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A Phase II, 6-week, multi-centre, randomised, double-blind (participant and investigator), placebo-controlled, dose-finding trial to evaluate the efficacy, tolerability, and safety of different doses of oral BI 1569912 as adjunctive therapy in patients with major depressive disorder

A study to test different doses of BI 1569912 in people with depression who take anti-depressive medicine

243

Demographic data were generally balanced across the treatment groups and consistent with the planned patient population. The mean age of patients was 45.7 years (standard deviation [SD]: 13.5). Participants were predominantly female (60.9%), White (64.6%; 59.5% in placebo group and 70.0%, 63.4%, and 67.5% in the 5 mg, 10 mg, and 20 mg BI 1569912 groups), and not Hispanic/Latino (87.7%; 88.6% in placebo group and 90.0%, 92.7%, and 83.1% in the 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). Japanese patients comprised the majority of patients within the Asian subcategory of race. The majority of patients (78.2%) had at least 1 baseline condition, with a larger number of patients in the 5 mg BI 1569912 group reporting baseline conditions (90.0%). Mean baseline MADRS score was 32.8 in the placebo group and 32.9, 32.6, and 31.4 in the 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). Most patients (58.0%) had used 1 previous antidepressant for the current depressive episode (not including the currently ongoing SSRI/SNRI monotherapy required for inclusion in the trial) with 56.4% of participants using an SSRI and 24.7% using an SNRI. The mean duration of the current episode was 54.1 weeks (SD: 83.6), with a median of 28 weeks, and the mean number of previous episodes was 5.1 (SD: 6.2).

A total of 454 patients were screened, of which 243 patients were randomised into the trial and received at least one dose of trial medication as planned (BI 1569912 or placebo). The majority of patients completed the 6-week double blind treatment period (76 patients [96.2%], 35 patients [87.5%], 38 patients [92.7%], and 75 patients [90.4%] in the placebo, and 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). The most common reason for treatment discontinuation in BI 1569912-treated patients was AE (6 patients, 3.7%); no patients in the placebo group discontinued trial medication due to an AE.

Fewer than half of patients experienced TEAEs during the study (42.1% overall; 44.3%, 32.5%, 39.0%, and48.2% of patients in the placebo, 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). The incidence of TEAEs showed a tendency to increase with increasing BI 1569912 dose levels; however, the incidence of TEAEs in the placebo group was similar to that of the 20 mg BI 1569912 group and slightly higher than the 10 mg BI 1569912 group. As such, no dose response trend was apparent compared with the placebo group. The most frequently reported TEAEs in the placebo group (occurring in >2 patients in any treatment group by preferred term) were upper respiratory tract infection and headache (5 patients each, 6.3%) and influenza, nausea, and nasopharyngitis (3 patients each, 3.8%). In patients treated with 5 mg, 10 mg, and 20 mg BI 1569912, the most frequently reported TEAEs were headache (3 [7.5%], 2 [4.9%], and 7 [8.4%] patients, respectively), nasopharyngitis (3 [7.5%], 0, and 4 [4.8%] patients, respectively), nausea and sinusitis (1 [2.5%], 0, and 4 [4.8%] patients, respectively), dizziness (1 [2.5%], 0, and 7 [8.4%] patients, respectively) and anxiety (0, 0, and 3 [3.6%] patients, respectively). Severe AEs during the study were rare and were limited to gastroenteritis viral and accidental respiratory fume inhalation disorder (fatal case described below) in the 10 mg BI 1569912 group (1 patient each) and 1 event of anxiety in the 20 mg BI 1569912 group. No AESIs were reported during the trial. A similar proportion of patients across treatment groups experienced TEAEs that were considered drug-related by the investigator (17.7%, 10.0%, 14.6%, and 22.9% of patients in the placebo, 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). The most common drug-related TEAEs in the placebo group were nausea, headache, dizziness, somnolence, and constipation. In the 5 mg, 10 mg, and 20 mg BI 1569912 groups, common drug-related AEs included dizziness, headache, nausea, and somnolence. Serious AEs were reported for 4 patients during the trial (1 patient each in the placebo, 10 mg BI 1569912 and 20 mg BI 1569912 groups during the on-treatment period; 1 patient the 20 mg BI 1569912 group during the follow-up period). A fatal, accidental event of respiratory fume inhalation disorder was reported in the 10 mg BI 1569912 group. Serious AEs of suicidal ideation were reported in individual patients in the placebo and 20 mg BI 1569912 groups (1 SAE each). An SAE of syncope was reported in the 5 mg BI 1569912 group during the follow-up period. None of the SAEs were considered drug related by the investigator. Events of palpitations, myalgia, and paraesthesia in the 5 mg BI 1569912 group, neutropenia in the 10 mg BI 1569912 group, and generalized anxiety disorder and panic attack in the 20 mg BI 1569912 group led to treatment discontinuation in individual patients. No patients in the placebo group discontinued treatment due to AEs. There were no clinically relevant changes or dose-dependent trends in clinical laboratory evaluations or vital signs. Adverse events related to abnormal ECG findings were rare, reported in 2 BI 1569912-treated patients (both palpitations). Heart rate-related findings were considered notable in 3 patients (1.8%) who received BI 1569912. There were no notable findings in the placebo group. No clinically relevant changes or dosedependent trends were noted in ECGs. In general, no safety issues were identified in Bowdle VAS and there were no signs of elevated suicidal risk in relation to BI 1569912 treatment. Based on the SMWQ, there no signs of withdrawal in the 8-14 days following cessation of treatment. Based on Bowdle VAS items, no signs or symptoms indicative for human abuse were observed.

Primary efficacy endpoint The primary endpoint of this trial was the change from baseline in MADRS total score at Week 6. MCPMod analysis did not demonstrate a non flat dose response relationship for the change from baseline in MADRS total score at Week 6. None of the five dose response models evaluated showed statistical significance for the primary endpoint. For all models, the calculated test statistics were below the critical value. MADRS total scores ranged from 0 to 60, with higher scores indicating greater severity of major depressive disorder. Baseline MADRS total scores were similar across treatment groups. Mean and standard deviation values were 32.8 and 5.3 in the placebo group, 32.9 and 4.7 in the 5 milligram BI 1569912 group, 32.6 and 4.8 in the 10 milligram BI 1569912 group, and 31.4 and 4.8 in the 20 milligram BI 1569912 group. The results of the mixed model for repeated measures analysis included fixed effects for treatment at each time point, cohort, and baseline MADRS total score at each time point. The adjusted mean change from baseline at Week 6 in MADRS total score was smallest in the 5 milligram BI 1569912 group and was similar among the placebo, 10 milligram BI 1569912, and 20 milligram BI 1569912 groups. Although numerical differences were observed in sensitivity analyses and some subgroup analyses, no evidence of statistical relevance or dose dependent trends was identified for the primary endpoint. Secondary efficacy endpoints Consistent with the primary endpoint, none of the five evaluated dose response models demonstrated statistical significance for the change from baseline in MADRS total score at Day 8. Compared with baseline, MADRS total score decreased in all treatment groups at the first measured time point. Adjusted mean changes from baseline were minus 6.4 in the placebo group, minus 5.2 in the 5 milligram BI 1569912 group, minus 5.9 in the 10 milligram BI 1569912 group, and minus 5.7 in the 20 milligram BI 1569912 group. At Day 8, the proportion of responders, defined as participants with a reduction in MADRS total score from baseline of at least fifty percent, was similar in the 5 milligram and 10 milligram groups and in the placebo group. The 20 milligram group showed a slightly higher proportion of responders. However, this difference was not considered statistically relevant based on odds ratio analysis. At Week 6, the proportion of responders increased in all treatment groups. The proportion of responders in the BI 1569912 treatment groups was comparable to or lower than that in the placebo group. The proportion of participants who achieved remission, defined as a MADRS total score of ten or lower, at Week 6 was numerically highest in the 10 milligram group. However, no relevant difference from the placebo group was identified, and the number of participants achieving remission was small. The adjusted mean change from baseline in SMDDS total score at Day 8 was similar across treatment groups. This score reflects the core symptoms of major depressive disorder from the patient perspective. The largest decrease was observed in the placebo group. At Week 4, the adjusted mean change from baseline in SMDDS total score continued to decrease in all treatment groups.

Based on the analysis of the efficacy endpoints, a therapeutic benefit of daily dosing with 5 mg, 10 mg, and 20 mg BI 1569912 as an adjunctive therapy to stable background antidepressants could not be established.

Mar. 28, 2026

https://clinicaltrials.gov/study/NCT06280235?term=1447-0005&viewType=Card&rank=1

No

Researcheres can refer to https://trials.boehringer-ingelheim.com/ to request access to raw data from the clinical trial

https://jrct.mhlw.go.jp/latest-detail/jRCT2031240035

Murakami Kanako

IQVIA Services Japan G.K.

4-10-18 Takanawa Minato-ku Tokyo Japan

BI1569912_Japan@iqvia.com

jRCT Inquiry Receipt Center

IQVIA Services Japan G.K.

4-10-18 Takanawa Minato-ku Tokyo Japan

+81-3-6859-9500

BI1569912_Japan@iqvia.com

Complete

July. 16, 2024

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

-Established diagnosis of MDD with a duration of current depressive episode >= 8 weeks at the time of screening visit
-Hamilton Depression Rating Scale 17 - Severity scale score >17
-A documented ongoing monotherapy treatment of >= 6 weeks at the randomization visit, with an SSRI or SNRI at adequate dose
-In the current episode, participants have shown insufficient treatment response
-Male and female participants, 18 to 65 years of age at the time of consent.
-Women who are of childbearing potential must be able and willing, to use two methods of contraception.

- Had ever met diagnostic criteria for schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar disorder, or delusional disorder
- Diagnosis with antisocial, paranoid, schizoid or schizotypal personality disorder, or MDD with psychotic features
- Any other personality disorder that significantly affects current psychiatric status and likely to impact trial participation, as per the judgement of investigator.
- Diagnosis of any other mental disorder that was the primary focus of treatment within 6 months prior to screening
- A current or recent history of clinically significant suicidal ideation with intent within the past 3 months or a suicidal attempt within the past year
- Diagnosis of a moderate to severe substance related disorder within 6 months prior to consent (with exception of caffeine and tobacco).
- Positive drug screen (amphetamines, opiates, cocaine, barbiturates, phencyclidine)
- Have started psychotherapy or other non-drug therapies (e.g. acupuncture, hypnosis) within 3 months prior to consent or plan to start at any time during the study
- Use of alternative or traditional medicine (e.g. Chinese traditional medicine, herbal medication, St. John's wort etc.) within 14 days prior to randomization and during the entire course of the study
- Use of NMDA inhibitors (including ketamine/esketamine) for the current ongoing depressive episode or any past treatment failure with ketamine.
- Use of psychotropic medication, outside of ongoing SSRI/SNRI monotherapy and certain exceptions, which was not discontinued at least 5 half-lives prior to randomization.

Both

Major depressive disorder

Drug: BI1569912
Other: Placebo

Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Day 8

+81-42-648-5551

April. 05, 2024

USA/China/Germany/Czech Republic/Bulgaria/Belgium