Osteoarthritis
Conditions
Brief summary
This study will evaluate a walking model of osteoarthritis for use in testing of new therapeutic agents. The primary hypothesis is that participants treated with Naproxen or Ultracet will have lower Pain Intensity (PI) than those treated with Placebo during self-paced walks on Day 3 of treatment.
Interventions
DRUGNaproxen
Naproxen tablets 500 mg twice daily on Day 1, a first dose at t = 0 hrs, and a second dose at t = 12 hrs. Twice daily on Day 2 and 500 mg once daily on Day 3. Walking tests will be performed on Days 1 and 3 of the treatment period.
DRUGPlacebo
Placebo capsules twice daily on Day 1, a first dose at t = 0 hrs, and a second dose at t = 12 hrs. Three times daily on Day 2, and 2 capsules on the morning of Day 3. Walking tests will be performed on Days 1 and 3 of the treatment period.
DRUGUltracet
Ultracet (tramadol/acetaminophen) 37.5/325 mg/mg capsules twice daily on Day 1, a first dose at t = 0 hrs, and a second dose at t = 12 hrs. Three times daily on Day 2, and two 37.5/325 mg capsules on the morning of Day 3. Walking tests will be performed on Days 1 and 3 of the treatment period.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has osteoarthritis of the knee and primary source of pain is knee * Females must not be pregnant or nursing and must agree to use birth control throughout the study * Is willing to limit alcohol and caffeine intake * Is willing to abstain from smoking during study visits * Must be able to walk on a treadmill at a pace of at least 1 mile/hour
Exclusion criteria
* Has a medical/arthritic disease that would interfere with evaluation * Is unable to take naproxen or Ultracet * Has congestive heart failure or angina * Has a history of stroke * Has a history of uncontrolled high blood pressure * Has a history of cancer * Regularly uses a walker or cane
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 3 | Baseline and Day 3 | Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes, rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following a single treatment on Day 3, PI was similarly measured over 20 minute self paced walks at 4 and 6 hrs post-dose. The difference between the TWA (0-20 minutes) PI determined at baseline, and the average of the two TWA (0-20 minutes) PI from the self-paced walks on Day 3 is reported as units on a scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 1 | Baseline and Day 1 | Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes, rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following the first treatment on Day 1, PI was similarly measured over 20 minute self-paced walks at 2, 4, and 6 hrs post-dose . The difference between the TWA (0-20 minutes) PI determined at baseline, and the average of the three TWA (0-20 minutes)PI from the self-paced walks on Day 1 is reported as units on a scale. |
| Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 1 | Baseline and Day 1 | Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes,rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following the first treatment on Day 1, PI was similarly measured over a 20 minute high-paced treadmill walk at 5 hrs post-dose. A high-paced walk is the highest pace that can be walked safely for at least 5 minutes that is at a 10-30% higher rate than a self-paced walk. The difference between the TWA (0-20 minutes) PI determined at baseline, and the TWA (0-20 minutes) PI of the high-paced walk on Day 1 is reported as units on a scale. |
| Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 3 | Baseline and Day 3 | Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes, rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following a single treatment on Day 3, PI was similarly measured over a 20 minute high-paced treadmill walk, at 5 hrs post-dose. A high-paced walk is the highest pace that can be walked safely for at least 5 minutes that is at a 10-30% higher rate than a self-paced walk. The difference between the TWA (0-20 minutes) PI determined at baseline, and the TWA (0-20 minutes) PI of the high-paced walk on Day 3 is reported as units on a scale. |
Participant flow
Recruitment details
First Patient Entered: 23 June 2008 Last Patient, Last Visit: 20 November 2008 2 sites
Pre-assignment details
Inclusion criteria: Patient has osteoarthritis of the knee and primary source of pain is knee Titration schedule for Ultracet® (Acetaminophen 325 mg and tramadol hydrochloride 37.5 mg): twice on Day 1, three times on Day 2, and twice on the morning of Day 3. Naproxen tablets 500 mg twice daily on Days 1 and 2 and 500 mg once daily on Day 3.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All randomized participants | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Break 1 (4-7 Days) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Crossover Treatment 1 | Adverse Event (Pain) | 0 | 0 | 0 | 1 | 0 | 0 |
| Crossover Treatment 3 | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 7.92 |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 22 | 0 / 22 | 2 / 20 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 20 |
Outcome results
Primary
Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 3
Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes, rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following a single treatment on Day 3, PI was similarly measured over 20 minute self paced walks at 4 and 6 hrs post-dose. The difference between the TWA (0-20 minutes) PI determined at baseline, and the average of the two TWA (0-20 minutes) PI from the self-paced walks on Day 3 is reported as units on a scale.
Time frame: Baseline and Day 3
Population: All treated participants who provided baseline and at least one on-treatment observation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 3 | -0.927 units on a scale |
| Naproxen | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 3 | -1.54 units on a scale |
| Ultracet | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 3 | -1.73 units on a scale |
p-value: 0.08990% CI: [-1.36, 0.14]ANCOVA
p-value: 0.04390% CI: [-1.57, -0.04]ANCOVA
Secondary
Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 1
Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes,rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following the first treatment on Day 1, PI was similarly measured over a 20 minute high-paced treadmill walk at 5 hrs post-dose. A high-paced walk is the highest pace that can be walked safely for at least 5 minutes that is at a 10-30% higher rate than a self-paced walk. The difference between the TWA (0-20 minutes) PI determined at baseline, and the TWA (0-20 minutes) PI of the high-paced walk on Day 1 is reported as units on a scale.
Time frame: Baseline and Day 1
Population: All treated participants who provided baseline and at least one on-treatment observation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 1 | 0.150 units on a scale |
| Naproxen | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 1 | -0.508 units on a scale |
| Ultracet | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 1 | -1.00 units on a scale |
p-value: 0.05290% CI: [-1.32, 0.01]ANCOVA
p-value: 0.00390% CI: [-1.81, -0.49]ANCOVA
Secondary
Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 3
Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes, rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following a single treatment on Day 3, PI was similarly measured over a 20 minute high-paced treadmill walk, at 5 hrs post-dose. A high-paced walk is the highest pace that can be walked safely for at least 5 minutes that is at a 10-30% higher rate than a self-paced walk. The difference between the TWA (0-20 minutes) PI determined at baseline, and the TWA (0-20 minutes) PI of the high-paced walk on Day 3 is reported as units on a scale.
Time frame: Baseline and Day 3
Population: All treated participants who provided baseline and at least one on-treatment observation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 3 | -0.234 units on a scale |
| Naproxen | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 3 | -1.11 units on a scale |
| Ultracet | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to High-paced Walks on Day 3 | -1.30 units on a scale |
p-value: 0.01990% CI: [-1.56, -0.19]ANCOVA
p-value: 0.00790% CI: [-1.77, -0.37]ANCOVA
Secondary
Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 1
Baseline measurements of participant-specific knee PI were gathered pre-dose on Day 1 from the briskest possible self-pace constant walks on a treadmill over the course of a 20 minute interval. Over this interval PI readings were taken at time points 0,3,6,9,12,15,18 and 20 minutes, rated on an 11-point numeric rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine. Following the first treatment on Day 1, PI was similarly measured over 20 minute self-paced walks at 2, 4, and 6 hrs post-dose . The difference between the TWA (0-20 minutes) PI determined at baseline, and the average of the three TWA (0-20 minutes)PI from the self-paced walks on Day 1 is reported as units on a scale.
Time frame: Baseline and Day 1
Population: All treated participants who provided baseline and at least one on-treatment observation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 1 | -0.438 units on a scale |
| Naproxen | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 1 | -0.956 units on a scale |
| Ultracet | Change From Baseline in Time Weighted Average (TWA) Pain Intensity (PI) on a Numeric Rating Scale (NRS) Due to Self-paced Walks on Day 1 | -1.47 units on a scale |
p-value: 0.04890% CI: [-1.03, -0.01]ANCOVA
p-value: 0.00190% CI: [-1.54, -0.53]ANCOVA