Moderate to Severe Chronic Pain
Conditions
Brief summary
The main purpose of this study is to evaluate the effect of NKTR-181 on brain activity in healthy, non-physically dependent recreational opioid users. This study will last about 88 days for each participant.
Detailed description
This study is a single-center study in which approximately 24 subjects will be randomized to one of two treatment groups. Subjects will enter a screening period between Day -28 and Day -2. Upon meeting all criteria for enrollment, on Day -1 subjects will enter the clinical research study unit (CRSU) for an overnight confinement. On Day 1, subjects will undergo a baseline MRI and will then be randomized to NKTR-181 or oxycodone immediate release (IR). Once randomized, subjects will receive a single dose of study drug (NKTR-181 or oxycodone IR) and matched alternate-treatment placebo. Subjects will undergo a series of three fMRIs (functional magnetic resonance imaging) post dose (at hours 1, 2, and 4). At post-dose hours 0.5, 1, 2, 3, 4, 5, 6, and 8, pupillometry will be performed and PK blood samples will be drawn. Following a 14- to 17-day safety follow-up period, subjects will return to the research facility clinic for the End of Study (EOS) visit (Day 16-19).
Interventions
DRUGNKTR-181
A combination of NKTR-181 and oxycodone IR placebo
DRUGOxycodone IR
A combination of oxycodone IR and NKTR-181 placebo
Sponsors
Nektar Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
A double-blind, double-dummy, parallel-group, randomized, positive control study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Healthy male and female recreational opioid users, 18-65 years of age inclusive. * Body Mass Index (BMI) between 19.0 to 45.0kg/m2 * Have at least one urine drug screen positive for opioids during Screening to confirm recreational opioid use. Subjects testing positive for methadone or buprenorphine prescribed for treatment will be excluded. * Subjects must agree to practice adequate contraception as outlined in the protocol. Key
Exclusion criteria
* Any metal fragments or other bodily metal that would pose a risk to subjects during MRI scanning as determined by the MRI technologist and/or MRI physicist * Any clinically significant disease or condition that might compromise the cardiovascular, hematological, renal, hepatic, pulmonary, endocrine, central nervous, or gastrointestinal systems or other conditions that may interfere with the absorption, distribution, metabolism, or excretion of the study drug or would place the subject at increased risk * History of clinically significant acute asthma or other obstructive airway disease requiring daily controller medication or any condition that may increase the risk for respiratory depression * Current neurologic conditions such as convulsive disorders, or history of severe head injury. * Any current DSM-5 axis I psychiatric disorder or neurological disorder requiring ongoing treatment * Current substance use disorder (moderate to severe), other than Opioid, Nicotine, THC (tetrahydrocannabinol), cocaine, or caffeine as defined by DSM-5 * Physical dependence of opioids * History of claustrophobia or any other psychiatric disorder that would preclude subject tolerance of MRI procedures. * Current use of any medication that could affect central nervous system blood flow (e.g. certain cardiovascular medications, triptan migraine medications) * Clinical Opiate Withdrawal Scale (COWS) score of greater than 5 during screening or prior to first scan. * Positive urine drug screen for buprenorphine or methadone immediately prior to the first scan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Activity Measured Via fMRI | 8 hour period following dose of NKTR-181 | The primary objective of the study was to evaluate the effects of NKTR-181 on brain activity. Functional MRI assessments in subjects administered opioids such as morphine, buprenorphine, and nalbuphine have shown drug-induced signaling changes in reward structures such as the nucleus accumbens, orbitofrontal cortex, and hippocampus, as well as changes in the functional connectivity of reward circuitry (Becerra, 2006; Gear, 2013; Upadhyay, 2012). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pupil Diameter Via Pupillometry | 24 hour period following dose administration Day 1 to 2 | Analysis of change in pupil diameter after administration of NKTR-181 or Oxycodone IR. |
| Plasma Drug Concentration | 24 hour period following dose administration Day 1 to 2 | Plasma drug concentration for NKTR-181 and Oxycodone IR over 24 hours. |
| Time to Maximum Concentration (Tmax) | 24 hour period following dose administration Day 1 to 2 | The amount of time needed for maximum drug concentration to be reached. |
| Treatment-Emergent Adverse Events (TEAEs) | 19 days | Number of patients who experienced any type of adverse event as a result of one of the treatments. |
Countries
United States
Participant flow
Pre-assignment details
Treatment assignments were based on a computer-generated randomization scheduled prepared by SynteractHCR Inc. prior to study start
Participants by arm
| Arm | Count |
|---|---|
| NKTR-181 Two 200 mg NKTR-181 tablets and 1 placebo capsule for oxycodone IR oxycodone IR | 4 |
| Oxycodone IR 40 mg One capsule of Oxycodone IR 40 mg and 2 placebo tablets for NKTR-181 | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Oxycodone IR 40 mg | NKTR-181 | Total |
|---|---|---|---|
| Age, Continuous | 43.5 years STANDARD_DEVIATION 3.42 | 38.5 years STANDARD_DEVIATION 7.42 | 41.0 years STANDARD_DEVIATION 5.98 |
| BMI (kg/m2) | 25.3 kilograms per meter squared STANDARD_DEVIATION 2.12 | 29.7 kilograms per meter squared STANDARD_DEVIATION 8.83 | 27.5 kilograms per meter squared STANDARD_DEVIATION 6.39 |
| Diastolic Blood Pressure (mm Hg) | 74.5 millimeters of Hg STANDARD_DEVIATION 12.66 | 91.3 millimeters of Hg STANDARD_DEVIATION 18.63 | 82.9 millimeters of Hg STANDARD_DEVIATION 17.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height (cm) | 182.0 centimeters STANDARD_DEVIATION 2.44 | 166.3 centimeters STANDARD_DEVIATION 5.94 | 174.1 centimeters STANDARD_DEVIATION 9.39 |
| Pulse Rate (bpm) | 74.3 beats per minute STANDARD_DEVIATION 4.35 | 74.5 beats per minute STANDARD_DEVIATION 6.4 | 74.4 beats per minute STANDARD_DEVIATION 5.07 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 3 Participants |
| Respiratory Rate (breaths per minute) | 17.5 breaths per minute STANDARD_DEVIATION 1 | 14.0 breaths per minute STANDARD_DEVIATION 2.31 | 15.8 breaths per minute STANDARD_DEVIATION 2.49 |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
| SpO2 (%) | 97.5 % STANDARD_DEVIATION 1.91 | 97.3 % STANDARD_DEVIATION 0.96 | 97.4 % STANDARD_DEVIATION 1.41 |
| Systolic Blood Pressure (mm Hg) | 127.3 millimeters of Hg STANDARD_DEVIATION 12.74 | 143.5 millimeters of Hg STANDARD_DEVIATION 11.47 | 135.4 millimeters of Hg STANDARD_DEVIATION 14.19 |
| Temperature (degrees Celsius) | 36.8 degrees Celsius STANDARD_DEVIATION 0.27 | 36.7 degrees Celsius STANDARD_DEVIATION 0.37 | 36.7 degrees Celsius STANDARD_DEVIATION 0.3 |
| Weight (kg) | 83.8 kilograms STANDARD_DEVIATION 5.93 | 81.5 kilograms STANDARD_DEVIATION 21.3 | 82.7 kilograms STANDARD_DEVIATION 14.52 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 1 / 4 | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Brain Activity Measured Via fMRI
The primary objective of the study was to evaluate the effects of NKTR-181 on brain activity. Functional MRI assessments in subjects administered opioids such as morphine, buprenorphine, and nalbuphine have shown drug-induced signaling changes in reward structures such as the nucleus accumbens, orbitofrontal cortex, and hippocampus, as well as changes in the functional connectivity of reward circuitry (Becerra, 2006; Gear, 2013; Upadhyay, 2012).
Time frame: 8 hour period following dose of NKTR-181
Population: Subjects who had sufficient MRI data for NKTR-181 or oxycodone IR treatment to allow for analysis of modulation of brain circuitry.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus at Baseline | 0.0 Correlation Coefficient | Standard Deviation 0.12 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 1 hour | 0.0 Correlation Coefficient | Standard Deviation 0.28 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 4 hours | 0.0 Correlation Coefficient | Standard Deviation 0.2 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 8 hours | -0.1 Correlation Coefficient | Standard Deviation 0.02 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC at Baseline | 0.1 Correlation Coefficient | Standard Deviation 0.38 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 1 hour | -0.2 Correlation Coefficient | Standard Deviation 0.41 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 2 hours | 0.2 Correlation Coefficient | Standard Deviation 0.21 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 4 hours | 0.2 Correlation Coefficient | Standard Deviation 0.26 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 8 hours | 0.1 Correlation Coefficient | Standard Deviation 0.54 |
| NKTR-181 | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 2 hours | 0.1 Correlation Coefficient | Standard Deviation 0.2 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC at Baseline | 0.0 Correlation Coefficient | Standard Deviation 0.14 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus at Baseline | 0.2 Correlation Coefficient | Standard Deviation 0.34 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 1 hour | 0.1 Correlation Coefficient | Standard Deviation 0.34 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 1 hour | 0.0 Correlation Coefficient | Standard Deviation 0.21 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 2 hours | -0.1 Correlation Coefficient | Standard Deviation 0.1 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 8 hours | 0.1 Correlation Coefficient | Standard Deviation 0.18 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 4 hours | 0.0 Correlation Coefficient | Standard Deviation 0.48 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 2 hours | 0.4 Correlation Coefficient | Standard Deviation 0.51 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between ACC and R Hippocampus after 8 hours | 0.2 Correlation Coefficient | Standard Deviation 0.07 |
| Oxycodone IR 40 mg | Brain Activity Measured Via fMRI | Effective Connectivity between R Amygdala and mPFC after 4 hours | 0.1 Correlation Coefficient | Standard Deviation 0.21 |
Secondary
Change in Pupil Diameter Via Pupillometry
Analysis of change in pupil diameter after administration of NKTR-181 or Oxycodone IR.
Time frame: 24 hour period following dose administration Day 1 to 2
Population: Subjects who received at least one dose of NKTR-181 or oxycodone IR and did not have unexpected pupillary dilation as a result of technical issues during the procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 8 Hours | 4.28 millimeters | Standard Deviation 1.161 |
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 1 Hour | 5.03 millimeters | Standard Deviation 0.443 |
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 12 Hours | 4.91 millimeters | — |
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 24 Hours | 4.61 millimeters | Standard Deviation 0.403 |
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 2 Hours | 4.82 millimeters | Standard Deviation 1.55 |
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 4 Hours | 4.34 millimeters | Standard Deviation 0.985 |
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 6 Hours | 3.99 millimeters | Standard Deviation 2.213 |
| NKTR-181 | Change in Pupil Diameter Via Pupillometry | Baseline Pupil Diameter | 4.45 millimeters | Standard Deviation 1.198 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 2 Hours | 4.97 millimeters | Standard Deviation 1.747 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Baseline Pupil Diameter | 4.81 millimeters | Standard Deviation 1.717 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 24 Hours | 4.20 millimeters | Standard Deviation 0.191 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 1 Hour | 4.87 millimeters | Standard Deviation 1.624 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 4 Hours | 5.32 millimeters | Standard Deviation 1.723 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 8 Hours | 5.07 millimeters | Standard Deviation 1.115 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 6 Hours | 5.01 millimeters | Standard Deviation 1.086 |
| Oxycodone IR 40 mg | Change in Pupil Diameter Via Pupillometry | Pupil Diameter After 12 Hours | 3.87 millimeters | — |
Secondary
Plasma Drug Concentration
Plasma drug concentration for NKTR-181 and Oxycodone IR over 24 hours.
Time frame: 24 hour period following dose administration Day 1 to 2
Population: Consisted of all subjects who had sufficient plasma concentration data to facilitate the calculation of maximum plasma drug concentration as determined by the pharmacokineticist.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NKTR-181 | Plasma Drug Concentration | Plasma Drug Concentration at Hour 2 | 2360 ng/mL | Standard Deviation 1230 |
| NKTR-181 | Plasma Drug Concentration | Plasma Drug Concentration at Hour 8 | 388 ng/mL | Standard Deviation 230 |
| NKTR-181 | Plasma Drug Concentration | Plasma Drug Concentration at Hour 12 | 185 ng/mL | Standard Deviation 30.4 |
| NKTR-181 | Plasma Drug Concentration | Plasma Drug Concentration at Hour 1 | 1970 ng/mL | Standard Deviation 477 |
| NKTR-181 | Plasma Drug Concentration | Plasma Drug Concentration at Hour 24 | 63.5 ng/mL | Standard Deviation 13.7 |
| NKTR-181 | Plasma Drug Concentration | Plasma Drug Concentration at Hour 4 | 1350 ng/mL | Standard Deviation 656 |
| Oxycodone IR 40 mg | Plasma Drug Concentration | Plasma Drug Concentration at Hour 24 | 3.9 ng/mL | — |
| Oxycodone IR 40 mg | Plasma Drug Concentration | Plasma Drug Concentration at Hour 4 | 46.7 ng/mL | Standard Deviation 15.3 |
| Oxycodone IR 40 mg | Plasma Drug Concentration | Plasma Drug Concentration at Hour 1 | 35.7 ng/mL | Standard Deviation 33.9 |
| Oxycodone IR 40 mg | Plasma Drug Concentration | Plasma Drug Concentration at Hour 8 | 27.1 ng/mL | Standard Deviation 7.47 |
| Oxycodone IR 40 mg | Plasma Drug Concentration | Plasma Drug Concentration at Hour 12 | 14.8 ng/mL | — |
| Oxycodone IR 40 mg | Plasma Drug Concentration | Plasma Drug Concentration at Hour 2 | 54.1 ng/mL | Standard Deviation 13.1 |
Secondary
Time to Maximum Concentration (Tmax)
The amount of time needed for maximum drug concentration to be reached.
Time frame: 24 hour period following dose administration Day 1 to 2
Population: Consisted of all subjects who had sufficient plasma concentration data to facilitate the calculation of the time to maximum plasma drug concentration as determined by the pharmacokineticist.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NKTR-181 | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 1 | 1970 ng/mL | Standard Deviation 477 |
| NKTR-181 | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 8 | 388 ng/mL | Standard Deviation 230 |
| NKTR-181 | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 12 | 185 ng/mL | Standard Deviation 30.4 |
| NKTR-181 | Time to Maximum Concentration (Tmax) | Time to Maximum Concentration (Tmax) measured in hours | 1.54 ng/mL | Standard Deviation 0.676 |
| NKTR-181 | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 2 | 2360 ng/mL | Standard Deviation 1230 |
| NKTR-181 | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 4 | 1350 ng/mL | Standard Deviation 656 |
| NKTR-181 | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 24 | 63.5 ng/mL | Standard Deviation 13.7 |
| Oxycodone IR 40 mg | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 12 | 14.8 ng/mL | — |
| Oxycodone IR 40 mg | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 1 | 35.7 ng/mL | Standard Deviation 33.9 |
| Oxycodone IR 40 mg | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 2 | 54.1 ng/mL | Standard Deviation 13.1 |
| Oxycodone IR 40 mg | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 8 | 27.1 ng/mL | Standard Deviation 7.47 |
| Oxycodone IR 40 mg | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 24 | 3.9 ng/mL | — |
| Oxycodone IR 40 mg | Time to Maximum Concentration (Tmax) | Plasma Drug Concentration at Hour 4 | 46.7 ng/mL | Standard Deviation 15.3 |
| Oxycodone IR 40 mg | Time to Maximum Concentration (Tmax) | Time to Maximum Concentration (Tmax) measured in hours | 2.21 ng/mL | Standard Deviation 1.02 |
Secondary
Treatment-Emergent Adverse Events (TEAEs)
Number of patients who experienced any type of adverse event as a result of one of the treatments.
Time frame: 19 days
Population: Consisted of all subjects who received at least 1 dose of NKTR-181 or Oxycodone IR.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NKTR-181 | Treatment-Emergent Adverse Events (TEAEs) | 1 Participants |
| Oxycodone IR 40 mg | Treatment-Emergent Adverse Events (TEAEs) | 0 Participants |