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Link to original content: https://pubmed.ncbi.nlm.nih.gov/30808022/
Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease - PubMed Skip to main page content
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Randomized Controlled Trial
. 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

Alan Whone  1   2 , Matthias Luz  3 , Mihaela Boca  2 , Max Woolley  4 , Lucy Mooney  2 , Sonali Dharia  2 , Jack Broadfoot  2 , David Cronin  2 , Christian Schroers  2 , Neil U Barua  2 , Lara Longpre  3 , C Lynn Barclay  3 , Chris Boiko  3 , Greg A Johnson  3 , H Christian Fibiger  3 , Rob Harrison  4 , Owen Lewis  4 , Gemma Pritchard  4 , Mike Howell  4 , Charlie Irving  4 , David Johnson  4 , Suk Kinch  4 , Christopher Marshall  5 , Andrew D Lawrence  6 , Stephan Blinder  7 , Vesna Sossi  7 , A Jon Stoessl  8 , Paul Skinner  4 , Erich Mohr  3 , Steven S Gill  2   4
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Randomized Controlled Trial

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

Alan Whone et al. Brain. .

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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Figures

Figure 1
Figure 1
Method of drug administration. (A) Drug delivery system used in the study. A manikin view of the delivery system is shown. Externally, when infusions are delivered, a titanium application set is attached to a skull-mounted port. The application set houses four independent external lines that feed back to four independent B. Braun pumps (not shown) for the administration of GDNF or placebo. Internally, from the skull mounted port, run four independent catheters. (B) The skull-mounted port is the only external component when the patient is not receiving an infusion. (C) Gadolinium test infusion. An axial MRI section at the level of the striatum is shown. Two of the four catheters (dorsal two catheters) can be seen entering either side of the brain posteriorly to penetrate the putamen. T1 imaging has been acquired post a test infusion of 2 mM gadolinium down the catheters and into each putamen. Gadolinium can be seen distributed through both putamen from the rostral to caudal extent. (D) A single patient during infusion. (E) Three patients receiving their monthly intraputamenal infusions from B. Braun pumps via their skull-mounted ports, in a standard day-case facility, observed by an accompanying nurse.
Figure 2
Figure 2
OFF state UPDRS motor score. (A) OFF state UPDRS motor score: percentage change over time. Note that data points represent means, and error bars represent standard errors. One GDNF patient had a conus injury due to a car accident and was included in the motor score without items 22, 27, 28, 29, and 30. The P-value is from a MMRM for the percentage change from baseline to Week 40 between treatment groups. (B) Frequency distribution of change from baseline to Week 40 in OFF state UPDRS motor score (intention-to-treat overall population = primary stage and pilot stage patients, n = 41).
Figure 3
Figure 3
Representative 18F-DOPA images from two patients, shown at baseline and end of double blind study. Top: Images are from a patient who was receiving placebo infusions every 4 weeks; 10 placebo infusions in total. Bottom: Images are from a patient who was receiving GDNF infusions every 4 weeks; 10 GDNF infusions in total.
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