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A Phase 3b, Multicenter, Randomized, Double-blind Extension Study to Evaluate the Continued Efficacy and Safety of Oral Edaravone Administered for an Additional Period of up to 48 Weeks Following Study MT-1186-A02 in subjects with Amyotrophic Lateral Sclerosis (ALS)

Efficacy and Safety Extension Study of Oral Edaravone Administered in Subjects With ALS

202

The Randomized Set included mostly male (245 [63.8%] subjects), white (224 [58.3%] subjects), and not Hispanic or Latino (370 [96.4%] subjects). Subjects ranged in age from 29 to 75 years, with a median age of 60 years. Most subjects were aged < 65 years (256 [66.7%] subjects), with 116 (30.2%) subjects between 50 and 59 years and 140 (36.5%) subjects between 60 and 69 years. No subject was aged < 20 years. Subject BMI ranged from 16.1 to 40.1 kg/m2, with a median BMI of 23.70 kg/m2. Most subjects resided in North America (131 [34.1%] subjects) or Japan (128 [33.3%] subjects). Overall, demographic and baseline characteristics were well balanced between the Once Daily and On/Off treatment groups.

In total, 384 subjects were enrolled and randomized 1:1 either to the Once Daily or the On/Off treatment group in MT-1186-A02 study. Subjects who completed MT-1186-A02 study and signed the ICF for rollover into MT-1186-A04 at Week 48 of MT-1186-A02, which was Screening/Day 1 of MT-1186-A04 were 202 (52.6%), 104 (54.2%) in the Once Daily and 98 (51.0%) in the On/Off treatment groups. A total of 48 (12.5%) subjects completed the 48-week DBT period of MT-1186-A04; those subjects who either completed or discontinued the DBT period of MT-1186-A04 and who entered the 2-week safety FU period were 141 (36.7%) subjects. Of the 154 (40.1%) subjects who discontinued study treatment, the most common reason for discontinuation was study terminated by Sponsor (96 [25.0%] subjects). Overall, the distribution of subject disposition was balanced between the treatment groups.

In total during MT-1186-A02 and MT-1186-A04 studies, 170 (88.5%) subjects (1279 events) in the Once Daily group and 180 (94.2%) subjects (1169 events) in the On/Off group experienced at least 1 TEAE during the study. TEAEs related to study drug were markedly more frequent in the Once Daily group (47 [24.5%] subjects; 78 events) compared with the On/Off group (32 [16.8%] subjects; 49 events). In total, 170 (88.5%) subjects in the Once Daily group and 180 (94.2%) subjects in the On/Off group experienced at least 1 TEAE. Gastrointestinal Disorders were the most frequently reported TEAEs by SOC both in the Once Daily group (103 [53.6%] subjects) and the On/Off group (96 [50.3%] subjects). The most common TEAE by PT was dysphagia in the Once Daily group (41 [21.5%] subjects) and fall (41 [21.5%] subjects) in the On/Off group. The second most common TEAEs were fall (40 [20.8%] subjects) in the Once Daily group and dysphagia in 34 [17.8%] subjects in the Once Daily group, followed by COVID-19 as the third most frequent TEAE in the Once Daily group (35 [18.2%] subjects) and constipation in the On/Off group (33 [17.3%] subjects).

Primary Efficacy Endpoint: - Time from the randomization date in Study MT-1186-A02 to at least a 12-point decrease in ALSFRS-R or death, whichever happens first. No statistically significant difference was observed by the primary analysis of the stratified Log-rank test (P=0.780) in the primary estimand. The sensitivity analysis by the COX proportional hazard model also showed no statistically significant differences with a hazard ration (HR) of 1.039 (80% 0.862, 1.252). The number of events (%) with at least a 12-point decrease in ALSFRS-R was similar for Once Daily group (86 [44.8%]) and On/Off group (82 [42.7%]), or death (Once Daily group: 10 [5.2%] and On/Off group was 12 [6.3%]), or censored (Once Daily group: 96 [50.0%] and On/Off group 98 [51.0%]). Secondary Endpoints: - CAFS Score at Week 96 At Week 48, the CAFS LS mean rank was 189.0 in the Once Daily group and 182.7 in the On/Off group. At Week 72, the CAFS LS mean rank was 193.6 in the Once Daily group and 189.1 in the On/Off group. At Week 96, the CAFS LS mean rank was 200.8 in the Once Daily group and 181.6 in the On/Off group. - Changes from Baseline in ALSAQ-40 at Week 96 At baseline of MT-1186-A02, the mean ALSAQ-40 total score was 78.6 (SD 20.1) in the Once Daily group and 77.8 (SD 21.5) in the On/Off group. The LS mean change from baseline in ALSAQ-40 total score at Week 96 was 54.83 (95% CI 46.83 to 62.84) in the Once Daily group and 57.91 (95% CI 49.75 to 66.07) in the On/Off group. - Changes from Baseline in ALSFRS-R Score at Week 96 At baseline of MT-1186-A02, the mean ALSFRS-R total score was 40.5 (SD 3.1) in the Once Daily group and 40.6 (SD 3.0) in the On/Off group. The LS mean change from baseline in ALSFRS-R total score at Week 96 was -18.21 (95% CI -20.80 to -15.61) in the Once Daily group and -20.95 (95% CI -23.55 to -18.35) in the On/Off group. - Time to Death, Tracheostomy or PAMV The median survival for the time to death could not be calculated due to the low number of events (only 33 and 32 events of death, tracheostomy, or PAMV in the Once Daily and On/Off groups, respectively), resulting in 159 and 160 censored observations in respective group. - Time to Death or PAMV The median survival for the time to death could not be calculated due to the low number of events (only 30 and 31 events of death or PAMV in the Once Daily and On/Off groups, respectively), resulting in 162 and 161 censored observations in respective group. - Time to Death The median survival for the time to death could not be calculated due to the low number of events (only 24 and 28 events of death in the Once Daily and On/Off groups, respectively), resulting in 168 and 164 censored observations in respective group.

MT-1186-A04 was a extension study designed to evaluate the efficacy and safety of 2 treatment regimens which are the Once Daily or the On/Off treatment group of edaravone for an additional period of up to 48 weeks. Overall, the Once Daily regimen did not show significantly better efficacy compared with the On/Off regimen. No significant differences in the incidence of TEAEs between treatment groups and no significant safety findings were observed. No new safety signal was identified.

Sept. 27, 2024

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210117

Kondo Kazuoki

Mitsubishi Tanabe Pharma Corporation

1-1-1 Marunouchi Chiyoda-ku, Tokyo

cti-inq-ml@ml.mt-pharma.co.jp

Clinical Trials Information Desk

Mitsubishi Tanabe Pharma Corporation

1-1-1, Marunouchi Chiyoda-ku, Tokyo

+81-3-5960-9608

cti-inq-ml@ml.mt-pharma.co.jp

Complete

Feb. 23, 2022

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

1. Subjects must provide a signed and dated informed consent form to participate in the study.
2. Subjects must be able (in the judgment of the Investigator) to understand the nature of the study and all risks involved with participation in the study.
3. Subjects must be willing to cooperate and comply with all protocol restrictions and requirements.
4. Subjects must have successfully completed all Study MT-1186-A02 visits and have been compliant with study drug.

1. Subjects of childbearing potential unwilling to use an acceptable method of contraception from the screening visit until 3 months after the last dose of study medication. Subjects who are sexually active who do not agree to use contraception during the study period.
2. Subjects who are female, of childbearing potential, and pregnant (a positive pregnancy test) or lactating at the screening visit.
3. Subjects who have a significant risk of suicide. Subjects with any suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with some intent to act, without a specific plan) or type 5 (active suicidal ideation with specific plan and intent) based on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Week 48 of Study MT-1186-A02.
4. Subjects who are not eligible to continue in the study, as judged by the Investigator in conjunction with the MTDA medical monitor.
5. Subjects who are unable to take their medications orally or through a PEG/RIG tube.

Both

Amyotrophic Lateral Sclerosis

- Oral edaravone administered once daily for up to 48 weeks or until the drug is commercially available in that country
- Oral edaravone administered for 10 days followed by 18-day placebo (regimen denoted as on/off) for up to
48 weeks or until the drug is commercially available in that country

Time from the randomization date in Study MT-1186-A02 to at least a 12-point decrease in ALSFRS-R or death, whichever happens first.

- Combined Assessment of Function and Survival(CAFS)
- ALSAQ40
- ALSFRS-R.
- Time (days) to death, tracheostomy, or permanent assisted mechanical ventilation (>= 23 hours/day)

+81-96-242-1000

Dec. 13, 2021

US/Canada/Germany/Italia/South Korea/Switzerland