Research
Original Investigation | CLINICAL TRIAL
Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease A Randomized Clinical Trial The Parkinson Study Group SURE-PD Investigators
IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate
elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).
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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 0.50 mg/dL) and serum (>6.0 mg/dL) predictive of slower disease progression in prior studies.11,12 This chronic “target engagement” in relevant peripheral and central nervous system compartments at safe and tolerable doses of inosine greatly strengthens the rationale for conducting disease modification studies using the higher dosing regimen for inosine. Whereas our findings support the safety of raising serum urate elevation to either 6.1 to 7.0 or 7.1 to 8.0 mg/dL, the latter was associated with a slower rate of clinical11,12 and particularly radiographic11 decline in prior PD studies. Refinements to the dose titration regimen used here should take into account our findings that the extent of the actual urate elevation is influenced by sex and the timing of serum sampling relative to dosing. The capacity to increase urate may be related to sex, with women in our trial having achieved greater increases in both serum and CSF because they had lower values than men at baseline (ie, with women enrolling with mean serum urate levels 0.5 mg/dL lower than those in men, whereas all participants were titrated to the same target ranges). Dosing was tied to urate levels in serum collected at random times after the morning dose. Based on pharmacokinetic data from
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Inosine to Increase Urate in Parkinson Disease
Original Investigation Research
the trial (The Parkinson Study Group SURE-PD Investigators, unpublished data, 2013), these sample urate values likely were close to peak levels, explaining why they exceeded trough values by approximately 1.0 mg/dL (Figure 2B). These data, suggesting trough sampling may provide an improved approach to approximating the intended target ranges for serum urate, illustrate the broader value (The Parkinson Study Group SURE-PD Investigators, unpublished data, 2013) of incorporating the experience gained in the SURE-PD trial into the design of future clinical trials of inosine. Preliminary assessments of the effects of inosine on clinical outcomes over 8 to 24 months further support clinical development of inosine in PD. A UPDRS-based futility analysis has been used by the NET-PD program to decide on the value of advancing leading candidate neuroprotectants to full efficacy trials.24,25 For example, a long-term phase 3 PD trial of creatine29 was developed based on its demonstration of nonfutility comparedwithhistoricalUPDRSscoreprogressiondata.25 Inthepresent study, inosine dosed to mildly or moderately elevate urate also suggested nonfutility by equivalent NET-PD methods except for our use of matched contemporary rather than historical controls, albeit with a small sample size. Similarly, efficacy
ARTICLE INFORMATION Accepted for Publication: October 25, 2013. Author Contributions: Drs Macklin and Schwarzschild had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Schwarzschild, Ascherio, Kieburtz, Macklin. Acquisition of data: Espay, Gartner, Hung, Bwala, Lenehan, Encarnacion, Ainslie, Castillo, Togasaki, Barles, Friedman, Niles, Carter, Murray, Goetz, Jaglin, Ahmed, D. S. Russell, Cotto, Goudreau, D. Russell, Parashos, Ede, Saint-Hilaire, Thomas, James, Stacy, Johnson, Gauger, de Marcaida, Thurlow, Isaacson, Carvajal, Rao, Cook, Hope-Porche, McClurg, Grasso, Logan, Orme, Ross, Brocht, Constantinescu, Sharma, Venuto, Weber, Eaton. Analysis and interpretation of data: Schwarzschild, Beal, Cudkowicz, Curhan, Hare, Hooper, Kieburtz, Macklin, Oakes, Rudolph, Shoulson, Tennis. Drafting of the manuscript: Schwarzschild, Ascherio, Macklin. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Macklin. Obtaining funding: Schwarzschild, Ascherio, Kieburtz, Macklin. Administrative, technical, and material support: Espay, Hung, Bwala, Lenehan, Encarnacion, Ainslie, Castillo, Togasaki, Barles, Niles, Murray, Goetz, Jaglin, D. S. Russell, Goudreau, D. Russell, Parashos, Ede, James, Johnson, de Marcaida, Thurlow, Isaacson, Rao, Cook, Hope-Porche, McClurg, Grasso, Logan, Orme, Ross, Brocht, Constantinescu, Sharma, Venuto, Weber, Eaton. Study supervision: Schwarzschild, Ascherio, Beal, Cudkowicz, Curhan, Hare, Hooper, Kieburtz, Macklin, Oakes, Rudolph, Shoulson, Tennis. Published Online: December 23, 2013. doi:10.1001/jamaneurol.2013.5528. The Parkinson Study Group SURE-PD Investigators: Michael A. Schwarzschild, MD, PhD;
analyses that incorporated UPDRS data over 2 years in SURE-PD corroborate the suggestion of a dose-dependent attenuation of clinical decline by inosine. Data on time to disability did not indicate delayed disability among participants receiving inosine, although power for this secondary analysis was minimal. Interestingly, treatment with inosine appeared to prevent slight worsening of depressive symptoms during the trial, a finding that if substantiated could strengthen the longstanding theory30 and early evidence31,32 of enhanced motivation as the basis for urate elevation during human evolution.
Conclusions The SURE-PD trial provides strong evidence that long-term administration of oral inosine can be generally safe and well tolerated by patients with early PD and increases both serum and CSF urate levels in a dose-dependent fashion. Secondary analyses suggest that a disease-modifying benefit of inosine is plausible. Together with previous findings, these of the present study support a more definitive trial of inosine as a potential treatment to slow the clinical progression of PD.
Alberto Ascherio, MD, DrPH; M. Flint Beal, MD; Merit E. Cudkowicz, MD; Gary C. Curhan, MD; Joshua M. Hare, MD; D. Craig Hooper, PhD; Karl D. Kieburtz, MD; Eric A. Macklin, PhD; David Oakes, PhD; Alice Rudolph, PhD; Ira Shoulson, MD; Marsha K. Tennis, RN; Alberto J. Espay, MD, MSc; Maureen Gartner, RN, MEd; Albert Hung, MD, PhD; Grace Bwala, MBBS; Richard Lenehan, MD; Elmyra Encarnacion, MD; Melissa Ainslie; Richard Castillo; Daniel Togasaki, MD, PhD; Gina Barles; Joseph H. Friedman, MD; Lisa Niles, MS; Julie H. Carter, RN, MN, ANP; Megan Murray, MA; Christopher G. Goetz, MD; Jeana Jaglin, RN, CCRC; Anwar Ahmed, MD; David S. Russell, MD, PhD; Candace Cotto, RN; John L. Goudreau, DO, PhD; Doozie Russell; Sotirios Andreas Parashos, MD, PhD; Patricia Ede, RN; Marie H. Saint-Hilaire, MD; Cathi-Ann Thomas, RN, MS; Raymond James; Mark A. Stacy, MD; Julia Johnson, MD; Lisa Gauger, BA; J. Antonelle de Marcaida, MD; Sheila Thurlow, MSN, BSN; Stuart H. Isaacson, MD; Lisbeth Carvajal; Jayaraman Rao, MD; Maureen Cook, RN, BSN; Charlise Hope-Porche, RN; Lauren McClurg; Daniela L. Grasso; Robert Logan, MS; Constance Orme, BA; Tori Ross; Alicia F. D. Brocht; Radu Constantinescu, MD; Saloni Sharma, MBBS; Charles Venuto, PharmD; Joseph Weber; Ken Eaton. The Parkinson Study Group SURE-PD Investigators Affiliations: Massachusetts General Hospital, Boston, Massachusetts (Schwarzschild, Cudkowicz, Macklin, Hung, Bwala); Harvard School of Public Health, Boston, Massachusetts (Ascherio); Cornell University, New York, New York (Beal); Brigham and Women’s Hospital, Boston, Massachusetts (Curhan); University of Miami, Miami, Florida (Hare); Thomas Jefferson University, Philadelphia, Pennsylvania (Hooper); University of Rochester, Rochester, New York (Kieburtz, Oakes, Rudolph); Georgetown University, Washington, DC (Shoulson); Peterborough, New Hampshire (Tennis); University of Cincinnati, Cincinnati, Ohio (Espay, Gartner); Scott & White Memorial Hospital/Texas A&M University, Temple (Lenehan, Encarnacion, Ainslie, Castillo); University of
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Southern California, Los Angeles (Togasaki, Barles); Butler Hospital, Providence, Rhode Island (Friedman, Niles); Oregon Health & Science University, Portland (Carter, Murray); Rush University Medical Center, Chicago, Illinois (Goetz, Jaglin); Cleveland Clinic, Cleveland, Ohio (Ahmed); Institute of Neurodegenerative Disorders, New Haven, Connecticut (D. S. Russell, Cotto); Michigan State University, East Lansing (Goudreau, D. Russell); Struthers Parkinson’s Center, Golden Valley, Minnesota (Parashos, Ede); Boston University, Boston, Massachusetts (Saint-Hilaire, Thomas, James); Duke University, Durham, North Carolina (Stacy, Johnson, Gauger); Eastern Connecticut Neurology Specialists, Manchester (Antonelle de Marcaida, Thurlow); Parkinson’s Disease & Movement Disorder Center of Boca Raton, Boca Raton, Florida (Isaacson, Carvajal); Ochsner Clinic Foundation, New Orleans, Louisiana (Rao, Cook, Hope-Porche); Administrative Coordination Center, Massachusetts General Hospital, Boston (McClurg, Grasso, Logan); Clinical Coordination Center, University of Rochester, Rochester, New York (Orme, Ross, Brocht, Constantinescu, Sharma, Venuto, Weber, Eaton). Conflict of Interest Disclosures: None of direct relevance to the drug development of inosine, the potential therapy under study. Note that in accordance with conflict of interest policy of Parkinson Study Group (http://www.parkinson -study-group.org/parkinson-research/constitution -and-bylaws) all SURE-PD steering committee members, site investigators, and site coordinators should have no financial relationship with any involved company during the study. Although the study received no commercial support, Kyowa Hakko USA Inc, its affiliate Kyowa Pharmaceutical Inc, and their parent company Kyowa Hakko Kirin Co Ltd were designated as the only “involved companies.” The designations were based on the use of Kyowa Hakko USA as the vendor from which inosine was obtained (as the active pharmaceutical ingredient for study drug manufacture) through an
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Research Original Investigation
Inosine to Increase Urate in Parkinson Disease
unsubsidized retail purchase. All authors provided signed attestation annually that they have no financial relationship with any involved company during the study, except that Dr Stacy indicated in 2013 that in 2012 he renewed a consulting relationship with Kyowa Hakko Kirin Co Ltd over a drug (istradefylline) intended to treat PD that is otherwise unrelated to inosine. Dr Goetz reports consulting and advisory board membership with honoraria from AOP Orphan, Addex Pharma, Advanced Studies of Medicine, Boston Scientific, CHDI, Health Advances, ICON Clinical Research, Ingenix (i3 Research), National Institutes of Health, Neurocrine, Oxford Biomedica, and Synthonics. He received grants/research funding from the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research (MJFF). Dr Goetz directs the Rush Parkinson’s Disease Research Center that receives support from the Parkinson’s Disease Foundation. He directs the translation program for the Movement Disorder Society–sponsored revision of the UPDRS and the Unified Dyskinesia Rating Scale and receives funds from the Movement Disorder Society for this effort. He also received honoraria from the Movement Disorder Society, American Academy of Neurology, University of Pennsylvania, University of Chicago, and University of Luxembourg. He has received royalties from Oxford University Press, Elsevier Publishers, and Wolters Kluwer Health Lippincott, Wilkins and Williams. No other disclosures were reported. Funding/Support: This project was funded by a grant from the MJFF. Additional support was provided by National Institutes of Health grant K24NS060991, Harvard NeuroDiscovery Center, the RJG Foundation, and the Parkinson’s Disease Foundation Advancing Parkinson’s Therapies initiative. Disclaimer: The views, findings, and opinions expressed in this publication are those of the authors and do not necessarily represent those of the MJFF. Dr Shoulson is the JAMA Neurology Section Editor for Clinical Trials but was not involved in the review process or the acceptance of the manuscript. Role of the Sponsor: No funder was involved in the design and conduct of the study, other than through the provisions of funds for the study. No funder had a role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We are grateful for the invaluable contributions of the study participants and their families, as well as for the key contributions and dedication of the Data and Safety Monitoring Committee members: Caroline M. Tanner, MD, PhD (chair), Bruce Levin, PhD, Grace S. Liang, MD, and Nina E. Tolkoff-Rubin, MD; MJFF staff and leadership serving as grantor/nonvoting members of the Steering Committee: Brian K. Fiske, PhD, Alison Urkowitz, and Todd B. Sherer, PhD; Project Advisors to the MJFF: Jeffrey M. Bronstein, MD, PhD, and David M. Weiner, MD; Clinical Materials Services Unit (www.clinicalmaterial.com) of the Center for Human Experimental Therapeutics at the University of Rochester Medical Center: Patrick Bolger, Tim Hackett, Cornelia Kamp, MBA, Ellen Weinberger, and Joan Woodcook; and other contributing clinical site staff including Linda Baldwin (deceased).
150
REFERENCES 1. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981;78(11):6858-6862. 2. Davies KJ, Sevanian A, Muakkassah-Kelly SF, Hochstein P. Uric acid-iron ion complexes: a new aspect of the antioxidant functions of uric acid. Biochem J. 1986;235(3):747-754. 3. Cipriani S, Desjardins CA, Burdett TC, Xu Y, Xu K, Schwarzschild MA. Urate and its transgenic depletion modulate neuronal vulnerability in a cellular model of Parkinson’s disease. PLoS One. 2012;7(5):e37331. 4. Gong L, Zhang QL, Zhang N, et al. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson’s disease: linking to Akt/GSK3β signaling pathway. J Neurochem. 2012;123(5): 876-885. 5. Chen X, Burdett TC, Desjardins CA, et al. Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration. Proc Natl Acad Sci U S A. 2013;110(1):300-305. 6. Davis JW, Grandinetti A, Waslien CI, Ross GW, White LR, Morens DM. Observations on serum uric acid levels and the risk of idiopathic Parkinson’s disease. Am J Epidemiol. 1996;144(5):480-484. 7. de Lau LM, Koudstaal PJ, Hofman A, Breteler MM. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol. 2005;58(5):797-800.
ASsociation of Inosine and Interferon beta in relapsing-remitting Multiple Sclerosis (ASIIMS) trial. Mult Scler. 2010;16(4):455-462. 18. Soltani Z, Rasheed K, Kapusta DR, Reisin E. Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rep. 2013;15(3):175-181. 19. Safety of urate elevation in Parkinson's disease (SURE-PD). http://clinicaltrials.gov/show /NCT00833690. Accessed September 25, 2013. 20. Cameron MA, Sakhaee K. Uric acid nephrolithiasis. Urol Clin North Am. 2007;34(3):335-346. 21. Siderowf A, McDermott M, Kieburtz K, Blindauer K, Plumb S, Shoulson I; Parkinson Study Group. Test-retest reliability of the Unified Parkinson’s Disease Rating Scale in patients with early Parkinson’s disease: results from a multicenter clinical trial. Mov Disord. 2002;17(4):758-763. 22. Zadikoff C, Fox SH, Tang-Wai DF, et al. A comparison of the mini mental state exam to the Montreal Cognitive Assessment in identifying cognitive deficits in Parkinson’s disease. Mov Disord. 2008;23(2):297-299. 23. Schrag A, Barone P, Brown RG, et al. Depression rating scales in Parkinson’s disease: critique and recommendations. Mov Disord. 2007;22(8):1077-1092.
8. Weisskopf MG, O’Reilly E, Chen H, Schwarzschild MA, Ascherio A. Plasma urate and risk of Parkinson’s disease. Am J Epidemiol. 2007;166(5):561-567.
24. Tilley BC, Palesch YY, Kieburtz K, et al; NET-PD Investigators. Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs. Neurology. 2006;66(5):628-633.
9. Parkinson Study Group PRECEPT Investigators. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology. 2007;69(15):1480-1490.
25. NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology. 2006;66(5):664-671.
10. Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1993;328(3):176-183.
26. Koski L, Xie H, Finch L. Measuring cognition in a geriatric outpatient clinic: Rasch analysis of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol. 2009;22(3):151-160.
11. Schwarzschild MA, Schwid SR, Marek K, et al; Parkinson Study Group PRECEPT Investigators. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol. 2008;65(6):716-723.
27. Spitsin S, Markowitz CE, Zimmerman V, Koprowski H, Hooper DC. Modulation of serum uric acid levels by inosine in patients with multiple sclerosis does not affect blood pressure. J Hum Hypertens. 2010;24(5):359-362.
12. Ascherio A, LeWitt PA, Xu K, et al; Parkinson Study Group DATATOP Investigators. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol. 2009;66(12):1460-1468.
28. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811-1821.
13. Yamamoto T, Moriwaki Y, Cheng J, et al. Effect of inosine on the plasma concentration of uridine and purine bases. Metabolism. 2002;51(4):438-442. 14. Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, Koprowskil H. Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler. 2001;7(5):313-319. 15. Toncev G. Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis. Vojnosanit Pregl. 2006;63(10):879-882. 16. Markowitz CE, Spitsin S, Zimmerman V, et al. The treatment of multiple sclerosis with inosine. J Altern Complement Med. 2009;15(6):619-625. 17. Gonsette RE, Sindic C, D’hooghe MB, et al; ASIIMS study group. Boosting endogenous neuroprotection in multiple sclerosis: the
29. Elm JJ; NINDS NET-PD Investigators. Design innovations and baseline findings in a long-term Parkinson’s trial: the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson’s Disease Long-term Study-1. Mov Disord. 2012;27(12):1513-1521. 30. Orowan E. The origin of man. Nature. 1955;175(4459):683-684. 31. Kasl SV, Brooks GW, Rodgers WL. Serum uric acid and cholesterol in achievement behavior and motivation, I: the relationship to ability, grades, test performance, and motivation. JAMA. 1970;213(7):1158-1164. 32. Kasl SV, Brooks GW, Rodgers WL. Serum uric acid and cholesterol in achievement behavior and motivation, II: the relationship to college attendance, extracurricular and social activities, and vocational aspirations. JAMA. 1970;213(8):1291-1299.
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Original Investigation | CLINICAL TRIAL
Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease A Randomized Clinical Trial The Parkinson Study Group SURE-PD Investigators
IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate
elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).
Supplemental content at jamaneurology.com CME Quiz at jamanetworkcme.com
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 0.50 mg/dL) and serum (>6.0 mg/dL) predictive of slower disease progression in prior studies.11,12 This chronic “target engagement” in relevant peripheral and central nervous system compartments at safe and tolerable doses of inosine greatly strengthens the rationale for conducting disease modification studies using the higher dosing regimen for inosine. Whereas our findings support the safety of raising serum urate elevation to either 6.1 to 7.0 or 7.1 to 8.0 mg/dL, the latter was associated with a slower rate of clinical11,12 and particularly radiographic11 decline in prior PD studies. Refinements to the dose titration regimen used here should take into account our findings that the extent of the actual urate elevation is influenced by sex and the timing of serum sampling relative to dosing. The capacity to increase urate may be related to sex, with women in our trial having achieved greater increases in both serum and CSF because they had lower values than men at baseline (ie, with women enrolling with mean serum urate levels 0.5 mg/dL lower than those in men, whereas all participants were titrated to the same target ranges). Dosing was tied to urate levels in serum collected at random times after the morning dose. Based on pharmacokinetic data from
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Inosine to Increase Urate in Parkinson Disease
Original Investigation Research
the trial (The Parkinson Study Group SURE-PD Investigators, unpublished data, 2013), these sample urate values likely were close to peak levels, explaining why they exceeded trough values by approximately 1.0 mg/dL (Figure 2B). These data, suggesting trough sampling may provide an improved approach to approximating the intended target ranges for serum urate, illustrate the broader value (The Parkinson Study Group SURE-PD Investigators, unpublished data, 2013) of incorporating the experience gained in the SURE-PD trial into the design of future clinical trials of inosine. Preliminary assessments of the effects of inosine on clinical outcomes over 8 to 24 months further support clinical development of inosine in PD. A UPDRS-based futility analysis has been used by the NET-PD program to decide on the value of advancing leading candidate neuroprotectants to full efficacy trials.24,25 For example, a long-term phase 3 PD trial of creatine29 was developed based on its demonstration of nonfutility comparedwithhistoricalUPDRSscoreprogressiondata.25 Inthepresent study, inosine dosed to mildly or moderately elevate urate also suggested nonfutility by equivalent NET-PD methods except for our use of matched contemporary rather than historical controls, albeit with a small sample size. Similarly, efficacy
ARTICLE INFORMATION Accepted for Publication: October 25, 2013. Author Contributions: Drs Macklin and Schwarzschild had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Schwarzschild, Ascherio, Kieburtz, Macklin. Acquisition of data: Espay, Gartner, Hung, Bwala, Lenehan, Encarnacion, Ainslie, Castillo, Togasaki, Barles, Friedman, Niles, Carter, Murray, Goetz, Jaglin, Ahmed, D. S. Russell, Cotto, Goudreau, D. Russell, Parashos, Ede, Saint-Hilaire, Thomas, James, Stacy, Johnson, Gauger, de Marcaida, Thurlow, Isaacson, Carvajal, Rao, Cook, Hope-Porche, McClurg, Grasso, Logan, Orme, Ross, Brocht, Constantinescu, Sharma, Venuto, Weber, Eaton. Analysis and interpretation of data: Schwarzschild, Beal, Cudkowicz, Curhan, Hare, Hooper, Kieburtz, Macklin, Oakes, Rudolph, Shoulson, Tennis. Drafting of the manuscript: Schwarzschild, Ascherio, Macklin. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Macklin. Obtaining funding: Schwarzschild, Ascherio, Kieburtz, Macklin. Administrative, technical, and material support: Espay, Hung, Bwala, Lenehan, Encarnacion, Ainslie, Castillo, Togasaki, Barles, Niles, Murray, Goetz, Jaglin, D. S. Russell, Goudreau, D. Russell, Parashos, Ede, James, Johnson, de Marcaida, Thurlow, Isaacson, Rao, Cook, Hope-Porche, McClurg, Grasso, Logan, Orme, Ross, Brocht, Constantinescu, Sharma, Venuto, Weber, Eaton. Study supervision: Schwarzschild, Ascherio, Beal, Cudkowicz, Curhan, Hare, Hooper, Kieburtz, Macklin, Oakes, Rudolph, Shoulson, Tennis. Published Online: December 23, 2013. doi:10.1001/jamaneurol.2013.5528. The Parkinson Study Group SURE-PD Investigators: Michael A. Schwarzschild, MD, PhD;
analyses that incorporated UPDRS data over 2 years in SURE-PD corroborate the suggestion of a dose-dependent attenuation of clinical decline by inosine. Data on time to disability did not indicate delayed disability among participants receiving inosine, although power for this secondary analysis was minimal. Interestingly, treatment with inosine appeared to prevent slight worsening of depressive symptoms during the trial, a finding that if substantiated could strengthen the longstanding theory30 and early evidence31,32 of enhanced motivation as the basis for urate elevation during human evolution.
Conclusions The SURE-PD trial provides strong evidence that long-term administration of oral inosine can be generally safe and well tolerated by patients with early PD and increases both serum and CSF urate levels in a dose-dependent fashion. Secondary analyses suggest that a disease-modifying benefit of inosine is plausible. Together with previous findings, these of the present study support a more definitive trial of inosine as a potential treatment to slow the clinical progression of PD.
Alberto Ascherio, MD, DrPH; M. Flint Beal, MD; Merit E. Cudkowicz, MD; Gary C. Curhan, MD; Joshua M. Hare, MD; D. Craig Hooper, PhD; Karl D. Kieburtz, MD; Eric A. Macklin, PhD; David Oakes, PhD; Alice Rudolph, PhD; Ira Shoulson, MD; Marsha K. Tennis, RN; Alberto J. Espay, MD, MSc; Maureen Gartner, RN, MEd; Albert Hung, MD, PhD; Grace Bwala, MBBS; Richard Lenehan, MD; Elmyra Encarnacion, MD; Melissa Ainslie; Richard Castillo; Daniel Togasaki, MD, PhD; Gina Barles; Joseph H. Friedman, MD; Lisa Niles, MS; Julie H. Carter, RN, MN, ANP; Megan Murray, MA; Christopher G. Goetz, MD; Jeana Jaglin, RN, CCRC; Anwar Ahmed, MD; David S. Russell, MD, PhD; Candace Cotto, RN; John L. Goudreau, DO, PhD; Doozie Russell; Sotirios Andreas Parashos, MD, PhD; Patricia Ede, RN; Marie H. Saint-Hilaire, MD; Cathi-Ann Thomas, RN, MS; Raymond James; Mark A. Stacy, MD; Julia Johnson, MD; Lisa Gauger, BA; J. Antonelle de Marcaida, MD; Sheila Thurlow, MSN, BSN; Stuart H. Isaacson, MD; Lisbeth Carvajal; Jayaraman Rao, MD; Maureen Cook, RN, BSN; Charlise Hope-Porche, RN; Lauren McClurg; Daniela L. Grasso; Robert Logan, MS; Constance Orme, BA; Tori Ross; Alicia F. D. Brocht; Radu Constantinescu, MD; Saloni Sharma, MBBS; Charles Venuto, PharmD; Joseph Weber; Ken Eaton. The Parkinson Study Group SURE-PD Investigators Affiliations: Massachusetts General Hospital, Boston, Massachusetts (Schwarzschild, Cudkowicz, Macklin, Hung, Bwala); Harvard School of Public Health, Boston, Massachusetts (Ascherio); Cornell University, New York, New York (Beal); Brigham and Women’s Hospital, Boston, Massachusetts (Curhan); University of Miami, Miami, Florida (Hare); Thomas Jefferson University, Philadelphia, Pennsylvania (Hooper); University of Rochester, Rochester, New York (Kieburtz, Oakes, Rudolph); Georgetown University, Washington, DC (Shoulson); Peterborough, New Hampshire (Tennis); University of Cincinnati, Cincinnati, Ohio (Espay, Gartner); Scott & White Memorial Hospital/Texas A&M University, Temple (Lenehan, Encarnacion, Ainslie, Castillo); University of
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Southern California, Los Angeles (Togasaki, Barles); Butler Hospital, Providence, Rhode Island (Friedman, Niles); Oregon Health & Science University, Portland (Carter, Murray); Rush University Medical Center, Chicago, Illinois (Goetz, Jaglin); Cleveland Clinic, Cleveland, Ohio (Ahmed); Institute of Neurodegenerative Disorders, New Haven, Connecticut (D. S. Russell, Cotto); Michigan State University, East Lansing (Goudreau, D. Russell); Struthers Parkinson’s Center, Golden Valley, Minnesota (Parashos, Ede); Boston University, Boston, Massachusetts (Saint-Hilaire, Thomas, James); Duke University, Durham, North Carolina (Stacy, Johnson, Gauger); Eastern Connecticut Neurology Specialists, Manchester (Antonelle de Marcaida, Thurlow); Parkinson’s Disease & Movement Disorder Center of Boca Raton, Boca Raton, Florida (Isaacson, Carvajal); Ochsner Clinic Foundation, New Orleans, Louisiana (Rao, Cook, Hope-Porche); Administrative Coordination Center, Massachusetts General Hospital, Boston (McClurg, Grasso, Logan); Clinical Coordination Center, University of Rochester, Rochester, New York (Orme, Ross, Brocht, Constantinescu, Sharma, Venuto, Weber, Eaton). Conflict of Interest Disclosures: None of direct relevance to the drug development of inosine, the potential therapy under study. Note that in accordance with conflict of interest policy of Parkinson Study Group (http://www.parkinson -study-group.org/parkinson-research/constitution -and-bylaws) all SURE-PD steering committee members, site investigators, and site coordinators should have no financial relationship with any involved company during the study. Although the study received no commercial support, Kyowa Hakko USA Inc, its affiliate Kyowa Pharmaceutical Inc, and their parent company Kyowa Hakko Kirin Co Ltd were designated as the only “involved companies.” The designations were based on the use of Kyowa Hakko USA as the vendor from which inosine was obtained (as the active pharmaceutical ingredient for study drug manufacture) through an
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Research Original Investigation
Inosine to Increase Urate in Parkinson Disease
unsubsidized retail purchase. All authors provided signed attestation annually that they have no financial relationship with any involved company during the study, except that Dr Stacy indicated in 2013 that in 2012 he renewed a consulting relationship with Kyowa Hakko Kirin Co Ltd over a drug (istradefylline) intended to treat PD that is otherwise unrelated to inosine. Dr Goetz reports consulting and advisory board membership with honoraria from AOP Orphan, Addex Pharma, Advanced Studies of Medicine, Boston Scientific, CHDI, Health Advances, ICON Clinical Research, Ingenix (i3 Research), National Institutes of Health, Neurocrine, Oxford Biomedica, and Synthonics. He received grants/research funding from the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Research (MJFF). Dr Goetz directs the Rush Parkinson’s Disease Research Center that receives support from the Parkinson’s Disease Foundation. He directs the translation program for the Movement Disorder Society–sponsored revision of the UPDRS and the Unified Dyskinesia Rating Scale and receives funds from the Movement Disorder Society for this effort. He also received honoraria from the Movement Disorder Society, American Academy of Neurology, University of Pennsylvania, University of Chicago, and University of Luxembourg. He has received royalties from Oxford University Press, Elsevier Publishers, and Wolters Kluwer Health Lippincott, Wilkins and Williams. No other disclosures were reported. Funding/Support: This project was funded by a grant from the MJFF. Additional support was provided by National Institutes of Health grant K24NS060991, Harvard NeuroDiscovery Center, the RJG Foundation, and the Parkinson’s Disease Foundation Advancing Parkinson’s Therapies initiative. Disclaimer: The views, findings, and opinions expressed in this publication are those of the authors and do not necessarily represent those of the MJFF. Dr Shoulson is the JAMA Neurology Section Editor for Clinical Trials but was not involved in the review process or the acceptance of the manuscript. Role of the Sponsor: No funder was involved in the design and conduct of the study, other than through the provisions of funds for the study. No funder had a role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We are grateful for the invaluable contributions of the study participants and their families, as well as for the key contributions and dedication of the Data and Safety Monitoring Committee members: Caroline M. Tanner, MD, PhD (chair), Bruce Levin, PhD, Grace S. Liang, MD, and Nina E. Tolkoff-Rubin, MD; MJFF staff and leadership serving as grantor/nonvoting members of the Steering Committee: Brian K. Fiske, PhD, Alison Urkowitz, and Todd B. Sherer, PhD; Project Advisors to the MJFF: Jeffrey M. Bronstein, MD, PhD, and David M. Weiner, MD; Clinical Materials Services Unit (www.clinicalmaterial.com) of the Center for Human Experimental Therapeutics at the University of Rochester Medical Center: Patrick Bolger, Tim Hackett, Cornelia Kamp, MBA, Ellen Weinberger, and Joan Woodcook; and other contributing clinical site staff including Linda Baldwin (deceased).
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