reading about them two years later in a potentially biased journal.

Regarding Cere 120, this interview tackles the hard questions, it sounds honest, and now potential phase III participants [should it occur] can go in with their eyes wide open. I think you'll be able to recruit advanced patients. Just as becoming elderly involves facing certain facts [which is sometimes labeled as negativity, but it isn't, IMHO]about a dwindling future, pwp cannot deny that they are facing some serious poor health and suffering in the near future. Expectations for a cure in our lifetime are not necessarily there. This could result in more wanting to help others down the line, and to take the risks in clinical trials when quality of life is deteriorating.

Also, no matter how many studies are published about DBS, there are many many pwp who do not believe they are worth the risk.

So I can't thank you enough for the article; its publication is consistent with your efforts to move at a quick pace. To me, tho, it reflects respect for patients and hopefully will result in increased trust, support and communication between the research and patient communities.

http://www.michaeljfox.org/research_viewpoints_newsInContext_article.cfm?ID=1 1

my wishes for success,
paula

[paula_w]

This issue must be addressed. I think we can do it, I sent almost all of this out to some groups already by email, not to agitate [I would just admit it if I was] but to...oh fill in the blank. There are many reasons - it's one of the main things. People with emotions are the reason we are all unpredictable - our mind/body connection separates us from animals [ at least in some pretty important ways] and money.

Sent last night:

After writing and being published with questions about trial protocols and sham surgery emphasized as being questionably ethical for the last several years, it seems that we are in the middle of what you could call an application phase. MJFF did the Bartus interview, which answered many of our questions, tackled the hard issues, and risked future business or interest in cere 120. It sounded honest, but now also seems like the most opportune moment to pull out the Declaration [formerly Bill of Rights] and see how their performance compares to our expectations, particularly regarding the sham surgery participants getting the treatment. Hopefully, both sides are listening.

This was a first that I know of- this interview - and I think it was a result of a lot of squawking on our part, along with a lot of hard work from all stakeholders - everyone. MJFF came thru with the info, and did it immediately..after funding it quickly. We were watchdogging right there all along as well. So let's take a look. Where is the latest copy of the Declaration and checklists? Is it all on the pipeline site?

Here's some information that could help. The full interview, a must read, is here: it is outstanding - the pd community has come a long way since GDNF.

http://www.michaeljfox.org/research_viewpoints_newsInContext_article.cfm?ID=1 1 (http://www.michaeljfox.org/research_viewpoints_newsInContext_article.cfm?ID=1 1)

Below are some very important comments.

Ray Bartus comment regarding those who received sham surgery about 'what's next'?

MJFF: If you launch a second CERE-120 trial, will you be able to re-enroll the trial participants who received sham treatment in the first study?

RB: I actually raised that issue and discussed it with my colleagues. Wouldn’t that be a great thing to do? You have these patients who were courageous enough to volunteer for this study, but they got sham treatment, so wouldn’t they, therefore, be great candidates? From a humanistic standpoint it would be a great thing to do. But from a scientific standpoint, you quickly realize that you would really compromise the program by going in that direction.

First of all, the patients have now progressed another year or two from where they started with our trial. There is a very general consensus, based on some data and a lot of intuition, that the more the disease progresses, the less benefit one might expect from CERE-120. Thus, using these patients for an important ‘go/no-go’ decision could represent a serious mistake if the dosing change indeed worked but we did not see a strong effect because of their disease progression.

Secondly, 70 percent of those patients have already showed a robust response — that is, a placebo response. If they already have an elevated baseline, we could be shooting ourselves in the foot trying to overcome that. You see how complicated it gets.

From two sham surgery participants:
Dottie
From Informed Consent:

If it is determined at the conclusion of this study that it is appropriate to provide CERE-120 to people with Parkinson's disease, those assigned to the sham surgery group may be permitted to enroll into an open-label follow-up study in which CERE-120 will be given"

The Questionnaire has this:

After the study is completed, you will be informed about which group (active treatment with Cere- 120 or sham surgery) you were assigned. If you were assigned to the sham surgery group, are you aware that you will have the option to receive active treatment with CERE-120? Yes/No

I [Dottie] sent the coordinator the following:
" Someone asked me about the option of having the surgery - did that end with the completion of phase 2 or does it carry over to phase ?

Her [coordtinator] reply:
"...I have not heard anything regarding a possible phase 3. I was told the last time I inquired that they were still in discussions as to what and if there would be a next step even with the sham group".

This is not complete or conclusive information. Dottie is still checking.

Tom819
From the consent form:

"If results confirm the continued safety and efficacy of CERE-120 following the conclusion of the trial, another study will be opened to allow subjects who received the sham surgery to receive the study drug CERE-120. Participation will be made available to all subjects deemed suitable for the surgical procedure by the subjects study neurologist and neurosurgeon."9

Perhaps none of the sham surgery participants will want the treatment now. But the question does need to be addressed if a Declaration is ever going to have meaning don't you think?

I think the interview is awesome and historic as clinical trials go, can we carry it through? The placebo and mind trickery really are a problem all around. I appreciate that everyone is trying to solve it and the speed at which it has been moving is as refreshing as a windy day in Florida.

Declaration of Rights and Resp. written by pd Pipeline Project and other pwp, along with PDF

Copy of corresponding expectations are largely in this section.

Clinical trial participants with Parkinson's disease have the right to post-study information and options for care including:


Trial results.
Information about the conditions which they may receive post-trial access to the experimental treatment.
Notification as to whether they received a placebo or the experimental treatment and at what dosage.
The option for participants in the experimental/treatment group to continue the treatment. Likewise, those who received placebo or low dose treatments, or sham surgery should have the option of receiving the experimental treatment at the full dose, upon conclusion of their trial.
Results of all tests and procedures and copies of scans, x-rays, MRI’s, etc. if requested by the participant.
Updates about all adverse events following trial conclusion.
http://www.pdpipeline.org/advocacy/rights.htm (http://www.pdpipeline.org/advocacy/rights.htm)
paula




.

[LindaH]

Both Dr. Bartus and the Fox Foundation should be applauded for their willingness to honestly and publicly discuss the CERE-120 trial results. It was also encouraging to hear that Ceregene is not abandoning the research, as so many other companies have done when their primary endpoints were not met. Instead Dr. Bartus stated that Ceregene is considering a new trial (phase 2 or 3?), Based on what they learned from the current trial, they would use a higher dose and target the nigra (nigral cell bodies ) as well as the putamen. These changes would require FDA approval.

Bravo Ceregene!

And I wish I could end this message right here. But there is another issue that begs for more discussion -- the availability of CERE 120 treatment for the Phase II sham surgery group, if any of these trial participants do wish to receive it.

From the Interview:

“MJFF: If you launch a second CERE-120 trial, will you be able to re-enroll the trial participants who received sham treatment in the first study?

“RB: I actually raised that issue and discussed it with my colleagues. Wouldn’t that be a great thing to do? You have these patients who were courageous enough to volunteer for this study, but they got sham treatment, so wouldn’t they therefore be great candidates? From a humanistic standpoint it would be a great thing to do. But from a scientific standpoint, you quickly realize that you would really compromise the program by going in that direction.
First of all, the patients have now progressed another year or two from where they started with our trial. There is a very general consensus, based on some data and a lot of intuition, that the more the disease progresses, the less benefit one might expect from CERE-120. Thus, using these patients for an important ‘go/no-go’ decision could represent a serious mistake if the dosing change indeed worked but we did not see a strong effect because of their disease progression.

Secondly, 70 percent of those patients have already showed a robust response — that is, a placebo response. If they already have an elevated baseline, we could be shooting ourselves in the foot trying to overcome that. You see how complicated it gets” (end of interview statement)

Yes, and this is where PWP and researchers may have differing outlooks.
“First of all, the patients have now progressed another year or two from where they started with our trial.” -- To me, isn’t that is exactly why the sham surgery participants should be offered treatment. They are getting worse day- by- day, and there is nothing else presently available for clinical use proven to stop the progression, as CERE120 is thought to do. They volunteered to participate in the Ceregene trial, both to help advance the research and also with hopes of improving their conditions. They entered the trial with the understanding that if CERE 120 was shown to be safe and effective, they could receive the treatment (see the two Informed Consent provisions posted by Paula on this thread on 1/31 “A Plan About Expectations”) Perhaps that was why they agreed to the possibility that they might receive sham surgery.
Additionally, from the Minutes of the NIH Recombinant DNA Advisory Committee meeting in 09/06 , that reviewed and approved the CERE120 phase II protocol at:
http://oba.od.nih.gov/oba/rac/minutes/RAC_minutes_09-06.pdf
RAC discussion: p.6
"Towards providing some potential for eventual benefit, if upon completion of the blinded portion of the trial CERE-120 is determined to be safe and effective, the sham subjects will gain access to CERE-120 in an open-label extension study.
p. 7-8
“Since participants have received a gene vector that may allow the protein to be expressed for the individual’s lifetime, the investigators will continue following these individuals over the long term. Dr. Bartus explained that the investigators are in the final stages of putting together a long-term followup protocol for all participants that would assess them every 6 months indefinitely. The investigators also intend to offer participants recruited into the proposed sham treatment group the opportunity for treatment following the break of the blind, and then they also would be followed long term following that treatment. “

p.9
Synopsis of RAC Discussion and RAC Observations and Recommendations
“Expand the discussion of the risk-benefit ratio for participants receiving sham surgery. Additional information also should be provided about the criteria that will be used to determine which participants in the control group will be eligible to receive CERE-120 at the end of the study. “

Dr. Bartus stated in the interview that there were no safety problems. Although the end points were not met, Ceregene thinks they know what went wrong (dose and target areas) and how to fix it in a future trial. If treatment can be given to a new phase II or III participants, why not to this sham surgery group in an open label extension trial? They could then also be part of the long-term followup studies. There are examples of other sponsors running concurrent placebo control and open label studies (for those who have completed the controlled study). Of course, maybe there are other factors we are not aware of.

Yes Paula, I think the Declaration of Rights provisions about post-study options were written to address situations like this one.
“Clinical trial participants with Parkinson's disease have the right to post-study information and options for care including:
• Trial results.
• Information about the conditions which they may receive post-trial access to the experimental treatment.
• Notification as to whether they received a placebo or the experimental treatment and at what dosage.
• The option for participants in the experimental/treatment group to continue the treatment. Likewise, those who received placebo or low dose treatments, or sham surgery should have the option of receiving the experimental treatment at the full dose, upon conclusion of their trial.
• Results of all tests and procedures and copies of scans, x-rays, MRI’s, etc. if requested by the participant.
• Updates about all adverse events following trial conclusion. “
http://www.pdpipeline.org/advocacy/rights.htm
Ceregene has been an admirable clinical trial sponsor, especially in moving the research along and trying to be responsive to patients. Hoping they will be willing to look into this issue as well.

[paula_w]

Just inserting here the fact that this issue is owned by everyone. Even tho not everyone wants to spend time on this particular aspect, everyone is invited to this discussion.

It's focused and moving. It's provocative but respectful. It's spontaneous but professional. I haven't called anyone a yellow bellied chicken liver for yet another week, taking into consideration that humor is only to be expressed ....somewhere else.

Thoughts don't count - :eek:

paula

[Jaye]

I usually don't say anything in these threads, I'm not sure why. I haven't read this one until this morning, and I know why. It's too real, it's too scary, it's too upsetting, I have spent enough energy staying tuned in my own little world recently. My doctors are very helpful in keeping me boosted, but there are so many things we don't understand, and to be told that I can't understand makes me angry, affecting my balance, mental and physical.

To we who live this thing, know this: every time a medical person asks me to what I attribute my slow progress and relatively good function, I list several fact-based reasons, including the fact that a lot of people are praying for me.

I have had periods of time when I decide to get better, and I do.

Beyond my self, stranger things happen. A friend who is a pianist burned her fingers over a steamy pot. As she soaked the fingers in ice water, I laid my hands on her burned one, and as a Reiki practitioner allowed some of the life force to flow through me to her injury. Some of the pain went away. What happened? I have no idea. It just works. (For Peg and Paula, I consider the Reiki force to be the holy spirit's work and the act of laying on hands to be a form of prayer.)

I am not asking for a study of religion (although that could be intriguing), but a study of attitude, as others above have suggested. For that, clients/patients/consumers/customers should surely be in a focus group with input to the researchers and their IRB, if not at the conference table.

Jaye

[Stitcher]

PDF - Clinical Research Learning Institute

[Now is the time to speak up and become part of this "focus group."]

The Clinical Research Learning Institute is an annual multi-day educational seminar for people with Parkinson’s. It provides the knowledge and skills for each participant to be an effective representative within the clinical research enterprise.

The Learning Institute aims to create a place at the table for people with Parkinson’s disease (PD) to share their viewpoints and experience – which is all too critical to moving the development of treatments for PD forward — yet it is all too often overlooked.

The 2008 Institute took place on Thursday, July 10 through Saturday, July 12 in Glen Cove, NY. It included 27 people with Parkinson's from across the country and Puerto Rico in its inaugural year. [Plans for 2009 are not yet announced.]

Learn more about the Learning Institute (http://www.pdf.org/en/crli):

[jeanb]

So PDF.org is looking for people to attend the 2009 institute?

That's terrific!!

[Stitcher]

Not yet, but there are plans to have an Insitute in the late-summer of fall of 2009.

If anyone would like more information about the Institute, then the link is in my post above.

[LindaH]

During yesterday's MJFF research forum Dr. Kordower answered a question about the use of sham surgery in gene therapy trials.. He mentioned that it passed the "Mom" test. Said if his mom was going to be in a clinical trial utilizing sham surgery, he would actually prefer that she be in the control group and receive the placebo (sham surgery) first. If the treatment were proven safe and effective, the control group could then receive it as part of an open label study, with less risk. Wondering if this option will be offered to the participants who received sham surgery in the CERE-120 trial, if Ceregene does go ahead with further trials?

[paula_w]

A friend received this post from the MJFF round table thread via email and asked me to repost it. I lost the post accidentally while trying to move it here. Anyway here it is again.

According to Dr. Gene Johnson of MJFF, growth factor research is still worth the effort. Naturally, most of us have follow up questions about this. Hopefully, no question or idea is too "stupid".

Would it be worth considering or even possible to run several growth factor clinical trials simultaneously, using different deliveries, dosages, even potentially substances? For example, could you have a ceregene phase III with different dosages, different patient subgroups, different deliveries within the study, and no placebo. The patients would know they are going to be compared to each other, but not lied to. It seems important to keep the participants apart for at least 6 months but only those in the same trial with the same treatment. The others could compare their progress.

In this speculation, ethically, the line would fall somewhere in the area of "who gets the treatment that has a better shot at succeeding"? One fair suggestion might be from a lottery draw of qualified participants. Would the lottery winners of the most coveted treatment delivery or dosage do better as a result of the higher expectations for these "winning" treatments?

Second guessing about an example [that's all I can do unless someone answers me], you could simultaneously offer the cere 120 sham surgery patients the treatment at a dosage above what was offered in phase II, and let them be one of several separate groups [open label] about which to collect data. Participants would not necessarily expect to be cured at this point, but would be helping as only humans can. This is what always happens anyway. Something like this is more honest going in.

Can animal research be limited to bare essentials for safety? They are not always reliable predictors. I 've never heard of a monkey dying from a dose of pd treatment that would be in the human range of delivery. Has anyone any info about this? Would DBS be the procedure that has caused the most damage and death to humans?

Here are my questions regarding the cere 120 trial, most of which can be applied to clinical trials in general.

Have sham surgery participants ever been given a pd treatment at trial's end?

Does their informed consent wording have a loophole that easily excludes sham surgery participants?

How much weight is given to the stress, anxiety,and depression that accompanies sham surgery knowing that the treatment is possibly going to work or has worked for some?

One could say that cere 120 isn't worth it for sham surgery participants. To make it so, don't they need to be given another open label trial with the changes made for phase III?

It sounds like what's been learned so far is that less advanced patients need to be used. That is what it is....and I believe it to be true. But why should it trump the sham surgery participants chances that it could work for them too? Neither has a known outcome at this time

I have the utmost respect for all of the people working on pd. But disagreement is healthy and the truth sets us free. The statement made in the webcast about the need for sham surgery "passes the mom test" does not pass the logic test from a patient perspective. It ignores time, which many of us do not have. The researchers may think this way, but at 20 years into my pd. it sounds a little patronizing, like a sales tactic. I have heard the statement before, without the mom test. I don't mean to offend anyone and sorry if I just did.

In summary,

it appears that cere 120 will continue to phase III. I am wondering how creatively it could be designed for speed and accuracy. multiple trials within one?

there is a group of us who probably will always want to find an alternative to sham surgery. but many patients accept it.

again, we are on the same team, and no one knows fully what patients can offer until we communicate and develop trust as a new paradigm.

Silence does nothing for anyone in this type of interaction- seeking attempt. Yet, many are silent, taking no risks.

Human beings have similarities, but at the core is something that can't be replicated [soul?] If you watched the MJFF webcast, emotional dysfunction was separated from executive dysfunction. These trials leave a trail of emotions to clean up and live with, as does taking the risk of posting to no response.

A friend of mine, who recently reconciled with her husband as I have, said when I asked what she did to help that happen and to adjust again, that "she looked within."
I have been doing that and this is true:

We are difficult.

So let's speed things along shall we?

thanks for reading and to all orgs for their webcasts.
paula

[paula_w]

Just remembered that sham surgery patients have received the treatment -because i have a friend in the original canadian fetal transplant trial - Lynda Mckenzie. We met in an obscure, underground ICQ chat room 10 years ago -the only ones that appeared. How could I forget this? She was being followed by a tv program [like Frontline or maybe it even was]...like a Canadian 60 Minutes.

She got the placebo and it took two years but she did get the treatment. She said she would do it all over again.

She has since had a DBS, and she visited last winter. SHe looks younger than me [we are close in age] and is doing better....for awhile she was very dyskinetic.

She is a very brave lady...quite exceptional.

paula

[Stitcher]

Paula, I do want to reply to post #53, but I have to go to bed. I have a meeting at 9am and I have never met these folks before and am walking into something that has been ongoing for a while and I need to be alert.

So, I will come back in the afternoon tomorrow and reply.

[pegleg]

You really thought out these questions about gene therapy, didn't you? They are quite good, I might add.

Having participated in a trial that required transplanting retinal cells into the brain, I;d like to comment on some things you brought up:

You asked:
Have sham surgery participants ever been given a pd treatment at trial's end?

The only case that I can think of is the fetal tissue trials (our friend Lynda from Canada was one who had sham surgery, then received the cells after not knowing if she did or did not get the "real thing." ) I wish she would come back to talk with us. Her online name was Mischef. It seems there was a year or so between sham surgery and getting the cells.

As many of you already know, the fetal cell trials were dropped because they could not control the reproducing or growth of the cells. The patients got too much of a good thing and suffered with horrible dyskinesaias. I believe Miischef has had DBS since then and is doing better.

You asked:
Does their informed consent wording have a loophole that easily excludes sham surgery participants?

Not exactly, but most say something like "IF the treatment is found to be safe and effective" those having sham surgery will be given the opportunity to have the real surgery. That's a might big IF in my opinion!

You asked:
How much weight is given to the stress, anxiety,and depression that accompanies sham surgery knowing that the treatment is possibly going to work or has worked for some?

I believe more attention should be given to this point you make, but Mischef's story puts a different twist to the emotional stress. I recall and even have the video made of Mischef's story of having the sham vs the real surgery. (It's on an old VHS tape. I'll try to drag it out and get it converted). I remember the video showing Mischef and her family waiting around the phone for the call after the results were made known. Her symptoms had worsened and if she had gotten the real cells, that would have meant that the fetal cells were NOT producing dopamine. It was a very emotional time for her and her family, and they were so relieved when she was told she had sham surgery. Then as I said before, she did get the real thing a year or so later.

There are other questions or comments you have made that I'd like to discuss, but it's almosto midnight and (yawn) I'll have to address them later.

Thanks for this thread.
Peg

[LindaH]

Lynda McKenzie very generously contributed her account of her experiences in the fetal cell transplant trial to a book i co-edited, "When Parkinson's Strikes Early. " You can read these sections from the book on Amazon.com. Search for the title. Then click on "Look Inside" and search for the word Lynda. Her story is mostly on pp. 178-84

She initially had the sham surgery, and although she felt some improvement at first, it only lasted about 4 months and could bbe a placebo effect. The difference is with some of the more recent studies, such as GDNF, some doctors said improvements that trial participants said lasted 3 and 4 years may also have been a placebo effect. Is this really possible? This question needs to be answered.
Lynda received the real treatment about 2 years later.
Lynda is a naturally upbeat, positive and optimistic person. She didn't believe the study was a "failure" because we learned so much from it. At the time she said she would do it all over again.

[pegleg]

Thanks, Linda. I knew I had read this somewhere other than just seeing the video. Wouldn't a study in attitude and length of placebo effect be interesting? I thik we need to go back to the Biofeedback and psychological counseling days. (I feel that if I did the study, however, it would be very biased with skewed results, because ATTITUDE IS EVERYTHING!)

Peg :)

Lynda McKenzie very generously contributed her account of her experiences in the fetal cell transplant trial to a book i co-edited, "When Parkinson's Strikes Early. " You can read these sections from the book on Amazon.com. Search for the title. Then click on "Look Inside" and search for the word Lynda. Her story is mostly on pp. 178-84

She initially had the sham surgery, and although she felt some improvement at first, it only lasted about 4 months and could bbe a placebo effect. The difference is with some of the more recent studies, such as GDNF, some doctors said improvements that trial participants said lasted 3 and 4 years may also have been a placebo effect. Is this really possible? This question needs to be answered.
Lynda received the real treatment about 2 years later.
Lynda is a naturally upbeat, positive and optimistic person. She didn't believe the study was a "failure" because we learned so much from it. At the time she said she would do it all over again.

[jeanb]

Does the sham surgery really make the trial blind? Did the patients who got the sham in the CERE trial have the exact physical reaction(s) (severe facial & eye swelling, etc) as those whose brains were invaded by the treatment?

If theír physical reactions were milder, then wouldn't the treating doctors & nurses see that and come to the obvious conclusion that they didn't get the real treatment?

Just wondering... how can we find out?

[Stitcher]

Jean, you have an excellent question. I would have to say NO to the swelling. But I don't know that any of the patients were told to expect facial swelling. I was not told to anticipate swelling of any degree, especially the amount of swelling I had.

I feel that if the participants in CERE had been told to expect swelling there that this would have pretty much unblinded the trial.

Because I lost those first 10 days and have never regained my memory of them, I only know how my face appeared the first day I have a memory of and that was day 11. And it was still swollen when I looked in the mirror that first day, but I was recognizable by Day 11.

I understand from family that my face was extremely swollen. Hence, just one more indication that I had the real "thing".

My first 30 days begs the question, how did that period of time effect me over the next 11 months post surgery? I still am not sure, but I have my thoughts on the topic.

[pegleg]

I had brain surgery and was not told to "expect" swelling (and I was in an open label study; i.e. I knew I was getting the real thing.) To say this would probably unblind the placebo group almost immediately. And for the most part I didn't have much swelling; I imagine the amount of swelling would be determined by how much trauma was inflicted to the brain.

There was a puffy kind of look on my eyelids (which several have said is indicative of brain surgery). It was like my eyelids became thin and fleshy and seemed to pile up on my lashes. Of course the doctors and nurses caring for these patients would recognize the post-op appearance of one who has had brain surgery, but they have been trained accordingly. Only the neurosurgeon would know.

I also know that each patient's response to any type of surgery varies greatly. For example, after my surgery (Spheramine) there was an overnight stay in ICU (Intensive Care Unit) built into the protocol. I recall awakening in the recovery room awaiting my transfer to ICU. However, I had this euphoric feeling (an almost "I'm cured!" feeling that lasted for about 2 weeks). I was very talkative and remember telling the male nurse in recovery every clean or semi-clean joke I knew (he was a cutie!). About a half hour later, I saw him on the telephone with his back to me, obviously trying to hide his conversation. He was talking with the neurosurgeon (I found out after he hung up). And this is what he said, "I CAN'T send her to ICU! She's sitting up telling jokes!" So I went straight to the regular room, where I stayed for 3 days.

I recall wondering why my movement disorder specialist didn't visit me (the research nurse did, but it was on my discharge day when swelling was very minimal). In retrospect it must have been because he would have recognized the swelling or "fleshy" eyelids and the study would have been unblinded.

But Jean, this means the bedside caregivers, and in this case POSSIBLY the research nurse, would recognize the after-effect of actual penetration of the brain's dura (in sham surgery, they drill the hole, but don't penetrate the dura). That is putting a lot of trust into those people, some even non-professionals. So there is a big chance someone might leak those receiving the real therapy, even unknowingly. Therefore, this is even more reason to add to taking a long look at the validity of using sham surgery.

Peg

[jeanb]

If the after-effect of actual penetration of the brain's dura (in sham surgery, they drill the hole, but don't penetrate the dura) is different from the after-effect of true invasive brain surgery, then how can researchers claim the study is blind?

This question must be pursued because in my opinion, if it turns out to be true, then it is a big strike against using sham surgery.

[Stitcher]

I too had brain surgery...in June 2007. I was not told that I would experience facial swelling.

My swelling was bad enough that even 10 days late is was rather significant. It is my understand from my family that I was pretty much unrecognizable immediately after the surgery.

I understand that this is an indication of invasion into the brain. My Principal Investigator had told me that he and the Trial Coordinator were not allowed to visit me until our first post-surgery trial evaluation. I did not ask at the time, but I can only assume that this is due to the telling factor of the facial swelling...that the brain had been invaded, hence the real surgery had taken place....not the sham surgery.

Or could the swelling be due to the frame that is placed on the head during brain surgery. Maybe a DBS patient can comment on this. I tried to search the Internet for the "post-surgical effect of stereotactic frame" and "brain surgery post-surgical facial swelling" and similar combination's and found nothing specific that spoke to any combination.

I do not have memory of my first 10 days post-surgery, none. So, I can speak to the recovery room as Peggy is able to do. I do know that my family was shocked, to say the least, at my appearance.

[olsen]

http://www.alzforum.org/new/detail.asp?id=2012#{68DBD971-5068-42CE-A192-DDE1CE32B3C8}

Within this news article is a discussion concerning Cere 120 trial results--cites researcher who feels delivery system at fault. Interesting/informative comments penned by Perry Cohen in comment section.

[paula_w]

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Submitted 12 February 2009


Don’t Jeopardize New Therapies With Sham Surgery Control—Placebo Responses May Be Part of Therapies

I was the patient representative on the FDA advisory panel that reviewed deep brain stimulation (DBS) in March of 2000, and later I participated in the Medicare National Coverage decision for DBS on behalf of the requester (not Medtronics but an individual person with Parkinson's). From these engagements, I recall this treatment was shown to be very effective (upwards of 85 percent have 50 percent improvement in motor symptoms). Such dramatic and lasting improvements would need to be expected to offer a treatment that makes it worthwhile to take the risk of brain surgery. After a delay of more than four years from the initial advisory group, DBS has been available to patients, as a near breakthrough option once first-line treatment fails. Indeed, it is the only major new therapy for PD in the 40 years since levodopa was discovered. Now the recent study published in JAMA continues to show efficacy and also shows that its adverse side effects for important functions like cognition are greater for DBS than with standard drug therapy. The DBS experience can be instructive for other surgical treatments for PD.


The question I want to raise regards the Ceregene 120 study, a gene therapy application of the nerve growth factor neurturin, NTN. The Phase 2 study "failed to meet primary endpoints" in comparison to a sham surgery placebo control. Similar to experiences with other surgically installed treatments, such as GDNF infusion pump and implantation of spheramine, a cell-based therapy using retinal dopaminergic cells, this latest placebo-controlled trial did not replicate the gains from the Phase 1 open-label study. The results of all of these studies are clouded from methodological issues such as differences in dosing between Phase 1 and Phase 2, dislodgement of pump connections, and differences in the use of other PD medications during the studies that may have affected the results. Even so, the fact remains that some study participants have experienced dramatic improvements lasting as long as six years and counting, and some have reduced their PD medications to near zero, being almost symptom-free after decades of increasing disability. A brain autopsy of one GDNF patient showed nerve growth in the side of the brain in which the treatment was administered during the trial. For all of these treatments, data point to improvements well beyond reasonable estimates of placebo effects.

Clearly placebo effects are very strong. Research on placebo response for a range of medical conditions including PD attributes these real physiological effects to expectations of benefit and conditioning established in the social context of administering a treatment. The greater the risk and notoriety of the intervention, and the more certain and authoritative the source, a greater placebo effect is produced. Maximum placebo effects, as would be expected, are found from brain surgery as well as from the safest form of sham brain surgery, where the brain is not penetrated but the patient goes through the same process including lengthy anesthesia. DBS patients report vast improvements in symptoms even before the stimulators are turned on. Clinical brain researchers (including more than 90 percent of the Parkinson's Study Group) agree that sham brain surgery is necessary to prove that improvements are attributable to the treatment beyond the placebo. On the other hand, an online survey of activist PD patients found that only 37 percent would participate in a sham surgery study. Closing this gap raises practical as well as ethical issues.

DBS was approved without sham surgery as a placebo control. So why aren't DBS's gains in motor scores attributed in part to a learned placebo response? Shouldn't the placebo effects that last multiple years be counted as part of the treatment, as they effectively are with DBS, and not written off as bias? The recent JAMA publication improved the evidence of efficacy for DBS by randomization to best medical treatment versus surgery. Why isn't random assignment to best medical practice a sufficient comparison for other surgical interventions?

Sham surgery is not a sugar pill; it is a powerful intervention, although you would probably be charged with fraud if you tried to sell it. Placebo studies on the experience of pain in fact demonstrate that the "bias" from patient hopes and expectations, a central element of all healing, is opposite of what has been assumed by science in experimental settings. That is, treatment effects are reduced and placebo effects are increased. That is so because random assignment dilutes positive effect of patients’ expectation that they will improve from the ongoing uncertainty about whether they are on the real thing, and conversely it elevates the placebo group’s expectation that they may be on the real thing. This biases the results toward type II errors (false negative), which are more important to patients with serious illness than are type I errors (false positive) that are the target of statistical models. The pain studies suggest that the placebo mechanism may be necessary to trigger the therapeutic effects of treatment. Elaborate deception to control this effect could be undermining its evaluation.

Sure, we need to control bias. But variability and bias can come from many sources, including, importantly the selection of participants and the variability of raters on subjective scales such as UPDRS. For example, are all study participants diagnosed correctly? And do they represent homogeneous types of patients? Depression medication trials, which also fail at high rates, have taught us that clearer distinction between treatment and placebo results from higher-quality central rating of subjective measurement scales. Multiple ratings of key measures reduce noise in data when averaged. Patients who have participated in PD clinical trials know that UPDRS "off" may describe different behavior on different days, and are not totally determined by the time since the last dose. Better understanding of these factors from the patient perspective is necessary to control this source of variability in the data.
Alternatively, where the sources of variability are unbiased, the problem can be fixed by increasing sample size to account for random fluctuations in the calculations of confidence of the result. This not only costs more, but it also may bump up against practical limitations including recruitment and FDA statisticians.

New Directions for the Twenty-first Century

As science progresses, we need to re-examine our assumptions about the standards for evidence in the assessment of safety and effectiveness. The gold standard of the randomized, prospective, double-blind placebo-controlled study cannot be applied as a one-size-fits-all to conditions on the cutting edge of medical science.


Medical miracles of the twentieth century mostly pertain to acute conditions, where linear assumptions of statistical models for hypothesis testing more closely approximate the relatively short-term interventions. As we deal with longer-term degenerative processes involving dynamic interaction and feedback to our conscious brain processes, assumptions from the experimental model become questionable. This is true even where all orthodoxies of statistics are followed and statistical significance is achieved.

Recent FDA law offers greater flexibility to align methods to the parameters of the specific case. Such alternative methods need to be qualified and used. Examples include Bayesian statistics for application to dose-finding tasks, or mathematical models of disease progression as historical controls. Crossover designs can detect differences in symptomatic benefits, and delayed start designs have shown promise to detect neuroprotection.

FDA law requires well-controlled randomized studies, not placebos. New policies put more emphasis on life cycle monitoring of treatments in real practice settings, and provide reimbursement coverage for access to new treatments while evidence of long-term safety and efficacy are established with greater certainty. Following patients more closely for a number of years to see the lasting effects can establish whether the treatment effects are purely placebo, at the same time that long-term safety is tracked.

Continuing failure of studies based on faulty assumptions about human behavior is not a viable option. A better understanding of placebo responses in the design of clinical trials points to new approaches in collaboration with patient advocates and communications to FDA. Perry D. Cohen directs the Parkinson Pipeline Project (http://www.pdpipeline.org/aboutus/community.htm).



reprinted with permission

paula



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[paula_w]

the icon is the result of dyskinesia - i feel very positive about this post...lol ...I like being thought of as a rosetta stone! We all are, and the interaction among the rosetta stones - the healthy being just temporarily healthy as Sheryl J. says - can produce a new language. It's time to gather. There is a funny story about the word gather. I will write about it soon. It's one of those confirmations that you are on a good track And it's funny.


Is it Ok to copy a blog post? let me know as i know you must if it is breaking copyright. read it first...lol

For the life of me i couldn't get rid of that bold above....sorry. ok here's a cheer from Faster Cures.
[I]Improving Clinical Trials: "Yes We Can" (http://fastercures.blogspot.com/2009/02/improving-clinical-trials-yes-we-can.html)


by Kristin Schneeman, Program Director, FasterCures (http://www.fastercures.org/index.cfm/AboutFasterCures/WhoWeAre/FasterCuresTeam/Kristin_Schneeman)

Probably one of the most persistent problems slowing medical research that we hear about at FasterCures is that the cost in time and dollars of clinical trials is crushing the discovery enterprise. Professionals from all corners of the clinical research enterprise express frustration with the complex web of problems and the long-term gridlock they perceive. They are weary of devoting time and energy to any effort – whether a one-time conference, an ongoing process, a consortium or alliance – that will revisit the “same old issues” surrounding clinical trials.


In the spirit of the New Year, we’d like to highlight some heartening efforts from a variety of quarters to stop griping and try to solve some of these thorny problems. They’re all very different, yet what links them is their optimism that change is possible.

The National Cancer Institute and the CEO Roundtable on Cancer are engaged in an ongoing effort to develop "model language (http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_100708/page2)" for use in the contract agreements that govern clinical trials. The model language covers seven areas in which negotiations regularly stall, including intellectual property, study data, indemnification, subject injury, confidentiality, publication rights, and biological samples.

Duke University is hosting an effort springing from FDA’s Critical Path effort, the Clinical Trials Transformation Initiative (http://www.fda.gov/oc/initiatives/criticalpath/clinicaltrials.html) (CTTI). CTTI is a public-private partnership that will include broad representation from government, industry, patient advocacy groups, professional societies, and academia. Its more than 50 members will work together to develop new standards and identify new methods and technologies that improve safety, boost the quality of information derived from clinical trials, and make the research process more efficient. This is not another exercise in analysis paralysis; it is meant to be a practical effort to generate data and test solutions.

And finally, the Dr. Susan Love Research Foundation (http://www.dslrf.org/index.asp)and the Avon Foundation (http://www.avoncompany.com/women/)have recently joined forces to launch the Army of Women Web site. This is a new and different way to engage people in clinical research – not a walk or a telethon, but an opportunity to directly contribute to research. Army of Women seeks to recruit one million healthy women of every age and ethnicity, including breast cancer survivors and women at high-risk for the disease, to partner with breast cancer researchers and directly participate in research; and to challenge the scientific community to expand its current focus to include breast cancer prevention research conducted on healthy women. Women can register to be notified (http://www.armyofwomen.org/) of opportunities to participate in research projects (by mailing in blood, saliva, even breast milk samples, filling out questionnaires, etc.).

Within each patient is a Rosetta Stone of information that could unlock the potential to cure disease. It’s nice to know not everyone has stopped trying to solve the puzzle.

[CTenaLouise]

we have more drugs on this earth than people,
and perhaps the flushing of 750 million pound per year by US hospitals may be the reason we are ill,
I will not argue this point -
ER meds are there to help a person stop bleeding to death -
the drug problem is bleeding the ill people to death,
you can not live on pills alone...

simplify your life
turn off our brains and sleep... we can not enjoy life if we do not rest.
learn to live simply
eat well
love people, love children,
perhaps a love study may have miraculas results
and we can do that for free...