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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

1
Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
2
Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK.
3
MedGenesis Therapeutix Inc., Victoria, BC, Canada.
4
Renishaw plc, New Mills, Wotton-under-Edge, Gloucestershire, UK.
5
The Wales Research and Diagnostic Positron Emission Tomography Imaging Centre (PETIC), Cardiff University, Cardiff, UK.
6
School of Psychology, Cardiff University, Cardiff, UK.
7
Department of Physics and Astronomy, The University of British Columbia, Vancouver, BC, Canada.
8
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.

Abstract

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.

KEYWORDS:

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

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