臨床研究等提出・公開システム

Zonisamide for the Efficacy of Sleep Abnormality in Parkinson's Disease:
A Randomized Single-Blind Placebo-Controlled Trial
(ZEAL)

ZEAL study (ZEAL)

70

The full analysis set (FAS) used as the primary analysis set for efficacy analysis was defined as "The study population enrolled and consented to the study, took study drug at least once, and the primary or secondary endpoint data were obtained." Out of the 70 study subjects enrolled, 67 were adopted as FAS, excluding 3 who were discontinued before the start of protocol treatment because they did not meet the major enrollment criteria, etc. The mean, median, minimum and maximum FAS values for the zonisamide and placebo groups are as follows: age: zonisamide group mean 72.8, minimum 54, median 75, maximum 86 years placebo group 71.9, 46, 73, 85 years old gender: zonisamide group: male 57.6%, female 42.4% placebo group: Male 52.9%, Female 47.1% disease duration of Parkinson's disease: zonisamide group mean 133.3, minimum 60, median 112, maximum 408 months placebo group 115, 60, 108, 276 months MMSE cognitive function: zonisamide group mean 28.6, minimum 26, median 29, maximum 30 points placebo group 28.4, 23, 29, 30 points PDSS total score zonisamide group mean 22.9, minimum 4, median 22, maximum 48 points placebo group 23.2, 5, 24, 41 points REM sleep behavior disorder (RBD) screening questionnaire zonisamide group mean 5.7, minimum 1, median 5, maximum 13 points placebo group 5.6, 1, 5.0, 12 points There were no statistically significant differences between the zonisamide and placebo groups.

We obtained the informed consent to participate in the study from 70 patients. Excluding 3 patients who discontinued treatment before starting protocol treatment for reasons such as not meeting main registration criteria, 67 patients were included in the efficacy analysis. 67 patients completed protocol treatment during the evaluation period. start of patient registration: March 24, 2021 initial treatment for the first patient: April 15, 2022 initial treatment for the last patient: May 18, 2023 last study visit of the last patient: June 15, 2023

Safety was analyzed in the "safety analysis set: SAS" (67 subjects). SAS was defined as "All populations enrolled and consented to the study who took at least one study drug and for whom data are available". There were no serious AE associated with protocol treatment and no serious AE which not associated with protocol treatment. There were 2 non-serious AEs that could not be denied a causal relationship to the protocol treatment (urinary incontinence, hypersomnia), and 3 non-serious adverse events that had no causal relationship to the protocol treatment as below. Non-serious AEs with a causal relationship to protocol treatment urinary incontinence was evident on February 2, 2023, one day after intake of zonisamide. outcome: complete recovery after stopping zonisamide. excess sleepiness was evident on November 13, 2021, two days after intake of zonisamide. outcome: complete recovery after stopping zonisamide. Non-serious AEs without a causal relationship to protocol treatment slight nausea was evident 10 days after intake of zonisamide. outcome: complete recovery. swelling of the left distal lower limb during zonisamide treatment.: complete recovery. It suspects bacterial infection and the subject was undertaken antibiotics. falling related to wearing off phenomenon during placebo treatment.

Primary endpoint The difference of sleep efficiency between the baseline and 28 days after study drug administration was for the zonisamide group (+0.21%) and the placebo group (-2.45%). No significant difference was observed between the two groups. Secondary endpoint total sleep time (TST) The difference from the baseline in the zonisamide group and placebo group was -11.77 and -15.78 minutes, respectively. No significant difference was observed between the two groups. wake time after sleep onset (WASO) The difference from the baseline in the zonisamide group and placebo group was -8.73 and +11.69 minutes, respectively. No significant difference was observed between the two groups. sleep onset latency (SOL) The difference from the baseline in the zonisamide group and placebo group was -2.17 and +3.69 minutes, respectively. No significant difference was observed between the two groups. REM sleep/non-REM sleep ratio The difference from the baseline in the zonisamide group and placebo group was -1.70 and -0.42%, respectively. No significant difference was observed between the two groups. deep sleep (N3) time The difference from the baseline in the zonisamide group and placebo group was -8.90 and -13.91minutes, respectively. No significant difference was observed between the two groups. ratio of RWA to total REM sleep epochs The difference from the baseline in the zonisamide group and placebo group was -0.48 and -0.46, respectively. PDSS-2 The difference between the values at the 14th or 28th day of study drug administration and the baseline was zonisamide group (-1.2) and placebo group (-0.1) at 14 weeks, and zonisamide group (-0.8) and placebo group (-3.7) at 28 weeks. Pittsburg Sleep Questionnaire The difference between the values at the 14th or 28th day of study drug administration and the baseline was zonisamide group (-0.3) and placebo group (0) at 14 weeks, and zonisamide group (-0.4) and placebo group (-0.3) at 28 weeks. REM sleep behavior disorder (RBD) screening questionnaire The difference between the values at the 14th or 28th day of study drug administration and the baseline was zonisamide group (-1,2) and placebo group (-0.4) at 14 weeks, and zonisamide group (-0.4) and placebo group (-1.1) at 28 weeks.

This study is a physician-led randomized control trial to evaluate the effects of zonisamide (ZNS) administration on both sleep disorders and REM sleep behavior disorder (RBD) in patients with Parkinson's disease who have sleep disorders or RBD. We conducted the current trial for the first time using a portable EEG/EOG recording system that can measure sleep abnormalities including RBD at home. We could not conclude that ZNS is effective for sleep disorders or RBD.

June. 02, 2024

No

Not applicable

https://jrct.mhlw.go.jp/latest-detail/jRCTs051200160

Hiroshi Kataoka

Nara Medical University Hospital

840 Shijo-cho Kashihara,Nara

hk55@naramed-u.ac.jp

Hiroshi Kataoka

Nara Medical University Hospital

840 Shijo-cho Kashihara,Nara

+81-744-29-8860

hk55@naramed-u.ac.jp

Complete

Mar. 24, 2021

Interventional

randomized controlled trial

single blind

placebo control

parallel assignment

treatment purpose

1. Patients at age of 41 years or older at the time of informed consent
2. Patients with Parkinson's disease (The use of other antiparkinson's disease drugs in addition to the levodopa-containing drugs did not work effectively)
3. Patients diagnosed with Parkinson's disease based on the International Parkinson and Movement Disorder Society (MDS) diagnostic criteria (The preganglionic dopaminergic decline in functional images does not matter)
4. Patients who have been treated with levodopa and a dopamine decarboxylase inhibitor for at least a consecutive month and responded to anti-Parkinson's drug
5. Patients with the regimen of levodopa and other anti-Parkinson's drug did not change from 2 weeks prior to participation into this study to the time of informed consent.
6. Patients with stages 1 to 4 in the Hoehn & Yahr severity classification
7. 22 points or more on the Mini-Mental State Examination (MMSE)
8. In Parkinson's disease sleep scale-2: PDSS-2 Japanese version item 1 those scored "Did you sleep well last week?" "Sometimes (2-3 times a week)" "Almost none (once a week)" "Nothing" or those who scored "Did you have a bad day at night?" "Sometimes (2-3 times a week)" "Many (4-5 times a week)" "So much (6-7 times a week)" in PDSS-2 Japanese version item 2 or those who scored 5 or more in the Japanese version of the REM sleep behavior disorder (RBD) screening questionnaire.
9. Patients who have given written consent from the patient or his / her substitute for participation in this study
10. Outpatient

1. Patients who have been treated with Zonisamide within 3 months prior to obtaining informed consent
2. Patients with a history of brain surgery including deep brain stimulation surgery
3. Patients with a history of other organic cerebral disorders such as stroke and epilepsy
4. Patients with serious renal dysfunction (eGFR is 30 and less) or hepatic disfunction within 6 months prior to patient's consent
5. Patients with a history of malignant syndrome
6. Patients with a history of suicide attempts
7. Patients taking antiepileptic drugs
8. Patients taking both MAO-B inhibitors and tricyclic antidepressants
9. Patients with severe dyskinesia
10. Patients with severe mental disease
11. Women with potential and intention to become pregnant
12. Patients who meet any of the following
Patients with a history of toxic epidermal necrolysis (TEN)
mucocutaneous ocular syndrome (Stevens-Johnson syndrome), and erythroderma (exfoliative dermatitis)
13. Patients with a history of hypersensitivity syndrome within 5 years prior to obtaining informed consent
14. Patients with a history of interstitial pneumonia within 5 years prior to obtaining informed consent
15. Patients with a history of rhabdomyolysis within 5 years prior to obtaining informed consent
16. Patients with aplastic anemia, agranulocytosis, pure red cell aplasia, thrombocytopenia
17. Patients using a pacemaker
18. Patients with a history of hypersensitivity to the components of Zonisamide
19. Patients participating in other clinical trials
20. Other patients who the principal investigator (sharing) judges to be inappropriate

Both

Parkinson's disease

70 patients with Parkinson's disease were allocated to Zonisamide tablets (Trelief OD tablets) 1T (25mg) or placebo 1T at a time before going to bed by randomizing soft, and the efficacy of zonisamide tablet (Trelief OD tablets) for sleep is investigated comparing the parallel-group before and after administration

Parkinson's disease,Somnipathy

Comparison of parallel-group

D010300

Objective sleep evaluation A: The following Sleep index analyzed from sleep electroencephalograms measured within 7 days before and 28 days (+ within 2days) after administration of the study drug using a portable electroencephalograph sleep graph
Sleep efficiency: Percentage of actual sleep time during sleep time (%)

Objective sleep evaluation B: The following 6 sleep indexes analyzed from sleep electroencephalograms measured within 7 days before and 28 days (+ within 2days) after administration of the study drug using a portable electroencephalograph sleep graph
Total sleep time: Time from falling asleep to final awakening (minutes)
Midway awakening: Total awakening time (minutes) during sleep
Initiation of sleep latency: Time from bedtime to initiation of sleep (minutes)
Sleep construction 1: REM sleep / non-REM sleep ratio (%)
Sleep construction 2: Deep sleep (N3) hours (minutes)
REM sleep behavior disorder (REM sleep without atony, RWA) : frequency of occurrence
Subjective sleep evaluation
1. PDSS-2 (Japanese version of Parkinson's disease sleep scale-2)
2. Pittsburg Sleep Questionnaire
3. REM sleep behavior disorder screening Japanese questionnaire

+81-744-29-8835

Feb. 10, 2021

none