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)
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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
60
MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1.
MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1.
MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1.
25Uni of Alabama at Birmingham
Birmingham, Alabama, United States
Research Centers of America LLC
Oakland Park, Florida, United States
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
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
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
PK of MIJ821 in Plasma for Maximum Serum Concentration (Cmax)
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0.9% sodium chloride solution administered as a single SC injection on Day 1.
Interventional Psychiatry Tampa Bay
Tampa, Florida, United States
Novartis Investigative Site
Yokohama, Kanagawa, Japan
Novartis Investigative Site
Kodaira, Tokyo, Japan
Novartis Investigative Site
Mitaka, Tokyo, Japan
Novartis Investigative Site
Bialystok, Poland
Novartis Investigative Site
Gdansk, Poland
Novartis Investigative Site
Swiecie North West, Poland
Novartis Investigative Site
Seville, Andalusia, Spain
...and 6 more locations
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
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
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
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
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
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
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
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