Antioxidant Therapy Tested in Early Parkinson’s
Treatment with the urate precursor inosine did not result in a significant difference in the rate of clinical disease progression in early Parkinson’s disease, the phase III SURE-PD3 trial showed.
Clinical progression rates, measured by the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) parts I-III, were not significantly different between Parkinson’s patients randomized to sustained oral inosine treatment (11.1 points per year, 95% CI 9.7-12.6) or placebo (9.9 points per year, 95% CI 8.4-11.3) for up to 2 years, reported Michael Schwarzschild, MD, PhD, of Massachusetts General Hospital in Boston, and co-authors in JAMA.
The difference in MDS-UPDRS scores was 1.26 points per year (95% CI -0.59 to 3.11; P=0.18). Based on a prespecified interim futility analysis, the trial closed early, with 273 randomized participants completing the study.
“The SURE-PD3 trial tested a compelling hypothesis that raising brain levels of a natural antioxidant, urate, slows progression of the disease,” Schwarzschild told MedPage Today. “Although the results provide strong evidence against the hypothesis, the rigor of the trial and its innovations improve the prospects that future trials will demonstrate benefit of disease-modifying therapy for people with Parkinson’s disease.”
SURE-PD3 was the first randomized placebo-controlled Parkinson’s trial to use brain imaging to limit enrollment to people with striatal dopamine transporter deficiency, Schwarzschild noted. “Only those candidates who were recently diagnosed based on clinical features and whose scans indicated substantial loss of the dopamine-producing brain cells characteristic of Parkinson’s disease were enrolled and randomized,” he said.
“The study represents an emerging trend toward developing precision medicine in Parkinson’s, with treatments tailored toward the subset of patients most likely to benefit,” he pointed out. “In SURE-PD3, only patients who had lower levels of urate were enrolled, to increase the chance of benefit and reduce the chance of side effects.”
Earlier research correlated high levels of the antioxidant molecule urate in early Parkinson’s patients with a lower chance of progressing to needing dopamine therapy over 2 years. These and other findings led to a phase II study that showed inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early Parkinson’s disease.
In the phase III trial, Schwarzschild and colleagues enrolled 298 Parkinson’s patients who did not yet need dopaminergic medication from August 2016 to December 2017 at 58 U.S. sites, following them through June 2019. All participants had striatal dopamine transporter deficiency and had serum urate below the population median concentration (<5.8 mg/dL). Mean age of participants was 63, and 49% were women.
Participants were randomized to placebo or oral inosine at doses of up to two 500-mg capsules three times daily for up to 2 years. Inosine doses were targeted to increase serum urate concentrations to 7.1-8.0 mg/dL.
The primary outcome was rate of change in the MDS-UPDRS parts I-III total score before starting dopaminergic drug therapy. The MDS-UPDRS ranges from 0-236, with higher scores indicating greater disability; the minimum clinically important difference is 6.3 points.
While clinical progression rates were not significantly different between the two groups, the inosine group had a sustained elevation of serum urate by 2.03 mg/dL from a baseline level of 4.6 mg/dL, compared with a 0.01 mg/dL change in the placebo group (difference 2.02 mg/dL, 95% CI 1.85-2.19 mg/dL, P<0.001).
No significant differences for secondary efficacy outcomes emerged, including dopamine transporter binding loss. The inosine group experienced fewer overall serious adverse events than the placebo group (7.4 vs 13.1 per 100 patient-years), but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).
“While the study does not rule out a protective effect of urate in Parkinson’s, it clearly showed that urate-elevating inosine did not slow the disease progression based on both clinical assessments and serial brain scan biomarkers of neurodegeneration,” Schwarzschild noted.
It also showed more kidney stones among people taking inosine and “based on these results, treatment of Parkinson’s disease with urate-elevating inosine is not advisable,” he added.
The study had several limitations, the researchers acknowledged. Because urate precursor inosine was administered rather than urate, it may have produced effects that offset the benefits of urate elevation, they noted.
The researchers added that inosine also may have benefit in a small subpopulation of Parkinson’s patients or at other stages of Parkinson’s disease.
This study was funded by the NIH/National Institute of Neurological Disorders and Stroke, with additional support from the Michael J. Fox Foundation for Parkinson’s Research and GE Healthcare (all DaTscan doses).
Schwarzschild reported no disclosures. The Parkinson Study Group investigators attested they had no conflicts of interest with any company determined to be involved in the study.
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