Levodopa is the most effective drug for the treatment of Parkinson disease (PD), but long-term levodopa use often causes motor complications such as wearing-off symptoms and dyskinesia.1 Dopamine agonists, monoamine oxidase B inhibitors, and COMT (catechol-O-methyl-transferase) inhibitors have been developed to overcome these problems; however, motor complications and dopaminergic adverse effects induced by long-term levodopa treatment are not yet fully resolved. The motor symptoms observed in PD are postulated to result from dopaminergic deficiency-related overactivation of the γ-aminobutyric acid (GABAergic)–mediated pathway from the striatum to the external pallidum, resulting in hyperactivation of the internal pallidum/substantia nigra pars reticulata and suppression of thalamocortical activation.2–4
Adenosine A2A receptors are predominantly expressed in the GABAergic striatoexternal pallidal projection neurons, and their activation enhances GABAergic transmission to the external pallidum.5–8 Therefore, adenosine A2A receptor blockade reduces the overactive striatopallidal output, resulting in an activation of the pallido-subthalamic GABAergic pathway of the PD brain.
Istradefylline is a nondopaminergic, selective adenosine A2A receptor antagonist, which was developed as an adjunctive therapy to levodopa in PD with motor complications.9,10 Phase 2B and 3 double-blind, placebo-controlled, clinical trials conducted in Japan demonstrated that 20 and 40 mg/d istradefylline significantly reduced the daily off time and further improved motor function, compared with placebo.11,12 Most of the off time reduction resulted in increased on time, without troublesome dyskinesia. Moreover, this effect was demonstrated under concomitant treatment with other drugs, such as dopamine-receptor agonists and COMT inhibitors. These findings indicated that istradefylline was effective and well tolerated, even when prescribed alongside other existing antiparkinsonian medications. The present study was conducted to examine the long-term safety and efficacy of istradefylline when given in combination with levodopa to PD patients experiencing wearing-off symptoms.
This study was conducted in compliance with the protocol and principles of the Declaration of Helsinki and in accordance with the International Conference on Harmonisation (Harmonised Tripartite Guideline for Good Clinical Practice) and Japanese Good Clinical Practice regulations. The clinical trial identifier number is NCT00957203. This open-label study was approved by institutional review boards for each of the 44 study sites, and informed consent was obtained from 313 patients.
We conducted a 52-week, open-label, nonrandomized extension study of istradefylline in patients with PD who completed the prior phase 3, placebo-controlled, double-blind, parallel-group, confirmatory study (6002-009 study). In the 6002-009 study, 373 patients were randomly assigned to receive istradefylline (20 or 40 mg) or placebo once daily for 12 weeks as a levodopa adjunctive therapy.12 Patients eligible for the present extension study had completed the previous double-blind placebo-controlled clinical study. Patients were judged by the investigator not to have had any safety concerns with the study drug during the double-blind study and were considered able to complete diaries accurately throughout the long-term study. Patients were excluded from the long-term study if they scored 23 or less in the Mini-Mental State Examination performed at the end of the 6002-009 study or if their treatment compliance was less than 70% during this study.
This long-term study consisted of 2 phases, a 1- to 4-week double-blind transition phase and a 52-week open-label phase. In the double-blind phase, the patients received the same treatment as that administered at the end of 6002-009 study, namely, placebo, istradefylline 20 mg, or istradefylline 40 mg, once daily.
During the double-blind phase, patient eligibility for the open-label phase was determined, and baseline assessments were conducted. In the open-label phase, all the eligible patients received istradefylline once daily for 52 weeks at a starting dosage of 20 mg/d. After 4 weeks (week 4), the dosage of istradefylline was increased to 40 mg/d if the patient's clinical response was considered to be unsatisfactory, and there were no safety concerns. After 8 weeks (week 8), the dosage of istradefylline was decreased to 20 mg/d if untoward effects had occurred. The dosage and dosing regimen of concomitant antiparkinsonian drugs was maintained constant as far as possible until week 8. After week 8, the istradefylline dose was not allowed to change for the remainder of the study period, and adjustments to other antiparkinsonian medications were only permitted by the investigator if patients had treatment-emergent adverse events (TEAEs) or the clinical response was considered to be unsatisfactory.
The patients' visits were scheduled at 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 weeks during the open-label phase. At every visit, vital signs were assessed. Laboratory parameters were assessed at 4, 8, 12, 24, 36, 48, and 52 weeks, and electrocardiogram was conducted every 12 weeks and at 52 weeks. Safety was assessed on the basis of TEAEs during the 52-week open-label phase. The patients completed diaries for 7 consecutive days before each visit. They were assessed using the Unified Parkinson Disease Rating Scale (UPDRS) parts I to IV at 2, 4, 8, 12, 24, 36, 48, and 52 weeks, and using Clinical Global Impression-Global Improvement (CGI-I) scale at 4, 8, 24, 36, 48, and 52 weeks.
All TEAEs that occurred during the 52 weeks of the open-label phase were tabulated. Treatment-emergent adverse events were based on symptoms, body weight, vital signs, laboratory results, electrocardiogram, and other data. A serious TEAE was defined as any untoward event that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability and/or incapacity, or was an event judged to be medically important.
Efficacy parameters included the change in the daily off time, change in the daily on time, UPDRS (parts I to III, total score, and the score of each part compared with that at day 1), and CGI-I (compared with that at the 6002-009 study baseline). Daily off time was calculated from patients' diaries, using a method developed by Hauser et al.13
Patients were placed in group 1, 2, or 3 if they had previously received placebo, istradefylline 20 mg/d, or 40 mg/d, respectively, in the 6002-009 study. Patients who received at least 1 dose of study drug and for whom any postbaseline safety data were available during the open-label phase were included in the safety analysis set. All TEAEs that occurred during the open-label phase were evaluated. Patients in group 2 and group 3 were combined regarding TEAEs, and the combined group was shown as group 2/3. The incidence of TEAEs was calculated by taking the total number of patients who reported the events. The safety variables were analyzed descriptively.
Patients who received at least 1 dose of study drug and submitted at least 1 set of diaries for evaluation for any assessment times during the open-label phase were included in the full analysis set (FAS). Descriptive statistics, such as mean and standard deviation, was calculated for each efficacy outcome.
Of the 313 patients whom informed consent was obtained, 308 patients received open-label treatment (Fig. 1). Five patients discontinued during the transition phase. Seventy-seven patients (group 1, 27; group 2, 28; group 3, 22) discontinued prematurely, and 231 patients (group 1, 73; group 2, 73; group 3, 85) completed this long-term study. Of the 297 patients who were receiving istradefylline in week 4, 165 received an increased dosage of 40 mg/d. In week 8, the dosage was reduced from 40 mg/d to 20 mg/d in 10 patients. Of the 231 patients who completed 52 weeks of treatment, 81 were receiving 20 mg/d istradefylline, and 150 were receiving 40 mg/d in week 52.
Baseline demographic data are presented in Table 1. The mean daily dosage of levodopa in the 6002-009 study was 416.3, 424.3, and 422.7 mg/d in groups 1, 2 and 3, respectively. Additional dopamine agonists were taken by 90.0% of patients in group 1, 89.1% of patients in group 2, and 83.2% of patients in group 3. Fewer males were included in group 2, more subjects used concomitant selegiline in group 3, and fewer subjects used concomitant entacapone in group 1. Other demographics and characteristics were comparable.
Treatment-emergent adverse events are summarized in Table 2. At least 1 TEAE was experienced by 93.0% in group 1 and 85.6% in group 2/3 (88.0% in total). The most frequently reported TEAEs in group 1 were nasopharyngitis (25.0%) and dyskinesia (25.0%), followed by visual hallucination (11.0%), contusion (9.0%), and weight decrease (8.0%). The most frequently reported TEAEs in group 2/3 were nasopharyngitis (24.0%), followed by dyskinesia (19.7%), contusion (11.1%), constipation (10.6%), and visual hallucination (7.7%). The severity of TEAEs was mild (72.0%), moderate (22.6%), or severe (5.4%) in group 1 and mild (71.9%), moderate (23.6%), or severe (4.5%) in group 2/3. Most patients (64.9%) who reported any TEAE experienced their first event during the first 12 weeks of the open-label phase. The incidence of drug-related TEAEs was 57.0% in group 1 and 45.2% in group 2/3. The most frequently reported drug-related TEAE was dyskinesia (group 1, 21.0%; group 2/3, 17.3%). No deaths were reported in the study. Serious TEAEs were reported by 12.0% in group 1 and 13.0% in group 2/3. The most frequent serious adverse event was spinal compression fracture (4 patients). Colonic polyp, femoral neck fracture, and gastric ulcer hemorrhage were reported in 2 patients each. All other serious adverse events occurred in 1 patient each.
Treatment-emergent adverse events that led to discontinuation of treatment occurred in 13.0% of group 1 and 5.3% of group 2/3.
No marked difference was observed in the safety profile between group 1 and group 2/3, and no clinically meaningful abnormalities were noted in laboratory parameters, vital signs, physical examinations, or other safety measures.
In group 1, 1 patient was excluded from the FAS because of the absence of at least 1 set of diaries at any of the postbaseline assessment time points. Therefore, 307 patients (group 1, 99; group 2, 101; group 3, 107) were included in the FAS for assessment of efficacy. The efficacy variables are shown in Table 3. In group 1, the mean change in the daily off time from day 1 of the open-label phase was −0.65 hour in week 2, fluctuating between −0.71 and −0.04 hour up to week 52. In group 2, it remained at similar levels between weeks 2 and 4, ranging from −0.10 to −0.08 hour, reached −0.34 hour in week 8, and fluctuated between −0.64 and −0.15 hour up to week 52. The mean change was −0.26 to 0.36 hour between weeks 2 and 52 in group 3. The mean daily off times from the end of the double-blind study, through week 52 of long-term study, are shown in Figure 2. Off time reduction was better in group 2 and group 3 compared with that in group 1, all the study period until week 52, but there was no statistical difference between them.
The off time reduction was maintained up to week 52 in all 3 groups. The mean changes in the daily on time with troublesome dyskinesia from day 1 of the open-label phase for group 1, group 2, and group 3 were −0.18, 0.01, and −0.01 hour, respectively in week 52. None of the groups showed an increase in daily on time with troublesome dyskinesia.
The mean change in UPDRS part III (on state) score from day 1 of the open-label phase was −2.9 in week 8, fluctuating between −3.4 and −2.7 until week 52 in group 1. It was −1.9 in week 8, fluctuating between −2.4 and −1.7 up to week 52 in group 2, and −1.5 in week 8, fluctuating between −1.8 and −1.1 until week 52 in group 3.
The percentage of patients in the “much improved” or better CGI-I category in week 52 was 17.3% (14/81) for group 1, 29.1% (23/79) for group 2, and 31.9% (29/91) for group 3. The percentage of patients in the “minimally improved” or better categories were 60.5% (49/81), 68.4% (54/79), and 65.9% (60/91), respectively.
This study evaluated the long-term safety and efficacy of istradefylline in Japanese PD patients with wearing-off symptoms on levodopa therapy. The most frequently reported TEAE was nasopharyngitis (group 1, 25.0%; group 2/3, 24.0%), and the most frequently reported drug-related TEAE was dyskinesia (group 1, 21.0%; group 2/3, 17.3%). However, all events of nasopharyngitis were considered by investigators to be unrelated to istradefylline. In the 6002-009 study,12 nasopharyngitis as a TEAE occurred in 8.7%, 8.1%, and 5.6% of patients in the placebo, istradefylline 20 mg/d, and istradefylline 40 mg/d groups, respectively, and it was also considered by investigators to be unrelated to istradefylline in all cases. An increase in reports of nasopharyngitis in the long-term study seems likely to be a result of the longer observation period (52 vs 12 weeks). All events of dyskinesia were mild to moderate in severity, and no patients experienced severe dyskinesia. The occurrence of dyskinesia as a TEAE could not be distinguished from levodopa-related dyskinesia because all of the patients received istradefylline in combination with levodopa for the entire study. In the 6002-009 study on advanced PD patients, dyskinesia as a drug-related TEAE occurred in 4.0%, 12.2%, and 12.1% of patients in the placebo, istradefylline 20 mg/d, and istradefylline 40 mg/d groups, respectively.12 An increase in reports of dyskinesia in the long-term study seems likely to be a result of the longer observation period (52 vs 12 weeks) or disease progression. Most of the reported TEAEs were mild to moderate in severity. More than half of the patients who reported any TEAE experienced their first event during the first 12 weeks of the open-label phase.
In the phase 2B study,11 the most frequently reported TEAE was nasopharyngitis, and the most frequently reported drug-related TEAE was dyskinesia. In the 6002-009 study,12 the most frequently reported TEAE and drug-related TEAE were both dyskinesia. In the phase 2B study and the 6002-009 study, most of the reported TEAEs were also mild to moderate in severity. There was no marked difference between the safety profiles of these double-blind studies and this open-label study.
In North America, 4 double-blinded studies14–17 have been conducted in advanced PD, and dyskinesia was the most frequently reported TEAE in all studies. Another long-term study conducted in North America with a similar study design (6002-US-007) identified no major differences in the profile of drug-related TEAEs as compared with the present study and also reported dyskinesia as the most frequent TEAE.18 Therefore, the long-term safety profile and incidence of istradefylline appeared to be similar in North American and Japanese PD patients.
In the double-blind study, the mean changes in daily off time from baseline to end point for placebo, istradefylline 20 mg/d, and 40 mg/d were −0.23 hour, −0.99 hour (P = 0.003), and −0.96 hour (P = 0.003), respectively.12 Group 1 switched from placebo to istradefylline when the present long-term study commenced and showed a reduction in mean daily off time in week 2, which was maintained up to week 52 (Fig. 2). Group 2 and group 3 both received istradefylline in the double-blind study12 and in the present open-label study, and also showed reduced mean daily off time until week 52. These data suggested that istradefylline was shown to be effective in PD patients experiencing wearing-off symptoms for at least 52 weeks. Moreover, istradefylline was effective in improving UPDRS part III (on state) for 52 weeks.
This study supports that the long-term administration of istradefylline was safe and produced a sustained reduction in off time and improvement in motor function during on state in advanced PD patients who have even already been on levodopa therapy and concomitantly treated with other available drugs. This might be because istradefylline is a selective adenosine A2A receptor antagonist, which has a different mechanism from that of other PD treatments.
The authors greatly appreciate the contributions of the study investigators, study coordinators, and participating patients to the study.
1. Rajput AH, Fenton ME, Birdi S, et al. Clinical-pathological study of levodopa complications. Mov Disord
2002; 17(2): 289–296.
2. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology
2001; 56(11 Suppl 5): S1–S88.
3. Obeso JA, Rodriguez MC, DeLong MR. Basal ganglia pathophysiology. A critical review. Adv Neurol
1997; 74: 3–18.
4. Gatev P, Darbin O, Wichmann T. Oscillations in the basal ganglia under normal conditions and in movement disorders. Mov Disord
2006; 21(10): 1566–1577.
5. Popoli P, Blum D, Pintor A. The controversial role of adenosine A2A
receptor antagonists as neuroprotective agents. Curr Med Chem CNS Agents
2004; 4: 35–45.
6. Jenner P. Istradefylline, a novel adenosine A2A
receptor antagonist, for the treatment of Parkinson's disease. Expert Opin Investig Drugs
2005; 14(6): 729–738.
7. Mori A, Shindou T. Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A
receptors: a potential mechanism for the antiparkinsonian effects of A2A
2003; 61(11 Suppl 6): S44–S48.
8. Kase H, Aoyama S, Ichimura M, et al. Progress in pursuit of therapeutic A2A
antagonists: the adenosine A2A
receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease. Neurology
2003; 61(11 Suppl 6): S97–S100.
9. Hauser RA, Hubble JP, Truong DD, et al. Randomized trial of the adenosine A2A
receptor antagonist istradefylline in advanced PD. Neurology
2003; 61(3): 297–303.
10. Park A, Stacy M. Istradefylline for the treatment of Parkinson's disease. Expert Opin Pharmacother
2012; 13(1): 111–114.
11. Mizuno Y, Hasegawa K, Kondo T, et al. Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study. Mov Disord
2010; 25(10): 1437–1443.
12. Mizuno Y, Kondo T. Adenosine A2A
receptor antagonist istradefylline reduces daily off time in Parkinson's disease. Mov Disord
2013; 28(8): 1138–1141.
13. Hauser RA, Deckers F, Lehert P. Parkinson's disease home diary: further validation and implications for clinical trials. Mov Disord
2004; 19(12): 1409–1413.
14. LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A
receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol
2008; 63(3): 295–302.
15. Stacy M, Silver D, Mendis T, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology
2008; 70(23): 2233–2240.
16. Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. Mov Disord
2008; 23(15): 2177–2185.
17. Pourcher E, Fernandez HH, Stacy M, et al. Istradefylline for Parkinson's disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord
2012; 18(2): 178–184.
18. Factor S, Mark MH, Watts R, et al. A long-term study of istradefylline in subjects with fluctuating Parkinson's disease. Parkinsonism Relat Disord
2010; 16: 423–426.
The Japanese Istradefylline Study Group Investigators included the following members: S. Hisahara (Sapporo Medical University Hospital), M. Baba (Aomori Prefectural Central Hospital), T. Abe (Abe Neurology Clinic), T. Maeda (Research Institute for Brain and Blood Vessels Akita), A. Takeda (Tohoku University Hospital), M. Suzuki (Sendai East Neurosurgical Hospital), R. Koike (Nishi-Niigata Chuo National Hospital), K. Hirata (Dokkyo Medical University Hospital), A. Tamaoka (Tsukuba University Hospital), K. Okamoto (Gunma University Hospital), H. Morita (Shinshu University Hospital), M. Asahina (Chiba University Hospital), S. Nogawa (Tokyo Dental College Ichikawa General Hospital), H. Shimura (Juntendo University Urayasu Hospital), N. Suzuki (Keio University Hospital), H. Utsumi (Tokyo Medical University Hospital), Y. Shimo (Juntendo University Hospital), R. Hanajima (The University of Tokyo Hospital), M. Murata (National Center of Neurology and Psychiatry), R. Okiyama (Tokyo Metropolitan Tama Medical Center), M. Yokochi (Ebara Hospital), S. Nakamura (Juntendo Tokyo Koto Geriatric Medical Center), K. Hasegawa (National Hospital Organization Sagamihara National Hospital), H. Takahashi (Tokai University Hospital), N. Kawashima (Kawashima Neurology Clinic), S. Ikebe (Ikebe Clinic), T. Ohashi (Seirei Hamamatsu General Hospital), T. Atsumi (Atsumi Neurology Clinic), T. Hattori (Honmachi Clinic), H. Sawada (National Hospital Organization Utano Hospital), Y. Tatsuoka (Tatsuoka Neurology Clinic), S. Matsumoto (Kitano Hospital), H. Fujimura (Toneyama National Hospital), K. Toda (Toda Internal Medicine and Rehabilitation Clinic), H. Miwa (Wakayama Medical University Hospital), M. Yamamoto (Kagawa Prefectural Central Hospital), M. Nagai (Ehime University Hospital), T. Yuhi (University of Occupational and Environmental Health, School of Medicine Hospital), Y. Tsuboi (Fukuoka University Hospital), S. Kuno (Kyoto Shijo Hospital), H. Mori (Kurashiki Central Hospital), M. Nagai (Kitasato University Hospital), J. Yoshinaga (Yoshinaga Neurology Clinic), and K. Uekawa (National Hospital Organization Kumamoto Minami Hospital).