Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

J. G. Nutt, K. J. Burchiel, C. L. Comella, J. Jankovic, A. E. Lang, E. R. Laws, A. M. Lozano, R. D. Penn, R. K. Simpson, M. Stacy, G. F. Wooten, L. Johnston, J. Lopez, M. Harrigan, F. F. Marciano, J. H. Carter, C. Stone, J. Trugman, E. Rost-Ruffner, C. O'Brien & 21 others J. H. McVicker, T. L. Davis, D. Charles, G. Allen, W. Weiner, H. J. Landy, J. Bronstein, W. Koller, R. Pahwa, S. Wilkinson, E. R. Siemers, Joanne Wojcieszek, T. Witt, P. J. Tuite, B. J. Ebbitt, R. Maxwell, M. Cravets, D. Hilt, M. Klein, D. R. Lee, B. Schultz

Research output: Contribution to journalArticle

588 Citations (Scopus)

Abstract

Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off' total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues - putamen and substantia nigra.

Original languageEnglish
Pages (from-to)69-73
Number of pages5
JournalNeurology
Volume60
Issue number1
StatePublished - Jan 14 2003
Externally publishedYes

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Glial Cell Line-Derived Neurotrophic Factor
Placebos
Parkinson Disease
Vascular Access Devices
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Injections
Hyponatremia
Paresthesia
Oxidopamine
Dopaminergic Neurons
Putamen
Parkinsonian Disorders
Anorexia
Substantia Nigra
Nausea
Vomiting
Haplorhini
Weight Loss

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Nutt, J. G., Burchiel, K. J., Comella, C. L., Jankovic, J., Lang, A. E., Laws, E. R., ... Schultz, B. (2003). Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology, 60(1), 69-73.

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. / Nutt, J. G.; Burchiel, K. J.; Comella, C. L.; Jankovic, J.; Lang, A. E.; Laws, E. R.; Lozano, A. M.; Penn, R. D.; Simpson, R. K.; Stacy, M.; Wooten, G. F.; Johnston, L.; Lopez, J.; Harrigan, M.; Marciano, F. F.; Carter, J. H.; Stone, C.; Trugman, J.; Rost-Ruffner, E.; O'Brien, C.; McVicker, J. H.; Davis, T. L.; Charles, D.; Allen, G.; Weiner, W.; Landy, H. J.; Bronstein, J.; Koller, W.; Pahwa, R.; Wilkinson, S.; Siemers, E. R.; Wojcieszek, Joanne; Witt, T.; Tuite, P. J.; Ebbitt, B. J.; Maxwell, R.; Cravets, M.; Hilt, D.; Klein, M.; Lee, D. R.; Schultz, B.

In: Neurology, Vol. 60, No. 1, 14.01.2003, p. 69-73.

Research output: Contribution to journalArticle

Nutt, JG, Burchiel, KJ, Comella, CL, Jankovic, J, Lang, AE, Laws, ER, Lozano, AM, Penn, RD, Simpson, RK, Stacy, M, Wooten, GF, Johnston, L, Lopez, J, Harrigan, M, Marciano, FF, Carter, JH, Stone, C, Trugman, J, Rost-Ruffner, E, O'Brien, C, McVicker, JH, Davis, TL, Charles, D, Allen, G, Weiner, W, Landy, HJ, Bronstein, J, Koller, W, Pahwa, R, Wilkinson, S, Siemers, ER, Wojcieszek, J, Witt, T, Tuite, PJ, Ebbitt, BJ, Maxwell, R, Cravets, M, Hilt, D, Klein, M, Lee, DR & Schultz, B 2003, 'Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD', Neurology, vol. 60, no. 1, pp. 69-73.
Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology. 2003 Jan 14;60(1):69-73.
Nutt, J. G. ; Burchiel, K. J. ; Comella, C. L. ; Jankovic, J. ; Lang, A. E. ; Laws, E. R. ; Lozano, A. M. ; Penn, R. D. ; Simpson, R. K. ; Stacy, M. ; Wooten, G. F. ; Johnston, L. ; Lopez, J. ; Harrigan, M. ; Marciano, F. F. ; Carter, J. H. ; Stone, C. ; Trugman, J. ; Rost-Ruffner, E. ; O'Brien, C. ; McVicker, J. H. ; Davis, T. L. ; Charles, D. ; Allen, G. ; Weiner, W. ; Landy, H. J. ; Bronstein, J. ; Koller, W. ; Pahwa, R. ; Wilkinson, S. ; Siemers, E. R. ; Wojcieszek, Joanne ; Witt, T. ; Tuite, P. J. ; Ebbitt, B. J. ; Maxwell, R. ; Cravets, M. ; Hilt, D. ; Klein, M. ; Lee, D. R. ; Schultz, B. / Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. In: Neurology. 2003 ; Vol. 60, No. 1. pp. 69-73.
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abstract = "Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. {"}On{"} and {"}off' total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues - putamen and substantia nigra.",
author = "Nutt, {J. G.} and Burchiel, {K. J.} and Comella, {C. L.} and J. Jankovic and Lang, {A. E.} and Laws, {E. R.} and Lozano, {A. M.} and Penn, {R. D.} and Simpson, {R. K.} and M. Stacy and Wooten, {G. F.} and L. Johnston and J. Lopez and M. Harrigan and Marciano, {F. F.} and Carter, {J. H.} and C. Stone and J. Trugman and E. Rost-Ruffner and C. O'Brien and McVicker, {J. H.} and Davis, {T. L.} and D. Charles and G. Allen and W. Weiner and Landy, {H. J.} and J. Bronstein and W. Koller and R. Pahwa and S. Wilkinson and Siemers, {E. R.} and Joanne Wojcieszek and T. Witt and Tuite, {P. J.} and Ebbitt, {B. J.} and R. Maxwell and M. Cravets and D. Hilt and M. Klein and Lee, {D. R.} and B. Schultz",
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TY - JOUR

T1 - Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

AU - Nutt, J. G.

AU - Burchiel, K. J.

AU - Comella, C. L.

AU - Jankovic, J.

AU - Lang, A. E.

AU - Laws, E. R.

AU - Lozano, A. M.

AU - Penn, R. D.

AU - Simpson, R. K.

AU - Stacy, M.

AU - Wooten, G. F.

AU - Johnston, L.

AU - Lopez, J.

AU - Harrigan, M.

AU - Marciano, F. F.

AU - Carter, J. H.

AU - Stone, C.

AU - Trugman, J.

AU - Rost-Ruffner, E.

AU - O'Brien, C.

AU - McVicker, J. H.

AU - Davis, T. L.

AU - Charles, D.

AU - Allen, G.

AU - Weiner, W.

AU - Landy, H. J.

AU - Bronstein, J.

AU - Koller, W.

AU - Pahwa, R.

AU - Wilkinson, S.

AU - Siemers, E. R.

AU - Wojcieszek, Joanne

AU - Witt, T.

AU - Tuite, P. J.

AU - Ebbitt, B. J.

AU - Maxwell, R.

AU - Cravets, M.

AU - Hilt, D.

AU - Klein, M.

AU - Lee, D. R.

AU - Schultz, B.

PY - 2003/1/14

Y1 - 2003/1/14

N2 - Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off' total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues - putamen and substantia nigra.

AB - Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off' total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues - putamen and substantia nigra.

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