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

Alan Whone,Lucy Mooney,Stephan Blinder,Gemma Pritchard,Vesna Sossi,Matthias Luz,Mike Howell,Jack Broadfoot,Paul Skinner,Charlie Irving,Sonali Dharia,Lara Longpre,Suk Kinch,Christian Schroers,Christopher Marshall,Rob Harrison,Max Woolley,Erich Mohr,David Cronin,Chris Boiko,Neil Barua ,A Jon Stoessl ,Andrew David Lawrence ,Greg A Johnson ,Owen T Lewis ,Catherine Barclay ,M Boca ,Hans C Fibiger ,David E Johnson ,Steven Gill

doi:10.1093/brain/awz023

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.

Highlights

Parkinson’s disease is the second most common neurodegenerative disorder (de Lau and Breteler, 2006)
Mean putamenal gadolinium-evidenced coverage on MRI showed only small differences between hemispheres, treatment groups and time points. Between all of these variables, it ranged from 67.1 Æ 15.3% to 78.5 Æ 14.2% for the putamenal volume of interest and from 47.8 Æ 13.5% to 55.0 Æ 17.1% for total putamen
Misalignment of the application set connector to the skull-mounted port was thought to account for early termination of four infusions in each group

Summary

Introduction

Parkinson’s disease is the second most common neurodegenerative disorder (de Lau and Breteler, 2006). Patients accrue both motor and cognitive disability and develop complications of dopaminergic therapies (Rascol et al, 2011). In patients with Parkinson’s disease, intracerebroventricular administration of GDNF did not show clinical benefit (Kordower et al, 1999; Nutt et al, 2003). In two open-label studies using continuous intraputamenal infusion, GDNF substantially improved motor function at 6 and 12 months (Gill et al, 2003; Slevin et al, 2005), associated with a focal increase in 18F-DOPA uptake at the site of infusion in posterior putamen (Gill et al, 2003). Single-case reports suggested dopaminergic sprouting (Love et al, 2005) and clinical benefit years beyond end of treatment (Patel et al, 2013). The favourable clinical outcome, could not be replicated in a randomized, placebo-controlled study using a similar infusion scheme over 6 months (Lang et al, 2006)

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Conclusion