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Parkinson's Disease Clinical Trials: Square Pegs in Round Holes?

Poster presented  by the Parkinson Pipeline Project at the
2009 American Society for Experimental Neurotherapeutics (ASENT) Conference

Click here to read update on this poster

Authors: Perry D. Cohen, Wilson H. DeCamp, Linda Herman, Arnold M. Kuzmack, Stan Planton, Carolyn Stephenson, Peggy Willocks and Paula Wittekind
Parkinson Pipeline Project, Washington, DC


This poster examines three failed clinical trials for promising new Parkinson’s therapies. All have similar designs that require surgical intervention to deliver the treatment and utilize sham brain surgery as a placebo control. It relates common reasons for their failure and gives close scrutiny to evidence on the benefits vs. risks of placebo brain surgery.

Phase II of all three trials were multicenter, randomized, double blind, sham surgery controlled studies All three showed favorable results in the open label Phase I trials, but did not meet their endpoints in Phase II.

All three trials were conducted using the dopamine replacement theory as treatment by either viability of available dopamine (GDNF), production of dopamine from transplanted cells (Spheramine), or genetic alteration for the production of dopamine (CERE 120).

GDNF (Neurotrophic factor) – recombinant GDNf delivered by pump infusion method

Amgen sponsored two open label phase I safety trials of GDNF in 15 patients. The studies were initially for six months, with some patients treated for up to 3 1/2 years. Based on the clinical endpoint of reduction in the UPDRS motor "off" score, the efficacy ranged from 39 to 57%.

Randomized, double blind, placebo controlled, parallel group phase II trials were initiated in 34 patients. The clinical endpoint was the Change in UPDRS motor score in the practically defined off condition at 6 months.

The sponsor (Amgen, Inc.) terminated the phase II trials in September 2004. The rationale given was that, “Six months of treatment with GDNF delivered to the putamen failed to improve UPDRS scores compared to placebo." There was “evidence of alteration of brain function,” a likely reference to changes on neuroimaging, but improvement on UPDRS scores did not meet the primary endpoint of the trial. However, a participant from the Bristol (UK) study died of an unrelated cause, and, upon examination of his brain via autopsy, neural sprouting was noted (the first report of its kind).

Open label extension studies were begun to resolve differing trial results. But in Sept. 2004, Amgen sent letters to clinical investigators halting further clinical studies, due to safety concerns – development of lesions in the cerebellum of 4 test monkeys and "anti r metHuGDNF neutralizing antibodies found in two of the study participants to date.”

Spheramine [Retinal Pigmented Epithelial (RPE) Cells]

In 2000, Titan Pharmaceuticals in a Phase I open label trial consisting of six participants with advanced disease (3 3.5 or greater on the Hoehn & Yahr scale) received unilateral treatment (for their “worst” side) transplanting RPE cells (without the use of immunosuppression), using a donor eye from a cadaver. (One eye can be used to treat hundreds or patients.) At 12 months, an average improvement of 48% in the UPDRS M (off) outcome measure was realized, along with improvements seen in other measures of motor function and quality of life. One participant dropped out because of a later diagnosis of Parkinson’s Plus. Participants continued to be followed through 48 months, maintaining a 44% average improvement and continue to be followed. It was reported, "The data also demonstrate a very good preliminary safety profile for Spheramine. There has been no evidence to date of any significant side effects in any of the patients . . . a reduction in dyskinesias for most patients and . . . no ‘off state’ dyskinesias . . . observed."  (Titan handout, April 2002)

In 2003, a phase II study was initiated with a randomized, double blind, placebo controlled (sham surgery) trial of 71 patients (78 were actually recruited) receiving treatment bilaterally, and received fast track approval by the FDA. Titan was joined with the U.S. Berlex sponsor, which is also Schering AG (Germany), and was later acquired by Bayer (Bayer Schering/Titan). In July 2008, Titan announced that Phase II did not meet its primary or secondary endpoints and Bayer Schering AG withdrew as a sponsor. The sponsors (Bayer Schering / Titan) announced that they had discontinued development of Spheramine in July 2008.

Titan stated that its "potential cell based treatment for Parkinson's Disease failed to meet its primary and secondary endpoints in a Phase IIb study, and likely won't be continued by partner Bayer Schering Pharma... Initial analysis of results from the 71 patient study of Spheramine designed to test the safety, tolerability and efficacy of the treatment found that it had no significant differences from sham surgery arms after 12 months of follow up." (Company press release dated 7/2/08)

CERE 120 (neurturin) – Gene therapy

CERE 120, a gene therapy product in development for the treatment of Parkinson’s disease, was administered to the putamen with adeno associated virus carrying the gene for neurturin, a growth factor related to GDNF and shown in experimental models to protect dopaminergic neurons from degeneration. Six patients received a low dose and six a high dose (1.4 x 10^11 vs. 5.7 vector genomes). Neurturin was well tolerated and appeared to reduce symptoms by approximately 40% (p<0.001), as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) motor “off” score, in an open label Phase 1 study in 12 patients with advanced disease. (Company press release dated 10/10/2006)

The sponsor (Ceregene) announced the phase II trial failure in Nov. 2008. Analysis of the phase II trial data 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."

A company spokesman stated "...we are stunned by the results of this trial and will continue to analyze the data in order to gain greater insight into the factors that may have contributed to this negative outcome, not only to build upon this insight for our Parkinson’s program, but also to help assure continued successful development of our product candidates for other diseases.” (Company press release dated 11/28/08)

In an in depth interview with the Michael J. Fox Foundation, Raymond T. Bartus, PhD, executive vice president and chief scientific officer of Ceregene, reported that they are attempting to redesign the Cere 120 trial to expand the delivery target area and increase dosage. Two trial participants died from unrelated causes, providing the opportunity to view the progress of the neurturin through autopsies. Discoveries were made that may enable research to continue in the near future.(http://www.michaeljfox.org/research_viewpoints_newsInContext_article.cfm?ID=11)


Based on the design of the three studies described above, we suggest two possible reasons for the unanticipated failures in phase II.

• Selection bias resulted in different types of PD patients being enrolled.

Examples of such bias are:

  • Be valued for the knowledge and skills we bring to the table.

    Examples of such bias are:

    • tremor dominant vs. rigidity dominant symptoms

    • responders vs. non responders to standard therapy

    • responders vs. non responders to placebo

    • optimized on medications vs. non optimized

    • Sham brain surgery as placebo may be so powerful that it overwhelms treatment effects for a time (maybe up to 2 or more years, but usually not more than 1 year).

    Such an effect could force type 2 errors when the interim study results are analyzed after a short time.

    Dr. Stanley Fahn of the Columbia University Medical Center has stated:

    “A negative trial result does not necessarily mean that the compound in question is of no therapeutic value – especially when that compound has demonstrated promise in animal studies and earlier, smaller, human trials. There could have been a problem with the study design or lack of optimum dosage of the experimental compound. A variation in the study design (e.g., different duration, different dosage, different patient selection criteria, a change in method of drug delivery) may yield different results, and should be explored before any particular approach is abandoned."

    Other Therapies terminated in late phases


    Sponsor Clinical Endpoint FDA Action:
    NA = not approvable
    Company Action



    disability requiring dopaminergic therapy


    phase 2/3 trial discontinued, 5/2005

    tesofensine (NS 2330)




    phase 3 canceled, 1/2006

    GPI 1485


    brain uptake of [123I}Beta‑CIT


    phase 3 terminated, 3/2006



    reduction in "off" time


    phase 3 trials terminated, 10/2007 and 4/2008





    phase 3 terminated, 6/2006



    alternate tapping of keys

    NA, 3/2006 & 1/2008

    terminated development, 4/2008



    reduction in "off" time

    NA 2/2008

    suspended phase 3 in North America, 6/2008

    Our analysis of the three recent failed trials points to questions that need to be addressed in order to justify what many consider to be unjustified risk to ask patients to take, given expectations that even if they do not benefit personally science will advance.

    1. What adjustments in the design of statistical controls are necessary to account for the impact of the context of an experimental protocol that alters expectations of participants by randomization into treatment and control groups?

    2. What scientific criteria are used to determine efficacy or the lack of efficacy of a treatment?

    3. What assumptions are made about the interaction effects between a treatment response and a placebo response?

    4. What factors should be considered when selecting samples from a heterogeneous populations as the evidence grows that some endpoints may be achievable only for patients (responders) with certain genetic variants or clinical sub types of the disease or are influenced by other factors including the method of delivery?

    This presentation adds urgency to the need for these discussions, because trials are failing, and promising therapies are being shelved in what has been called the “tyranny of the type 2 error". (M. Hutchinson, S. Gurney and R. Newson. GDNF in Parkinson disease: An object lesson in the tyranny of type II. Journal of Neuroscience Methods. 163, 2, July 2007, 190 92)


    The above failed phase II studies were for therapies that were known to work for some people over extended periods. The members of the Parkinson Pipeline Project have analyzed possible explanations for this poor record of accomplishment. We have come up with hypotheses that fit the pattern of results seen in these studies. Our goal is to present a clear and convincing argument that these are plausible hypotheses that merit further study and such a study is a very high priority.

    There is considerable research on pain, depression and the mechanism of the placebo effect. These studies suggest that an experimental protocol that views placebo surgery as a "bias" to be minimized may in fact undermine the validity of the study. Key questions are raised that researchers and regulators need to answer in order to prevent type 2 (false negative) errors. Based on the research literature and the experience from DBS (a surgical intervention and the most important new therapy for PD in the 40 years since Levodopa was introduced 40 years ago), alternative design features and methods are needed.

    Given the number of new, promising, surgically delivered, treatments in the PD pipeline, policy discussions among FDA officials, scientists and knowledgeable patient advocates (including patients that volunteer for experimental treatments) on both the scientific and ethical issues about what constitutes adequate control in the study design must be a high priority to provide guidance to sponsors. The topic needs to be addressed fully before other promising therapies are shelved based on faulty assumptions about human behavior and the response to medicines.

    The authors wish to acknowledge the support of the Parkinson's Disease Foundation to the work of the Parkinson Pipeline Project.


Copyright© 2012 Pipeline Project

All rights reserved. Revised: 01/26/12.