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

Alan Whone*, Matthias Luz, Mihaela Boca, Max Woolley, Lucy Mooney, Sonali Dharia, Jack Broadfoot, David Cronin, Christian Schroers, Neil U. Barua, Lara Longpre, C. Lynn Barclay, Chris Boiko, Greg A. Johnson, H. Christian Fibiger, Rob Harrison, Owen Lewis, Gemma Pritchard, Mike Howell, Charlie IrvingDavid Johnson, Suk Kinch, Christopher Marshall, Andrew D. Lawrence, Stephan Blinder, Vesna Sossi, A. Jon Stoessl, Paul Skinner, Erich Mohr, Steven S. Gill

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

180 Citations (Scopus)
287 Downloads (Pure)


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 μg 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 (≥10 points) in the OFF state (P = 0.0008). 18 F-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; P < 0.0001). 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. 18 F-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.

Original languageEnglish
Pages (from-to)512-525
Number of pages14
Issue number3
Early online date26 Feb 2019
Publication statusPublished - 1 Mar 2019


  • convection-enhanced delivery
  • GDNF
  • glial cell line-derived neurotrophic factor
  • neurorestoration
  • Parkinson's disease


Dive into the research topics of 'Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease'. Together they form a unique fingerprint.

Cite this