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

Sponsor

Duke University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04445792

Collaborator

(none)

4,509

Enrollment

Locations

Arms

34.6

Anticipated Duration (Months)

450.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

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.

Condition or Disease	Intervention/Treatment	Phase
Depression Acute Pain Chronic Pain	Other: Pharmacogenetic testing Other: Clinical decisions support	N/A

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

4509 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Immediate vs. delayed pharmacogenetic testing and genotype-guided pain or depression therapyImmediate vs. delayed pharmacogenetic testing and genotype-guided pain or depression therapy

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Depression and Opioid Pragmatic Trial in Pharmacogenetics

Actual Study Start Date :

Feb 10, 2021

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Acute Pain - 10 Day SIA Score Change from Baseline [Day of Surgery to 10 days post surgery]
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.
Chronic Pain -3 Month Pain Control Change from Baseline [Baseline to 3 months]
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
Depression - 3 Month Depression Symptom Control Change from Baseline [Baseline and 3 months]
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

Secondary Outcome Measures

Acute Pain -10 Day Pain Intensity Change from Baseline [10 days post-surgery]
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.
Acute Pain Trial - Post-surgery Opioid Usage Change from Baseline [day of surgery through 10 days post-surgery]
Opioid usage from surgery to10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75.
Acute Pain Trial - 3 Month Prescription Pain Medication Misuse Change from Baseline [3 months post surgery]
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.
Acute Pain - 1 Month Mobility Score Change from Baseline [1 month post surgery]
PROMIS mobility score at 1 month post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75.
Acute Pain - Opioid Persistence Change from Baseline [3-6 months post-surgery]
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
Chronic Pain - 3 Month Pain Reduction Change from Baseline [baseline and 3 months]
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.
Chronic Pain - 3 Month Clinically Significant Pain Reduction Change from Baseline [3 months]
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
Chronic Pain -3 Month Prescription Pain Medication Misuse Change from Baseline [3 months]
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
Depression - 3 Month Change in PHQ of Depression Symptomatology Change from Baseline Scores [baseline and 3 months]
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.
Depression - 3 Month Medication Side Effect Burden Change from Baseline [3 months]
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
Depression - 3 Month Medication Adherence Change from Baseline [3 months]
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
Depression - 6 Month Depression Remission Change from Baseline [6 months]
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.
All Trials Overall well-being, as measured by PROMIS 43 survey [At 6 month follow-up]
Overall well-being
All Trials Concordance between metabolizer phenotype and prescribed medication [At 6 month follow-up]
Concordance between metabolizer phenotype and prescribed medication
All Trials Sub-domain of the PROMIS 43 survey: Pain interference [At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain)]
The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do
All Trials Sub-domain of the PROMIS 43 survey: physical function [At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain)]
The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do
All Trials Sub-domain of the PROMIS 43 survey: sleep disturbance [At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain)]
The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do
All Trials Sub-domain of the PROMIS 43 survey: social role and activities functioning [At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain)]
The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do
All Trials Sub-domain of the PROMIS 43 survey: fatigue [At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain)]
The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do
All Trials Sub-domain of the PROMIS 43 survey: anxiety [At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain)]
The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do
All Trials Sub-domain of the PROMIS 43 survey: depression [At 6 months post return of results (chronic pain and depression; 6 months post surgery for acute pain)]
The assessment scale options are: without any difficulty, with a little difficulty, with some difficulty, with much difficulty or unable to do

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nemours/Alfred I. du Pont Hospital for Children	Wilmington	Delaware	United States	19803
2	University of Florida (Gainesville and Jacksonville)	Gainesville	Florida	United States	32610
3	Nemours Children's Health System	Jacksonville	Florida	United States	32207
4	Indiana University	Indianapolis	Indiana	United States	46202
5	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
6	The Institute for Family Health	New York	New York	United States	10035
7	Duke University	Durham	North Carolina	United States	27710
8	Sanford Health	Fargo	North Dakota	United States	58104
9	Meharry Medical College	Nashville	Tennessee	United States	37208
10	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232