A Randomized, Open-label, Rater-Blinded, Active-Controlled, International, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Flexibly Dosed Esketamine Nasal Spray Compared With Quetiapine Extended-Release in Adult and Elderly Participants With Treatment-Resistant Major Depressive Disorder Who Are Continuing a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor

Plain English Summary

A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder is a Phase 3 clinical trial sponsored by Janssen-Cilag International NV studying Depressive Disorder, Major. Tests the effectiveness of Esketamine nasal spray and Quetiapine XR in treating treatment-resistant major depressive disorder. For adults and elderly participants with moderate to severe depression who have not responded to previous treatments. Participation involves taking either Esketamine or Quetiapine XR in combination with a current SSRI/SNRI, with regular assessments. Alternative treatments include other antidepressants and psychotherapy. The trial aims to enroll 676 participants.

Official Summary

The primary purpose of this study is to evaluate the efficacy of flexibly dosed esketamine nasal spray compared with quetiapine extended-release (XR), both in combination with a continuing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI), in achieving remission in participants who have treatment-resistant major depressive disorder (MDD) with a current moderate to severe depressive episode.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults and elderly with treatment-resistant major depressive disorder. Must be on a current SSRI/SNRI and have shown minimal clinical improvement. No history of psychotic disorders, bipolar disorders, or suicidal behavior in the past year. Not received esketamine or quetiapine in the current episode of depression. This trial is studying Depressive Disorder, Major, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures the percentage of participants achieving remission, which means a significant reduction in depressive symptoms. The specific primary outcome measures are: Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8 (Week 8). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a significant gap in treatment options for those with treatment-resistant major depressive disorder. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Depressive Disorder, Major, where improved treatment options are needed.

Investor Insight

The large market size and high unmet need make this trial an attractive investment opportunity. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage. The large enrollment target of 676 participants suggests significant investment in this program.

Is This Trial Right for Me?

Ask your doctor if you have a history of treatment-resistant depression and are currently on an SSRI/SNRI. Participation involves regular clinic visits and assessments. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 676 participants

Interventions

• DRUG: Esketamine 28 mg — Esketamine will be self-administered at a dose of 28 mg as nasal spray.
• DRUG: Esketamine 56 mg — Esketamine will be self-administered at a dose of 56 mg as nasal spray.
• DRUG: Esketamine 84 mg — Esketamine will be self-administered at a dose of 84 mg (maximum uptitrated dose) as nasal spray.
• DRUG: Quetiapine XR 50 mg — Quetiapine XR will be administered at an initial dose of 50 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.
• DRUG: Quetiapine XR 100 mg — Quetiapine XR will be administered at a dose of 100 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.

Primary Outcomes

• Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8 (Week 8)

Secondary Outcomes

• Percentage of Participants With Both Remission at Week 8 and Relapse-free Until Week 32 (Week 32)
• Change From Baseline in Clinician-rated Overall MADRS Score (Baseline, Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32)
• Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) (Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32)
• Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score (Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32)
• Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF (Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32)

Full Eligibility Criteria

Inclusion Criteria:

* At screening, each participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) or recurrent MDD, without psychotic features, based on clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI)
* At screening and baseline, each participant must have an Inventory of Depressive Symptomatology - Clinician-rated, 30 item (IDS-C30) total score of greater than or equal to (\>=) 34
* Must be on a current antidepressive treatment that includes an selective serotonin reuptake inhibitor (SSRI)/ serotonin-norepinephrine reuptake inhibitor (SNRI) at screening that resulted in nonresponse (less than 25% improvement of symptoms) after having been given at an adequate dosage (based on antidepressive dosages from SmPC \[or local equivalent, if applicable\]) for an adequate duration of at least 6 weeks and having been uptitrated to the maximum tolerated dose; however, at screening the participant must show signs of minimal clinical improvement to be eligible for the study. Clinical improvement of a participant on their current AD treatment will be retrospectively evaluated in a qualified psychiatric interview performed by an experienced clinician. At baseline (Day 1) prior to randomization, the investigator will evaluate any changes in the participant's signs/symptoms of depression since the screening assessment and confirm that the inclusion criteria for the current AD treatment are still met (that is nonresponse and minimal clinical improvement)
* The current antidepressive treatment, was immediately preceded by nonresponse to at least 1 but not more than 5 different, consecutive treatments (all within the current moderate to severe antidepressive episode) with anti-depressants (ADs) taken at an adequate dosage for an adequate duration of at least 6 weeks and must be documented
* Must have been treated with at least 2 different antidepressive substance classes among the treatments taken at an adequate dosage for an adequate duration of at least 6 weeks resulting in nonresponse in the current moderate to severe depressive episode (including the current treatment with an selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\])
* Must be on a single oral SSRI/SNRI on Day 1 prior to randomization

Exclusion Criteria:

* Received treatment with esketamine or ketamine in the current moderate to severe depressive episode
* Received treatment with quetiapine extended- or immediate-release in the current moderate to severe depressive episode of a dose higher than 50 milligram per day (mg/day)
* Had depressive symptoms in the current moderate to severe depressive episode that previously did not respond to an adequate course of treatment with electroconvulsive therapy (ECT), defined as at least 7 treatments with unilateral/bilateral ECT
* Has no signs of clinical improvement at all or with a significant improvement on their current AD treatment that includes an SSRI/SNRI as determined at screening by an experienced clinician during the qualified psychiatric interview
* Received vagal nerve stimulation or has received deep brain stimulation in the current episode of depression
* has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the Mini International Neuropsychiatric Interview \[MINI\]), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, or antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
* age at onset of first episode of MDD was more than or equal to (\>=) 55 years
* has homicidal ideation or intent, per the investigator's clinical judgment; or has suicidal ideation with some intent to act within 1 month prior to screening, per the investigator's clinical judgment; or based on the Columbia-Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation, or a history of suicidal behavior within the past year prior to screening. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the acute phase should also be excluded

Trial Locations

• Fundacion para el Estudio y Tratamiento de las Enfermedades Mentales, Buenos Aires, Argentina
• FunDaMos, Buenos Aires, Argentina
• CEN Consultorios Especializados en Neurociencias, Córdoba, Argentina
• Fundacion Lennox, Córdoba, Argentina
• Instituto Medico DAMIC, Córdoba, Argentina
• Sanatorio Prof Leon S Morra S A, Córdoba, Argentina
• Instituto de Neurociencias San Agustin, La Plata, Argentina
• C I A P Centro de investigacion y Asistencia en Psiquiatria, Rosario, Argentina
• Medical University Graz, Graz, Austria
• Schmitz and Schmitz, Vienna, Austria
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Major Depressive Disorder
• Treatment-Resistant Depression
• Antidepressant Efficacy
• Mood Disorders
• Psychiatric Disorders
• Depression in Elderly
• Depression in Adults
• Antidepressant Therapy
• Psychopharmacology

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