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Parkinson's Clinical Trial Failure Detailed Libraries Medical News Keywords PARKINSON DISEASE GDNF GROWTH FACTOR CLINCAL TRIAL Contact Information: Available for logged-in reporters only Description: Details of a failed clinical trial of GDNF for Parkinson's disease are released, along with the announcement that the second phase of the trial has been halted due to safety concerns. Released: Tue 28-Sep-2004, 10:00 ET Embargo expired: Tue 05-Oct-2004, 11:30 ET Newswise — Earlier this year, it was announced that a double-blind clinical trial of glial-derived neurotrophic factor (GDNF), infused directly into the brain, had failed to produce significant clinical improvement in patients with Parkinson's disease. The specific data from that trial have now been reported on October 5, 2004, at the 129th annual meeting of the American Neurological Association in Toronto, along with the announcement that safety concerns have halted the open-label segment of the trial, which began when the double-blind segment ended. "The most important finding was a lack of significant difference in the primary outcome variable -- control of Parkinson's symptoms -- between patients receiving the active treatment compared to those who received placebo," said Anthony E. Lang, MD, of Toronto Western Hospital, who presented the data. Some patients in the GDNF group did show considerable clinical improvement, but Lang pointed out that this was also true of some patients in the placebo group. Growth factors like GDNF are critical to the maturation and survival of nerve cells. Based on promising results in animal models, scientists theorized that GDNF could protect Parkinson's patients from the death of nerve cells that use the neurotransmitter dopamine to help direct movement. Last year, a synthetic version of GDNF made by the pharmaceutical company Amgen appeared to have fulfilled that promise. A preliminary trial with patients in Bristol, England, found improvement in movement symptoms and reported minimal side effects. However, the English trial was open-label, meaning that patients knew they were receiving a trial drug. To avoid a placebo effect, drugs must ultimately be tested in a double-blind, controlled trial where some patients receive a placebo, and neither patients nor staff know which subjects are receiving the study drug until the trial is over. The current Amgen-sponsored trial of 34 patients with Parkinson's disease began with a double-blind, placebo controlled phase that lasted six months. Lang and colleagues now report that GDNF did not provide significant clinical benefits relative to placebo, as judged by a tests of movement during the "off" period, when Parkinson's disease symptoms were not adequately controlled. Additional assessments both on and off medications also failed to demonstrate significant clinical changes, although there were modest but significant improvements in a PET scan index of dopamine nerve cell function at the site of the GDNF infusion into the brain. "There were some differences in the method of infusion, primarily with respect to the catheter, and the dosage -- the Bristol patients received slightly higher doses -- between the two studies. However, it is unclear whether these differences could account for the negative outcome of this trial," said Lang. Lang also noted that additional problems for GDNF in Parkinson's have appeared on the horizon. "Subsequent to the completion of the double-blind component of the trial, new safety data has become available from toxicological studies in a small number of monkeys and immunological studies from patients who were participating in this trial. The trial has now been halted pending further analysis of this information," said Lang. [abstract] WIP Platform #1 Multicenter, double-blind, randomized, placebo-controlled, Phase 1/2 trial (RCT) of bilateral intraputamenal (IPu) infusion of glial derived neurotrophic factor (GDNF) in levodopa-responsive Parkinson's disease (PD): preliminary results. AE Lang;1 S Gill;2 D Brooks;3 MA Brodsky;4 K Burchiel;4 RJ Coffey;5 A Dalvi;6 V Dhawan;7 WJ Elias;8 P Heywood;1 G Hotton;3 M Hutchinson;9 P Kelly;9 ER Laws;10 A Lozano;11 J Matcham;12 E Moro;1 JG Nutt;4 NK Patel;2 R Penn;6 B Scott;13 M Stacy;14 AJ Stoessl;15 M Traub;16 D Turner;14 GF Wooten10 1Toronto Western Hospital, Toronto, Canada; 2Frenchay Hospital; Bristol, UK; 3Imperial College, Hammersmith Hospital, London, UK; 4Oregon Health & Science University, Parkinson Center of Oregon, Portland, OR; 5Medtronic Inc., Minneapolis, MN; 6University of Chicago, Chicago, IL; 7North Shore Long Island Jewish Research Institute, Long Island, NY; 8University of Virginia Health System, Charlottesville, VA; 9New York University Medical Center, NY, NY; 10University of Virginia, Charlottesville, VA; 11Toronto Western Research Institute, Toronto, Canada; 12Amgen Ltd., Cambridge, UK; 13Duke Movement Disorders Clinic, Durham, NC; 14Duke University, Durham, NC; 15University of British Columbia, Vancouver, Canada; 16Amgen Inc., Thousand Oaks, CA. An open-label trial of IPu infusion of GDNF in 5 PD subjects for 6 months improved the off-motor UPDRS score by 32%. We sought to confirm these findings in a RCT. Thirty-four PD subjects were randomized 1:1 to receive bilateral continuous IPu infusion of placebo or GDNF 15 ?g/putamen/day. At 6 months, the % change (mean [SE]) in the UPDRS motor score in the practically-defined off-period was no different (GDNF: -10.01 [6.07]; placebo: -4.52 [6.07]). Secondary endpoints were no different between the groups. A 32% treatment difference favoring GDNF in the 18F-dopa influx constant in the posterior putamen on PET (P=.0061) was observed. Clinically significant, severe, device-related events included the need to surgically reposition intraparenchymal catheters in 2 subjects, and explant the pumps and pump catheters due to infection in another. GDNF was relatively well-tolerated; paresthesia, headache, and upper respiratory tract infection were more common on GDNF. Methodological issues may in part account for the contrasting results in this RCT versus the smaller open-label study, eg, a lower total dose administered and a different method of intraparenchymal infusion. These and other potential confounding factors, including important placebo responses, need to be considered in planning further studies of this therapy. SOURCE: American Neurological Association (ANA) http://www.newswise.com/p/articles/view/507289/ * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn