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Safety and effectiveness of istradefylline as add-on therapy to levodopa in patients with Parkinson's disease: Final report of a post-marketing surveillance study in Japan

Open AccessPublished:October 28, 2022DOI:https://doi.org/10.1016/j.jns.2022.120479

      Highlights

      • PD patients may experience wearing-off symptoms after long-term levodopa use.
      • We studied long-term safety/effectiveness of real-world use of istradefylline for PD.
      • Common istradefylline adverse drug reactions included dyskinesia and hallucination.
      • <5% of patients experienced a psychiatric adverse drug reaction.
      • Istradefylline had broad effectiveness across multiple motor symptom assessments.

      Abstract

      Introduction

      Istradefylline is approved in Japan and the US for treatment of Parkinson's disease (PD) in adult patients who experience the wearing-off phenomenon while receiving levodopa; however, safety and efficacy data for real-world clinical use are lacking.

      Methods

      We report the final results of a prospective, long-term, post-marketing surveillance study of istradefylline adjunct to levodopa for adults with PD experiencing the wearing-off phenomenon. Patients across 214 study sites initiating treatment with oral istradefylline once-daily 20- or 40-mg were followed-up for 1 year. We collected demographic data, disease and treatment histories, and recorded adverse events and adverse drug reactions (ADRs). The priority survey item was the occurrence of psychiatric ADRs. Effectiveness was evaluated by the physician's global and motor function assessments.

      Results

      Case report forms were collected for 1320 patients, and the safety and effectiveness analysis sets included 1318 and 1284 patients, respectively. The mean age was 71.5 years and 56.2% of patients were women. A total of 274 patients (20.8%) experienced an ADR, 39 patients had a serious ADR, and 7 patients had a fatal ADR that was considered not related to istradefylline. Common ADRs included dyskinesia, hallucination, and visual hallucination. Sixty-five patients (4.9%) experienced a psychiatric ADR. Istradefylline was effective (physician-rated) in 59.8% of patients, and most patients had reduced or unchanged off-time duration, improved or unchanged off-time symptoms, and improved or unchanged motor symptoms.

      Conclusion

      Istradefylline safely and effectively improves motor symptoms in PD patients experiencing the wearing-off phenomenon with levodopa therapy in the real-world setting.

      Keywords

      Abbreviations:

      ADR (adverse drug reaction), AE (adverse event), COMT (catechol-O-methyltransferase), H&Y (Hoehn & Yahr), MAO-B (monoamine oxidase-B), MedDRA/J (Medical Dictionary for Regulatory Activities, Japanese version), PD (Parkinson's disease), PMS (post-marketing surveillance), SD (standard deviation), UPDRS (Unified Parkinson's Disease Rating Scale)

      1. Introduction

      Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which are now the leading cause of motor disability impacting quality of life [
      • Dorsey E.R.
      • Bloem B.R.
      The Parkinson pandemic—a call to action.
      ,
      GBD 2016 Parkinson’s Disease Collaborators
      Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.
      ]. Moreover, the PD “pandemic” is expanding at a faster rate than any other neurological disease [
      • Dorsey E.R.
      • Bloem B.R.
      The Parkinson pandemic—a call to action.
      ]. The global prevalence of PD has more than doubled over the past quarter of a century, from an estimated 2.5 million individuals in 1990 to over 6 million individuals in 2016 [
      GBD 2016 Parkinson’s Disease Collaborators
      Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.
      ], and is expected to exceed 14 million individuals by 2040 [
      • Dorsey E.R.
      • Bloem B.R.
      The Parkinson pandemic—a call to action.
      ]. Furthermore, because the incidence of PD increases with age [
      • Van Den Eeden S.K.
      • Tanner C.M.
      • Bernstein A.L.
      • et al.
      Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity.
      ], this is of particular relevance in Japan, owing to the country's aging population.
      PD is primarily associated with motor symptoms such as resting tremor, rigidity, akinesia/bradykinesia, postural instability, and gait disturbance [
      • Moustafa A.A.
      • Chakravarthy S.
      • Phillips J.R.
      • et al.
      Motor symptoms in Parkinson’s disease: a unified framework.
      ]. The pathophysiology of such motor symptoms has yet to be fully elucidated, but it is thought to be primarily a result of progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta [
      • Barzilai A.
      • Melamed E.
      Molecular mechanisms of selective dopaminergic neuronal death in Parkinson’s disease.
      ]. Recent research has also implicated non-dopaminergic pathways in disease progression with respect to motor symptoms [
      • Magrinelli F.
      • Picelli A.
      • Tocco P.
      • et al.
      Pathophysiology of motor dysfunction in Parkinson’s disease as the rationale for drug treatment and rehabilitation.
      ]. Patients with PD suffer deficits in quality of life owing to motor symptoms, illustrating the need for effective interventions to preserve physical function and patient wellbeing [
      • Zhao N.
      • Yang Y.
      • Zhang L.
      • et al.
      Quality of life in Parkinson’s disease: a systematic review and meta-analysis of comparative studies.
      ,
      • Kurihara K.
      • Nakagawa R.
      • Ishido M.
      • et al.
      Impact of motor and nonmotor symptoms in Parkinson disease for the quality of life: the Japanese Quality-of-Life Survey of Parkinson Disease (JAQPAD) study.
      ].
      The gold standard pharmacotherapy for PD since the 1960s has been dopamine replacement therapy with the dopamine precursor levodopa. Other therapies include dopamine receptor agonists, monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, and device-aided therapy such as deep brain stimulation [
      • Cacabelos R.
      Parkinson’s disease: from pathogenesis to pharmacogenomics.
      ]. Additionally, the anticonvulsant zonisamide is available in Japan as an adjunct to levodopa therapy for motor symptoms of PD [
      • Murata M.
      • Odawara T.
      • Hasegawa K.
      • et al.
      Adjunct zonisamide to levodopa for DLB parkinsonism: a randomized double-blind phase 2 study.
      ]. Despite the availability of therapeutic options, optimal treatment remains controversial, as the wearing-off phenomenon, dyskinesia, and cardiovascular, gastrointestinal, and psychiatric side effects remain common [
      • Connolly B.S.
      • Lang A.E.
      Pharmacological treatment of Parkinson’s disease: a review.
      ]. Furthermore, the improper stimulation of dopamine receptors in both the central nervous system and peripheral tissues can lead to dopamine dysregulation syndrome, which illustrates a need for non-dopaminergic treatment options [
      • Evans A.H.
      • Lees A.J.
      Dopamine dysregulation syndrome in Parkinson’s disease.
      ].
      Istradefylline is a first-in-class, selective adenosine A2A receptor antagonist with a mechanism of action that is unique among existing pharmacotherapies. Istradefylline does not target dopamine receptors or dopamine-associated enzymes (e.g., MAO-B, COMT) [
      • Saki M.
      • Yamada K.
      • Koshimura E.
      • Sasaki K.
      • Kanda T.
      In vitro pharmacological profile of the A2A receptor antagonist istradefylline.
      ] and is thought to act exclusively on adenosine A2A receptors, which localize in the striatopallidal pathway (indirect pathway) of the basal ganglia [
      • Mori A.
      How do adenosine A 2A receptors regulate motor function?.
      ]. Animal studies have demonstrated the ability of selective adenosine A2A receptor agonists to induce motor deficits, which can be reversed by A2A receptor antagonists, illustrating the potential of the A2A receptor as a pharmacological target for treatment of motor deficits in PD [
      • Jenner P.
      • Mori A.
      • Aradi S.D.
      • Hauser R.A.
      Istradefylline - a first generation adenosine A2A antagonist for the treatment of Parkinson’s disease.
      ]. Istradefylline was first approved in Japan in 2013 as add-on therapy to levodopa for adult patients experiencing the wearing-off phenomenon and was subsequently approved for this use in the US in 2019 [
      • Dungo R.
      • Deeks E.D.
      Istradefylline: first global approval.
      ,
      • US Food and Drug Administration
      FDA approves new add-on drug to treat off episodes in adults with Parkinson’s disease [press release].
      ].
      The present post-marketing surveillance (PMS) study was mandated by the Japanese regulations for PMS, in which the Pharmaceutical and Medical Devices Agency of Japan requires evaluations for safety and effectiveness of a newly approved drug to be conducted in real-world clinical settings. An interim analysis of this study was previously published [
      • Takahashi M.
      • Fujita M.
      • Asai N.
      • Saki M.
      • Mori A.
      Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan.
      ] and the present report describes the final results. The study objectives were to evaluate the incidence of adverse drug reactions (ADRs) with a particular focus on psychiatric ADRs, identify unexpected ADRs, and identify any factors potentially affecting the safety or effectiveness of the long-term use of istradefylline as add-on therapy to levodopa in patients with PD experiencing the wearing-off phenomenon. Notably, the interim analysis lacked sufficient patient numbers to evaluate psychiatric ADRs; thus, the present report aimed to clarify this outcome.

      2. Methods

      2.1 Study design

      This is the final report of an observational PMS study of istradefylline as add-on therapy to levodopa for patients with PD; the interim analysis was published previously [
      • Takahashi M.
      • Fujita M.
      • Asai N.
      • Saki M.
      • Mori A.
      Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan.
      ]. The registration period was from 30 May 2013 until 31 May 2017, and patients were to be followed for 1 year. Patients were centrally registered from 220 participating medical institutions within Japan, including national private and public hospitals, university hospitals, outpatient clinics, and specialized neuropsychiatric hospitals.
      The eligibility criteria were as follows: patients with PD initiating treatment with oral istradefylline (20 or 40 mg, once daily) for the first time to improve symptoms of the wearing-off phenomenon while receiving levodopa therapy were recruited. There were no exclusion criteria. The trial was registered in the UMIN Clinical Trials registry under the identifier UMIN000030014.

      2.1.1 Survey items and data collection

      An electronic data capture system was used to record patient data, and investigators were required to register and transmit the data within 14 days of initiating treatment. The survey items were previously described in the interim analysis [
      • Takahashi M.
      • Fujita M.
      • Asai N.
      • Saki M.
      • Mori A.
      Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan.
      ]. Briefly, we recorded patient demographics (age, sex) and disease/treatment history (duration of PD and motor symptoms, modified Hoehn & Yahr [H&Y] severity of illness stage [both off- and on-time], levodopa use, and surgical treatment). Adverse events (AEs), ADRs, and laboratory values were collected for safety monitoring. ADRs were defined as AEs for which a causal relationship with the study drug could not be ruled out, including those of unknown causation. AEs were coded according to the Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J) v22.1 and seriousness was classified according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (E2D) guidelines.
      The priority survey item was the occurrence of psychiatric ADRs. These were defined as those included in the Japanese package insert [

      Nouriast® (Istradefylline) tablets 20 mg; Kyowa Kirin Co., Ltd. Japanese package insert, September 2021 (5th Edition). Available at: https://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/230124_1169016F1020_1_06. Accessed September 15, 2021. In Japanese.

      ] as “clinically significant adverse reactions”: hallucinations (visual, auditory, or somatic), delusions, delirium, anxiety, depression, mania, agitation, impulse control disorder, or mental disorder.
      Effectiveness was assessed according to the physician's global assessment (treatment was rated as effective, ineffective, or unevaluable), motor dysfunction (described as markedly improved, improved, unchanged, worsened, or unevaluable), motor function (based on the Unified PD Rating Scale [UPDRS] Part III total and subscores in the ‘on-state’), the wearing-off phenomenon (described as markedly improved, improved, unchanged, worsened, or unevaluable), and the change in duration of off-time (reduced, unchanged, increased, or unevaluable).

      2.2 Ethics

      This study was conducted in accordance with the Good Post-marketing Study Practice protocol and applicable Japanese regulations. Informed consent and institutional review board approval were not required for this observational study, in compliance with Good Post-marketing Study Practice.

      2.3 Statistical analysis

      Based on Japanese clinical trials that showed two ADRs occurring in 649 patients (0.3%), the current study aimed to enroll at least 1000 patients so that psychiatric symptoms could be detected in at least one patient with >95% predictive accuracy. The safety analysis set included all patients who received at least one dose of istradefylline. Patients were excluded from the effectiveness analysis if they had off-label use of istradefylline (i.e., patients were found to be levodopa-naïve only after enrollment), or were missing data for H&Y severity stage during off- and/or on-time.
      Patient characteristics were compared using descriptive statistics, and the incidences of AEs and ADRs were reported for the safety analysis set. In light of the relatively high median age of patients included in the study, ADRs were also evaluated based on age (stratified as <75 years vs ≥75 years) as a post hoc analysis. To assess patient demographic factors associated with the incidence of ADRs and the effectiveness of istradefylline, a Fisher's (2 × 2) or Cochran–Armitage (2 × n) test was used with a significance level of p < 0.05 (two-tailed). The Wilcoxon signed-rank test among individual patients (pairwise testing) was used to assess changes in UPDRS Part III scores, and the threshold for statistical significance was defined as p < 0.025 to account for multiple hypothesis testing. The contract research organization EP Croit Co., Ltd. (Tokyo, Japan) conducted the statistical analyses using SAS software, version 9.3 (SAS Institute, Inc., Cary, NC, USA).

      3. Results

      3.1 Baseline demographics and background characteristics

      A total of 1356 patients were registered from 220 sites, and completed case report forms were ultimately collected from 1320 patients (214 study sites) (Fig. 1). The safety and effectiveness analysis sets included 1318 and 1284 patients, respectively. Two patients were excluded from the safety analysis set because they did not receive istradefylline. A further 34 patients were excluded from the effectiveness analysis set for off-label use of istradefylline (n = 33) and no record of H&Y severity stage (n = 1).
      Fig. 1
      Fig. 1Patient disposition. H&Y, Hoehn & Yahr
      The patient baseline characteristics are described in Table 1. The mean (standard deviation [SD]) age was 71.5 (9.1) years and 56.2% of patients were female. The mean (SD) duration of PD was 8.8 (5.6) years, and that of motor complications was 3.6 (4.1) years. Dyskinesia at baseline was reported in 35.1% of patients. The mean (SD) levodopa dose was 414 (182) mg/day and the mean (SD) levodopa-equivalent dose was 681 (364) mg/day. The mean (SD) UPDRS Part III total score among patients assessed for all components (n = 432) was 32.8 (17.4).
      Table 1Patient baseline characteristics, safety analysis set (N = 1318).
      Variable
      Age, years
       Mean ± SD71.5 ± 9.1
       Median (range)73.0 (38–100)
      Sex
       Male577 (43.8)
       Female741 (56.2)
      Body weight, kg (n = 849)
       Mean ± SD53.3 ± 11.8
       Median (range)52.0 (26–96)
      Duration of PD, years (n = 1273)
       Mean ± SD8.8 ± 5.6
       Median (range)8.0 (0–35)
      Duration of levodopa use, years (n = 1132)
       Mean ± SD6.4 ± 4.8
       Median (range)5.0 (0−31)
      Duration of motor complications, years (n = 1028)
       Mean ± SD3.6 ± 4.1
       Median (range)2.0 (0–26)
      Concurrent dyskinesia
       Absent855 (64.9)
       Present463 (35.1)
      Daily levodopa dose, mg (n = 1272)
       Mean ± SD414.2 ± 182.1
       Median (range)400.0 (50–2250)
      Daily levodopa-equivalent dose, mg (n = 1278)
       Mean ± SD680.8 ± 363.7
       Median (range)609.0 (37.5–3142.5)
      Modified H&Y severity stage (off-time)
       02 (0.2)
       15 (0.4)
       1.510 (0.8)
       262 (4.7)
       2.583 (6.3)
       3451 (34.2)
       4497 (37.7)
       5206 (15.6)
       Unknown2 (0.2)
      Modified H&Y severity stage (on-time)
       017 (1.3)
       153 (4.0)
       1.549 (3.7)
       2285 (21.6)
       2.5225 (17.1)
       3459 (34.8)
       4187 (14.2)
       542 (3.2)
       Unknown1 (0.1)
      H&Y, Hoehn & Yahr; PD, Parkinson's disease; SD, standard deviation.
      Data are n (%), mean ± SD, or median (range).

      3.2 Istradefylline exposure and concomitant treatments

      The mean (SD) dose of istradefylline at the end of the study was 22.9 (6.1) mg/day, and most patients (76.8%, 1012/1318) were receiving a daily dose of ≤20 mg. The mean (SD) duration of istradefylline therapy was 293.9 (151.0) days. In the safety analysis set, 29.8% of patients (393/1318) discontinued istradefylline treatment, primarily owing to AEs (n = 159). Other reasons for discontinuation included “other” (n = 133), patient transfer to another institution (n = 81), disease progression (n = 28), and death (n = 15).
      In the safety analysis set, 20.0% of patients (264/1318) with an initial daily istradefylline dose of 20 mg required a dose increase; the primary reason was lack of effectiveness (i.e., to improve motor function, in 83.0% of cases). Almost all patients (1314/1318, 99.7%) had concomitant drug use, the most common of which was levodopa (97.7%) with or without a COMT inhibitor, followed by dopamine agonists (69.4%). MAO-B inhibitors were used by 29.3% of patients, and 58.1% of patients had other concomitant anti-PD drug use.

      3.3 Safety

      3.3.1 ADRs

      A total of 274 patients (20.8%) experienced an ADR: 235 patients (17.8%) had a non-serious ADR, and 39 patients (3.0%) had a serious ADR (Fig. 2). Common ADRs (i.e., incidence ≥1%) included dyskinesia (4.9%), hallucination (2.4%), and visual hallucination (1.4%). The most common serious ADRs were delirium (0.3%), delusion, fall, depression, hallucination, and acute cardiac failure (0.2% each). Seven patients (0.5%) had an ADR with a fatal outcome, which included: acute myocardial infarction, myocardial infarction, heart failure, sudden death, death, disease progression, and acute heart failure; however, none of these ADRs were deemed to have had a reasonable possibility of a causal relationship to istradefylline. Of these patients, those who experienced acute myocardial infarction, heart failure, or sudden death also had concomitant ischemic cardiac disease at baseline.
      Fig. 2
      Fig. 2Incidence of adverse drug reactions (ADRs) by seriousness (safety analysis set, N = 1318). Patients with both serious and non-serious ADRs are included in the “serious” category. Among 39 patients with a serious ADR, seven had an outcome of death.
      Patients with pre-existing dyskinesia had a higher incidence of dyskinesia as an ADR than patients without baseline dyskinesia (10.8% vs 1.6%). The highest incidence of dyskinesia according to concomitant anti-PD medication was 8.9%, observed in patients receiving concomitant entacapone (31/348). Dyskinesia was observed in 12.6% of patients receiving a dopamine agonist, 11.1% of patients receiving levodopa with or without a COMT inhibitor, 10.1% receiving a MAO-B inhibitor, and 11.9% receiving any other kind of concomitant anti-PD medication (Supplementary Table 1).
      Of the 1278 patients who initiated istradefylline at a dose of 20 mg/day, 264 patients underwent a dose increase; the incidence of ADRs was higher after dose increase than before (11.0% vs 6.4%). Common ADRs experienced by patients receiving 40-mg istradefylline were dyskinesia (4.5%, 12/264), hallucination (1.5%, 4/264), visual hallucination (1.1%, 3/264), and insomnia (0.8%, 2/264). Serious ADRs included cardiac failure, delirium, and sudden onset of sleep (each 0.4%, 1/264).

      3.3.2 Subgroup analysis of the association between ADRs and patient background

      The results of the analysis of the association between ADRs and patient background factors are shown in Table 2. Factors with statistically significant differences in the incidence of ADRs were “duration of PD” (p < 0.001), “duration of motor complications” (p = 0.021), “concurrent dyskinesia” (p = 0.028), and “daily levodopa-equivalent dose” (p = 0.0047). There were no significant differences in ADR incidence based on sex or body weight.
      Table 2ADRs by patient characteristics and significant associations.
      Factors analyzedNPatients with ADR, n (%)
      Age<75 years778161 (20.7)
      ≥75 years540113 (20.9)
      SexMale577123 (21.3)
      Female741151 (20.4)
      Body weight<Median (52.0 kg)42099 (23.6)
      ≥Median (52.0 kg)429105 (24.5)
      Unknown46970 (14.9)
      Duration of PD
      Factors significantly associated with the incidence of ADRs:•Duration of PD: p < 0.001; Cochran–Armitage test•Duration of motor complications: p = 0.021; Cochran–Armitage test•Daily levodopa-equivalent dose: p = 0.0047; Fisher's test
      <5 years28738 (13.2)
      5 to <10 years509111 (21.8)
      ≥10 years477119 (25.0)
      Unknown456 (13.3)
      Duration of levodopa use<5 years46184 (18.2)
      5 to <10 years445100 (22.5)
      ≥10 years22654 (23.9)
      Unknown18636 (19.4)
      Duration of motor complications
      Factors significantly associated with the incidence of ADRs:•Duration of PD: p < 0.001; Cochran–Armitage test•Duration of motor complications: p = 0.021; Cochran–Armitage test•Daily levodopa-equivalent dose: p = 0.0047; Fisher's test
      <1 year20542 (20.5)
      1 to <3 years34959 (16.9)
      3 to <5 years17343 (24.9)
      ≥5 years30178 (25.9)
      Unknown29052 (17.9)
      Concurrent dyskinesia
      Factors significantly associated with the incidence of ADRs:•Duration of PD: p < 0.001; Cochran–Armitage test•Duration of motor complications: p = 0.021; Cochran–Armitage test•Daily levodopa-equivalent dose: p = 0.0047; Fisher's test
      Absent855162 (19.0)
      Present463112 (24.2)
      Daily levodopa dose<450 mg804164 (20.4)
      ≥450 mg468102 (21.8)
      No dose334 (12.1)
      Unknown134 (30.8)
      Daily levodopa-equivalent dose
      Factors significantly associated with the incidence of ADRs:•Duration of PD: p < 0.001; Cochran–Armitage test•Duration of motor complications: p = 0.021; Cochran–Armitage test•Daily levodopa-equivalent dose: p = 0.0047; Fisher's test
      <Median (609.0 mg)638112 (17.6)
      ≥Median (609.0 mg)640154 (24.1)
      No dose253 (12.0)
      Unknown155 (33.3)
      Modified H&Y severity stage

      (off-time)
      020
      152 (40.0)
      1.5102 (20.0)
      26213 (21.0)
      2.5837 (8.4)
      345190 (20.0)
      4497115 (23.1)
      520645 (21.8)
      Unknown20
      Modified H&Y severity stage (on-time)0173 (17.7)
      15312 (22.6)
      1.5499 (18.4)
      228552 (18.3)
      2.522546 (20.4)
      345999 (21.6)
      418747 (25.1)
      5426 (14.3)
      Unknown

      10
      ADR, adverse drug reaction; H&Y, Hoehn & Yahr; PD, Parkinson's disease.
      a Factors significantly associated with the incidence of ADRs:
      • Duration of PD: p < 0.001; Cochran–Armitage test
      • Duration of motor complications: p = 0.021; Cochran–Armitage test
      • Daily levodopa-equivalent dose: p = 0.0047; Fisher's test

      3.3.3 Incidence of psychiatric disorders (priority survey item)

      In the safety analysis set, 4.9% of patients (65/1318) experienced a psychiatric ADR. The most common of these (i.e., incidence ≥0.2%) were hallucination (2.4%, 31/1318), visual hallucination (1.4%, 18/1318), delusion (0.5%, 7/1318), delirium (0.3%, 4/1318), depression (0.2%, 3/1318), and auditory hallucination (0.2%, 3/1318). The results of the analysis on the association between psychiatric ADRs and patient background factors are shown in Table 3. There were no factors with significant differences in the incidence of psychiatric ADRs. The psychiatric ADRs were considered to be largely attributable to patient factors such as worsening or fluctuation of disease symptoms and effects of concomitant medications.
      Table 3Psychiatric ADRs by patient characteristics.
      Factors analyzedNPatients with psychiatric ADR, n (%)
      Age<75 years77834 (4.4)
      ≥75 years54031 (5.7)
      SexMale57734 (5.9)
      Female74131 (4.2)
      Body weight<Median (52.0 kg)42017 (4.1)
      ≥Median (52.0 kg)42925 (5.8)
      Unknown46923 (4.9)
      Duration of PD<5 years2879 (3.1)
      5 to <10 years50930 (5.9)
      ≥10 years47723 (4.8)
      Unknown453 (6.7)
      Duration of levodopa use<5 years46120 (4.3)
      5 to <10 years44528 (6.3)
      ≥10 years22610 (4.4)
      Unknown1867 (3.8)
      Duration of motor complications<1 year20510 (4.9)
      1 to <3 years34918 (5.2)
      3 to <5 years17311 (6.4)
      ≥5 years30114 (4.7)
      Unknown29012 (4.1)
      Concurrent dyskinesiaAbsent85543 (5.0)
      Present46322 (4.8)
      Daily levodopa dose<450 mg80439 (4.9)
      ≥450 mg46824 (5.1)
      No dose331 (3.0)
      Unknown131 (7.7)
      Daily levodopa-equivalent dose<Median (609.0 mg)63826 (4.1)
      ≥Median (609.0 mg)64037 (5.8)
      No dose251 (4.0)
      Unknown151 (6.7)
      Modified H&Y severity stage

      (off-time)
      020
      150
      1.5100
      2622 (3.2)
      2.5831 (1.2)
      345119 (4.2)
      449734 (6.8)
      52069 (4.4)
      Unknown20
      Modified H&Y severity stage (on-time)0170
      1533 (5.7)
      1.5491 (2.0)
      228514 (4.9)
      2.522511 (4.9)
      345926 (5.7)
      41879 (4.8)
      5421 (2.4)
      Unknown

      10
      ADR, adverse drug reaction; H&Y, Hoehn & Yahr; PD, Parkinson's disease.

      3.3.4 Safety in elderly patients

      There was no statistically significant difference in the incidence of ADRs in patients <75 years of age vs ≥75 years: 20.7% (161/778) vs 20.9% (113/540), respectively (p = 0.9450). ADRs experienced by ≥1% of patients in the younger group were dyskinesia (5.7%, 44/778), hallucination (1.9%, 15/778), visual hallucination (1.3%, 10/778), and somnolence (1.0%, 8/778). In the older group, dyskinesia occurred in 3.7% (20/540) of patients, hallucination in 3.0% (16/540), visual hallucination in 1.5% (8/540), and dizziness in 1.1% (6/540).

      3.4 Effectiveness

      3.4.1 Physician's rating of effectiveness and physician's global assessment

      Among the 1284 patients in the effectiveness analysis set, 34.0% had reduced off-time duration, 43.1% experienced improvement or marked improvement in off-time symptoms, and 45.8% experienced improvements in motor symptoms (Fig. 3). According to the physician's global assessment, istradefylline was rated as effective in 59.8% of patients, ineffective in 21.0%, and unevaluable in 19.2%.
      Fig. 3
      Fig. 3Physician's global assessment of istradefylline effectiveness (A), and physician's effectiveness assessment of (B) off-time duration, (C) off-time symptoms, and (D) motor symptoms (effectiveness analysis set, N = 1284).

      3.4.2 UPDRS

      The UPDRS Part III total score results are shown in Fig. 4. Among patients with all items evaluated, there was a statistically significant decrease in total score (SD) from 32.8 (17.4) at baseline to 29.6 (17.0) at 6 months, and the decrease was maintained up to 1 year: 28.9 (16.4). Results of the UPDRS Part III subscores are described in Table 4. Improvements were observed in most of the motor subscores including resting tremor, rigidity, posture, and gait.
      Fig. 4
      Fig. 4Unified Parkinson's Disease Rating Scale (UPDRS) Part III total scores in patients with complete data for all components.
      Table 4Unified Parkinson's Disease Rating Scale (UPDRS) Part III subscores.
      Baseline6 months12 monthsp-value
      p-value was calculated based on Wilcoxon signed-rank test (vs baseline).
      nMean ± SDnMean ± SDnMean ± SD
      Language5291.2 ± 1.05211.1 ± 0.94291.1 ± 0.9<0.001
      Facial expression5461.5 ± 1.05381.3 ± 0.94431.3 ± 0.9<0.001
      Resting tremor5282.1 ± 3.25201.8 ± 2.94281.6 ± 2.6<0.001
      Kinetic/postural tremor (hand)5271.0 ± 1.65190.9 ± 1.54240.8 ± 1.3<0.001
      Rigidity4906.7 ± 4.34825.9 ± 4.23935.8 ± 4.1<0.001
      Finger tapping4962.8 ± 1.84892.5 ± 1.83982.4 ± 1.8<0.001
      Hand movement4802.5 ± 1.84732.3 ± 1.83832.2 ± 1.8<0.001
      Hand pronation/supination5012.8 ± 1.84942.5 ± 1.84032.4 ± 1.8<0.001
      Lower extremity agility4743.0 ± 2.04672.8 ± 2.03762.8 ± 2.0<0.001
      Standing up from a chair5371.7 ± 1.35301.5 ± 1.24341.5 ± 1.2<0.001
      Posture5631.9 ± 1.05541.7 ± 1.04561.7 ± 1.1<0.001
      Gait6002.0 ± 1.15921.7 ± 1.04871.7 ± 1.0<0.001
      Postural stability5532.0 ± 1.15441.8 ± 1.14491.8 ± 1.1<0.001
      Slow motion and decreased movement5392.1 ± 1.15311.8 ± 1.04341.8 ± 1.0<0.001
      SD, standard deviation.
      a p-value was calculated based on Wilcoxon signed-rank test (vs baseline).

      3.4.3 Effectiveness based on patient demographics and istradefylline dose increase

      The physician's global assessment of effectiveness according to patient demographics is shown in Table 5. The physician effectiveness ratings stratified by whether patients underwent an istradefylline dose increase are shown in Supplementary Table 2. There were no statistically significant differences in the effectiveness as measured by the physician's global assessment, motor dysfunction, or off-time duration or symptoms in patients who underwent dose increases compared with those who did not.
      Table 5Physician's global assessment of effectiveness according to patient demographics.
      Factors analyzedNPatients in whom treatment was judged to be effective, n (%)
      Age<75 years758450 (59.4)
      ≥75 years526318 (60.5)
      SexMale561340 (60.6)
      Female723428 (59.2)
      Body weight<Median (52.0 kg)405235 (58.0)
      ≥Median (52.0 kg)420263 (62.6)
      Unknown459270 (58.8)
      Duration of PD
      Factors significantly associated with physician's global assessment of effectiveness:•Duration of PD: p = 0.016; Cochran–Armitage test•Duration of motor complications: p = 0.011; Cochran–Armitage test•Modified H&Y severity stage (on-time): p = 0.016; Cochran–Armitage test
      <5 years281179 (63.7)
      5 to <10 years491311 (63.3)
      ≥10 years469261 (55.7)
      Unknown4317 (39.5)
      Duration of levodopa use<5 years450276 (61.3)
      5 to <10 years432276 (63.9)
      ≥10 years220125 (56.8)
      Unknown18291 (50.0)
      Duration of

      motor complications
      Factors significantly associated with physician's global assessment of effectiveness:•Duration of PD: p = 0.016; Cochran–Armitage test•Duration of motor complications: p = 0.011; Cochran–Armitage test•Modified H&Y severity stage (on-time): p = 0.016; Cochran–Armitage test
      <1 years199133 (66.8)
      1 to <3 years345209 (60.6)
      3 to <5 years167100 (59.9)
      ≥5 years291160 (55.0)
      Unknown282166 (58.9)
      Concurrent dyskinesiaAbsent834501 (60.1)
      Present450267 (59.3)
      Daily levodopa dose<450 mg804493 (61.3)
      ≥450 mg467267 (57.2)
      Unknown138 (61.5)
      Daily levodopa-equivalent dose<Median (610.0 mg)633388 (61.3)
      ≥Median (610.0 mg)636371 (58.3)
      Unknown159 (60.0)
      Modified H&Y severity stage (off-time)022 (100.0)
      153 (60.0)
      1.586 (75.0)
      26026 (43.3)
      2.58141 (50.6)
      3440286 (65.0)
      4484300 (62.0)
      5202104 (51.5)
      Unknown20
      Modified H&Y severity stage

      (on-time)
      Factors significantly associated with physician's global assessment of effectiveness:•Duration of PD: p = 0.016; Cochran–Armitage test•Duration of motor complications: p = 0.011; Cochran–Armitage test•Modified H&Y severity stage (on-time): p = 0.016; Cochran–Armitage test
      0157 (46.7)
      15035 (70.0)
      1.54832 (66.7)
      2279175 (62.7)
      2.5216137 (63.4)
      3450260 (57.8)
      4185102 (55.1)
      54020 (50.0)
      Unknown

      10
      H&Y, Hoehn & Yahr; PD, Parkinson's disease.
      a Factors significantly associated with physician's global assessment of effectiveness:
      • Duration of PD: p = 0.016; Cochran–Armitage test
      • Duration of motor complications: p = 0.011; Cochran–Armitage test
      • Modified H&Y severity stage (on-time): p = 0.016; Cochran–Armitage test

      3.4.4 Change in daily levodopa dose based on duration of istradefylline use

      In patients who received istradefylline for at least 6 and 12 continuous months (effectiveness analysis set), the mean (SD) levodopa dose was 458.7 (244.95) mg/day and 426.6 (195.58) mg/day, respectively. There was a temporary increase in levodopa dose at the 6-month timepoint, which decreased by the end of the observation period.

      4. Discussion

      This is the final report of an observational, PMS study of istradefylline, which collected data from patients with PD treated under real-world clinical practice conditions in Japan. The data collected in the present study reflect the real-world clinical use of istradefylline, and therefore contribute to the existing base of knowledge about istradefylline's safety and efficacy gathered in pre-approval clinical trials.
      The present study showed that istradefylline was well tolerated with favorable effectiveness, similar to the results of the interim report [
      • Takahashi M.
      • Fujita M.
      • Asai N.
      • Saki M.
      • Mori A.
      Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan.
      ]. In both studies, 20.8% of patients experienced an ADR, and the most common ADRs were dyskinesia (4.9% vs 5.0%), hallucination (2.4% vs 3.4%), and visual hallucination (1.4% vs 1.3%) in the present study vs the interim report, respectively. The incidence of psychiatric disorders (priority survey item) was 4.9% in the present study, but this cannot be compared with the interim report as there were insufficient data available for comparison at that timepoint. Importantly, the incidence of psychiatric ADRs in the present study was consistent with the known safety profile for istradefylline.
      Treatment was rated as “effective” according to the physician's global assessment in 59.8% of patients in the current report, which was similar to the interim analysis (61.3%). Moreover, physician's ratings of effectiveness for off-time duration, off-time symptoms, and motor symptoms were also similar: 34.0% vs 38.2% of patients had reduced off-time in the present report vs the interim analysis; 43.1% vs 44.7% had improvement in off-time symptoms; and 45.8% vs 48.5% had improved motor symptoms.
      There were no clinically meaningful differences identified between our results and those of phase III clinical trials, despite the mean age being somewhat higher in the present study than in the clinical trials (71.5 years vs approximately 65 years) [
      • Kondo T.
      • Mizuno Y.
      • Japanese istradefylline study group
      A long-term study of istradefylline safety and efficacy in patients with Parkinson disease.
      ,
      • Mizuno Y.
      • Kondo T.
      Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease.
      ]. We found that there was an association between disease severity and istradefylline dose; >80% of patients underwent a dose increase to improve motor function. The necessity of dose increase varies depending on the individual. Our results demonstrated that effectiveness was maintained by using an appropriate dose for each patient, because patients who underwent a dose increase had similar physician-rated effectiveness to those who did not (64.5% and 57.8%, respectively).
      Our study showed that istradefylline effectively reduced off-time, which is consistent with the findings of a recent pooled analysis of eight studies that found istradefylline to be effective in reducing off-time at both 20- and 40-mg/day doses [
      • Hauser R.A.
      • Hattori N.
      • Fernandez H.
      • et al.
      Efficacy of istradefylline, an adenosine A2A receptor antagonist, as adjunctive therapy to levodopa in Parkinson’s disease: a pooled analysis of 8 phase 2b/3 trials.
      ]. The pooled analysis also confirmed improvements in UPDRS Part III scores regardless of dose, which was consistent with our results. Regarding safety, the above pooled analysis suggested an increased risk of dyskinesia as an ADR in patients who had already reported dyskinesia at baseline. In this study, we carried out a sub-analysis stratifying patients by the presence/absence of dyskinesia at baseline. The analysis showed a higher frequency of dyskinesia as an ADR in patients with pre-existing dyskinesia vs those without (10.8% vs 1.6%). It seems likely that the use of istradefylline adjuvant to levodopa does not newly induce dyskinesia, although it might exacerbate pre-existing dyskinesia, possibly related to the prolongation of on-time. The incidence of ADRs did not increase substantially following an increase in istradefylline dose, supporting the safety of the 40-mg daily dose. There were no new safety concerns identified in this surveillance.
      Our study was limited in that it was a non-interventional, non-randomized surveillance study, and as such, there was no control group. Also, it was limited in that the effectiveness was evaluated by the physician's global and motor function assessments, not by the patient's impressions of effectiveness.

      5. Conclusions

      Istradefylline safely and effectively improved motor symptoms for patients with PD who were experiencing the wearing-off phenomenon with levodopa treatment. Our results support those of the interim analysis. Continued use of istradefylline adjunct to levodopa is an additional treatment option, confirmed by the safety and effectiveness demonstrated in both elderly and non-elderly patients with PD.

      Funding

      This work was supported by Kyowa Kirin Co., Ltd.

      Author contributions

      Makio Takahashi contributed to data analysis, data interpretation, and drafting and editing of the manuscript. Satoru Ito contributed to data analysis, data interpretation, and drafting of the manuscript and revising it critically for intellectual content. Yukie Tsuji and Shuji Horiguchi contributed to study design, study conduct, data collection, data analysis, data interpretation, and drafting of the paper and revising it critically for intellectual content. All authors approved the final version and agree to be accountable for all aspects of the work.

      Data sharing

      Data cannot be shared with external researchers because the ethical approval did not include secondary use of this observational research.

      Declaration of competing interest

      Makio Takahashi has received consulting fees for manuscript writing from Kyowa Kirin Co., Ltd. Satoru Ito, Yukie Tsuji, and Shuji Horiguchi are employees of Kyowa Kirin Co., Ltd., which funded this study.

      Acknowledgements

      The authors wish to thank Mary Richardson, MSc, of Edanz, Japan, for providing medical writing support, which was funded by Kyowa Kirin Co., Ltd . through EMC K.K., Japan, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). The authors would also like to thank the study investigators and participating patients in this surveillance study.

      Appendix A. Supplementary data

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