A Depression and Opioid Pragmatic Trial in Pharmacogenetics (DCRI Coordinating Center)

Study Overview
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Brief Summary
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This study is comprised of three separate pharmacogenetic trials grouped into a single protocol due to similarities in the intervention, the hypotheses, and the trial design. The three trials are the Acute Pain Trial, the Chronic Pain Trial, and the Depression Trial. Participants can enroll in only one of the three trials. Each trial is listed individually on clinicaltrials.gov and includes PRO00104948 within the Unique Protocol ID: PRO00104948_A - Acute Pain Trial - NCT05966129 PRO00104948_B - Chronic Pain Trial - NCT05966142 PRO00104948_C - Depression Trial - NCT05966155 Acute Pain Trial: A prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria will be randomly assigned to either immediate pharmacogenetic testing and genotype-guided post-surgical opioid therapy (Intervention arm) or standard care and pharmacogenetic testing after 6 months (Control arm). The investigators will test the hypothesis that pharmacogenetic testing and genotype guided pain management therapy improves pain control after surgery in participants who's body processes some pain medicines slower than normal. Chronic Pain Trial: A prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria will be randomly assigned to either immediate pharmacogenetic testing and genotype-guided opioid therapy (Intervention arm) or standard care with 6-month delayed pharmacogenetic testing (Control arm). The investigators will test the hypothesis that pharmacogenetic testing and genotype guided pain therapy improves pain control after surgery in participants who's body processes some pain medicines slower than normal. Depression: A prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria will be randomly assigned to either immediate pharmacogenetic testing and genotype-guided anti-depressant therapy (Intervention arm) or standard care with 6-month delayed pharmacogenetic testing (Control arm). The investigators will test the hypothesis that pharmacogenetic testing and genotype-guided anti-depressant therapy will reduce depression symptoms in participants who's body processes some anti-depressants faster or slower than normal.

Detailed Description
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Pain and depression are conditions that impact substantial proportions of the US population. Finding safe and effective drug therapies for both conditions is challenging. In the case of treatment for acute and chronic pain, the challenge is finding effective therapy while minimizing adverse effects or opioid addiction (and the ensuing consequences). For depression, there are few clinically relevant predictors of successful treatment leading to multiple trials of inadequate therapy for some patients. Both opioid and antidepressant prescriptions can be guided by pharmacogenetics (PGx) data based on existing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC). This study is designed to evaluate the impact of pharmacogenetic testing and genotype-guided pain or anti-depressant therapy on pain control or depression symptoms in a pragmatic setting. The rationale for examining a genotype-guided approach to acute and chronic pain management is based on the importance of CYP2D6 for the bioactivation of tramadol, codeine, and hydrocodone and data from a pilot study supporting improved pain control in intermediate and poor CYP2D6 metabolizers in the genotype-guided arm who are taking these drugs at baseline. Similarly, the rationale for examining a genotype-guided approach to depression medication therapy is based on the demonstrated role of CYP2D6 in the bio inactivation and CYP2C19 oxidation of select, commonly used SSRIs. Secondly, data from industry sponsored trials support the hypothesis of improved depression symptom control in a genotype-guided arm. Study objectives: Acute Pain Trial: Determine if a genotype-guided approach to acute post-surgical pain therapy leads to improved pain control compared to usual care, as defined by a decrease in the SIA score. Secondarily, The investigators will evaluate whether this approach leads to reduced use of DEA Schedule II opioids and reduced pain intensity. Chronic Pain Trial: Determine if a genotype-guided approach to pain therapy in participants with at least 3 months of chronic pain leads to improved pain control compared to usual care. Depression Trial: Determine if genotype-guided dosing or selection of antidepressants among participants with at least 3 months of depressive symptoms who require new or revised antidepressant therapy leads to improved control of depression, compared to usual care.

Official Title
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A Depression and Opioid Pragmatic Trial in Pharmacogenetics

Conditions
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Depression, Acute Pain, Chronic Pain

Intervention / Treatment
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* Other: Pharmacogenetic testing
* Other: Clinical decisions support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute Pain Age ≥ 8 years English speaking or Spanish speaking Elective/planned surgery types with planned or anticipated to be treated with tramadol, hydrocodone, or codeine pain management at an enrolling site, which may include orthopedic surgeries (e.g. arthroplasty, spine, etc.), open abdominal surgery, or cardiothoracic surgery and others Chronic Pain Age ≥ 18 years English speaking or Spanish speaking Seen at primary care clinics (such as, but not limited to, Internal Medicine, Family Medicine or Pediatrics) or patients seen in pain-relevant specialty clinics History of pain for at least the last 3 months Currently treated or being considered for treatment with tramadol, hydrocodone, or codeine to improve pain management Depression Age ≥ 8 years English speaking or Spanish speaking Patients followed at psychiatry clinics or primary care clinics at an enrolling site (such as, but not limited to, Internal Medicine, Family Medicine, or Pediatrics) Documentation of depression and/or provider report of depression Evidence of depressive symptoms for at least 3 months based on patient interview or documentation in electronic health records Recent initiation of SSRI therapy, recent revised SSRI therapy, or anticipated need for revised or new SSRI therapy per health care provider Exclusion Criteria Trial-wide: Life expectancy less than 12 months Are too cognitively impaired to provide informed consent and/or complete study protocol Are institutionalized or too ill to participate (i.e. mental or nursing home facility or incarcerated) Have a history of allogeneic stem cell transplant or liver transplant People with prior clinical pharmacogenetic test results for genes relevant for the study in which they will enroll (CYP2D6 for the pain studies and CYP2D6 or CYP2C19 for depression) or already enrolled in an ADOPT PGx trial Acute Pain Undergoing a laparoscopic surgery Receiving chronic opioid therapy, defined as use of opioids on most days for >3 months Chronic Pain Plan to move out of the area within 6 months of enrollment Undergoing treatment for an active cancer diagnosis Currently taking daily opioids other than tramadol, codeine or hydrocodone Depression Plan to move out of the area within 6 months of enrollment Have active psychosis or diagnosed psychotic disorders (schizophrenia, schizoaffective disorder, delusional disorder, psychotic depression, substance induced psychosis, schizophreniform disorder) Have dementia or other neurocognitive disorders due to any cause, such as Alzheimer's disease, vascular/subcortical, lewy body disease, frontotemporal lobar degeneration Have cognitive developmental delay and/or cognitive disability, including autism spectrum disorders (Note: ADHD is not an exclusion criteria) Has a seizure disorder Have bipolar disorder

Ages Eligible for Study
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Minimum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Immediate vs. delayed pharmacogenetic testing and genotype-guided pain or depression therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute Pain - Immediate PGx Testing<br>Immediate genetic testing of CYP2D6 and clinical decisions support for pain management prescribing to the healthcare provider | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>Other: Clinical decisions support<br>* Prescribing recommendations to the provider based on the pharmacogenetic testing results<br>|
| Other: Acute Pain - Delayed PGx Testing<br>Delayed genetic testing of CYP2D6 and return of results after the conclusion of the 6-month follow-up period | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>|
| Experimental: Chronic Pain - Immediate PGx Testing<br>Immediate genetic testing of CYP2D6 and clinical decisions support for pain management prescribing to the healthcare provider | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>Other: Clinical decisions support<br>* Prescribing recommendations to the provider based on the pharmacogenetic testing results<br>|
| Other: Chronic Pain - Delayed PGx Testing<br>Delayed genetic testing of CYP2D6 and return of results after the conclusion of the 6-month follow-up period | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>|
| Experimental: Depression - Immediate PGx Testing<br>Immediate genetic testing of CYP2D6 and CYP2C19 and clinical decisions support for antidepressant prescribing to the healthcare provider | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>Other: Clinical decisions support<br>* Prescribing recommendations to the provider based on the pharmacogenetic testing results<br>|
| Other: Depression - Delayed PGx Testing<br>Delayed genetic testing of CYP2D6 and CYP2C19 and return of results after the conclusion of the 6-month follow-up period | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Pain - 10 Day SIA Score Change from Baseline | Acute Pain: A composite measure of pain and opioid usage, the Silverman Integrated Analgesic Assessment (SIA) score, at 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. | Day of Surgery to 10 days post surgery | 
| Chronic Pain -3 Month Pain Control Change from Baseline | Chronic Pain: Pain control, defined as change in the composite pain intensity score from baseline to 3-months in participants who have genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. The composite pain intensity score is derived from the PROMIS pain intensity scale | Baseline to 3 months | 
| Depression - 3 Month Depression Symptom Control Change from Baseline | Depression symptom control, defined as change in PROMIS depression T-scores from baseline to 3-months in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers | Baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Pain -10 Day Pain Intensity Change from Baseline | PROMIS Numeric Pain Rating Scale Pain intensity at 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. | 10 days post-surgery | 
| Acute Pain Trial - Post-surgery Opioid Usage Change from Baseline | Opioid usage from surgery to10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. | day of surgery through 10 days post-surgery | 
| Acute Pain Trial - 3 Month Prescription Pain Medication Misuse Change from Baseline | PROMIS prescription pain medication misuse T-scores at 3 months post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. | 3 months post surgery | 
| Acute Pain - 1 Month Mobility Score Change from Baseline | PROMIS mobility score at 1 month post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. | 1 month post surgery | 
| Acute Pain - Opioid Persistence Change from Baseline | Opioid persistence defined as a filled prescription for an opioid medication 3-6 months post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75 | 3-6 months post-surgery | 
| Chronic Pain - 3 Month Pain Reduction Change from Baseline | Pain reduction is defined as the ratio of the 3 month and baseline composite pain scores in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. | baseline and 3 months | 
| Chronic Pain - 3 Month Clinically Significant Pain Reduction Change from Baseline | PROMIS prescription pain medication misuse T-scores at 3 months post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75 | 3 months | 
| Chronic Pain -3 Month Prescription Pain Medication Misuse Change from Baseline | PROMIS prescription pain medication misuse T-scores at 3 months post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75 | 3 months | 
| Depression - 3 Month Change in PHQ of Depression Symptomatology Change from Baseline Scores | Change in PHQ-8 scores between baseline and 3 months in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers. Achieve 50% reduction in scores. | baseline and 3 months | 
| Depression - 3 Month Medication Side Effect Burden Change from Baseline | Side effect burden is defined as the number of side effects experienced from a specified list of possible side effects, weighted by the severity of each side effect in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers | 3 months | 
| Depression - 3 Month Medication Adherence Change from Baseline | Medication adherence score derived from the Voils Medication Adherence survey in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers | 3 months | 
| Depression - 6 Month Depression Remission Change from Baseline | Remission is defined as whether or not the summed raw responses to the PROMIS emotional distress depression survey is ≤ 16, corresponding to a participant respond rarely or never to most or all questions. | 6 months | 
| All Trials Overall well-being, as measured by PROMIS 43 survey | Overall well-being | At 6 month follow-up | 
| All Trials Concordance between metabolizer phenotype and prescribed medication | Concordance between metabolizer phenotype and prescribed medication | At 6 month follow-up | 
| All Trials Sub-domain of the PROMIS 43 survey: Pain interference | The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do | At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain) | 
| All Trials Sub-domain of the PROMIS 43 survey: physical function | The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do | At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain) | 
| All Trials Sub-domain of the PROMIS 43 survey: sleep disturbance | The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do | At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain) | 
| All Trials Sub-domain of the PROMIS 43 survey: social role and activities functioning | The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do | At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain) | 
| All Trials Sub-domain of the PROMIS 43 survey: fatigue | The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do | At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain) | 
| All Trials Sub-domain of the PROMIS 43 survey: anxiety | The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do | At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain) | 
| All Trials Sub-domain of the PROMIS 43 survey: depression | The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do | At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacogenetic, CYP2D6, CYP2C19