Optimized Predictive Treatment In Medications for Unipolar Major Depression (OPTIMUM-D)

Study Overview
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Brief Summary
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This is a study that will test a predictive biomarker algorithm based on results from a previous study. The goal of this study is to integrate clinical, imaging, EEG, and molecular data across 8 sites to predict treatment outcome for patients experiencing a major depressive episode (MDE).

Detailed Description
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This is a multi-site, randomized study with two treatment phases: a double-blind primary treatment phase of 8 weeks, and an open-label secondary extension phase of 4 weeks. This study aims to test a predictive biomarker algorithm to select medication treatment for patients with major depressive disorder (MDD) based on results from the recently completed Canadian Biomarker Integration Network in Depression (CAN-BIND)-1 study. This will be accomplished through collection of clinical, neurophysiological, and molecular measures from both MDD patients and healthy controls. This is not a study to evaluate efficacy of medications; medications in this study have been approved by Health Canada and are widely used for the treatment of MDD. In this study, individuals diagnosed with MDD in a current major depressive episode (MDE) will be randomly assigned to one of the two treatment groups: Personalized Assignment group or Random Assignment group. Patients in the Random Assignment group will randomly receive open-label escitalopram with the addition of either blinded placebo or brexpiprazole for 8 weeks. Patients in the Personalized Assignment group will receive open-label escitalopram with the addition of either placebo or blinded brexpiprazole for 8 weeks depending on what the predictive biomarker algorithm suggests. At Week 8, participants will be assessed for treatment response (defined as a ≥50% reduction in Montgomery Asberg Depression Rating Scale score). All patients who initially received both open-label escitalopram and blinded brexpiprazole (regardless of treatment group) will continue to receive these medications for another 4 weeks but the brexpiprazole will no longer be blinded. For those patients who initially received open-label escitalopram and blinded placebo (regardless of treatment group), nonresponders will receive open-label escitalopram and open-label brexpiprazole for another 4 weeks and responders will receive open-label escitalopram only for another 4 weeks. Over the 12 weeks, participants will attend 7 study visits where they will complete clinical assessments (clinician administered and self-report) and cognitive tests; provide blood, urine, and stool samples; undergo neuroimaging procedures (MRI and EEG); and provide speech samples. At the end of the study, modeling methods will be used to integrate data from these measures to determine the features that best predict treatment outcome.

Official Title
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Optimized Predictive Treatment In Medications for Unipolar Major Depression (OPTIMUM-D)

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Escitalopram
* Drug: Brexpiprazole


Participation Criteria
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Eligibility Criteria
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Patients Inclusion Criteria: Outpatients 18 to 60 years of age. Meet DSM-5 criteria for MDE in MDD as determined by the MINI. Episode duration ≥ 3 months. Free of psychotropic medications for at least 5 half-lives (e.g. 1 week for most antidepressants, 5 weeks for fluoxetine) before baseline Visit 1. MADRS score ≥ 24. Fluency in English, sufficient to complete the interviews and self-report questionnaires. Exclusion Criteria: Any diagnosis, other than MDD, that is considered the primary diagnosis. Bipolar I or Bipolar-II diagnosis. Presence of a significant Axis II diagnosis (borderline, antisocial). High suicidal risk, defined by clinician judgment. Substance dependence/abuse in the past 6 months. Presence of significant neurological disorders, head trauma, or other unstable medical conditions. Pregnant or breastfeeding. Failure of 4 or more adequate pharmacologic interventions (as determined by the Antidepressant Treatment History Form). Started psychological treatment within the past 3 months with the intent of continuing treatment. Patients who have previously failed escitalopram or showed intolerance to escitalopram or brexpiprazole, and patients at risk for hypomanic switch (i.e. with a history of antidepressant induced hypomania). Healthy Comparison (HC) Participants Inclusion Criteria: 18 to 60 years of age. No history of psychiatric disorders (as determined by the modified MINI v.6.0.) or significant physical conditions (e.g. arthritis, fibromyalgia). Fluency in English, sufficient to complete the interviews and self-report questionnaires.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Allocation by Predictive Biomarker Algorithm; Escitalopram + Brexpiprazole<br>Patients are randomly assigned to the Allocation by Predictive Biomarker Algorithm group. Based on the outcome result from the personalized predictive biomarker algorithm, patients predicted as non-responders to escitalopram monotherapy will receive open-label escitalopram (10-20 mg/d) and blinded brexpiprazole (0.5-2 mg/d) for the first 8 weeks of the study. For the final 4 weeks of the study, patients will continue to receive both medications but the brexpiprazole will no longer be blinded. | Drug: Escitalopram<br>* All patients will receive open-label escitalopram (10-20 mg/d) for the entire study duration (12 weeks).<br>* Other names: Cipralex;Drug: Brexpiprazole<br>* Depending on the initial randomization process, patients will either receive blinded brexpiprazole (0.5-2 mg/d) for the entire study duration (12 weeks) or for the last 4 weeks of the study if they received the placebo during the first 8 weeks of the study and were non-responders.<br>* Other names: Rexulti;|
| Placebo Comparator: Allocation by Predictive Biomarker Algorithm; Placebo<br>Patients are randomly assigned to the Allocation by Predictive Biomarker Algorithm group. Based on the outcome result from the personalized predictive biomarker algorithm, patients predicted to respond to escitalopram monotherapy will receive open-label escitalopram (10-20 mg/d) and blinded placebo for the first 8 weeks of the study. For the final 4 weeks of the study, responders will continue to receive open-label escitalopram without the placebo and non-responders will receive a combination of open-label escitalopram and open-label brexpiprazole. | Drug: Escitalopram<br>* All patients will receive open-label escitalopram (10-20 mg/d) for the entire study duration (12 weeks).<br>* Other names: Cipralex;|
| Active Comparator: Random Allocation; Escitalopram + Brexpiprazole<br>Patients are randomly assigned to the Random Allocation group and then randomly assigned to receive open-label escitalopram (10-20 mg/d) and blinded brexpiprazole (0.5-2 mg/d) for the first 8 weeks of the study. For the final 4 weeks of the study, patients will continue to receive both medications but the brexpiprazole will no longer be blinded. | Drug: Escitalopram<br>* All patients will receive open-label escitalopram (10-20 mg/d) for the entire study duration (12 weeks).<br>* Other names: Cipralex;Drug: Brexpiprazole<br>* Depending on the initial randomization process, patients will either receive blinded brexpiprazole (0.5-2 mg/d) for the entire study duration (12 weeks) or for the last 4 weeks of the study if they received the placebo during the first 8 weeks of the study and were non-responders.<br>* Other names: Rexulti;|
| Placebo Comparator: Random Allocation; Placebo<br>Patients are randomly assigned to the Random Allocation group and then randomly assigned to receive open-label escitalopram (10-20 mg/d) and blinded placebo for the first 8 weeks of the study. For the final 4 weeks of the study, responders will continue to receive open-label escitalopram without the placebo and non-responders will receive a combination of open-label escitalopram and open-label brexpiprazole. | Drug: Escitalopram<br>* All patients will receive open-label escitalopram (10-20 mg/d) for the entire study duration (12 weeks).<br>* Other names: Cipralex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery Asberg Depression Rating Scale (MADRS) scores from baseline | Measured as clinical response, defined as a decrease in Montgomery Asberg Depression Rating Scale (MADRS) score at the Week 8 visit, by 50% or greater, from MADRS score at Baseline visit (i.e., lower MADRS scores = better outcome) | Baseline to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | Defined as a decrease in MADRS score at the Week 8 visit, by 50% or greater, from MADRS score at Baseline visit | Baseline to Week 8 | 
| Time to clinical response | Defined as time (i.e., number of weeks) to achieve clinical response (i.e., decrease in MADRS score at the Week 8 visit, by 50% or greater, from MADRS score at Baseline visit) | Baseline to Week 8 | 
| Remission at Week 8 | Defined as MADRS score ≤10 at Week 8 | Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDD, major depression, major depressive disorder, escitalopram, brexpiprazole, neuroimaging, genomics, proteomics, metabolomics