Accepted Manuscript One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan Hirotaka Iwaki, Ando Rina, Noriyuki Miyaue, Satoshi Tada, Tomoaki Tsujii, Hayato Yabe, Noriko Nishikawa, Masahiro Nagai, Masahiro Nomoto PII: DOI: Reference: S0022-510X(17)34411-8 doi:10.1016/j.jns.2017.10.030 JNS 15625 To appear in: Journal of the Neurological Sciences Received date: Revised date: Accepted date: 20 August 2017 27 September 2017 23 October 2017 Please cite this article as: Hirotaka Iwaki, Ando Rina, Noriyuki Miyaue, Satoshi Tada, Tomoaki Tsujii, Hayato Yabe, Noriko Nishikawa, Masahiro Nagai, Masahiro Nomoto , One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi:10.1016/ j.jns.2017.10.030 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson’s disease in Japan. 1 1 1 1 1 1 Hirotaka Iwaki , Ando Rina , Noriyuki Miyaue , Satoshi Tada , Tomoaki Tsujii , Hayato Yabe , Noriko 1 1 Nishikawa , Masahiro Nagai , Masahiro Nomoto 1 T 1. Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, IP Japan CR Corresponding author: Hirotaka Iwaki US Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan Tel.: +81 89 960 5095 AC CE PT ED M AN email@example.com ACCEPTED MANUSCRIPT Keyword： Parkinson's disease; Inosine; Urate; Uric Acid; Clinical trial; Oxidative stress; Antioxy dant; Asian; T Abstract IP Background: Epidemiological studies have repeatedly reported that increased serum urate level is associated with a slower progress of Parkinson’s disease (PD). The urate precursor, CR inosine, raises the serum urate level and is therefore a candidate for a disease modifying treatment. However, an elevated serum urate level is a risk factor for gout, urolithiasis, and US cardiovascular diseases. Although there have been previous clinical studies, the use of inosine in a clinical setting is still limited, and its safety is unclear, especially in an Asian population. AN Methods: We conducted a single-arm, single-center clinical trial to assess the safety of inosine for PD patients with relatively low urate levels. After informed consent, 10 subjects M were orally administered inosine to maintain a target urate level between 6.0 mg/dl and 8.0 mg/dl for one year. All adverse effects were recorded and categorized by severity. Also, the ED efficacy of using inosine to raise the serum urate level was reported. Results: We did not observe any adverse events requiring termination or reduction of the study drug, although uric acid crystalluria was transiently observed in a single subject. An PT inosine dosage of 1070 (SD=501) mg/day significantly raises the urate level from 3.5 (0.84) mg/dl at baseline to 6.68 (1.11) mg/dl at the 52nd week. CE Conclusions: Inosine was safely used for one year and effectively raised urate levels in a small group of subjects. Our study is the first report to use inosine for patients with PD in AC an Asian population. ACCEPTED MANUSCRIPT Introduction Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases, affecting about 0.4 % of the general population between the ages of 60 to 69, and 1.0 % of those between 70 and 79. 1 The mechanism of developing PD is unknown but there is much evidence that an oxidative process is involved. 2–4 The most abundant antioxidant in the T human body is urate5,6. High serum urate levels have been shown to be associated with IP lower incidence as well as slower progression of PD 7– 11. Moreover. recent studies of urate supporting the causal link between urate and PD. CR transporter SNPs and PD support the hypothesis that urate is protective against PD, 12–14 US Urate is also regarded as a potential protective agent for Multiple Sclerosis (MS), and there have been several studies to investigate its potential. To raise serum urate levels in MS patients, a urate precursor, inosine, was orally administered in the clinical trials. 11 It has AN been used for up to three years for patients with MS,15,16 and successfully raised serum urate levels. The only serious adverse event was urolithiasis, which was safely controlled M with hydration and the cessation of inosine medication. Although a high serum urate level can result in gout and urolithiasis; and it is also reported to be associated with kidney ED dysfunction, stroke, and coronary heart disease1 7; these previous research results may advocate inosine usage in PD patients. In fact, after the initiation of our study, a clinical trial to apply inosine for PD patients (SURE-PD study) was reported from the United PT States. CE However, even combining MS patients and PD patients together, the total number of patients reported to have used inosine is only 206, 15,16,18–21, too few to conclude the safety AC profile for inosine. And most of those were MS patients (156 people), who are a relatively young population than those with PD. Moreover, all these studies were conducted in either Europe or the United States, illustrating the need for additional safety information, especially in an Asian population. We conducted rigorous safety assessments of the use of inosine for PD patients, as well as an assessment of the efficacy of using inosine to increase the serum urate level among Japanese PD patients, in a single-arm, single-center trial. This is the first report of clinical usage of inosine in PD patients in Asian population. ACCEPTED MANUSCRIPT Method Stu dy design and participants The study was a single-center, non-randomized, open-label trial conducted in Ehime T University Hospital in Ehime, Japan, from October 9th, 2012 to August 3rd, 2016. We IP enrolled patients older than 20 years old of age with idiopathic PD, diagnosed by UK Parkinson’s disease Brain Bank criteria, with lower serum urate levels than the average in CR the PD cohort of Ehime University Hospital (male 5.5 mg/dL, female 4.2 mg/dL). We excluded patients with low pH urine at baseline (< 5.0) or with a history of gout, US urolithiasis, chronic heart diseases or kidney diseases, due to the possibility of a higher risk of adverse events. All the participants gave informed consent to a protocol approved by Ehime University’s institutional review board of clinical research ethics. The outline of the AN protocol has been avalable as of October 9th, 2012, on the public database UMIN-CTR, editors (ICMJE). M which complies with recommendations of the International committee of medical journal (Publishing site; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000010637). ED Upon enrolment, patients undertook medical checkups as well as assessments of the severity of Parkinson’s disease using Hoehn and Yahr’s Stage and Unified Parkinson’s disease rating scale part II and III. Their medical history, other comorbidities, and PT medications were also recorded. Procedures CE In the study phase, oral inosine of 1000mg/day (morning and evening, 500 mg/tablet each) was administered to participants. Blood and urine samples were taken at each visit AC (usually 3-5 hours after inosine medication; Approximate peak 20). According to their serum urate levels, the dose was titrated between 500 and 2000 mg per day with a 250 mg ladder to achieve a serum urate level between 6.0 mg/dL to 8.0 mg/dL. The initial 12 weeks were defined as a titration period, where they visited us 2, 4, 8, and 12 weeks after initiation of the medication. Then, participants were scheduled to visit the study site with an interval of 8 weeks at the longest, for 52 weeks. The research investigators were allowed to change the dosage of inosine according to the participants’ serum urate levels in this maintenance period, if necessary. Inosine medication was finished at the visit in the 52nd week and, barring complications, participants were discharged from the study after the safety ACCEPTED MANUSCRIPT check-ups at the 56th week. Measurements At each visit, participants had routine medical examinations and any new symptoms or possible inosine complications were recorded in case reports. Because the doctors were able to adjust anti-Parkinson’s medications, any prescription change was also recorded at each T visit. Routine assessments of the severity of the disease were scheduled at the visits in the IP 4th, 16th, 36th, 52nd and 56th weeks. The complete blood counts and general lab tests such as liver enzymes and kidney function markers were checked. Urine analysis included urine pH, urate concentrations and urine density. Also, CR microscopic observation for stones, physiological studies such as kidney echogram, echocardiogram, and electrocardiograms US were checked every three months. Participants left the study when they withdrew informed consent or didn’t comply with the protocol at all (e.g., < 50% drug compliance), or when investigators found it difficult or harmful to continue the study. AN Statistical analysis For the safety analysis, we summarized all of the adverse events we observed and their M severity as: “severe” in cases of death, hospitalization, or any condition that would necessitate the subject being withdrawn from the study or told to stop taking the ED medication because of safety concerns; “moderate” when the dose of inosine should be reduced other than to achieve the target urate range; and “mild” as symptoms or phenomena that could be followed-up without intervention. To detect any asymptomatic or PT unnoticed adverse events, we also compared patients’ laboratory and physiological data as well as disease-specific scores at the 52nd week to baselines. The efficacy of inosine CE increasing serum urate levels in a target dose is described by the serum urate level at the 52nd week compared with the baseline. Also, the achievement ratio was calculated as AC follows: if the urate level was within the target level on a particular visit, the whole duration from one day after the last visit to the present day were counted as achieved, and it was divided by the entire duration of the maintenance period. Test results at the 52nd week (the end of medication) were compared between those at baseline with a paired t-test for continuous variables or signed rank test for non-parametric variables. We used the double-sided significance level of 0.05 in the analyses conducted with SAS® (version 9.4, SAS Institute Inc., Cary, NC, U.S.A). ACCEPTED MANUSCRIPT Results Among 23 screened, a total of 10 patients (4 males and 6 females) participated in the study. They all finished the last scheduled visit at the 56th week. Their baseline demographics are summarized in Table 1. Regarding safety, no severe or moderate complications were observed. All the adverse events defined as mild were transient, and these incidents were T likely unrelated to inosine (Table 2). Among lab tests of urine and blood, one patient had IP uric acid crystalluria, but it was only observed once and never again. CR When we compared the baseline data with those at the 52nd week, the urine pH at the 52nd week compared with the baseline showed a marginal difference (p = 0.07, Table 1), US and the chronological boxplots seemed to change downward after the initiation of inosine medication (Figure 1C). Also, the amount of urate per 1.0 g of urine creatinine increased as the serum level of urate increased. Vital signs such as body weight, blood pressure, heart AN rate, and the lab test results of the blood and the urine did not show significant changes at the 52nd week from the baseline. The disease-specific symptomatic markers did not differ M significantly between the baseline and the 52nd week with a similar level of treatment strength (Table 1 and Figure 1D). The physiological tests using echography or electric ED cardiograms did not detect any abnormality either. At the 52nd week, the mean serum urate level was 6.68 (SD; 1.11) mg/dL, which was significantly different from the baseline of 3.50 (0.84) mg/dL (p < 0.001), with the inosine PT dosage of 1075 (501) mg/day (Table 1). The ratio of achieving the serum urate level within the target range of 6.0-8.0 during the maintenance period was 61%. The mean urate levels, CE as well as the prescription dosage, were relatively stable over the medication period, with the swift return to baseline level as soon as four weeks from the termination of the AC medication (Figures 1A/B). Discussion We used inosine medication to raise the serum urate levels of patients with PD and with lower urate levels for one year, and did not observe any adverse events that required stopping or decreasing inosine. We adjusted the individual dosage to maintain the target serum urate level between 6.0 – 8.0 mg/dL, and the serum urate level was effectively increased by inosine. But the ratio of achieving the target range during maintenance period was 61%, lower than expected. We assume this was partially because we were trying to avoid the possible complications of high urate levels. In fact, participants had serum urate ACCEPTED MANUSCRIPT levels between 5.5 and 5.9 mg/dL, a little lower than the target range, in 16% (16/100) of the visits in the maintenance period. Serum urate fluctuations might also have affected the achievement. 11% of all visits (17/150) had more than a 1.5 mg/dL difference in the serum urate level from the previous visit with the same inosine dosage. If a subject forgot their morning medication, the serum urate level would on average decrease by 1.0 mg/dL from T the previous reports20, in addition to 0.5 mg fluctuations within individuals. 22 Therefore, IP the duration between the last medication and blood sampling mattered although we do not CR have the data to confirm this. We conducted post-hoc analysis of the dose response relationship and it indicates that the US serum urate level measured at the first visit after the initiation of inosine is useful to predict the maintenance dose (Supplement table). There may be other variables such as body weight and baseline urate levels, but our date size was too small to develop a full AN prediction model. Such an approach may be taken for future study. M The major difference of our study from previous studies is its population’s characteristics. Our participants were all Asians (Japanese) and the oldest among all the studies using ED inosine. Epidemiological studies reveal that the prevalence of gout in Japan is rarer than in western countries and the prevalence of patients with gout by age and sex are also different.23,24 In addition, the distribution of urate transporter related SNPs is different. 25 PT Yet despite these differences, we did not find any problematic comp lications, including the associated diseases. When using inosine, the most common adverse event reported is CE urolithiasis, but we did not observe this. It may relate to the small number of participants, but the relatively modest elevation of urate in our participants may be a reason, too. For AC example, SURE-PD study reported zero events in the placebo group, one event among 24 in the mild (6.1-7.0) urate elevation group, and two events among 26 in the moderate (7.1-8.0) urate elevation group.20 Another difference is that we observed a marginal decline in urine pH after inosine initiation. Considering our small study size, it is more likely an observation by chance, but can be a population difference. Acidic urine is a known risk factor for urolithiasis, 26 as well as a high concentration of urate in urine, which was observed in our analysis (Table 1). Also, the average increase in the serum urate level of inosine was larger in our study (+3.2 ACCEPTED MANUSCRIPT mg/dL by 1.08 g/day of inosine) than observed in SURE-PD (+2.3 mg/dL by 1.18 g/day and +3.0 mg/dL by 1.51 g/d ), which may reflect the population difference. Again, we stress the importance of titration according to individuals. In the secondary analysis of SURE-PD study, it showed UPDRS based non-futility of inosine as a disease modifier. Interestingly, our 10 participants did not show disease progression during the study period, and it made IP T us feel more optimistic about the disease-modifying potential of inosine. One limitation of our study was its small size. However, as this was the first study using CR inosine in an Asian PD population, we intentionally chose a small sample size. Although we don’t have enough data to conclude the safety of inosine, the sample size was still sufficient US to assess the efficacy of inosine to raise serum urate levels. Another limitation was the single-arm design, which precluded us from assessing the association of inosine medication and the incidence of adverse events by comparing them to a placebo group. However, we did AN not find any clinically relevant adverse events other than uric acid crystalluria, and as we described all the adverse events, the information may be useful for combined safety M analysis in the future. ED Out strength was that our vigorous safety assessment of using inosine for PD patients supports the safety of inosine in an older, Asian population, one that is distinct from the European and North American populations that have already been studied. These results PT warrant inosine application for wider populations, and support the next step of larger clinical trials to assess the further safety as well as efficacy of inosine for preventing or AC Conclusion CE modifying the development of Parkinson’s disease. We conducted the safety and efficacy assessment of using inosine for PD patients for the first time in an Asian population. Inosine effectively raised serum urate levels of participants with relatively low dosages than in other studies in Europe and the U.S., and we have not observed any problematic adverse effect. This study will encourage the next step in the assessment of the efficacy and the safety of using inosine for PD patients. Acknowledgment We thank Kanno Mari for her precise data handling and management. We also appreciate ACCEPTED MANUSCRIPT insight and advice of Donald Halsted and Karen Dobson, who were kind enough to review this manuscript. Contributors Dr. Iwaki and Dr. Nomoto contribute to the conception of the study. Dr.Iwaki also designed T the study and analyzed and interpreted the results. Dr. Ando, Dr.Miyaue, Dr.Tada, Dr. Tsujii, Dr. IP Yabe, Dr.Nishikawa, Dr. Nagai and Dr. Nomoto acquired the data and all of them contributed to the draft CR and gave the final approval of the manuscripts. Disclosure US Dr. Nomoto has received speaker's honoraria from Dainippon Sumitomo Pharma Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., Kyowa Hakko Kirin Co., Ltd., Novartis Pharma K.K., and Otsuka AN Pharmaceutical Co., Ltd. The other authors have nothing to disclose. Funding M This work was financially supported by a hospital research grant from Ehime University AC CE PT ED Hospital. ACCEPTED MANUSCRIPT References 1. Pringsheim T, Jette N, Frolkis A, Steeves TDL. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29(13):1583-1590. doi:10.1002/mds.25945. 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ACCEPTED MANUSCRIPT At 52nd week P value N 10, female 6 - - Race – Asian (%) 10 (100 %) - - Age, years 67.3 (10.9) - - BMI, kg/cm2 21.7 (2.5) - - Disease duration, years 8.7 [1.5, 13.0] - Wearing Off, N (%) 4 (40%) - Inosine dosage, mg/day - 1075 (501) - Serum level of urate, mg/dL 3.50 (0.84) 6.68 (1.11) <0.001 Urine pH 7.0 [6.0, 7.5] 6.5 [5.0, 7.0] 0.07 eGFR, ml/min/m2 79.0 (10.7) 73.5 (7.2) 0.108 Urine urate, mg /1.0 g creatinine 0.53 (0.18) 0.92 (0.29) 0.011 Hoehn and Yahr Scale 2.5 [2.0, 5.0] 2.5 [2.0, 4.0] 1.00 UPDRS part II 6.5 (4.1) 6.8 (4.2) 0.56 UPDRS part III 14.4 (7.5) 11.3 (6.6) 0.29 400 (225) 420 (224) 0.17 699 (417) 715 (420) 0.39 IP CR US ED Levodopa Equivalent Dose, mg/day M Levodopa Medication, mg/day T Baseline AN Table 1 Summary Characteristics - Values are means(SD) or Median [range], unless specified. PT BMI, body mass index; eGFR, estimated glomerular filtration rate; UPDRS, unified AC CE Parkinson’s disease rating scale. ACCEPTED MANUSCRIPT Table 2 Adverse events N (out of 10) 0 Moderate 0 Mild 15 T Severe 4 (3 unknowns, 1 herpes simplex virus) Pain 3 (1 back pain, 1 pelvic pain, 1 knee pain) Glucose Resistance 1 Nausea 1 Dizziness 1 Overacting bladder 1 Cyst formation under a lib bone 1 CR US AN Tinea pedis 1 1 M Hemorrhoids Asymptomatic CE PT ED Uric acid crystalluria AC IP Virus infection 1 1 ACCEPTED MANUSCRIPT Figure 1 Legend: The trend of the key measurements over the study duration. A: The serum urate level over the study period. (Error bar; SD) B: The mean inosine dosage over the study period. (Error bar; SD) C: Boxplot of urine pH over the study period. AC CE PT ED M AN US CR IP T D: UPDRS part III score over the study period.(Error bar; SD) ACCEPTED MANUSCRIPT Figure 1 C B D AC CE PT ED M AN US CR IP T A ACCEPTED MANUSCRIPT Highlights Inosine was used for the first time in clinical research with an Asian population with Parkinson’s disease. There were no problematic adverse effects in a small group of patients. Inosine effectively raised serum urate levels of participants with relatively lower AC CE PT ED M AN US CR IP T dosages than in other studies in Europe and the U.S.