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Intervention study for the effect of Istradefylline on adjustment of Levodopa in Parkinson's Disease (Istra adjust PD)

N/A (N/A)

105

Among the Istradefillyne (IST)-treated and IST-untreated groups, the mean age (standard deviation [SD]) was 65.6 (8.9) and 65.0 (8.6) years, respectively, and the proportions of males were 50.0% (26 patients) and 43.4% (23 patients), respectively. There was no numerical difference between the two groups. There was no numerical difference in the duration of Parkinson's disease (PD), age of PD onset, duration of wearing-off, or presence/absence of dyskinesia between the two groups, and no significant deviation in the distribution of the modified Hoehn and Yahr scale (on/off) between the two groups. Also, daily dose of levodopa-containing drugs, levodopa equivalent daily dose, MDS-UPDRS (parts I-IV), PDQ-39, CGI-S, and PGI-S did not differ between the two groups. There were 48 patients in the IST-treated group and 47 patients in the IST-untreated group in the data collected from wearable devices. There were no numerical differences between the two groups in many data items.

A total of 115 patients were enrolled in the study, of which 114 were randomly assigned in a 1:1 ratio to the IST-treated or IST-untreated group. 57 patients were assigned to the ISTtreated or IST-untreated group, respectively. The method used for randomization was the minimization method, and the following stratification factors were selected: age < 60 years/>= 60 years, levodopa equivalent daily dose < 400 mg/day/>= 400 mg/day, and presence/absence of dyskinesia. Patients included in the efficacy and safety analyses were 52 and 53 patients in the IST-treated group and the IST-untreated group, respectively.

Adverse events (AEs) occurred in 32 patients (61.5%) in the IST-treated group and 23 patients (43.4%) in the IST-untreated group. Adverse drug reactions (ADRs) occurred in 15 patients (28.8%) in the IST-treated group and 7 patients(13.2%) in the IST-untreated group. The numbers of AEs in the IST-treated and ISTuntreated groups were 66 and 41, respectively, and the number of serious adverse events (SAEs) was 5 in both groups. The numbers of AEs for which causality to the study was judged to be "related or undeniable" were 21 in the ISTtreated group and 7 in the IST-untreated group. As ADRs, dyskinesia occurred only in the ISTtreated group (3 [3 patients [5.8%]). Somnolence: 3 (3 patients [5.8%]) and 1 (1 patient [1.9%]), nausea: 4 (3 patients [5.8%]) and 2 (2 patients [3.8%]), in the IST-treated group and the IST-untreated group, respectively.

Primary endpoint Accumulated additional dose of levodopacontaining drugs (area under the curve [AUC] of additional dose during the treatment period) The mean (SD) dose of the accumulated additional dose of levodopa-containing drugs at the last observation was 3229.8 mg (5692.7) and 15056.6 mg (5187.1) in the IST-treated group and the IST-untreated group, respectively, indicating significantly lower in the IST-treated group than in the IST-untreated group (p<0.0001). Secondary endpoints Comparison of additional dose of every time point after Week 4until Week 36 At all observation points after Week 4 until Week 36, the IST-treated group received lower additional dose of levodopa-containing drugs per day than the IST-untreated group, indicating a statistically significant difference (p<0.0001: Week 4 to 36). Comparison of the number of days to first dose increase after Week 4 The numbers of patients with levodopacontaining drug dose increase after Week 4 in the IST-treated and IST-untreated groups were 19 (36.5%) and 25 (47.2%), respectively, and the incidence rates of levodopa-containing drug dose increase were estimated to be 61.9 (95% confidence interval (CI): 34.1 - 89.8) and 87.6 (95% CI: 53.3 - 122.0) per 100 person-years, respectively. There was no statistically significant difference between the two groups in the number of days until the initial dose increase of levodopa-containing drugs after Week 4 (log-rank test: p=0.2912, Cox proportional hazards model: p=0.2946). The mean (SD) numbers of days to initial dose increase in the IST-treated and IST-untreated groups after Week 4 were 120.1 days (74.3) and 120.7 days (74.7), respectively. Change in the dose of levodopa-containing drugs until Week 36 (after the decision to increase the dose at Week 36 ) In both the IST-treated and IST-untreated groups, the dose of levodopa-containing drugs increased numerically from Week 4 to Week 36, and the mean (SD) additional dose of levodopa at Week 36 was 25.0 mg/day (40.2) in the ISTtreated group and 73.6 mg/day (43.9) in the IST-untreated group. CGI-S score and change in CGI-S The CGI-S score at all observation points after Week 4 significantly decreased compared with Week 0 in the IST-treated and IST-untreated groups all observation points. There was no statistically significant difference in CGI-S score between the two groups at all observation points. CGI-I (degree of improvement from previous assessment) score There was no statistically significant difference in CGI-I score between the two groups at all observation points. PGI-S score and change in PGI-S In the IST-treated group, the PGI-S score was numerically decreased at all observation points after Week 4 compared with Week 0, and statistically significant differences were observed at Week 4, 16, 20, and 24. On the other hand, there was no statistically significant difference in the IST-untreated group at all observation points after Week 4 compared with Week 0. Moreover, there was no statistically significant difference in the PGI-S scores between the two groups at all observation points. PGI-I (degree of improvement from previous assessment) score There was no statistically significant difference in PGI-I score between the two groups at all observation points. Modified Hoehn and Yahr scale (on/off) score and change in modified Hoehn and Yahr scale (on/off) score Compared with Week 0, there was no statistically significant difference in the modified Hoehn and Yahr scale (on) at Week 12, 24, and 36 in the IST-treated and IST-untreated groups. In addition, there was no statistically significant difference in the scores of the modified Hoehn and Yahr scale (on) at Weeks 0, 12, 24, and 36 between the two groups. There was a statistically significant improvement in the modified Hoehn and Yahr scale (off) at Weeks 12 and 24 in the IST-treated group compared with Week 0, but no statistically significant difference at all observation points in the IST-untreated group. In addition, there was no statistically significant difference between the two groups in the scores at Weeks 0, 12, 24 and 36. MDS-UPDRS Part I-IV scores and change in MDSUPDRS Part I-IV scores Compared with Week 0, the MDS-UPDRS Part I scores were numerically decreased only in the IST-treated group at all observation points, and there were statistically significant differences at Week 12 and 36. There was no statistically significant difference in the MDS-UPDRS Part I scores between the two groups at all observation points. Although the MDS-UPDRS Part II scores were numerically decreased from Week 0 to Week 12 and 24 in the two groups, the difference was statistically significant only at Week 12 and 24 in the IST-untreated group. There was no statistically significant difference in the MDS-UPDRS Part II scores between the two groups at all observation points. There was a statistically significant decrease in the MDS-UPDRS Part III scores in the both groups at all observation points compared with Week 0. There was no statistically significant difference in the MDS-UPDRS Part III scores between the groups at all observation points. There was a statistically significant decrease in the MDS-UPDRS Part IV scores in the both groups at all observation points compared with Week 0. Moreover, there was no statistically significant difference between the two groups in the MDS-UPDRS Part IV scores at all observation points. PDQ-39 and change in PDQ-39 score Compared with Week 0, the PDQ-39 scores were decreased in the IST-treated group at all observation points, and a statistically significant difference was observed only at Week 12. On the other hand, in the IST-untreated group, numerical decreases were observed at all observation points except Week 36, whereas the difference was not statistically significant. Moreover, there was no statistically significant difference between the two groups in the PDQ-39 scores at all observation points. Assessment using the wearable devices The IST-treated group showed statistically significant differences in numerical decrease in steps per minute, gait balance, sleep efficiency, and time spent on low intensity exercise (<1.5 METs) at Week 36 compared with Week 0. There were also statistically significant differences in numerical increase in the frequency of daily exercise, frequency of exercise during wakefulness, frequency of exercise during sleep, daily exercise intensity, exercise intensity during wakefulness, exercise intensity during sleep, and time spent on light intensity exercise (>=1.5, <3 METs). On the other hand, a statistically significant difference was observed in numeric decrease in time spent on moderate to vigorous intensity exercise (>=3 METs) in the IST-untreated group.

The accumulated additional dose of levodopacontaining drugs in the IST-treated group was approximately 5 times lower than that in the ISTuntreated group, indicating a statistically significant difference. In objective exercise assessment using wearable devices, only the IST-treated group showed a significant improvement at Week 36, compared with Week 0. This study clarified the effectiveness of adjunctive IST compared with increase dose of levodopa-containing drugs in PD patients with wearing-off.

Sept. 20, 2022

No

none

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180248

Hatano Taku

Juntendo University Hospital

3-1-3 Hongo, Bunkyo-ku, Tokyo

thatano@juntendo.ac.jp

Matsuzaki Yoshiyuki

Mebix Co., Ltd.

3-8-21 Toranomon, Minato-ku, Tokyo

+81-3-4362-4504

yoshiyuki.matsuzaki@mebix.co.jp

Complete

Mar. 01, 2019

Interventional

randomized controlled trial

open(masking not used)

no treatment control/standard of care control

parallel assignment

treatment purpose

1) Current use of levodopa-containing drugs more than
300mg/day and less than 400mg/day administered at least
three times daily
2) Patients with wearing-off
3) >= 30 to < 85 years of age at the time of registration
for the study
4) Diagnosed as Parkinson's disease based on the
International Parkinson and Movement Disorder Society
(MDS)
5) Stages <=3 in the ON state for Modified Hoehn and Yahr
Scale
6) Patients who have given written consent if the patient
has difficulty in writing due to his or her condition,
a representative may sign the written consent, subject
to the patient's prior oral consent

1) Use of Istradefylline in the past
2) Current use of an investigational drug (within 4 months
prior to the registration for the study)
3) Patients with dementia or a score of 23 or less on the
Mini-Mental State Examination (MMSE)
4) Patients with a previous history of brain surgery for
the treatment of Parkinson's disease at the time point
of the registration
5) Current use or plan to administer levodopa/carbidopa
intestinal gel at the time point of the registration
6) Patients with moderate to severe hepatic disorder
7)Use of a new anti-Parkinson's disease drugs or change
in the treatment of anti-Parkinson's disease drugs
within 14 days prior to the registration for the study
8) Current use of a strong inhibitor of CYP3A4
(Itraconazole, Clarithromycin) within 14days prior to
the registration of the study
9) Female patients who are pregnant, trying to become
pregnant or nursing (lactating) an infant
10) Patients who are in the Investigator's judgment
unlikely to comply with medical regimens or study
requirements

Both

Parkinson's disease

Arm with treatment of Istradefylline and levodopa
Treatment with Istradefylline will be started at a dose of
20 mg administered once daily at Week 0. The dose of
Istradefylline will be increased to 40 mg once daily if
the patient has no tolerability issues and still has motor
symptoms at Week 1. Dose reduction is possible if the
patient has tolerability issues.
Patients will visit every 4 weeks from the following day
of Week0, and 50mg levodopa will be added of if CGI-S score
>=4 every time. Dose reduction is possible if the patient
has tolerability issues.
Arm without treatment of Istradefylline
50mg levodopa will be added at Week 0. Patients will visit
every 4 weeks from the following day of Week0, and 50mg
levodopa will be added of if CGI-S score >=4 every time.
Dose reduction is possible if the patient has tolerability
issues.

Accumulated dose of Levodopa

Additional dose of every time points after Week4 until Week36
Number of the days to the first additional dose from Week0
Change in the dose of levodopa until Week36
CGS-S score and change in CGS-S
CGS-I score from the previous visit
PGS-S score and change in PGS-S
PGS-I score from the previous visit
Change in modified Hoehn & Yahr scale
Movement Disorder Society-Unified Parkinson's Disease
Rating Scale (MDS-UPDRS) Part1,2,3,4 score and total score
Change in Movement Disorder Society-Unified Parkinson's
Disease Rating Scale (MDS-UPDRS) Part1,2,3,4 score and
total score
Change in Parkinson's Disease Questionnaire (PDQ)-39 score
Correlation among the score change presented
Analysis of the motion (frequency, strength), gait(counts,pitch, balance), sleeping (bedtime, Wake-up time, time of sleeping, sleep efficiency, sleep onset latency, frequency and intensity of physical activity during sleep, total time of bed-leaving, REM/Non-REM) using wearable device

+81-3-5802-1584

Feb. 26, 2019

none