Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

Published

Journal Article

Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.clinicaltrials.gov Identifier: NCT00833690.

Full Text

Cited Authors

  • 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, C-A; 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, AFD; Constantinescu, R; Sharma, S; Venuto, C; Weber, J; Eaton, K

Published Date

  • February 2014

Published In

Volume / Issue

  • 71 / 2

Start / End Page

  • 141 - 150

PubMed ID

  • 24366103

Pubmed Central ID

  • 24366103

Electronic International Standard Serial Number (EISSN)

  • 2168-6157

International Standard Serial Number (ISSN)

  • 2168-6149

Digital Object Identifier (DOI)

  • 10.1001/jamaneurol.2013.5528

Language

  • eng