A Depression and Opioid Pragmatic Trial in Pharmacogenetics (Chronic 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 Chronic Pain Trial within the ADOPT-PGx protocol. The Chronic 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 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.

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 pain therapy in participants with at least 3 months of chronic pain leads to improved pain control compared to usual care.

Official Title
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A Depression and Opioid Pragmatic Trial in Pharmacogenetics

Conditions
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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: Chronic Pain Trial 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 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 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

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: 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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3 Month Pain Control Change from Baseline | 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 | 

Secondary Outcome Measures

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

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