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Brain. 2019 Mar 1;142(3):512-525. doi: 10.1093/brain/awz023.

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

Author information

Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK.
MedGenesis Therapeutix Inc., Victoria, BC, Canada.
Renishaw plc, New Mills, Wotton-under-Edge, Gloucestershire, UK.
The Wales Research and Diagnostic Positron Emission Tomography Imaging Centre (PETIC), Cardiff University, Cardiff, UK.
School of Psychology, Cardiff University, Cardiff, UK.
Department of Physics and Astronomy, The University of British Columbia, Vancouver, BC, Canada.
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.


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). 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; 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. 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.


GDNF; Parkinson’s disease; convection-enhanced delivery; glial cell line-derived neurotrophic factor; neurorestoration

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