Pharmacogenomic Decision Support With GeneSight Psychotropic to Guide the Treatment of Major Depressive Disorder
|Depressive Disorder, Major Depression Depressive Disorder||Genetic: GeneSight Psychotropic (GEN) Genetic: Enhanced-GeneSight Psychotropic (E-GEN) Other: Treatment as Usual (TAU)||Phase 4|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Outcomes Assessor
Primary Purpose: Treatment
|Official Title:||A Three-arm, Parallel Group, Multicentre, Double-blind, Randomized Controlled Trial Evaluating the Impact of GeneSight Psychotropic and Enhanced-GeneSight Psychotropic, on Response to Psychotropic Treatment in Outpatients Suffering From a Major Depressive Disorder (MDD) and Having Had - Within the Current Episode - an Inadequate Response to at Least One Psychotropic Medication Included in GeneSight Psychotropic|
- Change in depressive symptoms as assessed by the 17-item Hamilton Depression (HAM-D17) score [ Time Frame: From baseline to Week 8 ]Mean change in the 17-item Hamilton Depression (HAM-D17) score from baseline to Week 8 of the study
- Change in depressive symptoms as assessed by the 16-Item Clinician Quick Inventory of Depressive Symptomatology (QIDS-SR16) [ Time Frame: Baseline, Weeks 8 and 12, and Month 12 ]
- Change in depressive symptoms as assessed by the 9-Item Patient Health Questionnaire (PHQ-9) [ Time Frame: Baseline, Weeks 8 and 12, and Month 12 ]
- Change in anxiety symptoms as assessed by theGeneralized Anxiety Disorder 7-Item (GAD-7) Scale [ Time Frame: Baseline, Weeks 8 and 12, and Month 12 ]
- Change in severity of illness as assessed by the Clinical Global Impression of Severity (CGI-S) [ Time Frame: Baseline, Week 12 and Month 12 ]
- Change in global improvement as assessed by the Clinical Global Impression of Improvement (CGI-I) [ Time Frame: Week 12, and Month 12 ]
- Change in global therapeutic benefit and global severity of side effects as assessed by the Clinical Global Impression Efficacy Index [ Time Frame: Week 12 and Month 12 ]
- Changes to initial prescribing based on availability of pharmacogenomic data [ Time Frame: Screening and Baseline ]
- Response rates to psychotropic medication [ Time Frame: Baseline, Weeks 8 and 12, Months 6, 9 and 12 ]A responder is defined as a participant with 50% decrease in HAM-D17 score from baseline.
- Remission rates [ Time Frame: Baseline, Weeks 8 and 12, Months 6, 9 and 12 ]A remitter is defined as a participant with HAM-D17 score equal or less that 7.
- Time to response [ Time Frame: Baseline, Weeks 8 and 12, Months 6, 9 and 12 ]
- Time to remission [ Time Frame: Baseline, Weeks 8 and 12, Months 6, 9 and 12 ]
- Change in psychotropic medication side effects as assessed by the Udvalg for Kliniske Undersogeler (UKU) Side Effect Rating Scale [ Time Frame: Baseline, Weeks 8 and 12, and Month 12 ]
- Change in global measure of side effects (frequency, intensity, and burden domains) as assessed by the Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) [ Time Frame: Baseline, Weeks 8 and 12, and Month 12 ]
- Weight gain [ Time Frame: Baseline, Weeks 8 and 12, and Month 12 ]Subject's weight
- Waist-to-hip ratio [ Time Frame: Baseline, Weeks 8 and 12, and Month 12 ]Subject's waist and hip measurements
- Change in health related quality of life as assessed by the EuroQol (EQ-5D-5L) [ Time Frame: Baseline, Week 12, Months 6, 9 and 12 ]
- Change in health related quality of life as assessed by the Short Form (36) Health Survey (SF-36) [ Time Frame: Baseline, Week 12, Months 6, 9 and 12 ]
- Pharmacogenetics in Psychiatry Follow-up Questionnaire (PIPFQ) [ Time Frame: Baseline, when prescription changes are made (expected average of every 4 weeks), and Month 12 ]The PIPFQ is a questionnaire developed by CAMH to evaluate each physician's attitude and experience to pharmacogenomic testing. Information is solicited from the physician on three different domains: the processing of the physician's last referral, the contact and outcome of the physician's patient, and the physician's perspective on the future of genetic studies in psychiatric drug treatment.
- Healthcare resource utilization (Composite measure of healthcare costs): physician visits, hospital utilization, emergency department visits, medication use, and laboratory tests [ Time Frame: Baseline, Weeks 8 and 12, Months 6, 9 and 12 ]
- Productivity losses (measured as economic costs) [ Time Frame: Baseline, Weeks 8 and 12, Months 6, 9 and 12 ]
|Study Start Date:||June 2015|
|Estimated Study Completion Date:||June 2018|
|Estimated Primary Completion Date:||June 2017 (Final data collection date for primary outcome measure)|
Experimental: GeneSight Psychotropic (GEN)
The GeneSight Psychotropic (GEN) product is a pharmacogenomic decision support tool that helps clinicians to make informed, evidence-based decisions about proper drug selection. More specifically, patients are tested for clinically important genetic variants of multiple pharmacokinetic and pharmacodynamic genes that affect a patient's ability to metabolize, tolerate or respond to medications.
Genetic: GeneSight Psychotropic (GEN)
Patient DNA will be collected for all subjects and measured for variations in drug target genes and in drug metabolizing genes.Recommendations for optimal choices and dose adjustments for the 33 most commonly prescribed antidepressant and antipsychotic medications will be provided to subjects randomized to the GEN arm. This pharmacogenomic-based interpretive report will be provided to treating clinicians of patients in the GEN arm of the study, allowing clinicians to use the report to support their treatment decisions.
Experimental: Enhanced-GeneSight Psychotropic (E-GEN)
The current GEN test lacks predictive genes for antipsychotic-induced weight gain (AIWG), a major complication of antipsychotic drug use. Therefore, the Enhanced-GeneSight Psychotropic (E-GEN), which is an enhanced version of the GEN test, was developed by incorporating 6 new genes (represented by 7 SNPs) that are predictive for AIWG, to those used in the GEN algorithm. An increasing risk level associated with AIWG is estimated by an increasing number of risk genotypes that a given patient possesses among the 7 SNPs.
Genetic: Enhanced-GeneSight Psychotropic (E-GEN)
The E-GEN test incorporates into the existing GEN product new markers that are predictive of side effect of antipsychotic-induced weight gain (AIWG). The pharmacogenomic-based interpretive report from E-GEN will be provided to treating clinicians of patients in the E-GEN arm of the study, allowing clinicians to use the report to support their treatment decisions.
Active Comparator: Treatment as Usual (TAU)
The comparator chosen for this study provides a "real world" comparison of standard of care for patients who receive no pharmacogenomics guidance.
Patients randomized to the TAU arm will also have their DNA collected and a pharmacogenomic-based interpretive report will be generated using GEN testing. However, this report will not be shared with the treating clinicians until completion at 12 months of the study. Therefore, patients in this arm will receive clinical treatment as usual, without the use or knowledge of genotyping results by their treating clinicians.
Other: Treatment as Usual (TAU)
Subjects randomized to the TAU arm will also require collection of patient DNA. A pharmacogenomic-based interpretive report will be generated from GEN, however, this report is not provided to the treating clinician until completion of the study.
The primary objectives of this study are 1) to compare the efficacy of GEN to treatment as usual (TAU) in improving response to psychotropic treatment in outpatients suffering from a MDD and having had - within the current episode - an inadequate response to at least one psychotropic medication included in GEN; and 2) to validate the utility of the new CAMH markers and demonstrate the superior predictive capabilities and greater clinical utility of E-GEN as compared to GEN.
This study is designed as a three-arm multi-centre, double-blind (participants and raters), randomized controlled trial to compare the clinical and economic outcomes of GEN, E-GEN and TAU for patients suffering from a MDD and having had - within the current episode - an inadequate response to at least one psychotropic medication included in GEN. Participants will be randomized in a 1:1:1 ratio to each of the three treatment arms. Recruitment will be 24 months. Follow-up will be 12 months.
Subjects will complete short diagnostic interviews specific to their clinical diagnosis, basic metabolic measures (eg. blood pressure, weight), and provide buccal swab samples for genetic analysis (the unanalyzed buccal swabs and associated DNA will be biobanked). During the first visit, blood and urine samples will be required for laboratory panel screening and blood biobanking. Subjects will be monitored over a one year period and clinical measures and healthcare resource utilization will be obtained. Treating clinicians in the GEN and E-GEN arms will receive an easy to implement report providing pharmacogenomic guidance for prescribing psychotropic medications to their patients.
The study will recruit subjects from 10 sites, stratified into 2 clusters. Nine study sites altogether will form one of the two stratified clusters. CAMH will constitute the tenth study site and the second stratified cluster.The sample size required for this study was calculated using effect size estimates drawn from a previous study conducted by Hall-Flavin et al [Pharmacogenetics Genomics 2013; 23(10)]. Assuming an effect size of 0.30 in HAM-D17 score favoring the treatment group, intra class coefficient between clusters of 20%, statistical power of 90%, an alpha level of 0.05, and an expected 16.7% rate of premature discontinuation by Week 8 (primary endpoint), a total of 570 subjects (i.e., 190 per treatment arm) are required to detect the same effect in this study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02466477
|Contact: James Bowen, BScPhm, MSc||905-522-1155 ext email@example.com|
|Chatham-Kent Clinical Trials Research Center||Active, not recruiting|
|Chatham, Ontario, Canada, N7L 1B7|
|St. Joseph's Healthcare Hamilton (SJHH)||Active, not recruiting|
|Hamilton, Ontario, Canada, L8N 3K7|
|London Health Sciences Centre||Completed|
|London, Ontario, Canada, N6A 5W9|
|Parkwood Institute, London||Completed|
|London, Ontario, Canada, N6C 0A7|
|Ottawa, Ontario, Canada, K1K0T2|
|Thornhill Medical Centre||Completed|
|Thornhill, Ontario, Canada, L4J 1E9|
|Women's College Hospital||Completed|
|Toronto, Ontario, Canada, M5S 1B2|
|Sinai Health System||Completed|
|Toronto, Ontario, Canada, M5T 3L9|
|Centre for Addiction and Mental Health (CAMH)||Recruiting|
|Toronto, Ontario, Canada, M6J 1H4|
|Contact: Robert Levitan, MD, MSc 416-535-8501 ext 4020 firstname.lastname@example.org|
|Principal Investigator: Robert Levitan, MD, MSc|
|Sub-Investigator: Zafiris Jeffrey Daskalakis, MD, PhD|
|Sub-Investigator: Daniel Mueller, MD, FRCPC|
|Sub-Investigator: Peter Voore, MD, FRCPC|
|Study Chair:||Jean-Eric Tarride, PhD||St. Joseph's Healthcare Hamilton/McMaster University|
|Principal Investigator:||James L Kennedy, MD||Centre for Addiction and Mental Health|
|Principal Investigator:||C Anthony Altar, PhD||Assurex Health Inc.|