Study Rationale:
The loss of glutathione in the brain of individuals with PD occurs years before the onset of motor symptoms. Glutathione has been proposed as neuroprotective therapy in PD for decades, but the therapy has been limited by the lack or oral availability and the invasiveness of intravenous administration. Recently, a Phase I Study of glutathione nasal spray concluded the therapy is safe and tolerable; Surprisingly, this non-dopaminergic therapy was associated with an improvement in clinical symptoms. In order to design the most appropriate study to evaluate the efficacy of (in)GSH as a PD therapeutic, it must first be determined whether or not (in)GSH affects PD symptoms. The goal of this study is to determine whether (in)GSH improves clinical symptoms of PD over placebo.
Hypothesis:
The hypothesis of this study is that both low and high doses of (in)GSH will improve PD clinical symptoms over placebo, as measured by the Unified PD Rating Scale (UPDRS).
Study Design:
45 individuals with PD will be recruited from the community to receive either placebo, 300 mg, or 600 mg intranasal glutathione, (in)GSH, daily. Participants will be asked to spray 1 ml of study medication (or placebo) up their nose three times daily for three months. Participants will be asked to come to a clinic visit once a month for 5 months, for a total of 5 study visits. All individuals will have clinical exams, blood draws, and urine collection; 15 individuals will be invited to volunteer for additional MRI measurements.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Like dopamine, glutathione is a naturally occurring molecule in the human body that is insufficiently produced in PD. The underlying hypothesis is that supplementation with glutathione may slow disease progression and/or improve PD symptoms. Successful completion of this trial will inform whether or not to evaluate glutathione only as a disease-modifying agent, or as both a disease-modifying agent and a symptomatic therapy.
Next Steps for Development:
If this study demonstrates (in)GSH is more effective than placebo at reducing PD symptoms, the phase III disease-modification trial will employ a delayed-start design. The next steps for evaluating (in)GSH as a symptomatic therapy will include varying dose schedules and delivery methods.
Final Outcome
In the brain, GSH is essential for clearing cellular and environmental waste and eliminating free radicals. Three decades of research suggests that the PD brain has depleted levels of glutathione (GSH) and that GSH deficiency contributes to PD progression. Previously, a Phase I study of intranasal GSH, (in)GSH, demonstrated a mild symptomatic improvement that was not seen in the placebo arm. This Phase IIb Study was designed to see whether the symptomatic improvements seen in the first intranasal, (in)GSH, study are reproducible. The secondary aim was to try and identify outcome measures to use in future trials. As was done in the Phase I study, (in)GSH was given for three months and then participants were observed for a month after stopping. All groups improved over their baseline PD scores. As was seen in the Phase I study, the high-dose group had an approximate 4 point improvement in PD severity score, as measured by the Unified PD Rating Scale (UPDRS), a benefit not seen in the lower-dose group. Unlike the previous study, the improvements seen in the placebo group were three times as robust, with the placebo group benefiting equally to the high-dose group. The unusually strong and sustained placebo response deserves further attention. As there is no convincing evidence that (in)GSH results in a measurable symptomatic effect over placebo, future research efforts should focus on the capacity of (in)GSH to slow PD progression (not treat symptoms).