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Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease

Whone, Alan, Luz, Matthias, Boca, Mihaela, Woolley, Max, Mooney, Lucy, Dharia, Sonali, Broadfoot, Jack, Cronin, David, Schroers, Christian, Barua, Neil U., Longpre, Lara, Barclay, C. Lynn, Boiko, Chris, Johnson, Greg A., Fibiger, H. Christian, Harrison, Rob, Lewis, Owen, Pritchard, Gemma, Howell, Mike, Irving, Charlie, Johnson, David, Kinch, Suk, Marshall, Christopher ORCID:, Lawrence, Andrew D. ORCID:, Blinder, Stephan, Sossi, Vesna, Stoessl, A. Jon, Skinner, Paul, Mohr, Erich and Gill, Steven S. 2019. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease. Brain 142 (3) , pp. 512-525. 10.1093/brain/awz023

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We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson’s disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35–75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2–3 and Unified Parkinson’s Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 mg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 17.6% in the active group and 11.8 15.8% in the placebo group (least squares mean difference: 4.9%, 95% CI: 16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (510 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P50.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Cardiff University Brain Research Imaging Centre (CUBRIC)
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License
Publisher: Oxford University Press
ISSN: 0006-8950
Date of First Compliant Deposit: 18 March 2019
Date of Acceptance: 12 December 2018
Last Modified: 06 May 2023 06:50

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