Study Rationale:
The loss of the antioxidant glutathione in the brain of individuals with Parkinson’s disease (PD) occurs years before the onset of motor symptoms. Glutathione has been proposed as a neuroprotective therapy for PD for decades, but the therapy has been limited by the lack of oral availability and the invasiveness of intravenous administration. Recently, a Phase I study of glutathione nasal spray [(in)GSH] concluded the therapy is safe and tolerable and is 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, we must first determine whether or not (in)GSH affects PD symptoms.
Hypothesis:
Both low and high doses of (in)GSH will improve PD clinical symptoms over placebo, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS).
Study Design:
Forty-five individuals with PD will be recruited from the community to receive either placebo or 300 mg or 600 mg of intranasal glutathione 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 five months. 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.
Trial Phase: IIb
Final Outcome
In the brain, glutathione (GSH) is essential for clearing cellular and environmental waste and eliminating free radicals. Three decades of research suggests that individuals with PD have reduced levels of GSH that contributes to progression of the disease. A Phase I study of intranasal GSH, (in)GSH, demonstrated a mild symptomatic improvement that was not seen in the placebo group. This Phase IIb study was designed to determine whether symptomatic improvements in the first intranasal (in) GSH study are reproducible. The secondary aim was to identify outcome measures to use in future trials.
As in the Phase I study, (in)GSH was given for three months and participants were observed for a month after treatment. All groups improved over their baseline PD scores. As in the Phase I study, the high-dose group had an approximate four-point improvement in PD severity score, as measured by the Unified Parkinson's Disease 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 as the high-dose group. The unusually strong and sustained placebo response deserves further study.
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 rather than its effects on symptoms.
Presentations & Publications
These findings were presented at the 2016 Movement Disorder Society conference in Berlin, Germany. A manuscript summarizing these findings is currently in development.
October 2016