Clinical trial NCT02573168: Pharmacogenomic Decision Support With GeneSight Psychotropic to Guide the Treatment With Antipsychotics
Official title: A Three-arm, Parallel Group, Multicentre, Double-blind, Randomized Controlled Trial Evaluating the Impact of GeneSight Psychotropic and Enhanced-GeneSight Psychotropic, on Change in Weight Following Antipsychotic Treatment in Patients Suffering From Disorders Indicated for Antipsychotic Utilization
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Schizophrenia
Schizoaffective Disorder
Keywords: Pharmacogenomic
Pharmacogenomic Testing
Pharmacogenomics
Genetic Testing
Genetics
GeneSight
Enhanced GeneSight
Psychotropic
Lead sponsor: St. Joseph's Healthcare Hamilton
Sponsor class: OTHER
Collaborators: name: Programs for Assessment of Technology in Health Research Institute
name: Centre for Addiction and Mental Health
name: Genome Canada
name: AssureRx Canada Ltd
name: Assurex Health Inc.
name: Mars Excellence in Clinical Innovation and Technology Evaluation
First posted: 2015-10-09
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Antipsychotics are approved to treat several conditions, including Schizophrenia, Schizoaffective Disorder, Bipolar Disorder, and Major Depressive Disorder among others. The typical and atypical antipsychotics, derive their therapeutic benefit predominantly from the antagonism of dopamine D2 and 5-HT2A receptors. Many of these compounds are associated with common and significant adverse effects (e.g. weight gain, extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction, and cardiac effects) which negatively impact on adherence. Today, antipsychotic induced weight gain (AIWG) is a leading cause for antipsychotic discontinuation. Importantly as well, approximately 20-30% of all patients with schizophrenia do not respond adequately to an initial antipsychotic trial, and strikingly, 83% of those who go on to a second antipsychotic trial do not meet criteria for response.

To-date, no RCT has been conducted to evaluate the outcomes in patients taking antipsychotics following the use of pharmacogenomic guidance of treatment selections. Therefore, the rationale for this trial is to utilize a double-blinded RCT design to evaluate and compare the clinical outcomes in participants treated with the benefit of GEN and E-GEN testing. Furthermore, this trial also intends to develop an evidence- based case for the value of GEN and E-GEN to Canadian health-care payers.

Detailed description: The primary objective for this study is to validate the clinical utility of the new Centre for Addiction in Mental Health (CAMH) antipsychotic induced weight gain (AIWG) markers and demonstrate the superior predictive capabilities of E-GEN as compared to GEN/TAU.

The second primary objective of this study is to compare the efficacy of GEN to treatment as usual (TAU) in improving response to psychotropic treatment in the subset of patients suffering from schizophrenia/schizoaffective disorder.

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 psychiatric disorders indicated for antipsychotic utilization. Participants will be randomized in a 1:1:1 ratio to each of the three treatment arms. Recruitment will be 36-months and follow-up 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 participants from 3 sites, stratified into 2 clusters. Chatham-Kent and Ontario Shores will form one of the stratified clusters. CAMH will constitute the second stratified cluster. The sample size required for this study was calculated for a large effect size (Cohen's d = 0.8) for weight change between treatment groups (GEN and E-GEN) and TAU. Sample size calculations are based on the weight gain differences observed between carriers and non-carriers of genetic risk markers in the CAMH discovery studies (18, 19, 20, 21, 22, 23). Assuming intraclass coefficient between clusters of 20%, statistical power of 80%, an alpha level of 0.05, and an expected drop-out rate of 28.3% by Week 12, a total of 90 participants (i.e., 30 per treatment arm) are required to detect the same effect in this study. Sample size calculations were determined using G\*Power (version 3.1.9.2, Germany).

Eligibility criteria: Inclusion Criteria:

1. 18 years of age or older;
2. Suffer from schizophrenia, schizoaffective disorder, schizophreniform disorder, psychosis not otherwise specified, bipolar disorder (I, II, NOS) or major depressive disorder meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria;
3. Have moderate to severe psychiatric symptoms;
4. Intending to switch to, or start a new antipsychotic medication;:
5. Be capable and willing to provide written informed consent to participate in this study;
6. Agree to abide by the study protocol and its restrictions and be able to complete all aspects of the study, including all visits and tests.

Exclusion Criteria:

1. Patients posing a serious suicidal risk and/or violence as judged by the investigator;
2. Patients with a current Axis I diagnosis of:

   * Delirium
   * Dementia
   * Amnestic and other cognitive disorder;
3. Patients who are on restricted diets (e.g., diabetes), who have an eating restriction disorder (e.g., bulimia, anorexia), or who are undergoing weight-reducing interventions (e.g. metformin, or structured diet program).
4. Patients with a history of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic or euthyroid for 6 months;
5. Patients who meet DSM-IV-TR criteria for any significant current substance dependence;
6. Patients with:

   * hepatic insufficiency (three times the upper limit of normal (ULN) for aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)); liver transplant recipient; cirrhosis of the liver;
   * malignancy (except basal cell carcinoma) and/or chemotherapy within 1 year prior to screening; malignancy more than 1 year prior to screening must have been local and without metastasis and/or recurrence, and if treated with chemotherapy, without nervous system complications;
   * significant unstable medical condition or life threatening disease with anticipated survival of less than 6 months;
   * need for therapies that may obscure the results of treatment and/or of the study
7. Participation in another clinical trial within 30 days of the screening visit;
8. Anticipated inability to attend scheduled study visits;
9. Patients who in the judgment of the Investigator may be unreliable or uncooperative with the evaluation procedure outlined in this protocol;
10. Patients with a history of prior pharmacogenomic testing;
11. Any change in psychotropic medication (including change in dosage) between screening and baseline;
12. Patients who are known to be pregnant or lactating;
13. Patients with a history of gastric bypass surgery.

Primary outcomes:
measure: Change in patients' weight and waist-to-hip ratio
timeFrame: From baseline to week 12
measure: Change in schizophrenic symptoms as assessed by the Positive and Negative Syndrome
timeFrame: From baseline to Week 12
Secondary outcomes:
measure: Time between baseline and discontinuation of treatment for any cause
timeFrame: Baseline, Weeks 8 and 12, Months 6 and 12
measure: Change in severity of illness as assessed by the Clinical Global Impression of Severity (CGI-S)
timeFrame: Baseline, Week 12, Months 6 and 12
measure: Change in global improvement as assessed by Clinical Global Impression of Improvement (CGI-I)
timeFrame: Week 12, Months 6 and 12
measure: Change in global therapeutic benefit and global severity of side effects as assessed by Clinical Global Impression Efficacy Index (CGI-EI)
timeFrame: Week 12, Months 6 and 12
measure: Changes to initial prescribing based on availability of pharmacogenomic data
timeFrame: Screening and Baseline
measure: Response rates to psychotropic medication
timeFrame: Baseline, Weeks 8 and 12, Months 6 and 12
measure: Time to response
timeFrame: Baseline, Weeks 8 and 12, Months 6 and 12
measure: Change in psychotropic medication side effects as assessed by the Udvalg for Kliniske Undersogeler (UKU) Side Effect Rating Scale
timeFrame: Baseline, Weeks 8 and 12, Months 6 and 12
measure: Change in severity of dyskinesias as assessed by the Abnormal Involuntary Movement Scale (AIMS)
timeFrame: Baseline and Month 12
measure: Change in health related quality of life as assessed by the EuroQol (EQ-5D-5L)
timeFrame: Baseline, Week 12, Months 6 and 12
measure: Change in health related quality of life as assessed by the Short Form (36) Health Survey (SF-36)
timeFrame: Baseline, Week 12, Months 6 and 12
measure: Pharmacogenetics in Psychiatry Follow-Up Questionnaire (PIP-FQ)
timeFrame: Baseline, when prescription changes are made (expected average of every 4 weeks), Months 6 and 12
measure: Healthcare resource utilization (Composite measure of healthcare costs): physician visits, hospital utilization, emergency department visits, medication use, and laboratory tests
timeFrame: Baseline, Weeks 8 and 12, Months 6 and 12
measure: Productivity losses (measured as economic costs)
timeFrame: Baseline, Weeks 8 and 12, Months 6 and 12
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Centre for Addiction and Mental Health
state: Ontario
Study officials:
affiliation: St.Joseph's Healthcare, Hamilton/Mcmaster University
name: Jean-Eric Tarride, PhD
role: STUDY_CHAIR
affiliation: Centre for Addiction and Mental Health
name: James L Kennedy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assurex Health Inc.
name: Bryan Dechairo, PhD
role: PRINCIPAL_INVESTIGATOR
References: