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A phase 3 study of S-812217 in combination with an antidepressant in patients with major depressive disorder consisting of randomized, double-blind, placebo-control part and extension, open-label, re-treatment part

A phase 3 study of S-812217 in combination with an antidepressant in patients with major depressive disorder

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[Part A] 52.7% of the 30 mg group and 53.8% of the placebo group were male, while 47.3% and 46.2% were female. The median age was 40.0 years in the 30 mg group and 39.0 years in the placebo group. The mean BMI was 24.79 in the 30 mg group and 25.26 in the placebo group. Concomitant antidepressants were selective serotonin reuptake inhibitors (SSRIs) in 54.5% of the 30 mg group, serotonin norepinephrine reuptake inhibitors (SNRIs) in 23.6%, and serotonin reuptake inhibitors/receptor modulators (S-RIMs) in 21.8% of the placebo group, and 61.5%, 23.1%, and 15.4%, respectively. [Part B] The breakdown of participants administered S-812217 in Part B was as follows: 52.3% of the participants who were in the 30 mg group in Part A (30 mg/30 mg group) were male, 62.5% of the participants who were in the placebo group in Part A (placebo/30 mg group), and 47.7% and 37.5% were female, respectively. The median age was 40.5 years in both the 30 mg/30 mg group and the placebo/30 mg group. The mean BMI was 25.11 in the 30 mg/30 mg group and 25.46 in the placebo/30 mg group. Concomitant antidepressants were SSRIs in 52.3%, SNRIs in 25.0%, and S-RIMs in 22.7% of the 30 mg/30 mg group, and 59.4%, 21.9%, and 18.8%, respectively, in the placebo/30 mg group. There were no significant differences in the demographic and baseline characteristics of study participants administered S-812217 in Part B compared with Part A. In addition, demographic and baseline characteristics were collected for each S-812217 treatment cycle in Part B, and no significant differences were found between treatment cycles.

[Part A] 108 participants (55 in the 30 mg group, 53 in the placebo group) were enrolled, of which 101 completed Part A and 7 discontinued. The safety analysis population and FAS consisted of 107 participants (55 in the 30 mg group, 52 in the placebo group), excluding one participant who was not administered S-812217 (placebo group). [Part B] 82 participants were enrolled, of which 5 completed Part B and 77 discontinued. Part B was terminated during the study at the discretion of the sponsor, accounting for 48 of the 77 discontinuations. Furthermore, according to the study protocol, treatment cycles were limited to a maximum of 6, participants who met the criteria for starting the treatment period after completing Cycle 6 were discontinued. Six of the 77 patients met this criteria.

[Part A] The incidence of treatment emergent adverse events (TEAEs) was 67.3% (37/55 cases) in the 30 mg group and 42.3% (22/52 cases) in the placebo group. There were no deaths, and a serious adverse event other than death was observed in one participant in the placebo group (preferred term: hepatic function abnormal). TEAEs leading to treatment discontinuation were observed in one participant in the 30 mg group (preferred term: asthenia). TEAEs occurring in 5% or more of either group during the treatment period were somnolence (20.0% [11/55 cases] in the 30 mg group, 3.8% [2/52 cases] in the placebo group, same below), dizziness (7.3% [4/55 cases], 1.9% [1/52 cases]), and nausea (7.3% [4/55 cases], 0% [0/52 cases]), and during the follow-up period were nasopharyngitis (5.5% [3/55 cases], 3.8% [2/52 cases]), nausea (5.5% [3/55 cases], 3.8% [2/52 cases]), and back pain (0% [0/55 cases], 5.8% [3/52 cases]). [Part B] The incidence of TEAEs in each treatment cycle in the 30 mg/30 mg group was 45.5% (20/44 cases) in Cycle 1, 55.6% (20/36 cases) in Cycle 2, 57.7% (15/26 cases) in Cycle 3, 57.9% (11/19 cases) in Cycle 4, 45.5% (5/11 cases) in Cycle 5, and 28.6% (2/7 cases) in Cycle 6. In the placebo/30 mg group, the incidences were 59.4% (19/32 cases), 48.0% (12/25 cases), 68.4% (13/19 cases), 53.3% (8/15 cases), 44.4% (4/9 cases), and 57.1% (4/7 cases), respectively. In both groups, there was no tendency for the incidence of TEAEs to increase with the number of treatment cycles. There were no deaths, and one serious adverse event other than death was reported in the 30mg/30mg group (preferred term: hepatic function abnormal). TEAEs leading to discontinuation of treatment occurred in 6.4% (3/47 cases, preferred term: one case each of insomnia, dizziness, and hepatic function abnormal) in the 30mg/30mg group and 2.9% (1/35 cases, preferred term: dizziness) in the placebo/30mg group.

The baseline 17-item Hamilton Depression Rating Scale (HAM-D17) total score was 20.1 in the 30 mg group and 20.8 in the placebo group. The primary endpoint, the HAM-D17 response rate (the percentage of participants with at least a 50% reduction from baseline in HAM-D17 total score), was 13.2% (7/53 cases) in the 30 mg group and 21.6% (11/51 cases) in the placebo group. The adjusted odds ratio (95% CI) at Day 15 in the 30 mg group compared with the placebo group, estimated using an IPW-GEE, was 0.56 (0.20, 1.59), which did not exceed the prespecified threshold of 1.14, and the primary endpoint was not achieved. As a secondary endpoint, the change from baseline in the HAM-D17 total score decreased over time during the treatment period (Days 1 to 15) in both the 30 mg group and the placebo group in Part A, and the score at Day 15 was generally maintained during the follow-up period (Days 22 to 57). The change from baseline on Day 15 (adjusted mean) was -4.94 in the 30 mg group and -5.24 in the placebo group, and the difference in adjusted mean between the 2 groups (95% CI) was 0.30 (-1.75, 2.36). In Part B, the HAM-D17 total score decreased from baseline in both the 30 mg/30 mg group and the placebo/30 mg group at all treatment cycles. The mean changes from baseline in HAM-D17 total score (with SD) at Day 15 for each treatment were -3.7 (4.6), -3.2 (3.7), -4.0 (3.2), -4.3 (4.2), -2.7 (2.0), and -2.3 (2.4) for the Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, and Cycle 6, respectively. For the placebo/30 mg group, the changes were -3.6 (5.1), -5.3 (6.3), -4.8 (6.2), -3.5 (3.7), -3.2 (3.2), and -4.7 (3.9), respectively.

In patients with major depressive disorder receiving antidepressant treatment, administration of S-812217 30 mg or placebo once daily for 14 days did not demonstrate efficacy for S-812217 30 mg as an add-on treatment. Because the primary endpoint (HAM-D17 response rate at Day 15 [end of the 14-day dosing period]) was not met in Part A, interpretation of the results of Part B was challenging. Regarding safety, S-812217 30 mg was generally safe and well tolerated when added to antidepressants.

Aug. 31, 2025

Yes

Individual patients data will be shared according to the Clinical Trial Data Transparency Policy of Shionogi (http://www.shionogi.co.jp/en/company/policy/cl inical-trial.html). Requests from researchers will be reviewed by an Independent Review Panel, consisting of third-party experts, with regard to the validity and feasibility of the research that the researchers intend to carry out. When the request is approved by the panel, the researchers will be requested to execute a contract (which will have certain requirements with respect to personal data privacy, confidentiality, and compliance with the law) with Shionogi before being provided with access to the clinical trial data. Individual patient data will be shared after anonymization in order to protect the privacy of study participants and to comply with laws and regulations (including but not limited to the terms of the patient informed consent forms).

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220423

Gomez Juan Carlos

Shionogi & Co., Ltd.

1-8, Doshomachi 3-chome, Chuo-ku, Osaka, Osaka

shionogiclintrials-admin@shionogi.co.jp

Corporate Communications Department

Shionogi & Co., Ltd.

1-8, Doshomachi 3-chome, Chuo-ku, Osaka, Osaka

+81-6-6209-7885

shionogiclintrials-admin@shionogi.co.jp

Complete

Nov. 01, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

Patients who have been interviewed using Mini-International Neuropsychiatric Interview (M.I.N.I.) and had diagnosis of depression according to the DSM-5, and who meet the following 2 conditions:
- The current episode is ongoing for at least 8 weeks prior to the day of signing the ICF
- Duration of current episode is <=12 months prior to signing the ICF
Patients who are taking one antidepressant (SSRI, SNRI, serotonin reuptake inhibitor/serotonin receptor modulator) within the approved dosage for at least 4 weeks before Day 1 (no change in dosage).

Patients with treatment-resistant depression; no improvement in depressive symptoms even though at least two different antidepressants, except for antipsychotics, have been administered for treatment of an existing depressive episode at adequate doses approved in the countries for 4 weeks. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) will be evaluated only at Day 1.

Both

depression

Part A (randomized, double-blind, placebo-control part): S-812217 or Placebo oral administration in combination with an antidepressant
Part B (extension, open-label, re-treatment part): S-812217 oral administration in combination with an antidepressant

Presence or absence of HAM-D17 response (HAM-D17 total score decreased by 50% or more from baseline) on Day 15 of Part A

+81-42-648-5551

Oct. 13, 2022

none