A clinical trial, is by definition an experiment or a test — an effort to determine if something works, or doesn’t. Sometimes, although the intended outcome of a clinical trial may fall short of expectations, the results are nevertheless intriguing and may spark additional avenues of investigation. Such is the case in a clinical trial of glial cell line derived neurotrophic factor (GDNF) intraputaminal infusion whose results were just recently published.
Between the years of 2012-2017 a clinical trial at the University of Bristol in the United Kingdom was conducted in which GDNF was infused directly into the putamen, a deep brain structure, using a unique drug delivery system that was developed for the trial. GDNF is a nerve growth factor, a protein which enhances the survival of nerve cells. Because the main problem in Parkinson’s disease (PD) is the death of neurons, the potential use of growth factors to keep cells alive for longer is an exciting avenue of PD research.
The initial study enrolled 35 people who had the special delivery system surgically implanted into their brain and then received monthly infusions of GDNF. The first study lasted 40 weeks and was placebo controlled – which means half the participants received the medication and half underwent all the steps of the infusion but did not receive medication. The two groups were compared and these results were published in the journal Brain. Although there was a trend toward improvement in the treatment groups as compared to the placebo group when evaluated off of medication, the trend was not statistically significant and therefore the trial did not ultimately prove that GDNF infusion was helpful for symptoms of PD.
Despite this disappointment, there were some intriguing findings which suggest that further study is warranted. A post-hoc analysis of the participants (that is, statistical tests that were not pre-planned before the trial) showed that in nine patients who received the treatment, and in none of the patients who received the placebo, there was a statistically significant improvement in their symptoms. This may suggest that certain people with PD may benefit from the treatment and more research is necessary to understand who those people may be. In addition, PET imaging demonstrated increased uptake of dopamine in the treated group and not in the placebo group. The uptake in dopamine took place, in some cases, in the entire putamen which suggests that the unique delivery system that was developed for this trial worked as designed.
The research group continued to treat this group of patients for an additional 40 weeks. In this second stage of the trial, all patients received GDNF, without a placebo group. The results of this phase of the trial was recently published in the Journal of Parkinson’s Disease. This phase of the study did not show a statistically significant improvement in motor functioning when comparing the group that received placebo/GDNF to the group that received GDNF/GDNF over the full 80 weeks. However, both groups showed significant improvements from week 40 to week 80. The results could indicate that GDNF infusion requires more time than 40 weeks to show its full effect. However, any conclusions derived from the second part of the trial must take into account the fact that all patients received the drug. It is a well-researched phenomenon that knowing that one has received treatment can be therapeutic in and of itself; this is known as the placebo effect. Without a group that did not receive the drug, it is impossible to know what role the placebo effect played in the improvements seen in the second phase of the trial.
The trial did not provide definitive answers. However, it did use a new drug delivery system that effectively and safely reached the deep parts of the brain, which is certainly a success for the PD community. More research is necessary to explore the possibility that a particular profile of PD patient may benefit from this treatment and to determine if sustained GDNF infusions will be a viable treatment option.