A Study to Evaluate the Effect of Analgesics on a Walking Model of Knee Pain (0000-105)(COMPLETED)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00772967
• Collaborator: (none)
• Enrollment: 22
• Arms: 6
• Duration (Months): 5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis	Drug: Naproxen; Drug: Placebo; Drug: Ultracet	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Diagnostic
• Official Title: A Double-Blind, Placebo-Controlled, 3-Period Crossover Study to Evaluate the Analgesic Effects of Naproxen and Ultracet in a Walking Model of Osteoarthritis Knee Pain
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo, Naproxen, Ultracet Participants were treated with Placebo for 3 days in Treatment Period 1, Naproxen for 3 days in Treatment Period 2, and Ultracet for 3 days in Treatment Period 3. The treatment periods were separated by a 4-6 day break.	Drug: Naproxen; 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.; Drug: Placebo; 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.; Drug: Ultracet; 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.
Experimental: Naproxen, Ultracet, Placebo Participants were treated with Naproxen for 3 days in Treatment Period 1, Ultracet for 3 days in Treatment Period 2, and Placebo for 3 days in Treatment Period 3. The treatment periods were separated by a 4-6 day break.	Drug: Naproxen; 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.; Drug: Placebo; 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.; Drug: Ultracet; 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.
Experimental: Ultracet, Placebo, Naproxen Participants were treated with Ultracet for 3 days in Treatment Period 1, Placebo for 3 days in Treatment Period 2, and Naproxen for 3 days in Treatment Period 3. The treatment periods were separated by a 4-6 day break.	Drug: Naproxen; 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.; Drug: Placebo; 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.; Drug: Ultracet; 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.
Experimental: Placebo, Ultracet, Naproxen Participants were treated with Placebo for 3 days in Treatment Period 1, Ultracet for 3 days in Treatment Period 2, and Naproxen for 3 days in Treatment Period 3. The treatment periods were separated by a 4-6 day break.	Drug: Naproxen; 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.; Drug: Placebo; 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.; Drug: Ultracet; 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.
Experimental: Naproxen, Placebo, Ultracet Participants were treated with Naproxen for 3 days in Treatment Period 1, Placebo for 3 days in Treatment Period 2, and Ultracet for 3 days in Treatment Period 3. The treatment periods were separated by a 4-6 day break.	Drug: Naproxen; 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.; Drug: Placebo; 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.; Drug: Ultracet; 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.
Experimental: Ultracet, Naproxen, Placebo Participants were treated with Ultracet for 3 days in Treatment Period 1, Naproxen for 3 days in Treatment Period 2, and Placebo for 3 days in Treatment Period 3. The treatment periods were separated by a 4-6 day break.	Drug: Naproxen; 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.; Drug: Placebo; 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.; Drug: Ultracet; 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00772967
• Other Study ID Numbers: 0000-105; 2008_566
• First Posted: Oct 15, 2008
• Last Update Posted: Nov 20, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Osteoarthritis; Naproxen

Study Results

Participant Flow

Recruitment Details	First Patient Entered: 23 June 2008 Last Patient, Last Visit: 20 November 2008 2 sites
Pre-assignment Detail	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.

Arm/Group Title	Placebo, Naproxen, Ultracet	Naproxen, Ultracet, Placebo	Ultracet, Placebo, Naproxen	Placebo, Ultracet, Naproxen	Naproxen, Placebo, Ultracet	Ultracet, Naproxen, Placebo
Arm/Group Description	Placebo in Treatment Period 1, Naproxen in Treatment Period 2, Ultracet in Treatment Period 3.	Naproxen in Treatment Period 1, Ultracet in Treatment Period 2, Placebo in Treatment Period 3.	Ultracet in Treatment Period 1, Placebo in Treatment Period 2, Naproxen in Treatment Period 3.	Placebo in Treatment Period 1, Ultracet in Treatment Period 2, Naproxen in Treatment Period 3.	Naproxen in Treatment Period 1, Placebo in Treatment Period 2, Ultracet inTreatment Period 3.	Ultracet in Treatment Period 1, Naproxen in Treatment Period 2, Placebo in Treatment Period 3.
Period Title: Crossover Treatment 1
STARTED	3	5	3	4	4	3
COMPLETED	3	5	3	3	4	3
NOT COMPLETED	0	0	0	1	0	0
Period Title: Crossover Treatment 1
STARTED	3	5	3	3	4	3
COMPLETED	3	4	3	3	4	3
NOT COMPLETED	0	1	0	0	0	0
Period Title: Crossover Treatment 1
STARTED	3	4	3	3	4	3
COMPLETED	3	4	3	3	4	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Crossover Treatment 1
STARTED	3	4	3	3	4	3
COMPLETED	3	4	3	3	4	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Crossover Treatment 1
STARTED	3	4	3	3	4	3
COMPLETED	3	4	3	3	3	3
NOT COMPLETED	0	0	0	0	1	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All randomized participants
Overall Participants	22
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.6 (7.92)
Sex: Female, Male (Count of Participants)
Female	14 63.6%
Male	8 36.4%

Outcome Measures

1. Primary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

All treated participants who provided baseline and at least one on-treatment observation

Arm/Group Title	Placebo	Naproxen	Ultracet
Arm/Group Description	Participants treated with at least one dose of Placebo	Participants treated with at least one dose of Naproxen	Participants treated with at least one dose of Ultracet.
Measure Participants	20	21	19
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.927	-1.54	-1.73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Naproxen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.611
	Confidence Interval	() 90%; -1.36 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ultracet
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.804
	Confidence Interval	() 90%; -1.57 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

All treated participants who provided baseline and at least one on-treatment observation

Arm/Group Title	Placebo	Naproxen	Ultracet
Arm/Group Description	Participants treated with at least one dose of Placebo	Participants treated with at least one dose of Naproxen	Participants treated with at least one dose of Ultracet.
Measure Participants	21	21	21
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.438	-0.956	-1.47

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Naproxen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.518
	Confidence Interval	() 90%; -1.03 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ultracet
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.03
	Confidence Interval	() 90%; -1.54 to -0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

All treated participants who provided baseline and at least one on-treatment observation

Arm/Group Title	Placebo	Naproxen	Ultracet
Arm/Group Description	Participants treated with at least one dose of Placebo	Participants treated with at least one dose of Naproxen	Participants treated with at least one dose of Ultracet.
Measure Participants	21	21	21
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.150	-0.508	-1.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Naproxen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.052
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.658
	Confidence Interval	() 90%; -1.32 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ultracet
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.15
	Confidence Interval	() 90%; -1.81 to -0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

All treated participants who provided baseline and at least one on-treatment observation

Arm/Group Title	Placebo	Naproxen	Ultracet
Arm/Group Description	Participants treated with at least one dose of Placebo	Participants treated with at least one dose of Naproxen	Participants treated with at least one dose of Ultracet.
Measure Participants	20	21	19
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.234	-1.11	-1.30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Naproxen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.875
	Confidence Interval	() 90%; -1.56 to -0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ultracet
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	1-sided, alpha = 0.05
	Method	ANCOVA
	Comments	Baseline measurement included as covariate: Time-weighted average pain intensity during pretreatment walk
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.07
	Confidence Interval	() 90%; -1.77 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse experiences (AEs) were collected from the time the consent is signed through the 14 day follow up period after all treatment periods were completed.
Adverse Event Reporting Description	AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (hematology, chemistry, urinalysis), and ECG at timepoints specified in the study. Patients were queried at each visit for any adverse experiences since the previous visit.
Arm/Group Title	Placebo		Naproxen		Ultracet
Arm/Group Description	Participants treated with at least one dose of Placebo		Participants treated with at least one dose of Naproxen		Participants treated with at least one dose of Ultracet. Two participants were not treated due to discontinuation.
All Cause Mortality
	Placebo		Naproxen		Ultracet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Naproxen		Ultracet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Naproxen		Ultracet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)		2/20 (10%)
Metabolism and nutrition disorders
Gout	0/22 (0%)		0/22 (0%)		1/20 (5%)
Nervous system disorders
Somnolence	0/22 (0%)		0/22 (0%)		1/20 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.