Osteoarthritis of the Knee
Conditions
Keywords
Nektar, NKTR-181
Brief summary
NKTR-181 is being developed as an analgesic compound for the treatment of moderate to severe chronic pain - active as a mu agonist, but with inherent molecular properties designed to provide a unique clinical profile, including most notably, reduced CNS side effects and an attenuated attractiveness as a target of abuse.
Interventions
DRUGNKTR-181
DRUGPlacebo
Placebo dosing will be only in the double-blind randomization arm and will be identical in form to the Experimental NKTR-181
Sponsors
Nektar Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to give written informed consent; * Willing and able to understand the study procedures, and comply with all study procedures; * Females or males, age ≥ 18 years old; * Body mass index 18-39, inclusive; * In good general health; * Clinical diagnosis of OA in one or both knees; * Have been on a stable regimen of pain medication for the management of OA knee pain; * Not experiencing adequate pain relief with their current dosing regimen; * Women of childbearing potential (WCBP) must agree to use highly effective methods of birth control. Male subjects must agree to use contraception.
Exclusion criteria
* Females who are pregnant or lactating; * Known history of hypersensitivity, intolerance, or allergy to opioids; * Diagnosed as having any chronic pain symptom that in the Investigator's opinion would interfere with the assessment of pain and other symptoms of OA; * Presence of any medical condition that would preclude study participation in the opinion of the investigator; * Clinically significant abnormalities of vital signs or clinical laboratory results; * Clinically significant electrocardiographic abnormalities; * Received systemic corticosteroids within 30 days prior to signing the consent form; * Subjects who are known or suspected to be currently abusing alcohol or drugs; * Positive urine drug screen, or alcohol breath test during Screening Period testing; * Positive serology for the surface antigen of Hepatitis B (HBsAg) or Hepatitis C (anti-HCV) during Screening Period testing; * Known to be human immunodeficiency virus (HIV) positive; * Donation of blood or plasma within 30 days prior to signing the consent form; * Participation in another drug or biologic study within 30 days prior to signing the consent form; * Any other reason that, in the opinion of the Investigator or Medical Monitor, would render the subject unsuitable for participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Mean Change From Baseline Pain Score to Pain Score at the End of the Double-blind Randomized Treatment Period. | Baseline and Visit 10 (day 69) | The first phase of this trial involved an open-label titration period where patients were given NKTR-181 at increasing doses up to a maximum of 400 mg twice daily until adequate pain control was achieved. Patients achieving adequate pain control were then progressed to the second phase of the trial where patients were randomized in a 1:1 ratio to receive either placebo or their tolerable dose level of NKTR-181. All efficacy data for NKTR-181 patients was combined into one group regardless of tolerable dose level. For this outcome, the subjects had to rate their worst pain intensity during the past 4 hours from 0 to 10 on an 11-point scale, where 0 represented one end of the continuum (i.e., no pain) and 10 represented the other extreme of pain intensity (i.e., worst pain imaginable). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Discontinuation During the Double-blind Randomized Treatment Period for Any Reason | Randomization Treatment period is 24 days | The first phase of this trial involved an open-label titration period where patients were given NKTR-181 at increasing doses up to a maximum of 400 mg twice daily until adequate pain control was achieved. Patients achieving adequate pain control were then progressed to the second phase of the trial where patients were randomized in a 1:1 ratio to receive either placebo or their tolerable dose level of NKTR-181. All efficacy data for NKTR-181 patients was combined into one group regardless of tolerable dose level. |
Countries
United States
Participant flow
Pre-assignment details
A total of 296 subjects were enrolled in this study. Of these, one subject did not receive study drug in the open-label Titration Period because she had a history of drug abuse and thus did not meet entry criteria. Of the 295 subjects dosed during the open-label Titration Period, 213 subjects were randomized to treatment. All 295 subjects who received study drug were included in the safety analysis population.
Participants by arm
| Arm | Count |
|---|---|
| 100 mg NKTR-181 100 mg of NKTR-181 in tablet form, BID. Dosing to occur at Titration period up to 30 days and at Randomization period up to 24 days.
NKTR-181 | 48 |
| 200 mg NKTR-181 200 mg of NKTR-181 in tablet form, BID. Dosing to occur at Titration period up to 30 days and at Randomization period up to 24 days.
NKTR-181 | 31 |
| 300 mg NKTR-181 300 mg of NKTR-181 in tablet form, BID. Dosing to occur at Titration period up to 30 days and at Randomization period up to 24 days
NKTR-181 | 18 |
| 400 mg NKTR-181 400 mg of NKTR-181 in tablet form, BID. Dosing to occur at Titration period up to 30 days and at Randomization period up to 24 days
NKTR-181 | 10 |
| Placebo Placebo dosing will be only in the double-blind randomization arm and will be identical in form to the Experimental NKTR-181.
Placebo: Placebo dosing will be only in the double-blind randomization arm and will be identical in form to the Experimental NKTR-181 | 106 |
| Total | 213 |
Baseline characteristics
| Characteristic | 100 mg NKTR-181 | 200 mg NKTR-181 | 300 mg NKTR-181 | 400 mg NKTR-181 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 9.77 | 57.6 years STANDARD_DEVIATION 11.43 | 60.6 years STANDARD_DEVIATION 9.57 | 59.8 years STANDARD_DEVIATION 9.51 | 60.1 years STANDARD_DEVIATION 9.55 | 60.1 years STANDARD_DEVIATION 9.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 6 Participants | 4 Participants | 3 Participants | 21 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 25 Participants | 14 Participants | 7 Participants | 83 Participants | 169 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Height | 170.1 centimeters STANDARD_DEVIATION 10.84 | 169.5 centimeters STANDARD_DEVIATION 11.55 | 169.7 centimeters STANDARD_DEVIATION 9.41 | 168.0 centimeters STANDARD_DEVIATION 11.37 | 167.2 centimeters STANDARD_DEVIATION 10.4 | 168.4 centimeters STANDARD_DEVIATION 10.62 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 10 Participants | 2 Participants | 1 Participants | 20 Participants | 40 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 19 Participants | 16 Participants | 8 Participants | 82 Participants | 164 Participants |
| Sex: Female, Male Female | 27 Participants | 18 Participants | 9 Participants | 7 Participants | 66 Participants | 127 Participants |
| Sex: Female, Male Male | 21 Participants | 13 Participants | 9 Participants | 3 Participants | 40 Participants | 86 Participants |
| Weight | 89.27 kilograms STANDARD_DEVIATION 17.496 | 90.75 kilograms STANDARD_DEVIATION 22.355 | 85.85 kilograms STANDARD_DEVIATION 16.739 | 84.27 kilograms STANDARD_DEVIATION 18.918 | 89.57 kilograms STANDARD_DEVIATION 19.116 | 89.11 kilograms STANDARD_DEVIATION 18.967 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 31 | 0 / 18 | 0 / 10 | 0 / 106 |
| other Total, other adverse events | 27 / 48 | 19 / 31 | 11 / 18 | 5 / 10 | 54 / 106 |
| serious Total, serious adverse events | 0 / 133 | 1 / 84 | 0 / 46 | 1 / 32 | 0 / 0 |
Outcome results
Primary
The Mean Change From Baseline Pain Score to Pain Score at the End of the Double-blind Randomized Treatment Period.
The first phase of this trial involved an open-label titration period where patients were given NKTR-181 at increasing doses up to a maximum of 400 mg twice daily until adequate pain control was achieved. Patients achieving adequate pain control were then progressed to the second phase of the trial where patients were randomized in a 1:1 ratio to receive either placebo or their tolerable dose level of NKTR-181. All efficacy data for NKTR-181 patients was combined into one group regardless of tolerable dose level. For this outcome, the subjects had to rate their worst pain intensity during the past 4 hours from 0 to 10 on an 11-point scale, where 0 represented one end of the continuum (i.e., no pain) and 10 represented the other extreme of pain intensity (i.e., worst pain imaginable).
Time frame: Baseline and Visit 10 (day 69)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NKTR-181 | The Mean Change From Baseline Pain Score to Pain Score at the End of the Double-blind Randomized Treatment Period. | -0.06 Change in Pain Score | Standard Error 0.162 |
| Placebo | The Mean Change From Baseline Pain Score to Pain Score at the End of the Double-blind Randomized Treatment Period. | -0.01 Change in Pain Score | Standard Error 0.168 |
Secondary
Time to Discontinuation During the Double-blind Randomized Treatment Period for Any Reason
The first phase of this trial involved an open-label titration period where patients were given NKTR-181 at increasing doses up to a maximum of 400 mg twice daily until adequate pain control was achieved. Patients achieving adequate pain control were then progressed to the second phase of the trial where patients were randomized in a 1:1 ratio to receive either placebo or their tolerable dose level of NKTR-181. All efficacy data for NKTR-181 patients was combined into one group regardless of tolerable dose level.
Time frame: Randomization Treatment period is 24 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NKTR-181 | Time to Discontinuation During the Double-blind Randomized Treatment Period for Any Reason | 20.2 days | Standard Deviation 4.21 |
| Placebo | Time to Discontinuation During the Double-blind Randomized Treatment Period for Any Reason | 20.2 days | Standard Deviation 3.86 |