Dataset Information

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

ABSTRACT:

Importance

Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).

Objective

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.

Design, setting, and participants

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.

Interventions

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.

Main outcomes and measures

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.

Conclusions and relevance

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.

Trial registration

clinicaltrials.gov Identifier: NCT00833690.

SUBMITTER: Parkinson Study Group SURE-PD Investigators

PROVIDER: S-EPMC3940333 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Schwarzschild Michael A MA Ascherio Alberto A Beal M Flint MF Cudkowicz Merit E ME Curhan Gary C GC Hare Joshua M JM Hooper D Craig DC Kieburtz Karl D KD Macklin Eric A EA Oakes David D Rudolph Alice A Shoulson Ira I Tennis Marsha K MK Espay Alberto J AJ Gartner Maureen M Hung Albert A Bwala Grace G Lenehan Richard R Encarnacion Elmyra E Ainslie Melissa M Castillo Richard R Togasaki Daniel D Barles Gina G Friedman Joseph H JH Niles Lisa L Carter Julie H JH Murray Megan M Goetz Christopher G CG Jaglin Jeana J Ahmed Anwar A Russell David S DS Cotto Candace C Goudreau John L JL Russell Doozie D Parashos Sotirios Andreas SA Ede Patricia P Saint-Hilaire Marie H MH Thomas Cathi-Ann CA James Raymond R Stacy Mark A MA Johnson Julia J Gauger Lisa L Antonelle de Marcaida J J Thurlow Sheila S Isaacson Stuart H SH Carvajal Lisbeth L Rao Jayaraman J Cook Maureen M Hope-Porche Charlise C McClurg Lauren L Grasso Daniela L DL Logan Robert R Orme Constance C Ross Tori T Brocht Alicia F D AF Constantinescu Radu R Sharma Saloni S Venuto Charles C Weber Joseph J Eaton Ken K

JAMA neurology 20140201 2

<h4>Importance</h4>Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).<h4>Objective</h4>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.<h4>Design, setting, and participants</h4>The Safety of Urate Elevation in PD (SURE-PD) ...[more]

PMID: 24366103

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Project description:ImportanceUrate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.ObjectiveTo determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.Design, participants, and settingRandomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.InterventionsInosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.Main outcomes and measuresThe primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.ResultsBased on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).Conclusions and relevanceAmong patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.Trial registrationClinicalTrials.gov Identifier: NCT02642393.

Project description:ImportanceNeurofilament light in biofluids has been associated with progression of Parkinson disease (PD), but the association between neurofilament heavy (NfH) and progression of PD has not been investigated.ObjectiveTo evaluate the associations of cerebrospinal fluid (CSF) NfH (cNfH) levels and motor and cognitive progression in PD.Design, setting, and participantsThis cohort study used data from the Parkinson Progression Marker Initiative ranging from June 2010 to November 2018. Participants were recruited from 24 participating sites worldwide (United States, Europe, and Australia). Data were analyzed from October 20 to December 18, 2021.ExposuresConcentrations of NfH in CSF.Main outcomes and measuresThe primary outcomes were Movement Disorder Society-sponsored revisions of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part III; scores range from 0 to 132, with higher scores indicating worse motor function, and Montreal Cognitive Assessment (MoCA); scores range from 0 to 30, with higher scores indicating better cognitive function. The associations of cNfH levels and longitudinal change in MDS-UPDRS-Part-III and MoCA were examined using linear mixed-effects models with PD duration as the time scale. Partial correlation analysis was conducted to examine the associations of cNfH levels and α-synuclein, amyloid-β 1-42 (Aβ42), phosphorylated tau at threonine 181 position (P-tau), and total tau (T-tau) levels in CSF.ResultsA total of 404 patients with PD (mean [SD] age, 61.7 [9.7] years; 263 were men [65.1%]; within 2 years of diagnosis; Hoehn and Yahr <3) were included. Higher baseline cNfH levels were associated with greater increases in MDS-UPDRS Part-III (β = 0.39; 95% CI, 0.12-0.66; P = .003) and faster decreases in MoCA (β = -0.18; CI, -0.24 to -0.11; P < .001). Levels of cNfH were correlated with CSF levels of α-synuclein (Spearman r = 0.25; 95% CI, 0.15-0.34; P < .001), Aβ42 (Spearman r = 0.18; 95% CI, 0.08-0.27; P < .001), P-tau (Spearman r = 0.25; 95% CI, 0.15-0.35; P < .001), and T-tau (Spearman r = 0.31; 95% CI, 0.21-0.40; P < .001) at baseline.Conclusions and relevanceHigher baseline cNfH levels were associated with faster motor and cognitive progression. This finding suggests that cNfH may be of some value for stratifying patients with PD who have different progression rates.

Project description:ImportanceAfter aneurysmal subarachnoid hemorrhage, the use of lumbar drains has been suggested to decrease the incidence of delayed cerebral ischemia and improve long-term outcome.ObjectiveTo determine the effectiveness of early lumbar cerebrospinal fluid drainage added to standard of care in patients after aneurysmal subarachnoid hemorrhage.Design, setting, and participantsThe EARLYDRAIN trial was a pragmatic, multicenter, parallel-group, open-label randomized clinical trial with blinded end point evaluation conducted at 19 centers in Germany, Switzerland, and Canada. The first patient entered January 31, 2011, and the last on January 24, 2016, after 307 randomizations. Follow-up was completed July 2016. Query and retrieval of data on missing items in the case report forms was completed in September 2020. A total of 20 randomizations were invalid, the main reason being lack of informed consent. No participants meeting all inclusion and exclusion criteria were excluded from the intention-to-treat analysis. Exclusion of patients was only performed in per-protocol sensitivity analysis. A total of 287 adult patients with acute aneurysmal subarachnoid hemorrhage of all clinical grades were analyzable. Aneurysm treatment with clipping or coiling was performed within 48 hours.InterventionA total of 144 patients were randomized to receive an additional lumbar drain after aneurysm treatment and 143 patients to standard of care only. Early lumbar drainage with 5 mL per hour was started within 72 hours of the subarachnoid hemorrhage.Main outcomes and measuresPrimary outcome was the rate of unfavorable outcome, defined as modified Rankin Scale score of 3 to 6 (range, 0 to 6), obtained by masked assessors 6 months after hemorrhage.ResultsOf 287 included patients, 197 (68.6%) were female, and the median (IQR) age was 55 (48-63) years. Lumbar drainage started at a median (IQR) of day 2 (1-2) after aneurysmal subarachnoid hemorrhage. At 6 months, 47 patients (32.6%) in the lumbar drain group and 64 patients (44.8%) in the standard of care group had an unfavorable neurological outcome (risk ratio, 0.73; 95% CI, 0.52 to 0.98; absolute risk difference, -0.12; 95% CI, -0.23 to -0.01; P = .04). Patients treated with a lumbar drain had fewer secondary infarctions at discharge (41 patients [28.5%] vs 57 patients [39.9%]; risk ratio, 0.71; 95% CI, 0.49 to 0.99; absolute risk difference, -0.11; 95% CI, -0.22 to 0; P = .04).Conclusion and relevanceIn this trial, prophylactic lumbar drainage after aneurysmal subarachnoid hemorrhage lessened the burden of secondary infarction and decreased the rate of unfavorable outcome at 6 months. These findings support the use of lumbar drains after aneurysmal subarachnoid hemorrhage.Trial registrationClinicalTrials.gov Identifier: NCT01258257.

Dataset Information

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

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Conclusions and relevance

Trial registration

Publications

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

Similar Datasets

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