A Depression and Opioid Pragmatic Trial in Pharmacogenetics (Acute Pain Trial)

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. All three trials were registered on ClinicalTrials.gov under NCT04445792. In July 2023 each of the three treatment trials was registered under a separate NCT# and NCT04445792 was converted to a screening record per recent guidance on master protocol research programs (MPRPs). This record is specific to the Acute Pain Trial within the ADOPT-PGx protocol. The Acute Pain Trial is 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.

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: 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.

Official Title
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A Depression and Opioid Pragmatic Trial in Pharmacogenetics

Conditions
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Acute 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 Trial 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 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 Trial Undergoing a laparoscopic surgery Receiving chronic opioid therapy, defined as use of opioids on most days for >3 months

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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 10 Day SIA Score Change from Baseline | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

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