Acute Pain
Conditions
Brief summary
Phase 4, multicenter, open-label, multiple-dose study of the pharmacokinetics (PK) and safety of XARTEMIS XR in postsurgical adolescent subjects aged 12 to 17 years with moderate to severe acute pain. The study will assess the safety of administering multiple doses of XARTEMIS XR in this population.
Interventions
DRUGXARTEMIS XR
XARTEMIS XR \[7.5 mg oxycodone hydrochloride and 325 mg acetaminophen (APAP)\] Extended-Release Tablets
Sponsors
Mallinckrodt
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Male or nonpregnant, nonlactating females between 12 and 17 years of age. 2. Minimum weight of 100 pounds (45 kg); body mass index (BMI) \>5% and \<95% for their age. 3. Moderate or severe acute pain \[as determined from the Numerical Pain Rating scale (NPRS)\]; must have a level of 4 or more) after surgical procedure requiring hospitalization. 4. If, of child-bearing/reproductive potential, must abstain from unprotected sexual activity during study and 2 weeks after study exit. 5. Females of childbearing potential must have negative pregnancy test. 6. Subject's legally authorized representative (eg, parent, legal guardian) must sign a parental permission/informed consent and subject must sign an assent. 7. Subject and subject's parent/legal guardian must be able to read, understand, and follow study procedures and requirements and communicate meaningfully in English.
Exclusion criteria
1. Subject is from a vulnerable population (including mentally disabled children), other than a pediatric population. 2. Subject requires surgery that could influence the study outcome. 3. Abnormal electrocardiogram (ECG). 4. Screening pulse oximetry reading of \<95% while awake. 5. Has presence of human immunodeficiency virus (HIV) or indications of hepatitis A, B or C. 6. Lab values greater than 2 times the upper limit of normal. 7. History of renal disease or bleeding or clotting disorders or conditions. 8. Known or suspected alcoholism, marijuana or illicit drug abuse or misuse within 2 years before screening. 9. Smoked or used nicotine-containing products within 6 months prior to screening. 10. Psychiatric disorders, such as major depression disorder, anxiety disorders, or psychotic disorders within 6 months prior to screening. A history of attention deficit hyperactivity disorder requiring medication is acceptable. 11. Diagnosis of epilepsy or other seizure disorder. 12. Previous cardiothoracic surgery. 13. Conditions which might be specifically contraindicated or require caution while using OC, APAP, and/or ibuprofen. 14. Drug allergy, hypersensitivity, or intolerance including OC, APAP, ibuprofen or excipients, or any opioid drug product. 15. Donated or had significant loss of whole blood (480 mL or more) within 30 days of or plans to donate blood or plasma during the course of the study. 16. Pathologic, iatrogenic or surgical condition that would compromise subject's ability to swallow, absorb, metabolize, or excrete XARTEMIS XR. 17. History of a GI event within 6 months prior to screening. 18. Subject has used any product containing OC or APAP within 48 hours prior to the first dose of XARTEMIS XR. 19. Any other medical condition, abnormal vital sign (blood pressure, pulse rate, respiratory rate), body temperature, pulse oximetry; or any physical examination or ECG finding at screening which would preclude safe participation in a clinical study. 20. Received any investigational product or device within 30 days before screening, or is scheduled to receive an investigational device or another investigational drug during the course of this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Steady State | within 60 hours | The time to reach steady state in participants who received all 5 doses |
| Area Under the Concentration-time Curve (AUC) From Time Zero (AUC0) to the Time of the Last Quantifiable Plasma Sample (AUClast) | within approximately 12 hours (12.08 hours) | Elimination constant estimates required for the calculation of the planned AUC0-12 hours were not available. AUClast therefore provided the best available measure of exposure, effectively representing AUC0-12 hours for both moieties. While considered the best available measure, it also remains inaccurate because of the extended-release formulation and the lack of data beyond the 12.08-hour time point. |
| Maximum Observed Plasma Concentration (Cmax) | within approximately 12 hours (12.08 hours) | The highest concentration of study drug within 12 hours. |
| Apparent Plasma Terminal Drug Elimination Half-life (T1/2) | within approximately 12 hours (12.08 hours) | PK parameters are determined after a single administration of study drug on Day 1. Plasma concentrations that are below the level of quantification (BLQ) are set to 0 before Tmax, with the exception that a BLQ value occurring between measurable concentrations is set to missing. BLQ values that occur after Tmax are set to missing. |
| Time of Maximum Observed Plasma Concentration (Tmax) | within approximately 12 hours (12.08 hours) | The time at which the maximum plasma concentration (Cmax) is reached. |
Countries
United States
Participant flow
Recruitment details
The study was conducted from November 20, 2015 to April 26, 2017 and enrolled participants from the United States.
Participants by arm
| Arm | Count |
|---|---|
| XARTEMIS XR XARTEMIS XR is a combination of oxycodone and acetaminophen administered to postsurgical adolescent participants with moderate to severe acute pain. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Emesis | 3 |
| Overall Study | Pain Score <4 | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Trial terminated by sponsor | 5 |
| Overall Study | Withdrawal by Caregiver | 8 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | XARTEMIS XR |
|---|---|
| Age, Continuous | 14.7 years STANDARD_DEVIATION 1.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 23 |
| other Total, other adverse events | 7 / 23 |
| serious Total, serious adverse events | 3 / 23 |
Outcome results
Primary
Apparent Plasma Terminal Drug Elimination Half-life (T1/2)
PK parameters are determined after a single administration of study drug on Day 1. Plasma concentrations that are below the level of quantification (BLQ) are set to 0 before Tmax, with the exception that a BLQ value occurring between measurable concentrations is set to missing. BLQ values that occur after Tmax are set to missing.
Time frame: within approximately 12 hours (12.08 hours)
Population: PK population with BLQ values set to missing
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XARTEMIS XR | Apparent Plasma Terminal Drug Elimination Half-life (T1/2) | 0.52 hours |
| Acetaminophen | Apparent Plasma Terminal Drug Elimination Half-life (T1/2) | 0.00 hours |
Primary
Area Under the Concentration-time Curve (AUC) From Time Zero (AUC0) to the Time of the Last Quantifiable Plasma Sample (AUClast)
Elimination constant estimates required for the calculation of the planned AUC0-12 hours were not available. AUClast therefore provided the best available measure of exposure, effectively representing AUC0-12 hours for both moieties. While considered the best available measure, it also remains inaccurate because of the extended-release formulation and the lack of data beyond the 12.08-hour time point.
Time frame: within approximately 12 hours (12.08 hours)
Population: PK population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XARTEMIS XR | Area Under the Concentration-time Curve (AUC) From Time Zero (AUC0) to the Time of the Last Quantifiable Plasma Sample (AUClast) | 76.8 ng*hr/mL |
| Acetaminophen | Area Under the Concentration-time Curve (AUC) From Time Zero (AUC0) to the Time of the Last Quantifiable Plasma Sample (AUClast) | 20571.4 ng*hr/mL |
Primary
Maximum Observed Plasma Concentration (Cmax)
The highest concentration of study drug within 12 hours.
Time frame: within approximately 12 hours (12.08 hours)
Population: PK population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| XARTEMIS XR | Maximum Observed Plasma Concentration (Cmax) | 12.8 ng/mL | Standard Deviation 4.6 |
| Acetaminophen | Maximum Observed Plasma Concentration (Cmax) | 2886.1 ng/mL | Standard Deviation 881.68 |
Primary
Time of Maximum Observed Plasma Concentration (Tmax)
The time at which the maximum plasma concentration (Cmax) is reached.
Time frame: within approximately 12 hours (12.08 hours)
Population: PK population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XARTEMIS XR | Time of Maximum Observed Plasma Concentration (Tmax) | 7.9 hour |
| Acetaminophen | Time of Maximum Observed Plasma Concentration (Tmax) | 4.03 hour |
Primary
Time to Reach Steady State
The time to reach steady state in participants who received all 5 doses
Time frame: within 60 hours
Population: Steady-state pharmacokinetic (PK) parameters were to be determined for those participants administered all 5 doses. However, no participant received all 5 doses; therefore, steady state PK parameters were not derived.