Randomized controlled trial of intraputaminal glial cell line-derived neurotrophic factor infusion in Parkinson disease
Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, et al.;
Commented by , 23 May 2006
Background
Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic effects on midbrain dopaminergic neurons. In a small, open label study, infusion of recombinant human GDNF into striatum has been previously described to be beneficial in patients with advanced PD (ref. 1).
Aim
The aim of this study was to assess the benefits of intraputaminal infusion of recombinant human GDNF (liatermin) in patients with PD, with a randomized, controlled design.
Methods
This was a randomized, placebo controlled trial. Thirty-four patients with advanced PD were randomized equally to receive either bilateral continous intraputaminal infusion of liatermin 15 microg/putamen/day or placebo. The primary endpoint was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary endpoints included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake.
Results
At 6 months, mean percentage changes in "off’"UPDRS motor score were -10% and -4.5% in the liatermin and placebo groups respectively; the difference between the two groups was statistically not significant (95% confidence interval, -23 to 12, p=0.53). Results for the secondary endpoints were similar between the two groups. A 32.5% tretament difference in favor of liatermin was observed in mean (18)F-dopa influx constant (p= 0.019).
Serious device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing anti-liatermin antibodies were detected in three patients, one during the core and two in the open-label extension study.
Professor Emre's comments
In this randomized, controlled study liatermin did not confer the predetermined level of clinical benefits despite increased (18)F-dopa uptake. The benefits described in the earlier open-label study could not be confirmed. In that study, which was conducted in five patients, there was an improvement of 57% in the UPDRS motor score after 2 years, as opposed to 10% over 6 months in this study (ref. 1). It is unclear if the same amount of improvement would have been reached, had this study been continued up to two years; development of neutralizing antibodies in three patients was alarming.
This is another example of disparate outcomes between open-label and double-blind, randomized, controlled surgical studies. A similar example was the discrepancy between the beneficial results seen in open label studies of fetal nigral transplants (ref. 2) versus lack of clinical benefits in a randomized controlled study, despite strong evidence of transplant survival and establishment of neural connections with the host tissue (ref. 3).
It is not certain if technical differences between this trial and the open-label study with positive outcome may explain the disparate results. Hence the final verdict on the efficacy of GDNF in PD may not be out yet. Nevertheless this case demonsrates once more the necessity of controlled studies, also for surgical interventions, however difficult they may be to organize.
References
1. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Annals of Neurology 2005; 57; 298-302
2. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. New England Journal of Medicine 2001; 344; 710-719
3. Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Annals of Neurology 2003; 54; 403-414