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

Major Depressive Disorder Clinical Trial

— CAN-BIND-17  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05017311
• Other study ID #: 1027397
• Status: Recruiting
• Phase: Phase 4
• Start date: January 20, 2023
• Est. completion date: April 30, 2029

Study information

• Verified date: March 2024
• Source: Nova Scotia Health Authority
• Contact: Nicole Stinson, BSc
• Phone: 9024735313
• Email: nicole.stinson[@]nshealth.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: April 30, 2029
• Est. primary completion date: December 31, 2028
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Patients

Inclusion Criteria:

• Outpatients 18 to 65 years of age.

• Meet DSM-5 criteria for MDE in MDD as determined by SCID-5.

• 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 (exceptions: stable use of hypnotics; stable use of stimulants for attention-deficit/hyperactive disorder).

• 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 65 years of age.

• No history of psychiatric disorders (as determined by SCID-5) or significant physical conditions (e.g. arthritis, fibromyalgia).

• Fluency in English, sufficient to complete the interviews and self-report questionnaires.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• Escitalopram
All patients will receive open-label escitalopram (10-20 mg/d) for the entire study duration (12 weeks).
• Brexpiprazole
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.

Locations

Country	Name	City	State
Canada	University of Calgary	Calgary	Alberta
Canada	Nova Scotia Health Authority	Halifax	Nova Scotia
Canada	McMaster University	Hamilton	Ontario
Canada	Queen's University	Kingston	Ontario
Canada	Centre for Addiction and Mental Health	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario
Canada	University of British Columbia	Vancouver	British Columbia

Sponsors (12)

Lead Sponsor	Collaborator
Nova Scotia Health Authority	Centre for Addiction and Mental Health, Dalhousie University, McGill University, McMaster University, Queen's University, Simon Fraser University, Unity Health Toronto, University of British Columbia, University of Calgary, University of Michigan, University of Ottawa

Country where clinical trial is conducted

Canada, 

References & Publications (17)

Alders GL, Davis AD, MacQueen G, Strother SC, Hassel S, Zamyadi M, Sharma GB, Arnott SR, Downar J, Harris JK, Lam RW, Milev R, Muller DJ, Ravindran A, Kennedy SH, Frey BN, Minuzzi L, Hall GB; CAN-BIND Investigator Team. Escitalopram ameliorates differences in neural activity between healthy comparison and major depressive disorder groups on an fMRI Emotional conflict task: A CAN-BIND-1 study. J Affect Disord. 2020 Mar 1;264:414-424. doi: 10.1016/j.jad.2019.11.068. Epub 2019 Nov 13. — View Citation

Allen TA, Harkness KL, Lam RW, Milev R, Frey BN, Mueller DJ, Uher R, Kennedy SH, Quilty LC. Interactions between neuroticism and stressful life events predict response to pharmacotherapy for major depression: A CAN-BIND 1 report. Personal Ment Health. 2021 Nov;15(4):273-282. doi: 10.1002/pmh.1514. Epub 2021 May 18. — View Citation

Allen TA, Lam RW, Milev R, Rizvi SJ, Frey BN, MacQueen GM, Muller DJ, Uher R, Kennedy SH, Quilty LC. Early change in reward and punishment sensitivity as a predictor of response to antidepressant treatment for major depressive disorder: a CAN-BIND-1 report. Psychol Med. 2019 Jul;49(10):1629-1638. doi: 10.1017/S0033291718002441. Epub 2018 Sep 17. — View Citation

Ayyash S, Davis AD, Alders GL, MacQueen G, Strother SC, Hassel S, Zamyadi M, Arnott SR, Harris JK, Lam RW, Milev R, Muller DJ, Kennedy SH, Rotzinger S, Frey BN, Minuzzi L, Hall GB; CAN-BIND Investigator Team. Exploring brain connectivity changes in major depressive disorder using functional-structural data fusion: A CAN-BIND-1 study. Hum Brain Mapp. 2021 Oct 15;42(15):4940-4957. doi: 10.1002/hbm.25590. Epub 2021 Jul 23. — View Citation

Caspani G, Turecki G, Lam RW, Milev RV, Frey BN, MacQueen GM, Muller DJ, Rotzinger S, Kennedy SH, Foster JA, Swann JR. Metabolomic signatures associated with depression and predictors of antidepressant response in humans: A CAN-BIND-1 report. Commun Biol. 2021 Jul 22;4(1):903. doi: 10.1038/s42003-021-02421-6. — View Citation

Chakrabarty T, Harkness KL, McInerney SJ, Quilty LC, Milev RV, Kennedy SH, Frey BN, MacQueen GM, Muller DJ, Rotzinger S, Uher R, Lam RW. Childhood maltreatment and cognitive functioning in patients with major depressive disorder: a CAN-BIND-1 report. Psychol Med. 2020 Nov;50(15):2536-2547. doi: 10.1017/S003329171900268X. Epub 2019 Oct 4. — View Citation

Chakrabarty T, McInerney SJ, Torres IJ, Frey BN, Milev RV, Muller DJ, Rotzinger S, Kennedy SH, Lam RW; CAN-BIND Investigator Team. Cognitive Outcomes with Sequential Escitalopram Monotherapy and Adjunctive Aripiprazole Treatment in Major Depressive Disorder: A Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report. CNS Drugs. 2021 Mar;35(3):291-304. doi: 10.1007/s40263-021-00793-1. Epub 2021 Mar 8. — View Citation

Dunlop K, Rizvi SJ, Kennedy SH, Hassel S, Strother SC, Harris JK, Zamyadi M, Arnott SR, Davis AD, Mansouri F, Schulze L, Ceniti AK, Lam RW, Milev R, Rotzinger S, Foster JA, Frey BN, Parikh SV, Soares CN, Uher R, Turecki G, MacQueen GM, Downar J. Clinical, behavioral, and neural measures of reward processing correlate with escitalopram response in depression: a Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report. Neuropsychopharmacology. 2020 Jul;45(8):1390-1397. doi: 10.1038/s41386-020-0688-x. — View Citation

Farzan F, Atluri S, Frehlich M, Dhami P, Kleffner K, Price R, Lam RW, Frey BN, Milev R, Ravindran A, McAndrews MP, Wong W, Blumberger D, Daskalakis ZJ, Vila-Rodriguez F, Alonso E, Brenner CA, Liotti M, Dharsee M, Arnott SR, Evans KR, Rotzinger S, Kennedy SH. Standardization of electroencephalography for multi-site, multi-platform and multi-investigator studies: insights from the canadian biomarker integration network in depression. Sci Rep. 2017 Aug 7;7(1):7473. doi: 10.1038/s41598-017-07613-x. — View Citation

Kennedy SH, Lam RW, Rotzinger S, Milev RV, Blier P, Downar J, Evans KR, Farzan F, Foster JA, Frey BN, Giacobbe P, Hall GB, Harkness KL, Hassel S, Ismail Z, Leri F, McInerney S, MacQueen GM, Minuzzi L, Muller DJ, Parikh SV, Placenza FM, Quilty LC, Ravindran AV, Sassi RB, Soares CN, Strother SC, Turecki G, Vaccarino AL, Vila-Rodriguez F, Yu J, Uher R; CAN-BIND Investigator Team. Symptomatic and Functional Outcomes and Early Prediction of Response to Escitalopram Monotherapy and Sequential Adjunctive Aripiprazole Therapy in Patients With Major Depressive Disorder: A CAN-BIND-1 Report. J Clin Psychiatry. 2019 Feb 5;80(2):18m12202. doi: 10.4088/JCP.18m12202. — View Citation

Lam RW, Milev R, Rotzinger S, Andreazza AC, Blier P, Brenner C, Daskalakis ZJ, Dharsee M, Downar J, Evans KR, Farzan F, Foster JA, Frey BN, Geraci J, Giacobbe P, Feilotter HE, Hall GB, Harkness KL, Hassel S, Ismail Z, Leri F, Liotti M, MacQueen GM, McAndrews MP, Minuzzi L, Muller DJ, Parikh SV, Placenza FM, Quilty LC, Ravindran AV, Salomons TV, Soares CN, Strother SC, Turecki G, Vaccarino AL, Vila-Rodriguez F, Kennedy SH; CAN-BIND Investigator Team. Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort. BMC Psychiatry. 2016 Apr 16;16:105. doi: 10.1186/s12888-016-0785-x. — View Citation

Lopez JP, Fiori LM, Cruceanu C, Lin R, Labonte B, Cates HM, Heller EA, Vialou V, Ku SM, Gerald C, Han MH, Foster J, Frey BN, Soares CN, Muller DJ, Farzan F, Leri F, MacQueen GM, Feilotter H, Tyryshkin K, Evans KR, Giacobbe P, Blier P, Lam RW, Milev R, Parikh SV, Rotzinger S, Strother SC, Lewis CM, Aitchison KJ, Wittenberg GM, Mechawar N, Nestler EJ, Uher R, Kennedy SH, Turecki G. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat Commun. 2017 May 22;8:15497. doi: 10.1038/ncomms15497. — View Citation

McInerney SJ, Chakrabarty T, Maciukiewicz M, Frey BN, MacQueen GM, Milev RV, Ravindran AV, Rotzinger S, Kennedy SH, Lam RW; CAN-BIND Investigator Team. Cognition and Its Association with Psychosocial and Occupational Functioning during Treatment with Escitalopram in Patients with Major Depressive Disorder: A CAN-BIND-1 Report: La Cognition Et Son Association Avec Le Fonctionnement Psychosocial Et Professionnel Durant Le Traitement Par Escitalopram Chez Des Patients Souffrant De Trouble Depressif Majeur: Une Etude Can-Bind-1. Can J Psychiatry. 2021 Sep;66(9):798-806. doi: 10.1177/0706743720974823. Epub 2020 Dec 23. — View Citation

Morton E, Bhat V, Giacobbe P, Lou W, Michalak EE, McInerney S, Chakrabarty T, Frey BN, Milev RV, Muller DJ, Parikh SV, Rotzinger S, Kennedy SH, Lam RW; CAN-BIND Investigator Team. Predictors of Quality of Life Improvement with Escitalopram and Adjunctive Aripiprazole in Patients with Major Depressive Disorder: A CAN-BIND Study Report. CNS Drugs. 2021 Apr;35(4):439-450. doi: 10.1007/s40263-021-00803-2. Epub 2021 Apr 16. — View Citation

Nogovitsyn N, Muller M, Souza R, Hassel S, Arnott SR, Davis AD, Hall GB, Harris JK, Zamyadi M, Metzak PD, Ismail Z, Downar J, Parikh SV, Soares CN, Addington JM, Milev R, Harkness KL, Frey BN, Lam RW, Strother SC, Rotzinger S, Kennedy SH, MacQueen GM. Hippocampal tail volume as a predictive biomarker of antidepressant treatment outcomes in patients with major depressive disorder: a CAN-BIND report. Neuropsychopharmacology. 2020 Jan;45(2):283-291. doi: 10.1038/s41386-019-0542-1. Epub 2019 Oct 14. — View Citation

Uher R, Frey BN, Quilty LC, Rotzinger S, Blier P, Foster JA, Muller DJ, Ravindran AV, Soares CN, Turecki G, Parikh SV, Milev R, MacQueen G, Lam RW, Kennedy SH; CAN-BIND Investigator Team. Symptom Dimension of Interest-Activity Indicates Need for Aripiprazole Augmentation of Escitalopram in Major Depressive Disorder: A CAN-BIND-1 Report. J Clin Psychiatry. 2020 Jun 16;81(4):20m13229. doi: 10.4088/JCP.20m13229. — View Citation

Yrondi A, Fiori LM, Frey BN, Lam RW, MacQueen GM, Milev R, Muller DJ, Foster JA, Kennedy SH, Turecki G. Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report. Int J Neuropsychopharmacol. 2020 Feb 1;23(2):88-95. doi: 10.1093/ijnp/pyz066. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Week 12 clinical outcome - Response	Response at Week 12 - defined as a decrease in MADRS score at the Week 12 visit, by 50% or greater, from MADRS score at Baseline visit and Week 8	Baseline to Week 8 and Week 8 to Week 12
Other	Week 12 clinical outcome - Remission	Defined as MADRS score =10 at Week 12	Week 12
Primary	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	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
Secondary	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
Secondary	Remission at Week 8	Defined as MADRS score =10 at Week 8	Week 8