Treatment-Resistant Depression
Conditions
Keywords
Treatment-Resistant Depression, Major Depressive Episode, Major Depressive Disorder, MIJ821, Anti-depressive Agent, Subcutaneous, Placebo, Adult
Brief summary
The main purpose of this study was to evaluate safety and efficacy of a single injection of MIJ821 in addition to standard of care (SoC) pharmacological anti-depressant treatment in participants with treatment-resistant depression (TRD)
Detailed description
The trial included a screening period of up to 28 days. On Day 1, after screening, eligible participants were randomized to one of the treatment arms (1 mg, 4 mg, or 10 mg of MIJ821) or placebo and received study treatment administered as a single subcutaneous injection. Participants remained at the clinic for at least 4 hours after administration of study treatment for safety observation including assessment of local tolerability by visual inspection of the injection area. Post-dose clinic visits occurred 24 hours post dose (Day 2), Days 8, 15, 22 and 29 to evaluate efficacy and safety. Efficacy assessments included the Montgomery-Asberg Depression Scale (MADRS) and other clinical outcome assessments (COAs). Safety assessments included laboratory tests, ECGs, vital signs and physical examinations. In addition, phone calls were conducted 3 days after each on-site clinic visit with the exception of the End-of-study (EOS) visit. EOS visit was completed on site on Day 29. Including screening, participants were in the study for up to 8 weeks (57 days).
Interventions
DRUGMIJ821 Subcutaneous Injection 1 mg
MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1.
DRUGMIJ821 Subcutaneous Injection 4 mg
MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1.
DRUGMIJ821 Subcutaneous Injection 10 mg
MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1.
0.9% sodium chloride solution administered as a single SC injection on Day 1.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent obtained prior to participation in the study * Male and female participants, 18 to 65 years of age (inclusive) at screening * DSM-5 defined major depressive disorder (MDD) and a current major depressive episode (MDE) * MADRS score ≥ 24 * Failure to respond to 2 or more antidepressant treatments where the two failed treatments are two different antidepressants
Exclusion criteria
* Any prior or current diagnosis of MDD with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder * Participants with acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification, or participants who went through detoxification treatment within 1 month before Screening * Participants with current borderline personality disorder or antisocial personality disorder * Current clinical diagnosis of autism, dementia, or intellectual disability
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score 24 Hours (Day 2) After Injection | Baseline and 24 hours after SC injection | 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 scores were collected electronically by qualified personnel. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) of MIJ821 in Plasma for Area Under the Curve From the Time of Dosing to the Time of the Last Measurable Concentration (AUClast) | Baseline, 0.17 hour, 0.33 hour, 0.5 hour, 0.75 hour, 1, 1.5, 2, 4 and 24 hours post injection | Blood samples were collected at the indicated time points for PK analysis. AUClast was defined as the area under the curve from time zero to the last measurable concentration sampling time (tlast). |
| PK of MIJ821 in Plasma for Maximum Serum Concentration (Cmax) | Baseline, 0.17 hour, 0.33 hour, 0.5 hour, 0.75 hour, 1, 1.5, 2, 4 and 24 hours post injection | Blood samples were collected at the indicated time points for PK analysis. Cmax was defined as the maximum (peak) observed plasma drug concentration after single dose administration. |
| PK of MIJ821 in Plasma for Time to Maximum Drug Concentration (Tmax) | Baseline, 0.17 hour, 0.33 hour, 0.5 hour, 0.75 hour, 1, 1.5, 2, 4 and 24 hours post injection | Blood samples were collected at the indicated time points for PK analysis. Tmax was defined as the time to reach maximum (peak) plasma drug concentration after single dose administration (time). |
| Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Baseline, Days 8, 15, 22 and 29 | The 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 scores were collected electronically by qualified personnel. |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | From Day 1 after SC injection to end of study, up to 29 Days | A TEAE was defined as an adverse event starting or worsening after the administration of study medication and up to the end of study visit. The following events were considered AESIs: * Dissociation * Sedation * Cardiovascular effects (Blood Pressure changes and QT interval prolongation on electrocardiogram \[ECG\]) * Respiratory effects (difficulty in breathing, changes in oxygen saturation) * Suicidality (suicidal ideation or behavior) * Memory gaps/amnesia * Cystitis or lower urinary tract adverse events |
| Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameters: Placebo Effect E0, Emax | Baseline, Day 2, 15, 22 and 29 | The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter. |
| Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: EC50 (Cmax) | Baseline, Day 2, 15, 22 and 29 | The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter. |
| Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: EC50 (AUClast) | Baseline, Day 2, 15, 22 and 29 | The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter. |
| Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: Hill Parameter | Baseline, Day 2, 15, 22 and 29 | The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter. |
| Dose-response (DR) Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score at 24 Hours After Single SC Injection | Baseline up to 24 Hours | The multiple comparison procedure - modelling (MCP-Mod) approach was an integrated approach used to investigate DR relationships, while confirming efficacy of the test product based on hypothesis testing. A set of candidate models was tested using Multiple Comparison Procedures (MCP) that preserve the family-wise error rate (FWER) to determine the model best representing the underlying DR. Efficacy via DR was established when at least one of the model tests was significant. |
Countries
Japan, Poland, Spain, United States
Participant flow
Pre-assignment details
All inclusion and exclusion criteria were checked during screening and on Day 1, prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| MIJ821 10 mg Participants received a single dose of 10 mg MIJ821 administered as a subcutaneous injection on Day 1. | 15 |
| MIJ821 4 mg Participants received a single dose of 4 mg MIJ821 administered as a subcutaneous injection on Day 1. | 14 |
| MIJ821 1 mg Participants received a single dose of 1 mg MIJ821 administered as a subcutaneous injection on Day 1. | 14 |
| Placebo Participants received a single dose of 0.9% sodium chloride solution administered as a subcutaneous injection on Day 1. | 17 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | MIJ821 10 mg | MIJ821 4 mg | MIJ821 1 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 47.8 years STANDARD_DEVIATION 12.36 | 43.9 years STANDARD_DEVIATION 11.29 | 46.9 years STANDARD_DEVIATION 9.73 | 47.1 years STANDARD_DEVIATION 12.05 | 46.5 years STANDARD_DEVIATION 11.26 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 3 Participants | 0 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 11 Participants | 11 Participants | 17 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian / Japanese | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 15 Participants | 13 Participants | 12 Participants | 17 Participants | 57 Participants |
| Sex/Gender, Customized Female | 11 Participants | 10 Participants | 9 Participants | 7 Participants | 37 Participants |
| Sex/Gender, Customized Male | 4 Participants | 4 Participants | 5 Participants | 10 Participants | 23 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 14 | 0 / 14 | 0 / 17 | 0 / 43 | 0 / 60 |
| other Total, other adverse events | 10 / 15 | 6 / 14 | 4 / 14 | 7 / 17 | 20 / 43 | 27 / 60 |
| serious Total, serious adverse events | 0 / 15 | 0 / 14 | 0 / 14 | 0 / 17 | 0 / 43 | 0 / 60 |
Outcome results
Primary
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score 24 Hours (Day 2) After Injection
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 scores were collected electronically by qualified personnel.
Time frame: Baseline and 24 hours after SC injection
Population: The Full Analysis Set (FAS) included all randomized participants who received a dose of the randomized treatment. Participants were analyzed according to the assigned treatment groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MIJ821 10 mg | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score 24 Hours (Day 2) After Injection | -14.1 Scores on a Scale | Standard Error 1.95 |
| MIJ821 4 mg | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score 24 Hours (Day 2) After Injection | -11.4 Scores on a Scale | Standard Error 2.04 |
| MIJ821 1 mg | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score 24 Hours (Day 2) After Injection | -8.4 Scores on a Scale | Standard Error 2.02 |
| Placebo | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score 24 Hours (Day 2) After Injection | -8.9 Scores on a Scale | Standard Error 1.82 |
90% CI: [-9.6, -0.7]ANCOVA
90% CI: [-7, 2.1]ANCOVA
90% CI: [-4, 5.1]ANCOVA
Secondary
Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits
The 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 scores were collected electronically by qualified personnel.
Time frame: Baseline, Days 8, 15, 22 and 29
Population: The Full Analysis Set (FAS) included all randomized participants who received a dose of the randomized treatment. Participants were analyzed according to the assigned treatment groups.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MIJ821 10 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 8) | -15.3 Scores on a Scale | Standard Error 2 |
| MIJ821 10 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 15) | -14.0 Scores on a Scale | Standard Error 2.2 |
| MIJ821 10 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 22) | -14.9 Scores on a Scale | Standard Error 2.2 |
| MIJ821 10 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 29) | -14.9 Scores on a Scale | Standard Error 2.3 |
| MIJ821 4 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 15) | -8.5 Scores on a Scale | Standard Error 2.2 |
| MIJ821 4 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 22) | -10.7 Scores on a Scale | Standard Error 2.3 |
| MIJ821 4 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 29) | -12.7 Scores on a Scale | Standard Error 2.4 |
| MIJ821 4 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 8) | -9.9 Scores on a Scale | Standard Error 2.1 |
| MIJ821 1 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 22) | -9.7 Scores on a Scale | Standard Error 2.3 |
| MIJ821 1 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 15) | -11.0 Scores on a Scale | Standard Error 2.2 |
| MIJ821 1 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 29) | -10.7 Scores on a Scale | Standard Error 2.4 |
| MIJ821 1 mg | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 8) | -8.2 Scores on a Scale | Standard Error 2 |
| Placebo | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 29) | -7.0 Scores on a Scale | Standard Error 2.1 |
| Placebo | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 15) | -7.7 Scores on a Scale | Standard Error 2 |
| Placebo | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 8) | -7.4 Scores on a Scale | Standard Error 1.8 |
| Placebo | Change From Baseline in the MADRS Total Scores at Day 8, 15, 22 and 29 Visits | Change from Baseline (Day 22) | -7.0 Scores on a Scale | Standard Error 2 |
Secondary
Dose-response (DR) Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score at 24 Hours After Single SC Injection
The multiple comparison procedure - modelling (MCP-Mod) approach was an integrated approach used to investigate DR relationships, while confirming efficacy of the test product based on hypothesis testing. A set of candidate models was tested using Multiple Comparison Procedures (MCP) that preserve the family-wise error rate (FWER) to determine the model best representing the underlying DR. Efficacy via DR was established when at least one of the model tests was significant.
Time frame: Baseline up to 24 Hours
Population: The Full Analysis Set (FAS) included all randomized participants who received a dose of the randomized treatment. Participants were analyzed according to the assigned treatment groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MIJ821 10 mg | Dose-response (DR) Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score at 24 Hours After Single SC Injection | -14.1 Scores on a Scale | Standard Error 1.95 |
| MIJ821 4 mg | Dose-response (DR) Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score at 24 Hours After Single SC Injection | -11.4 Scores on a Scale | Standard Error 2.04 |
| MIJ821 1 mg | Dose-response (DR) Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score at 24 Hours After Single SC Injection | -8.4 Scores on a Scale | Standard Error 2.02 |
| Placebo | Dose-response (DR) Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score at 24 Hours After Single SC Injection | -8.9 Scores on a Scale | Standard Error 1.82 |
Comparison: MCP-Mod was used to check if there was a DR relationship between the change from baseline to 24 hours in MADRS total score and the doses received. The Least squares means under the primary estimand were used to test the null hypothesis of a flat DR relationship at a one-sided significance level of 5% against the alternative hypothesis of a non-flat DR curve. Six candidate DR curves were used to derive the optimal model contrasts for the multiple contrast tests. A monotone DR was assumed.p-value: 0.0242Multiple contrast test
Secondary
Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: EC50 (AUClast)
The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter.
Time frame: Baseline, Day 2, 15, 22 and 29
Population: The PK analysis set included all participants with at least one available, valid PK concentration measurement, who received any study drug and with no protocol deviations that had an impact on PK data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: EC50 (AUClast) | NA h*ng/mL |
Secondary
Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: EC50 (Cmax)
The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter.
Time frame: Baseline, Day 2, 15, 22 and 29
Population: The PK analysis set included all participants with at least one available, valid PK concentration measurement, who received any study drug and with no protocol deviations that had an impact on PK data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: EC50 (Cmax) | NA ng/mL |
Secondary
Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: Hill Parameter
The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter.
Time frame: Baseline, Day 2, 15, 22 and 29
Population: The PK analysis set included all participants with at least one available, valid PK concentration measurement, who received any study drug and with no protocol deviations that had an impact on PK data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: Hill Parameter | Exposure-response Relationship Cmax: Hill parameter | NA Hill coefficient |
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameter: Hill Parameter | Exposure-response Relationship AUClast: Hill parameter | NA Hill coefficient |
Secondary
Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameters: Placebo Effect E0, Emax
The exposure-response relationship was investigated considering PK exposure parameters (AUClast and Cmax) and the change from baseline MADRS score derived at 4 h and 24 h after injection and Day 8, Day 15, Day 22 and Day 29 during the follow-up. The emax model or sigmoid emax model were planned to be fitted for the change from baseline at each follow up visit and the PK exposure parameters, Cmax and AUClast. If the model converges, parameters estimated from the Sigmoid emax model are: the placebo effect E0, EC50, Emax and the hill parameter.
Time frame: Baseline, Day 2, 15, 22 and 29
Population: The PK analysis set included all participants with at least one available, valid PK concentration measurement, who received any study drug and with no protocol deviations that had an impact on PK data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameters: Placebo Effect E0, Emax | Exposure-response Relationship Cmax: placebo effect E0 | NA Scores on a scale |
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameters: Placebo Effect E0, Emax | Exposure-response Relationship Cmax: Emax | NA Scores on a scale |
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameters: Placebo Effect E0, Emax | Exposure-response Relationship AUClast: placebo effect E0 | NA Scores on a scale |
| MIJ821 10 mg | Exposure-response Relationship of MIJ821 With Respect to Change From Baseline in MADRS Total Score. Estimated Parameters: Placebo Effect E0, Emax | Exposure-response Relationship AUClast: Emax | NA Scores on a scale |
Secondary
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs)
A TEAE was defined as an adverse event starting or worsening after the administration of study medication and up to the end of study visit. The following events were considered AESIs: * Dissociation * Sedation * Cardiovascular effects (Blood Pressure changes and QT interval prolongation on electrocardiogram \[ECG\]) * Respiratory effects (difficulty in breathing, changes in oxygen saturation) * Suicidality (suicidal ideation or behavior) * Memory gaps/amnesia * Cystitis or lower urinary tract adverse events
Time frame: From Day 1 after SC injection to end of study, up to 29 Days
Population: The Safety Analysis Set included all participants who received any study drug. Participants were analyzed according to the study treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Sedation | 1 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Somnolence | 4 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Amnesia | 1 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Derealization | 1 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Dissociation | 5 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AESI | 9 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AE | 10 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Vision blurred | 0 Participants |
| MIJ821 10 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Blood pressure increased | 0 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Dissociation | 2 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Derealization | 0 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Vision blurred | 0 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Amnesia | 0 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Somnolence | 1 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Sedation | 1 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AE | 6 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AESI | 5 Participants |
| MIJ821 4 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Blood pressure increased | 1 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Somnolence | 0 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Vision blurred | 1 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Dissociation | 0 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Sedation | 0 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Blood pressure increased | 1 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AE | 4 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Derealization | 0 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AESI | 2 Participants |
| MIJ821 1 mg | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Amnesia | 0 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Vision blurred | 0 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Blood pressure increased | 0 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Dissociation | 2 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AESI | 3 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Sedation | 0 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Derealization | 0 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Somnolence | 1 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | Amnesia | 0 Participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Including Adverse Events of Special Interest (AESIs) | With at least one AE | 7 Participants |
Secondary
Pharmacokinetics (PK) of MIJ821 in Plasma for Area Under the Curve From the Time of Dosing to the Time of the Last Measurable Concentration (AUClast)
Blood samples were collected at the indicated time points for PK analysis. AUClast was defined as the area under the curve from time zero to the last measurable concentration sampling time (tlast).
Time frame: Baseline, 0.17 hour, 0.33 hour, 0.5 hour, 0.75 hour, 1, 1.5, 2, 4 and 24 hours post injection
Population: The PK analysis set included all participants with at least one available, valid PK concentration measurement, who received any study drug and with no protocol deviations that had an impact on PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MIJ821 10 mg | Pharmacokinetics (PK) of MIJ821 in Plasma for Area Under the Curve From the Time of Dosing to the Time of the Last Measurable Concentration (AUClast) | 231 h*ng/mL | Geometric Coefficient of Variation 33.5 |
| MIJ821 4 mg | Pharmacokinetics (PK) of MIJ821 in Plasma for Area Under the Curve From the Time of Dosing to the Time of the Last Measurable Concentration (AUClast) | 89.5 h*ng/mL | Geometric Coefficient of Variation 45.7 |
| MIJ821 1 mg | Pharmacokinetics (PK) of MIJ821 in Plasma for Area Under the Curve From the Time of Dosing to the Time of the Last Measurable Concentration (AUClast) | 5.92 h*ng/mL | Geometric Coefficient of Variation 85.1 |
Secondary
PK of MIJ821 in Plasma for Maximum Serum Concentration (Cmax)
Blood samples were collected at the indicated time points for PK analysis. Cmax was defined as the maximum (peak) observed plasma drug concentration after single dose administration.
Time frame: Baseline, 0.17 hour, 0.33 hour, 0.5 hour, 0.75 hour, 1, 1.5, 2, 4 and 24 hours post injection
Population: The PK analysis set included all participants with at least one available, valid PK concentration measurement, who received any study drug and with no protocol deviations that had an impact on PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MIJ821 10 mg | PK of MIJ821 in Plasma for Maximum Serum Concentration (Cmax) | 42.7 ng/mL | Geometric Coefficient of Variation 37.2 |
| MIJ821 4 mg | PK of MIJ821 in Plasma for Maximum Serum Concentration (Cmax) | 17.5 ng/mL | Geometric Coefficient of Variation 46.7 |
| MIJ821 1 mg | PK of MIJ821 in Plasma for Maximum Serum Concentration (Cmax) | 2.32 ng/mL | Geometric Coefficient of Variation 55.4 |
Secondary
PK of MIJ821 in Plasma for Time to Maximum Drug Concentration (Tmax)
Blood samples were collected at the indicated time points for PK analysis. Tmax was defined as the time to reach maximum (peak) plasma drug concentration after single dose administration (time).
Time frame: Baseline, 0.17 hour, 0.33 hour, 0.5 hour, 0.75 hour, 1, 1.5, 2, 4 and 24 hours post injection
Population: The PK analysis set included all participants with at least one available, valid PK concentration measurement, who received any study drug and with no protocol deviations that had an impact on PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MIJ821 10 mg | PK of MIJ821 in Plasma for Time to Maximum Drug Concentration (Tmax) | 0.750 hour (h) |
| MIJ821 4 mg | PK of MIJ821 in Plasma for Time to Maximum Drug Concentration (Tmax) | 0.500 hour (h) |
| MIJ821 1 mg | PK of MIJ821 in Plasma for Time to Maximum Drug Concentration (Tmax) | 0.500 hour (h) |