Study of Efficacy, Safety, Tolerability and Pharmacokinetics of MIJ821 in Participants With Treatment- Resistant Depression (TRD)

Phase 2

Completed

Conditions: Treatment-Resistant Depression

Interventions: Drug: MIJ821 Subcutaneous Injection 1 mg
Drug: MIJ821 Subcutaneous Injection 4 mg
Drug: Placebo Subcutaneous Injection
Drug: MIJ821 Subcutaneous Injection 10 mg

Registration Number: NCT05454410

Lead Sponsor: Novartis Pharmaceuticals

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MIJ821 1 mg	MIJ821 Subcutaneous Injection 1 mg	Participants received a single dose of 1 mg MIJ821 administered as a subcutaneous (SC) injection on Day 1.
MIJ821 4 mg	MIJ821 Subcutaneous Injection 4 mg	Participants received a single dose of 4 mg MIJ821 administered as an SC injection on Day 1.
Placebo	Placebo Subcutaneous Injection	Participants received a single dose of 0.9% sodium chloride solution administered as an SC injection on Day 1.
MIJ821 10 mg	MIJ821 Subcutaneous Injection 10 mg	Participants received a single dose of 10 mg MIJ821 administered as an SC injection on Day 1.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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).
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.

Trial Locations

Locations (4): 25Uni of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Research Centers of America LLC
🇺🇸
Oakland Park, Florida, United States
Interventional Psychiatry Tampa Bay
🇺🇸
Tampa, Florida, United States
Novartis Investigative Site
🇪🇸
Barcelona, Spain