Chronic Pain
Conditions
Keywords
Pharmacogenetic, CYP2D6, CYP2C19
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. 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
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.
Interventions
Genetic testing of CYP2D6 and CYP2C19
Prescribing recommendations to the provider based on the pharmacogenetic testing results
Sponsors
National Human Genome Research Institute (NHGRI)
University of Florida
Vanderbilt University Medical Center
Indiana University School of Medicine
Icahn School of Medicine at Mount Sinai
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Immediate vs. delayed pharmacogenetic testing and genotype-guided pain or depression therapy
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain Intensity | Baseline to 3 months | The composite pain intensity score is derived from the 3-time PROMIS (Patient-Reported Outcomes Measurement Information System) pain intensity scale. Composite pain intensity score is the sum of the 3 questions and ranges from 3 (no pain) to 15 (intense pain). Change in composite pain intensity score ranges from -12 (change from the highest level of pain to the lowest level of pain) to 12 (change from the lowest level of pain to the highest level of pain). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Reduction Magnitude | Baseline to 3 months | Ratio of Composite Pain Score at 3 months relative to baseline. Composite pain intensity scores were shifted to range 0-12 and the pain reduction magnitude is reported as the ratio of pain at 3 months relative to pain at baseline using this adjusted scale. Statistical analyses were conducted using the log ratio pain at 3 months relative to pain at baseline. Due to the presence of 0 values in the ratios, the log ratios include a +.5 offset, i.e. log(3-month pain +.5 / baseline pain + 0.5). |
| Number of Participants With Clinically Significant Pain Reduction | Baseline to 3 months | Clinically significant pain reduction defined as ratio of 3-month composite pain score relative to baseline is \< 0.7, corresponding to a 30% or more improvement in pain scores. |
| Prescription Pain Medication Misuse as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | 3 months | The 7-item PROMIS questionnaire assesses the extent to which participant experience prescription pain medication misuse symptoms in the past 3 months using a 5-point Likert scale. Participants are asked if they have had a prescription for pain medication in the last 3 months. If no, the questionnaire is not administered, if yes, the questionnaire is administered. For the completed questionnaires. Raw scores ranging from 7 to 35. Raw scores are converted to T-scores using the PROMIS conversion table, with T-scores ranging 36.3 to 54.1. Higher T-scores reflect greater symptom severity. |
| Number of Participants With Drug-Gene Concordance | 3 months | Concordance between the participant reported opioid medications at 3 months and CYP2D6 phenotype. |
Countries
United States
Participant flow
Recruitment details
This record is specific to the Chronic Pain Trial within the ADOPT PGx protocol. It only contains the participants consented to the Chronic Pain Trial.
Pre-assignment details
There were 1092 participants consented into the Chronic Pain trial. Of the 1092, 44 were not randomized into the trial and were not assigned to a treatment arm. The remaining 1048 consented participants were randomized and assigned into the treatment arms. The 1048 randomized participants will be described moving forward.
Participants by arm
| Arm | Count |
|---|---|
| Chronic Pain - Immediate PGx Testing Immediate genetic testing of CYP2D6 and clinical decisions support for pain management prescribing to the healthcare provider. | 527 |
| Chronic Pain - Delayed PGx Testing Delayed genetic testing of CYP2D6 and return of results after the conclusion of the 6-month follow-up period. | 521 |
| Total | 1,048 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 3 |
| Overall Study | Duplicate Enrollment | 1 | 0 |
| Overall Study | Lost to Follow-up | 55 | 52 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Study Logistical Reason | 1 | 0 |
| Overall Study | Unable to complete follow up due to change in health | 1 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 8 |
Baseline characteristics
| Characteristic | Chronic Pain - Delayed PGx Testing | Total | Chronic Pain - Immediate PGx Testing |
|---|---|---|---|
| Age, Continuous | 57.8 years STANDARD_DEVIATION 11.3 | 57.9 years STANDARD_DEVIATION 11.1 | 58.2 years STANDARD_DEVIATION 12.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 93 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 469 Participants | 937 Participants | 468 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 48 Participants | 97 Participants | 49 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 8 Participants | 13 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 44 Participants | 97 Participants | 15 Participants |
| Race (NIH/OMB) White | 75 Participants | 490 Participants | 66 Participants |
| Region of Enrollment United States | 521 Participants | 1048 Participants | 527 Participants |
| Sex: Female, Male Female | 115 Participants | 210 Participants | 95 Participants |
| Sex: Female, Male Male | 146 Participants | 297 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 527 | 3 / 521 |
| other Total, other adverse events | 0 / 527 | 0 / 521 |
| serious Total, serious adverse events | 0 / 527 | 0 / 521 |
Outcome results
Primary
Change in Pain Intensity
The composite pain intensity score is derived from the 3-time PROMIS (Patient-Reported Outcomes Measurement Information System) pain intensity scale. Composite pain intensity score is the sum of the 3 questions and ranges from 3 (no pain) to 15 (intense pain). Change in composite pain intensity score ranges from -12 (change from the highest level of pain to the lowest level of pain) to 12 (change from the lowest level of pain to the highest level of pain).
Time frame: Baseline to 3 months
Population: Modified Intent to Treat (mITT) population with completed baseline and 3-month pain surveys.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain - Immediate PGx Testing | Change in Pain Intensity | -0.7 score on a scale | Standard Deviation 2.3 |
| Chronic Pain - Delayed PGx Testing | Change in Pain Intensity | -0.8 score on a scale | Standard Deviation 2.4 |
p-value: 0.591395% CI: [-0.42, 0.74]t-test, 2 sided
Secondary
Number of Participants With Clinically Significant Pain Reduction
Clinically significant pain reduction defined as ratio of 3-month composite pain score relative to baseline is \< 0.7, corresponding to a 30% or more improvement in pain scores.
Time frame: Baseline to 3 months
Population: Modified Intent to Treat (mITT) population with completed baseline and 3-month pain surveys.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chronic Pain - Immediate PGx Testing | Number of Participants With Clinically Significant Pain Reduction | 17 Participants |
| Chronic Pain - Delayed PGx Testing | Number of Participants With Clinically Significant Pain Reduction | 27 Participants |
p-value: 0.1228Chi-squared
Secondary
Number of Participants With Drug-Gene Concordance
Concordance between the participant reported opioid medications at 3 months and CYP2D6 phenotype.
Time frame: 3 months
Population: Modified Intent to Treat (mITT) participants with prescription pain medication data collected.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chronic Pain - Immediate PGx Testing | Number of Participants With Drug-Gene Concordance | 33 Participants |
| Chronic Pain - Delayed PGx Testing | Number of Participants With Drug-Gene Concordance | 36 Participants |
p-value: 0.9657Chi-squared
Secondary
Pain Reduction Magnitude
Ratio of Composite Pain Score at 3 months relative to baseline. Composite pain intensity scores were shifted to range 0-12 and the pain reduction magnitude is reported as the ratio of pain at 3 months relative to pain at baseline using this adjusted scale. Statistical analyses were conducted using the log ratio pain at 3 months relative to pain at baseline. Due to the presence of 0 values in the ratios, the log ratios include a +.5 offset, i.e. log(3-month pain +.5 / baseline pain + 0.5).
Time frame: Baseline to 3 months
Population: Modified Intent to Treat (mITT) population with completed baseline and 3-month pain surveys.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain - Immediate PGx Testing | Pain Reduction Magnitude | -0.1 log ratio | Standard Deviation 0.4 |
| Chronic Pain - Delayed PGx Testing | Pain Reduction Magnitude | -0.1 log ratio | Standard Deviation 0.5 |
p-value: 0.6803t-test, 2 sided
Secondary
Prescription Pain Medication Misuse as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System)
The 7-item PROMIS questionnaire assesses the extent to which participant experience prescription pain medication misuse symptoms in the past 3 months using a 5-point Likert scale. Participants are asked if they have had a prescription for pain medication in the last 3 months. If no, the questionnaire is not administered, if yes, the questionnaire is administered. For the completed questionnaires. Raw scores ranging from 7 to 35. Raw scores are converted to T-scores using the PROMIS conversion table, with T-scores ranging 36.3 to 54.1. Higher T-scores reflect greater symptom severity.
Time frame: 3 months
Population: Modified Intent to Treat (mITT) participants who indicate having taken a prescription for pain medication in the past 3 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain - Immediate PGx Testing | Prescription Pain Medication Misuse as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | 40.1 T-score | Standard Deviation 4.8 |
| Chronic Pain - Delayed PGx Testing | Prescription Pain Medication Misuse as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | 40.5 T-score | Standard Deviation 4.8 |
p-value: 0.525295% CI: [-1.7, 0.9]t-test, 2 sided