Osteoarthritis of the Knee
Conditions
Keywords
delta opioid receptor agonist, osteoarthritis, pain
Brief summary
The purpose of this study is to determine the efficacy of ADL5859 versus placebo and ADL5747 versus placebo in relieving pain in participants with osteoarthritis of the knee.
Interventions
Sponsors
Pfizer
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
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 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * a man or woman between 18 and 75 years of age, inclusive * for women of childbearing potential, be using an insertable, injectable, transdermal, or combination oral contraceptive deemed highly effective by the United States Food and Drug Administration from the first dose of study medication through the end of the study and have negative findings on pregnancy tests performed at screening and randomization (women who are surgically sterile \[for example, hysterectomy, tubal ligation\] or postmenopausal \[if ≥55 years old, no menses for at least 2 years; if \<55 years old, follicle-stimulating hormone concentrations within the postmenopausal range of \>40 milli-international units per milliliter (mIU/mL) and 17 β-estradiol levels of \<37 picograms per milliliter (pg/mL)\] are also eligible to participate) * for male participants, be surgically sterile or agree to use an appropriate method of contraception (that is, use a barrier method in conjunction with spermicide or have a sexual partner who is surgically sterile, postmenopausal, or using an insertable, injectable, transdermal, or combination oral contraceptive deemed highly effective by the United States Food and Drug Administration) from the first dose of study medication through the end of the study * have a body weight between 45 and 150 kilograms (kg), inclusive * have had pain in the index knee for at least the past 6 months * meet the following criteria for osteoarthritis of the knee established by the American College of Rheumatology (radiographs must have been taken within the last year; if none is available, a radiograph must be taken and the diagnostic criteria must be confirmed before the participant is enrolled in the study): have index knee pain plus at least 1 moderate or definite osteophyte on radiographs. Must also have at least 1 of the following: be more than 50 years old, have morning stiffness for less than 30 minutes, or have crepitus on active motion * have an average weekly pain score of at least 4.00 on the numeric pain rating scale (NPRS) for the index knee during the baseline week before randomization (to be eligible for randomization, participants must report their NPRS score via the interactive voice-response system (IVRS) for at least 4 of the 7 days immediately before randomization, with the first score being recorded on Day -6) * if receiving nonselective or selective cyclooxygenase (COX) inhibitors, have a stable daily dose regimen for at least 4 weeks before screening; if receiving nonselective or selective COX inhibitors on an as needed basis, have discontinued use by Day -14; if receiving angiotensin-converting enzyme (ACE) inhibitors, have a stable dose regimen for at least 4 weeks before screening Key
Exclusion criteria
* have undergone arthroscopy on the index knee within 6 months before study entry * have other severe pain that, in the opinion of the investigator, may impair the assessment of the pain due to osteoarthritis * have a history of hypersensitivity or intolerance to opioids (including tramadol and tapentadol) * have, as determined by the investigator or the sponsor's medical monitor, a history or clinical manifestations of significant renal, hepatic, hematologic, cardiovascular, metabolic, gastrointestinal, neurologic, psychiatric, or another condition that would preclude participation in the study or affect the outcome of the study * have taken oral or intramuscular corticosteroids within 30 days before study entry (inhaled or topical corticosteroids are permitted) * have received intra-articular injections of corticosteroids into the index joint within 12 weeks before screening * have received intra-articular injections of hyaluronic acid into the index joint within 24 weeks before screening * currently taking medications other than nonsteroidal anti-inflammatory drugs prescribed for chronic pain (such as duloxetine or pregabalin)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Average Pain Score (NPRS) for Week 2 | Baseline, Week 2 | The mean of the daily average scores were calculated from the NPRS pain assessment for the previous 24 hours obtained once a day for at least 4 days from Day -6 through Day 1 (Baseline assessment) and everyday from Day 2 through Day 15 (Treatment Phase assessment). The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ADL5859 One 50-mg ADL5859 capsule, one 100-mg ADL5859 capsule, and 2 placebo capsules administered orally BID for 14 days | 101 |
| ADL5747 One 150-mg ADL5747 capsule and 3 placebo capsules administered orally BID for 14 days | 99 |
| Oxycodone CR One 10-mg Oxycodone CR capsule and 3 placebo capsules administered orally BID Days 1 through 4
One 20-mg Oxycodone CR capsule and 3 placebo capsules administered orally BID Days 5 through 14 | 104 |
| Placebo Four placebo capsules administered orally BID for 14 days | 104 |
| Total | 408 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 | 17 | 4 |
| Overall Study | Lack of Efficacy | 1 | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | ADL5859 | ADL5747 | Oxycodone CR | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 8.15 | 57.3 years STANDARD_DEVIATION 8.74 | 57.8 years STANDARD_DEVIATION 8.39 | 56.5 years STANDARD_DEVIATION 8.11 | 57.0 years STANDARD_DEVIATION 8.34 |
| Sex: Female, Male Female | 59 Participants | 57 Participants | 63 Participants | 61 Participants | 240 Participants |
| Sex: Female, Male Male | 42 Participants | 42 Participants | 41 Participants | 43 Participants | 168 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 50 / 101 | 40 / 99 | 75 / 104 | 37 / 104 |
| serious Total, serious adverse events | 2 / 101 | 1 / 99 | 0 / 104 | 1 / 104 |
Outcome results
Primary
Change From Baseline in the Average Pain Score (NPRS) for Week 2
The mean of the daily average scores were calculated from the NPRS pain assessment for the previous 24 hours obtained once a day for at least 4 days from Day -6 through Day 1 (Baseline assessment) and everyday from Day 2 through Day 15 (Treatment Phase assessment). The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain.
Time frame: Baseline, Week 2
Population: All participants who received at least 1 dose of study medication and had at least evaluable 1 NPRS postdose measurement. Last-observation-carried-forward (LOCF) was used to impute missing postbaseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Average Pain Score (NPRS) for Week 2 | -2.20 units on a scale | Standard Deviation 2.088 |
| Oxycodone CR | Change From Baseline in the Average Pain Score (NPRS) for Week 2 | -2.24 units on a scale | Standard Deviation 2.162 |
| ADL5747 | Change From Baseline in the Average Pain Score (NPRS) for Week 2 | -1.57 units on a scale | Standard Deviation 1.656 |
| ADL5859 | Change From Baseline in the Average Pain Score (NPRS) for Week 2 | -1.77 units on a scale | Standard Deviation 1.776 |