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Inosine for Parkinson's Disease: Safety and Trial Design Optimization

The Phase III trial is currently recruiting. Learn more:

Urate – a natural metabolite and major antioxidant in humans – is emerging as a predictor of both the risk and the progression of typical Parkinson’s disease (PD). Studies of healthy individuals have linked urate levels in the upper normal range to a reduced risk of developing PD. Similarly, studies of individuals recently diagnosed with PD have found that the disease tends to progress more slowly in those with higher urate levels in their blood and cerebrospinal fluid, the fluid that surrounds the brain. The findings raise the possibility that boosting brain urate by treatment with the urate precursor inosine could slow the brain cell degeneration of PD. Before embarking on a neuroprotection trial of inosine for PD, careful assessment of the safety, validity and methodology of this approach is warranted.

Project Description:
Ninety subjects with recently diagnosed PD will be enrolled in a randomized, double-blinded clinical trial of inosine. The study will determine whether and at what dose inosine can safely elevate levels of urate in the fluid around the brain. Subjects will take capsules containing inosine or placebo in combinations designed to produce no, mild or moderate elevation of urate. Because kidney stones and gout are known risks and cardiovascular disease is a possible risk of higher urate levels, safety measures will be in place to help avoid these conditions, and to detect and treat them should they arise. Three months after enrollment cerebrospinal fluid will be tested for urate levels. If a tolerable dose of inosine adequately increases urate in the cerebrospinal fluid then subjects would continue on treatment for up to two years to assess long-term safety.

Relevance to Treatment of Parkinson’s Disease/ Anticipated Outcome: 
The identification of urate as an unprecedented predictor of better outcomes in Parkinson’s disease has encouraged consideration of its precursor inosine as a potential neuroprotectant in PD. This project would shorten substantially the lead time to develop a full neuroprotection trial, and through optimization of key design features would considerably enhance the likelihood of its safety and success.

Final Outcome

The SURE-PD (Safety of Urate Elevation in Parkinson’s Disease) trial successfully investigated the safety and feasibility of using inosine to raise levels of the natural antioxidant urate as a potential therapy to slow the worsening of PD. With the support of The Michael J. Fox Foundation and the guidance of the U.S. Food and Drug Administration, the SURE-PD trial demonstrated that the urate precursor molecule inosine taken by mouth was generally very well-tolerated, safe and capable of substantially increasing levels of urate in blood and around the brain over months to years. These positive results support advancing to a larger clinical trial to definitively test for disease-modifying benefits of urate-elevating inosine treatment in PD. The SURE-PD trial also collected valuable additional information, for example on inosine dosing, blood urate monitoring, safety precautions, recruitment strategies and antioxidant biomarkers, that will improve the design and prospects for success of a pivotal trial of inosine for PD. In addition, SURE-PD patient volunteers provided blood, urine and cerebrospinal fluid samples for future PD research, maximizing the impact of their contributions. This project demonstrates the feasibility of conducting high-quality clinical research on promising non-commercial candidate therapeutics through a PD community partnership between philanthropic organizations like MJFF, experienced investigators like the coordinators and neurologists of the Parkinson Study Group, and people with Parkinson’s and their families.

Presentations & Publications:

Parkinson Study Group SURE-PD Investigators (Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K.) Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014 Feb;71(2):141-50.

Parkinson Study Group SURE-PD Investigators. “Safety of Urate Elevation in Parkinson's Disease (SURE-PD)”: National Institutes of Health trial website:

Schwarzschild MA, Macklin EA, Ascherio A; Parkinson Study Group SURE-PD Investigators. Urate and neuroprotection trials. Lancet Neurol. 2014 Aug;13(8):758.

Bhattacharyya S, Bakshi R, Logan R, Ascherio A, Macklin E, Schwarzschild M, on behalf of the Parkinson Study Group SURE-PD Investigators. Oral Inosine Persistently Elevates Plasma Antioxidant Capacity in Early Parkinson's Disease. American Academy of Neurology 66th Annual Meeting, April 26 to May 3, 2014 (Philadelphia, PA); platform presentation; abstract #1709.

Selected Presentations
2008 “Antioxidant & Anti-inflammatory Strategies in Parkinson's Disease” Royal Society of Medicine Symposium / Cure Parkinson's Trust (London)

2009 Eweson Lectureship of the American Federation for Aging Research: "Purine Targets in Neurotherapeutics: Adenosine, caffeine & urate in Parkinson's" (Winter Conference on Brain Research; Copper Mountain)

2010 "Caffeine, Adenosine & Urate: from Molecular Epi to Drug Trials" World Parkinson Congress (Glasgow)

2012 "Protective Potential of Purines against Neurodegeneration of PD" US Department of Defense Neurotoxin Exposure Treatment and Parkinson’s Research Program’s national symposium, Parkinson’s Disease Models, Biomarkers & Biochemical Pathways (New York City)

2012 "Novel non-dopaminergic targets for the motor symptoms of Parkinson’s disease" Movement Disorders Society’s International Parkinson’s Disease and Other Movement Disorders Congress (Dublin)

2013 "Inosine for Parkinson's Disease: Safety and Trial Design Optimization” The Michael J. Fox Foundation for Parkinson's Research and the New York Academy of Sciences; Seventh Annual Parkinson's Disease Therapeutics Conference (New York City)

2014 “Purine Targets in Parkinson’s Trials” Purines 2014 -- International Conference on Nucleotides, Nucleosides and Nucleobases (Bonn)

July 2014

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  • Michael A. Schwarzschild, MD, PhD

    Boston, MA United States

  • Alberto Ascherio, MD, DrPH

  • Karl Kieburtz, MD, MPH

    Rochester, NY United States

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