Background: In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson's disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. Methods: We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinson's disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4×1011 vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson's disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. Results: Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0·31 [SE 2·63], 95% CI -5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. Interpretation: Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. Funding: Ceregene and Michael J Fox Foundation for Parkinson's Research.
Bibliographical noteFunding Information:
All authors listed as study investigators were reimbursed for budgeted expenses related to this study by their respective institution, which had negotiated a budget with Ceregene; the institution (not the investigator) was paid directly. No author was paid to write this paper. WJM is a study investigator and a paid consultant and lecturer for Medtronic. RTB and JS are employees of Ceregene and have been granted stock options. CSD received fees for statistical consultation and for some of the analyses for the study and is a paid consultant for Ceregene. AL is a paid member of Ceregene's scientific advisory board and owns stock options. NB, RW, and RA are study investigators and paid consultants to Ceregene after the database was locked. JV is a study investigator; a paid consultant to Medtronic, Boston Scientific, St Jude Medical, and Cleveland Medical; and a lecturer for University of Alabama Lecture Courses. MSta is a study investigator; is a paid consultant to Biogen, Osmotica, General Electric, Neurologix, and Synosia; has received grants from IMPAX, Neuraltus, Novartis, Schering-Plough, and the Parkinson's Study Group; and is a paid lecturer for Allergan, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva Pharmaceuticals. DT, LV, RB, BG, GB, and PAS are study investigators. JJ is a study investigator; is a scientific board member of the Michael J Fox Foundation for Parkinson's Research and The Neurotoxin Institute; is a paid consultant for Allergan, Chelsea Therapeutics, EMD-Serono, Lundbeck, Merz Pharmaceuticals, and Teva Pharmaceuticals; is a paid lecturer for the American Academy of Neurology; and has received royalties from Elsevier, Lippincott Williams and Wilkins, and UpTODate. RS is a study investigator and a board member, paid consultant, and lecturer for Medtronic and has received grants from St Jude Medical. MT is a study investigator; is a paid consultant for St Jude Medical and Medtronic; is a paid lecturer for Medtronic, Allergan, GlaxoSmithKline, Boehringer Ingelheim, and Novartis; and has received grants from Medtronic, St Jude Medical, Abbott, Allergan, and Teva Pharmaceuticals. MSte is a study investigator; a paid consultant for Teva Pharmaceuticals, Merck-Schering-Plough, Novartis, Adamas, and Ipsen Group; a paid lecturer for Novartis and Medtronic; and an officer for the Movement Disorder Society. PSL is a study investigator, is a paid consultant to Ceregene after the database was locked, and has received grants from Genzyme. JLO is a study investigator and has received grants from Medtronic and Allergan and lecture fees from Allergan. JN is a study investigator and paid consultant for Xenoport, Impax Laboratories, Neurogen, Synosia, Neuroderm, Merck, Lilly and Medtronics, Elan Pharmaceuticals, Addex Pharma, and Lundbeck; has received grants from Schering-Plough (now Merck); and has received lecture fees from Novartis and Teva Pharmaceuticals. KK has received research grant support from the National Institutes of Health, the Michael J Fox Foundation, Medivation, Neurosearch, and Pfizer; serves as a consultant to the US Food and Drug Administration, the Veteran's Administration, the National Institutes of Health, Abbott, Biogen Idec, Boehringer Ingelheim, EMD Serono, FoldRx, Impax, Ipsen, Isis, Lilly, Lundbeck, Merz, Novartis, Orion, Otsuka, Prestwick, Schering-Plough, Sienna Biotech, Synosia, Solvay, Teva Pharmaceuticals, UCB Pharma, and Xenoport; and provides legal consulting to Pfizer and the Welding Rod Litigation Defendants. JHK is a paid member of the scientific advisory board of, owns stock options from, and has received grant support from Ceregene. CWO is a paid member of the scientific advisory board of and owns stock options in Ceregene and is a paid consultant for Novartis, Orion, Teva Pharmaceuticals, Lundbeck, Merck-Serono, and Abbott.
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