Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.
OBJECTIVE
Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).


METHODS
Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake.


RESULTS
At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension).


CONCLUSIONS
Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.
Lang
Anthony E
AE
Toronto Western Hospital, University of Toronto, Ontario, Canada. lang@uhnres.utoronto.ca
Gill
Steven
S
Patel
Nik K
NK
Lozano
Andres
A
Nutt
John G
JG
Penn
Richard
R
Brooks
David J
DJ
Hotton
Gary
G
Moro
Elena
E
Heywood
Peter
P
Brodsky
Matthew A
MA
Burchiel
Kim
K
Kelly
Patrick
P
Dalvi
Arif
A
Scott
Burton
B
Stacy
Mark
M
Turner
Dennis
D
Wooten
V G Frederich
VG
Elias
William J
WJ
Laws
Edward R
ER
Dhawan
Vijay
V
Stoessl
A Jon
AJ
Matcham
James
J
Coffey
Robert J
RJ
Traub
Michael
M
D000328:Adult; D000704:Analysis of Variance; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016503:Drug Delivery Systems; D004341:Drug Evaluation; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011699:Putamen / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
D051100:Glial Cell Line-Derived Neurotrophic Factor; D011994:Recombinant Proteins; D004295:Dihydroxyphenylalanine