Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study

Taku Hatano; Renpei Sengoku; Hiroshi Nagayama; Naotake Yanagisawa; Asako Yoritaka; Keisuke Suzuki; Noriko Nishikawa; Yohei Mukai; Kyoichi Nomura; Norihito Yoshida; Morinobu Seki; Miho Kawabe Matsukawa; Hiroo Terashi; Katsuo Kimura; Jun Tashiro; Shigeki Hirano; Hidetomo Murakami; Hideto Joki; Tsuyoshi Uchiyama; Hideki Shimura; Kotaro Ogaki; Jiro Fukae; Yoshio Tsuboi; Kazushi Takahashi; Toshimasa Yamamoto; Kenichi Kaida; Ryoko Ihara; Kazutomi Kanemaru; Osamu Kano

doi:10.1007/s40120-023-00574-6

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study

Neurol Ther. 2024 Apr;13(2):323-338. doi: 10.1007/s40120-023-00574-6. Epub 2024 Jan 16.

Authors

Taku Hatano¹, Renpei Sengoku², Hiroshi Nagayama³, Naotake Yanagisawa⁴, Asako Yoritaka⁵, Keisuke Suzuki⁶, Noriko Nishikawa⁷, Yohei Mukai⁸, Kyoichi Nomura⁹, Norihito Yoshida¹⁰, Morinobu Seki¹¹, Miho Kawabe Matsukawa¹², Hiroo Terashi¹³, Katsuo Kimura¹⁴, Jun Tashiro¹⁵, Shigeki Hirano¹⁶, Hidetomo Murakami¹⁷, Hideto Joki^{18

19}, Tsuyoshi Uchiyama²⁰, Hideki Shimura^{21

22}, Kotaro Ogaki²³, Jiro Fukae²⁴, Yoshio Tsuboi²⁵, Kazushi Takahashi²⁶, Toshimasa Yamamoto²⁷, Kenichi Kaida¹⁰, Ryoko Ihara¹², Kazutomi Kanemaru¹², Osamu Kano²⁸

Affiliations

¹ Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. thatano@juntendo.ac.jp.
² Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, Tokyo, Japan.
³ Department of Neurology, Nippon Medical School, Tokyo, Japan.
⁴ Medical Technology Innovation Center, Juntendo University and Juntendo Clinical Research and Trial Center, Tokyo, Japan.
⁵ Department of Neurology, Juntendo University Koshigaya Hospital, Saitama, Japan.
⁶ Department of Neurology, Dokkyo Medical University Hospital, Tochigi, Japan.
⁷ Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
⁸ Department of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁹ Department of Neurology, Higashimatsuyama Municipal Hospital, Saitama, Japan.
¹⁰ Department of Neurology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
¹¹ Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
¹² Department of Neurology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan.
¹³ Department of Neurology, Tokyo Medical University, Tokyo, Japan.
¹⁴ Department of Neurology, Yokohama City University Medical Center, Yokohama, Japan.
¹⁵ Sapporo Parkinson MS Neurological Clinic, Sapporo, Japan.
¹⁶ Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
¹⁷ Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan.
¹⁸ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
¹⁹ Department of Neurology, National Hospital Organization Yokohama Medical Center, Yokohama, Japan.
²⁰ Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.
²¹ Department of Neurology, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan.
²² Department of Neurology, Juntendo University Koshigaya Hospital, Koshigaya, Japan.
²³ Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.
²⁴ Department of Neurology, Juntendo University Nerima Hospital, Tokyo, Japan.
²⁵ Department of Neurology, Fukuoka University, Fukuoka, Japan.
²⁶ Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
²⁷ Department of Neurology, Saitama Medical University, Saitama, Japan.
²⁸ Department of Neurology, Toho University, Faculty of Medicine, Tokyo, Japan.

Abstract

Introduction: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off.

Methods: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes.

Results: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group.

Conclusion: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD.

Trial registration: Japan Registry of Clinical Trials: jRCTs031180248.

Keywords: Adenosine A2A receptor antagonist; Istradefylline; Levodopa; Levodopa dose; Parkinson’s disease.