Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease

Anthony E. Lang, Steven Gill, Nik K. Patel, Andres Lozano, John Nutt, Richard Penn, David J. Brooks, Gary Hotton, Elena Moro, Peter Heywood, Matthew Brodsky, Kim Burchiel, Patrick Kelly, Arif Dalvi, Burton Scott, Mark Stacy, Dennis Turner, V. G Frederich Wooten, William J. Elias, Edward R. LawsVijay Dhawan, A. Jon Stoessl, James Matcham, Robert J. Coffey, Michael Traub

Research output: Contribution to journalArticle

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Abstract

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 15μg/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 18F-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 18F-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). Interpretation: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

Original languageEnglish (US)
Pages (from-to)459-466
Number of pages8
JournalAnnals of Neurology
Volume59
Issue number3
DOIs
StatePublished - Mar 2006

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Glial Cell Line-Derived Neurotrophic Factor
Parkinson Disease
Randomized Controlled Trials
Dihydroxyphenylalanine
Placebos
Device Removal
Dopaminergic Neurons
Putamen
Dyskinesias
Mesencephalon
Neutralizing Antibodies
Catheters
Confidence Intervals
Equipment and Supplies
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

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Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. / Lang, Anthony E.; Gill, Steven; Patel, Nik K.; Lozano, Andres; Nutt, John; Penn, Richard; Brooks, David J.; Hotton, Gary; Moro, Elena; Heywood, Peter; Brodsky, Matthew; Burchiel, Kim; Kelly, Patrick; Dalvi, Arif; Scott, Burton; Stacy, Mark; Turner, Dennis; Wooten, V. G Frederich; Elias, William J.; Laws, Edward R.; Dhawan, Vijay; Stoessl, A. Jon; Matcham, James; Coffey, Robert J.; Traub, Michael.

In: Annals of Neurology, Vol. 59, No. 3, 03.2006, p. 459-466.

Research output: Contribution to journalArticle

Lang, AE, Gill, S, Patel, NK, Lozano, A, Nutt, J, Penn, R, Brooks, DJ, Hotton, G, Moro, E, Heywood, P, Brodsky, M, Burchiel, K, Kelly, P, Dalvi, A, Scott, B, Stacy, M, Turner, D, Wooten, VGF, Elias, WJ, Laws, ER, Dhawan, V, Stoessl, AJ, Matcham, J, Coffey, RJ & Traub, M 2006, 'Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease', Annals of Neurology, vol. 59, no. 3, pp. 459-466. https://doi.org/10.1002/ana.20737
Lang, Anthony E. ; Gill, Steven ; Patel, Nik K. ; Lozano, Andres ; Nutt, John ; Penn, Richard ; Brooks, David J. ; Hotton, Gary ; Moro, Elena ; Heywood, Peter ; Brodsky, Matthew ; Burchiel, Kim ; Kelly, Patrick ; Dalvi, Arif ; Scott, Burton ; Stacy, Mark ; Turner, Dennis ; Wooten, V. G Frederich ; Elias, William J. ; Laws, Edward R. ; Dhawan, Vijay ; Stoessl, A. Jon ; Matcham, James ; Coffey, Robert J. ; Traub, Michael. / Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. In: Annals of Neurology. 2006 ; Vol. 59, No. 3. pp. 459-466.
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T1 - Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease

AU - Lang, Anthony E.

AU - Gill, Steven

AU - Patel, Nik K.

AU - Lozano, Andres

AU - Nutt, John

AU - Penn, Richard

AU - Brooks, David J.

AU - Hotton, Gary

AU - Moro, Elena

AU - Heywood, Peter

AU - Brodsky, Matthew

AU - Burchiel, Kim

AU - Kelly, Patrick

AU - Dalvi, Arif

AU - Scott, Burton

AU - Stacy, Mark

AU - Turner, Dennis

AU - Wooten, V. G Frederich

AU - Elias, William J.

AU - Laws, Edward R.

AU - Dhawan, Vijay

AU - Stoessl, A. Jon

AU - Matcham, James

AU - Coffey, Robert J.

AU - Traub, Michael

PY - 2006/3

Y1 - 2006/3

N2 - 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 15μg/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 18F-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 18F-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). Interpretation: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

AB - 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 15μg/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 18F-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 18F-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). Interpretation: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

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