Major Depressive Disorder With Suicidal Ideation With Intent
Conditions
Keywords
Major Depressive Disorder, Mental disorder, Mood disorder, Depression, Suicide, Suicidal Ideation, Suicidal intent, Suicidal risk, Self-Injurious Behavior, MIJ821, Antidepressive Agent, Psychotropic Drug, Hospitalization, Intravenous, Placebo, Adult
Brief summary
Study of efficacy and safety of MIJ821 in addition to comprehensive standard of care on the rapid reduction of symptoms of Major Depressive Disorder (MDD) in subjects who have suicidal ideation with intent
Detailed description
The main purpose of this study was to support the dose selection for future Phase III clinical trials by evaluating efficacy and safety of four MIJ821 doses (very low, low, high and very high) administered every other week for 6 weeks (3 infusions) by intravenous infusion on top of pharmacological antidepressant treatment, compared with placebo, for the rapid reduction of the symptoms of MDD in participants who have suicidal ideation with intent. In addition, the study explored the effect of single dose administration of very high and high doses to treat MDD in participants who have suicidal ideation with intent. The study consisted of three periods: a Screening Period (up to 48 hrs), a double-blind Core Period (6 weeks) and Extension Period (up to 52 weeks). The Extension Period explored durability of the effect of the study treatment and the effect of MIJ821 on relapse rate, as well as safety of MIJ821 administration. Those patients that responded to treatment at the end of the Core period were followed for up to a 52-week Extension period and were allowed to be retreated due to a relapse once with the same active treatment regimen as in the Core period (participants treated with placebo in the Core period were randomly switched to an MIJ821 regimen).
Interventions
DRUGMIJ821 Intravenous Injection
MIJ821 supplied in vials to be prepared on a mg/kg basis and to be administered for 40 minutes IV infusion on Day 1, Day 15 and Day 29
40 minutes IV infusion of 0.9% sodium chloride solution on Day1, Day 15 and Day 29
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study 2. Male and female participants, 18 to 65 years of age (inclusive) at screening 3. DSM-5 defined major depressive disorder (MDD) with a current major depressive episode (MDE) without psychotic features at the time of screening based upon clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (M.I.N.I.) assessed at Screening 4. Participants must have current suicidal ideation with intent, confirmed by a "Yes" response to Question B3 AND either Question B10 or Question B11 obtained from the M.I.N.I., assessed at Screening 5. Current suicidal ideation with intent, confirmed by "Yes" response to Question 3 AND either Question 9 or Question 10 obtained from the SSTS at Baseline 6. Montgomery-Åsberg Depression Rating Scale (MADRS) score \> 28 at Screening and before randomization on Day 1 7. Participants must agree to receive pharmacological standard of care treatment to treat their MDD (as determined by the treating physician(s) based on clinical judgement and local treatment guidelines) during the trial duration 8. In the physician's opinion, acute psychiatric hospitalization is clinically warranted to treat the patient's condition, and the patient is either already in the hospital or agrees to be hospitalized voluntarily for the required per protocol period
Exclusion criteria
1. Any prior or current diagnosis of bipolar disorder, MDD with psychotic features, schizophrenia, or schizoaffective disorder as obtained from M.I.N.I. at Screening 2. Patients with acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification, or patients who went through detoxification treatment (inpatient or outpatient) within 1 month before Screening. 3. Participant has a current clinical diagnosis of autism, dementia, or intellectual disability 4. History of seizures. Note: childhood febrile seizures are not exclusionary 5. Participants with current borderline personality disorder as obtained from M.I.N.I. at Screening. 6. Participants with suicidal ideation or behavior caused primarily by another non-MDD condition as obtained from M.I.N.I. at Screening 7. Participants taking medications prohibited by the protocol 8. Intake of the following medications/ psychotherapy: 1. Esketamine or Ketamine 2 months before Screening 2. Current Monoamine oxidase inhibitors (MAOIs) 14 days before Screening 3. known worsening or new appearance of suicidal ideation or behavior during a prior treatment, or within 2 months after last administration 9. Any other condition (e.g. known liver disease/liver dysfunction, active malignancy, etc.) which in the opinion of the investigator would put the safety of the participant at risk, impede compliance or hinder completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Total Score of the Montgomery Åsberg Depression Rating Scale (MADRS) | Baseline, 24 hours | The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 0 - 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts and suicidal thoughts. The MADRS was collected electronically by qualified personnel. Since the MADRS total score at 24 hours was evaluated post the single first infusion (prior to the second infusion), the bi-weekly and single dosing regimens of the same dose level are pooled as one arm for 0.048 mg/kg and 0.16 mg/kg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESI) During the Core Period | 6 weeks | Treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESIs) in Core period |
| AUClast - Pharmacokinetics (PK) of MIJ821 in Plasma | Pre-dose, 20min, 40min, 4hours and 24hours post 1st infusion | AUClast of MIJ821 in plasma after 1st infusion. AUClast is the Area Under the Curve (AUC) from time zero to the last measurable concentration sampling time (tlast). Since PK was evaluated post the single first infusion, the bi-weekly and single dosing regimens of the same dose level are pooled as one arm for 0.048 mg/kg and 0.16 mg/kg. |
| Cmax - Pharmacokinetics (PK) of MIJ821 in Plasma | Pre-dose, 20min, 40min, 4hours and 24hours post 1st infusion | Cmax of MIJ821 in plasma after 1st infusion. AUClast is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration. Since PK was evaluated post the single first infusion, the bi-weekly and single dosing regimens of the same dose level are pooled as one arm for 0.048 mg/kg and 0.16 mg/kg. |
| Number of Participants Meeting Response Criteria of ≥50% Reduction in MADRS Total Score. | 6 weeks | Response criteria of ≥50% reduction from baseline in MADRS total score over time in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition. |
| Number of Participants Meeting Criteria for Sustained Response of ≥50% Reduction in MADRS Total Score | 6 weeks | Sustained response (≥50% reduction from baseline) from baseline in MADRS total score for a period of at least four weeks in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition. |
| Number of Participants Meeting Remission Criteria of MADRS Total Score of ≤12 | 6 weeks | Remission criteria of MADRS total score of ≤12 over time in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition. |
| Number of Participants Meeting Sustained Remission Criteria of MADRS Total Score of ≤12 | 6 weeks | Remission criteria of MADRS total score of ≤12 sustained for a period of at least four weeks in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition. |
| Number of Participants Meeting Criteria for Relapse in the Extension Period | From 6 weeks up to 58 weeks | For participants classified as responders in the core period who entered the extension period. Response is defined as a ≥ 50% reduction from the baseline MADRS score at any visit during the study. All participants meeting criteria for relapse over fixed period in the Extension Period. A relapse manifests as the appearance of new depressive symptoms or worsening of previously stable or improving MDD symptoms. During the Extension Period, participants experiencing deterioration must be assessed by the treating physician and the relapse must be confirmed by assessment with MADRS during scheduled or unscheduled visit. |
| Number of Relapsing Participants Meeting Response Criteria After the First Retreatment Infusion in the Extension Period | Up to 52 weeks after first retreatment infusion. Timepoints are relative to first retreatment (R) infusion for each patient, including Follow Up (F/U). | Relapsing participants meeting response criteria or remission criteria after the first infusion of MIJ821 retreatment in the Extension Period. Response criteria (\>=50% reduction from baseline in MADRS total score). Reinfusions are given at Day 1, 15 and 29 after relapse. |
| Number of Relapsing Participants Meeting Remission Criteria After the First Retreatment Infusion in the Extension Period | Up to 52 weeks after first retreatment infusion. Timepoints are relative to first retreatment (R) infusion for each patient, including Follow Up (F/U). | Relapsing participants meeting response criteria or remission criteria after the first infusion of MIJ821 retreatment in the Extension Period. Remission criteria (MADRS total score \<=12). Reinfusions are given at Day 1, 15 and 29 after relapse. |
Countries
Argentina, Brazil, Canada, Germany, Japan, Malaysia, Mexico, Netherlands, Poland, Russia, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants took part in 39 investigative sites in 14 countries.
Pre-assignment details
The Screening period started when the participant signed the informed consent form. The eligibility of the participant was determined based on assessments performed at the Screening visit (up to 48 h) and also on Day 1 before randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 39.2 years STANDARD_DEVIATION 12.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 27 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 162 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 34 | 0 / 25 | 0 / 18 | 0 / 34 | 0 / 30 | 1 / 34 |
| other Total, other adverse events | 25 / 31 | 27 / 34 | 18 / 25 | 13 / 18 | 20 / 34 | 29 / 30 | 19 / 33 |
| serious Total, serious adverse events | 5 / 31 | 7 / 34 | 6 / 25 | 4 / 18 | 4 / 34 | 5 / 30 | 8 / 33 |
Outcome results
None listed