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A 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 in patients with major depressive disorder

A study to test different doses of BI 1569912 in people with depression

225

The majority of treated patients (76.9%) had at least 1 baseline condition, with a slightly larger proportion of patients in the 20 mg BI 1569912 group reporting baseline conditions (82.2%). Most patients (76.0%) had not used a previous antidepressant for the current depressive episode. A total of 54 (24.0%) patients used 1 previous antidepressant for the current depressive episode, with 39 (17.3%) patients using an SSRI. The mean duration of the current episode was 34.3 weeks (SD: 24.0), with a median of 25 weeks, and the mean number of previous episodes was 5.9 (SD: 7.5). Mean MADRS score at baseline was consistent across treatment groups (31.1, 31.3, 30.9, and 31.1 in the placebo and 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). Demographic data for treated patients were generally balanced across the treatment groups and consistent with the planned patient population. The mean age of patients was 41.4 years (standard deviation [SD]: 13.4) and there were slightly more females than males in the placebo (56.6% and 43.4%, respectively) and BI 1569912 overall (54.2% and 45.8%, respectively) groups. Patients were predominantly White (46.2% based on single race respondents; 52.6% in placebo group and 43.0% in the BI 1569912 overall group); 27.6% of patients were Black or African American (18.4% in placebo group and 32.2% in the BI 1569912 overall group), 17.8% of patients were Asian (22.4% in placebo group and 15.4% in the BI 1569912 overall group), and 0.9% were American Indian or Alaska Native (0 in placebo group and 1.3% in the BI 1569912 overall group). The majority of patients were not Hispanic/Latino (78.7%; 84.2% in placebo group and 75.8% in the BI 1569912 overall group). Japanese patients comprised half of patients within the Asian subcategory of race (22 of 44 Asian patients based on single and multiple race respondents).

A total of 431 patients were screened, of which 225 patients were randomised into the trial and treated with trial medication (BI 1569912 or placebo). The majority of patients completed the 6-week double blind treatment period (63 patients [82.9%], 29 patients [82.9%], 35 patients [85.4%], and 66 patients [90.4%] in the placebo, and 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). The most common reasons for treatment discontinuation in placebo- and BI 1569912-treated patients were other (5 [6.6%] and 5 [3.4%] patients, respectively; primarily conflicts related to work or relocation), no reason available (2 [2.6%] patients and 5 [3.4%] patients, respectively), and adverse event (2 [2.6%] patients and 4 [2.7%] patients, respectively). One patient in the placebo group received an incorrect medication kit and was erroneously dosed with 20 mg BI 1569912 for 3 days. The patient was provided with the correct medication kit on Day 5 and they received placebo for the remainder of the trial. A review of the patient file established that no TEAEs were reported and no safety concerns were demonstrated based on laboratory results, vital signs, and ECG.

Approximately half of patients experienced TEAEs (46.3% overall; 47.4%, 51.4%, 48.8%, and 42.5% of patients in the placebo, 5 mg, 10 mg, and 20 mg BI 1569912 groups, respectively). No dose response trend was apparent. The most frequently reported TEAEs (occurring in >2 patients in any treatment group by preferred term) in the placebo group were headache (6 patients, 7.9%), influenza (5 patients, 6.6%), and nasopharyngitis (3 patients, 3.9%). In patients treated with 5 mg, 10 mg, and 20 mg BI 1569912, the most frequently reported TEAEs were headache (5 [14.3%], 4 [9.8%], 9 [12.3%] patients, respectively), dizziness (1 [2.9%], 2 [4.9%], and 3 [4.1%] patients, respectively), nasopharyngitis (1 [2.9%], 2 [4.9%], and 6 [8.2%] patients, respectively), nausea (1 [2.9%], 0, and 3 [4.1%] patients, respectively), and anxiety (1 [2.9%], 0, and 3 [4.1%] patients, respectively). Severe TEAEs were rare and were limited to 1 event of influenza in the placebo group (1.3%) and 1 event of anxiety in the 20 mg BI 1569912 group (1.4%). The incidence of drug-related TEAEs was low and comparable between the placebo and BI 1569912 overall groups (18.4% and 16.8%, respectively). The most common drug-related TEAE (reported in >2 patients in any treatment group) in the placebo group was headache (3 patients, 3.9%). In the 5 mg, 10 mg, and 20 mg BI 1569912 groups, common drug-related TEAEs included headache (4 [11.4%], 3 [7.3%], and 6 [8.2%] patients, respectively) and dizziness (1 [2.9%], 2 [4.9%], and 3 [4.1%] patients, respectively). Two patients experienced AESIs of potential severe drug-induced liver injury, including 1 patient in the placebo group and 1 patient in the 10 mg BI 1569912 group, assessed by the investigator as related and not related, respectively, to trial treatment. These cases were evaluated and had several confounders; thus, they did not trigger a safety signal. Serious TEAEs were reported for 2 patients, including suicidal ideation in 1 (1.3%) patient in the placebo group and 1 (2.4%) patient in the 10 mg BI 1569912 group with SAEs of acute left ventricular failure and acute kidney injury. During the follow up period, an additional patient in the 10 mg BI 1569912 group experienced SAEs of suicidal ideation and suicide attempt. No SAEs were reported in the 5 mg or 20 mg BI 1569912 groups. No fatal AEs occurred during the trial. Events of nausea, liver injury, dizziness, headache, anxiety, and thinking abnormal led to treatment discontinuation in 4 patients (2.7%) treated with BI 1569912. None of the TEAEs were reported in >1 patient in any treatment group. In the placebo group, patients discontinued treatment due to AEs of liverinjury and insomnia (1 patient each).There were no clinically relevant changes or dose-dependent trends in clinical laboratory evaluations or vital signs. No notable findings related to QTcF interval or QT interval were reported for any treatment group during the trial. Heart rate-related findings were rare, with notable findings in 2 patients who received BI 1569912 (5 mg and 20 mg BI 1569912 groups; heart rate increased and decreased, respectively) and 1 patient who received placebo (heart rate increased). In general, no safety issues were identified and there were no signs of elevated suicidal risk in relation to BI 1569912 treatment. Based on the SMWQ, there were no signs of withdrawal symptoms in the 8-14 days following cessation of treatment. Based on Bowdle VAS items, no signs or symptoms indicative for human abuse or dissociation were observed.

The primary endpoint of this trial was change from baseline in MADRS total score at Week 6. Results of MCPMod analysis did not demonstrate a non-flat dose response relationship on change from baseline in MADRS total score at Week 6. None of the 5 dose response models evaluated was statistically significant for the primary endpoint; the calculated test statistic for all models fell below the critical value. MADRS total scores (ranging from 0 to 60, with higher scores indicating increased severity of MDD) at baseline were similar across treatment groups, with mean (SD) values of 31.6 (4.7) in the placebo group, 32.0 (4.1) in the 5 mg BI 1569912 group, 32.2 (4.5) in the 10 mg BI 1569912 group, and 32.2 (4.2) in the 20 mg BI 1569912 group. The adjusted mean change from baseline at Week 6 in MADRS total score was greatest in the 5 mg BI 1569912 group (-13.6 [95% CI: -17.8, -9.4]) and was similar across the placebo (-10.3 [95% CI: -13.1, -7.5]), 10 mg BI 1569912 (-10.6 [95% CI: -14.5, -6.7]), and 20 mg BI 1569912 (-10.0 [95% CI: -12.9, -7.2]) groups. Sensitivity analysis results were generally consistent with the primary analysis and, despite numerical differences in treatment effects observed in some subgroup analyses, there was no indication of statistical relevance or dose-dependent trends for the primary endpoint.

Overall, daily doses of 5 mg, 10 mg, and 20 mg of BI 1569912 were safe and well tolerated by adult patients with moderate to severe MDD. No increase in suicidality or dissociative symptoms was observed and there were no signs or symptoms indicative for human abuse. Based on the analysis of the efficacy endpoints, a benefit of daily dosing with 5 mg, 10 mg, or 20 mg BI 1569912 could not be established.

https://clinicaltrials.gov/study/NCT06558344?term=1447-0012&viewType=Card&rank=1&tab=study

Yes

Researchers can refer to https://trials.boehringer-ingelheim.com/ to request access to raw data from our clinical studies.

https://jrct.mhlw.go.jp/latest-detail/jRCT2061240061

Taguchi Aya

Boehringer Ingelheim

2-1-1 Osaki, Shinagawa-ku, Tokyo

medchiken.jp@boehringer-ingelheim.com

Yamada Nobuko

Boehringer Ingelheim

2-1-1 Osaki, Shinagawa-ku, Tokyo

+81-120-189-779

medchiken.jp@boehringer-ingelheim.com

Complete

Nov. 08, 2024

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1) Male and female participants, 18 to 65 years of age
2) Women who are of childbearing potential (WOCBP) must be able and willing, to use two methods of contraception
3) Established diagnosis of MDD, single episode or recurrent with a duration of current depressive episode more than equal to 8 weeks and less than equal to 24 months at the time of randomisation
4) Hamilton Depression Rating Scale 17 (HDRS 17) - Severity score 20 and over
5) Clinical Global Impression Severity Scale (CGI S) score 4 and over

1) Have ever met diagnostic criteria for schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar disorder, or delusional disorder
2) Diagnosis with antisocial, paranoid, schizoid or schizotypal personality disorder, or MDD with psychotic features at the time of screening visit. Any other personality disorder that significantly affects current psychiatric status and likely to impact trial participation, as per the judgement of investigator
3) Diagnosis of any other mental disorder that was the primary focus of treatment within 6 months prior to screening, as per clinical discretion of the investigator
4) Treatment failure to 2 or more antidepressants in the current episode
5) 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
6) Participants with a body mass index (weight (kg) / height (m)2) lower than 18 kg / m2 or greater than 40 kg / m2 at screening
7) Diagnosis of a moderate to severe substance related disorder within 6 months prior to screening visit (with exception of caffeine and tobacco)
8) Frequent use of benzodiazepines
9) Positive drug screen (amphetamines, opiates, cocaine, barbiturates, phencyclidine) at screening. Participants with positive cannabis and benzodiazepine tests can be included if the investigator confirms that there is no moderate to severe substance related disorder or chronic benzodiazepine use
10) Have started psychotherapy or other non drug therapies (e.g. acupuncture, hypnosis) within 3 months prior to screening or plan to start at any time during the study
11) Use of NMDA inhibitors (including ketamine / esketamine) for the current ongoing depressive episode or any past treatment failure with ketamine
12) Use of psychotropic medication (including antidepressant and antipsychotic therapy) which was not discontinued at least 5 half lives prior to randomization
13) Prior use of any investigational product within 6 months prior to randomization
14) Have failed a 3rd party eligibility assessment within the 6 months prior screening
15) Known history of HIV infection and/or a positive result for an active Hepatitis B or C infection

Both

Major Depressive Disorder

Drug: BI1569912
Other: Placebo

D003865

D000284

Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 6

United States