A Study to Compare the Frequency of Constipation Symptoms With Tapentadol Immediate Release (IR) Treatment Versus Oxycodone IR Treatment in Patients With End-stage Joint Disease

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00784277
• Collaborator: Grünenthal GmbH (Industry)
• Enrollment: 597
• Arms: 7
• Duration (Months): 9

Study Details

Study Description

Brief Summary

The purpose of this study is to compare bowel function/constipation that occurs during tapentadol treatment with that occuring during oxycodone treatment, as measured by the frequency of spontaneous bowel movements per week. The frequency of spontaneous bowel movements will be determined from a Bowel Function Patient Diary completed by the enrolled sujbects.

Condition or Disease	Intervention/Treatment	Phase
Joint Diseases; Arthritis; Osteoarthritis	Drug: oxycodone CR; Drug: oxycodone IR; Drug: Tapentadol ER (CG5503); Drug: Tapentadol IR (CG5503); Drug: Tapentadol IR (CG5503); Drug: placebo; Drug: placebo	Phase 3

Detailed Description

Chronic pain from end-stage degenerative joint disease is often moderate to severe in intensity and results in a relatively constant level of pain requiring continuous pain relief medication. Despite available pain relief medications, 60% to 80% of subjects suffering from chronic pain are currently inadequately treated. Opioid pain medications are central to the effective treatment of moderate to severe pain. However, opioid therapy is frequently complicated by side effects. Constipation is one of the most commonly reported side effects and most debilitating. An opioid medication that provides pain relief with a reduced incidence of constipation symptoms would improve the capability of subjects to stay on medication to achieve the long-term relief they need. This is a randomized, double-blind, placebo- and active-controlled, parallel-arm, multicenter study with 4 treatment groups of subjects who have moderate to severe chronic pain from end-stage degenerative joint disease of the hip or knee and who are candidates for primary total or partial joint replacement. The study consists of 3 periods: a pretreatment period (a 14-day screening for study eligibility and a 7-day washout of any previously taken opioid medication), a double-blind treatment period (a 14-day IR treatment phase followed by a 28-day ER treatment phase), and a follow-up period (1 study-site visit within 4 days after the last dose of study drug is taken and 1 telephone contact within 10 to 14 days after the last dose of study drug is taken). On Day 1 of the IR treatment phase, patients will be randomly assigned to 1 of 4 possible treatment groups to receive 50 mg CG5503 IR, 75 mg CG5503 IR, 10 mg oxycodone IR, or placebo daily every 4 to 6 hours. At the beginning of the ER treatment phase, patients' study drugs will be transitioned to the ER form (by conversion from the IR to approximate equivalent total daily doses of the ER form) of their randomly assigned study drug of tapentadol ER, oxycodone CR, or placebo. The ER study drugs will be taken every 12 hours b.i.d. Dosages will be adjustable, with the study site personnel oversight, to ensure adequate pain relief is provided. Beginning with the washout period, patients will be given hand-held computer diaries in which to record their pain intensity, pain relief, bowel movement information, and answer questions on any nausea or vomiting that may occur. In addition, patients will write down the times and dosages of all medications they take during the study in a medication diary. Safety and tolerability will be assessed using physical examination, monitoring of adverse events, clinical and laboratory measures, and 12 lead ECG results. The first study hypothesis is that both tapentadol IR dosages are more effective than placebo in relieving pain based on the SPID score recorded by the patients over the first 5 days of the study. The second study hypothesis is that the Bowel Function Patient Diary results for both tapentadol IR dosages demonstrate improved tolerability compared to oxycodone IR 10 mg, based on the number of spontaneous bowel movements per week over the first 2 weeks of the study. In the IR treatment phase, each patient will take CG5503 IR 50 mg, CG5503 IR 75 mg, oxycodone IR 10 mg, or placebo orally every 4 to 6 hours for 14 days. In the ER treatment phase, dosages of the IR treatment groups will be converted to approximately equivalent dosages of the ER form of the assigned study drug: tapentadol ER, oxycodone CR, or placebo. Dosages may range from 100 to 500 mg/day of tapentadol ER and 20 to 60 mg/day of oxycodone CR taken orally 2x daily for 28 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 597 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel-Arm, Multicenter Study in Subjects With End-Stage Joint Disease to Compare the Frequency of Constipation Symptoms in SubjectsTreated With Tapentadol IR and Oxycodone IR Using a Bowel Function Patient Diary
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 Tapentadol IR (CG5503) 50mg for 14 days	Drug: Tapentadol IR (CG5503); 50mg for 14 days
Experimental: 002 Tapentadol IR (CG5503) 75mg for 14 days	Drug: Tapentadol IR (CG5503); 75mg for 14 days
Active Comparator: 003 oxycodone IR 10mg for 14 days	Drug: oxycodone IR; 10mg for 14 days
Placebo Comparator: 004 placebo 1 capsule for 14 days	Drug: placebo; 1 capsule for 14 days
Experimental: 005 Tapentadol ER (CG5503) flexible dose tablets and capsules 2 x a day for 28 days (100-500mg/day)	Drug: Tapentadol ER (CG5503); flexible dose tablets and capsules 2 x a day for 28 days (100-500mg/day)
Active Comparator: 006 oxycodone CR flexible dose tablets and capsules 2 x a day for 28 days (20-60mg/day)	Drug: oxycodone CR; flexible dose tablets and capsules 2 x a day for 28 days (20-60mg/day)
Placebo Comparator: 007 placebo Tablets and capsules 2 x a day for 28 days	Drug: placebo; Tablets and capsules 2 x a day for 28 days

Outcome Measures

Primary Outcome Measures

1. 5-Day Sum of Pain Intensity Difference (SPID5) [Day 1 to Day 5]

   SPID5 was calculated as the weighted (weights is taken as the number of hours elapsed since the previous measurement) sum of the PID collected up to 5 days. Pain intensity (PI) score is calculated as the average PI over the past 12 hours using an 11-point (0 to 10) numerical rating scale (NRS) where "0" is no pain and "10" is pain as bad as you can imagine. The difference between baseline PI at the qualifying period and current PI is pain intensity difference (PID).

2. Spontaneous Bowel Movements Per Week (SBMs/Week) [Week 1 to Week 2]

   The number of SBM over the 14-day IR treatment phase was determined from the Bowel Function Patient Diary and factored to enable a per week value to be used. An SBM is defined as any BM that has occurred without the use of a laxative, enema, suppository, or manual manipulation within the previous 24 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A clinical diagnosis of osteoarthritis of the hip or knee

• End-stage degenerative joint disease

• Eligibility for primary unilateral total or partial joint replacement surgery

• Pain level moderate to severe and at such a level as to require daily doses of an opioid analgesic medication

Exclusion Criteria:

• Has a life-long history of seizure disorder or epilepsy

• Had any of the following within the preceding 1 year: mild or moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm

• Had a severe traumatic brain injury within 15 years of screening (consisting of one or more of the following: brain contusion, intracranial hematoma, either unconsciousness or post traumatic amnesia lasting for more than 24 hours)

• Joint pain not associated with gout, fibromyalgia, rheumatoid arthritis, other autoimmune disease

• History of alcohol or drug abuse

• chronic hepatitis B and C or HIV, active hepatitis B and C within 3 months

• Severely impaired renal function or moderately to severely impaired hepatic function

• History of cancer within past 2 years

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• Grünenthal GmbH

Investigators

• Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00784277
• Other Study ID Numbers: CR014326; KF5503/41
• First Posted: Nov 2, 2008
• Last Update Posted: Feb 13, 2012
• Last Verified: Jan 1, 2012

• Keywords provided by , ,: Pain medication; Arthritis; Joint pain; Analgesia; Analgesics; tapentadol; CG5503; Nucynta
• Additional relevant MeSH terms: Arthritis; Joint Diseases; Constipation; Oxycodone; Tapentadol

Study Results

Participant Flow

Recruitment Details	A total of 1000 participants were screened, 598 were randomized, 596 participants received medication in the first part of the double-blind treatment period (IR treatment phase). A total of 463 participants received medication in the second part of the double-blind treatment period (ER treatment phase).

Arm/Group Title	Placebo	Tapentadol 50 mg	Tapentadol 75 mg	Oxycodone	Placebo ER	Tapentadol ER	Oxycodone CR
Arm/Group Description	IR Treatment : 1 capsule for 14 days	IR Treatment : 50mg for 14 days	IR Treatment : 75mg for 14 days	IR Treatment : 10mg for 14 days	ER Treatment : Tablets and capsules 2 x a day for 28 days	ER Treatment : flexible dose tablets and capsules 2 x a day for 28 days (100-500mg/day)	ER Treatment : flexible dose tablets and capsules 2 x a day for 28 days (20-60mg/day)
Period Title: IR Treatment
STARTED	148	151	154	143	0	0	0
COMPLETED	132	134	126	100	0	0	0
NOT COMPLETED	16	17	28	43	0	0	0
Period Title: IR Treatment
STARTED	0	0	0	0	122	250	91
COMPLETED	0	0	0	0	113	226	76
NOT COMPLETED	0	0	0	0	9	24	15

Baseline Characteristics

Arm/Group Title	Placebo	Tapentadol 50 mg	Tapentadol 75 mg	Oxycodone	Total
Arm/Group Description	IR Treatment : 1 capsule for 14 days	IR Treatment : 50mg capsule for 14 days	IR Treatment : 75mg capsule for 14 days	IR Treatment : 10mg capsule for 14 days	Total of all reporting groups
Overall Participants	148	151	154	143	596
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	110 74.3%	113 74.8%	114 74%	109 76.2%	446 74.8%
>=65 years	38 25.7%	38 25.2%	40 26%	34 23.8%	150 25.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.8 (9.57)	58 (9.47)	58.4 (7.66)	59.4 (7.94)	58.7 (8.70)
Sex: Female, Male (Count of Participants)
Female	100 67.6%	93 61.6%	75 48.7%	81 56.6%	349 58.6%
Male	48 32.4%	58 38.4%	79 51.3%	62 43.4%	247 41.4%
Region Enroll (Number) [Number]
Canada	32 21.6%	36 23.8%	37 24%	34 23.8%	139 23.3%
USA	116 78.4%	115 76.2%	117 76%	109 76.2%	457 76.7%

Outcome Measures

1. Primary Outcome

Title	5-Day Sum of Pain Intensity Difference (SPID5)
Description	SPID5 was calculated as the weighted (weights is taken as the number of hours elapsed since the previous measurement) sum of the PID collected up to 5 days. Pain intensity (PI) score is calculated as the average PI over the past 12 hours using an 11-point (0 to 10) numerical rating scale (NRS) where "0" is no pain and "10" is pain as bad as you can imagine. The difference between baseline PI at the qualifying period and current PI is pain intensity difference (PID).
Time Frame	Day 1 to Day 5

Outcome Measure Data

Analysis Population Description

Intention To Treat (ITT) population : One participant who has been treated is not included in the ITT population as no baseline pain assessment was available (Arm: Tapentadol 50 mg).

Arm/Group Title	Placebo	Tapentadol 50 mg	Tapentadol 75 mg	Oxycodone
Arm/Group Description	IR Treatment : 1 capsule for 14 days	IR Treatment : 50mg capsule for 14 days	IR Treatment : 75mg capsule for 14 days	IR Treatment : 10mg capsule for 14 days
Measure Participants	148	150	154	143
Mean (Standard Deviation) [Units on a scale]	98.6 (134.73)	153.1 (184.07)	161.8 (187.31)	218.4 (208.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tapentadol 50 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	P-value is adjusted for multiplicity for comparison against placebo using Hochberg's test.
	Method	ANCOVA
	Comments	The model includes treatment and pooled center as factors and baseline pain intensity score as covariate.
Method of Estimation	Estimation Parameter	Difference in Least-Squares Means
	Estimated Value	55.1
	Confidence Interval	() 95%; 15.11 to 95.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.37
	Estimation Comments	The 95% confidence interval is unadjusted for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tapentadol 75 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	P-value is adjusted for multiplicity for comparison against placebo using Hochberg's test.
	Method	ANCOVA
	Comments	The model includes treatment and pooled center as factors and baseline pain intensity score as covariate.
Method of Estimation	Estimation Parameter	Difference in Least-Squares Means
	Estimated Value	63.4
	Confidence Interval	() 95%; 23.67 to 103.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.23
	Estimation Comments	The 95% confidence interval is unadjusted for multiplicity.

2. Primary Outcome

Title	Spontaneous Bowel Movements Per Week (SBMs/Week)
Description	The number of SBM over the 14-day IR treatment phase was determined from the Bowel Function Patient Diary and factored to enable a per week value to be used. An SBM is defined as any BM that has occurred without the use of a laxative, enema, suppository, or manual manipulation within the previous 24 hours.
Time Frame	Week 1 to Week 2

Outcome Measure Data

Analysis Population Description

Intention To Treat (ITT) population : One participant who has been treated is not included in the ITT population as no baseline pain assessment was available (Arm: Tapentadol 50 mg).

Arm/Group Title	Placebo	Tapentadol 50 mg	Tapentadol 75 mg	Oxycodone
Arm/Group Description	IR Treatment : 1 capsule for 14 days	IR Treatment : 50mg capsule for 14 days	IR Treatment : 75mg capsule for 14 days	IR Treatment : 10mg capsule for 14 days
Measure Participants	148	150	154	143
Mean (Standard Deviation) [number of stools/week]	9.9 (5.16)	9.0 (4.04)	8.6 (4.65)	6.7 (5.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Oxycodone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is adjusted for multiplicity for comparison against Oxycodone using Hochberg's test.
	Method	ANCOVA
	Comments	The model includes treatment and pooled center as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Difference in Least-Squares Means
	Estimated Value	3.1
	Confidence Interval	() 95%; 2.22 to 4.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.46
	Estimation Comments	The 95% confidence interval is unadjusted for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tapentadol 50 mg, Oxycodone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is adjusted for multiplicity for comparison against Oxycodone using Hochberg's test.
	Method	ANCOVA
	Comments	The model includes treatment and pooled center as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Difference in Least-Squares Means
	Estimated Value	2.2
	Confidence Interval	() 95%; 1.34 to 3.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.45
	Estimation Comments	The 95% confidence interval is unadjusted for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tapentadol 75 mg, Oxycodone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is adjusted for multiplicity for comparison against Oxycodone using Hochberg's test.
	Method	ANCOVA
	Comments	The model includes treatment and pooled center as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Difference in Least-Squares Means
	Estimated Value	1.6
	Confidence Interval	() 95%; 0.72 to 2.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.45
	Estimation Comments	The 95% confidence interval is unadjusted for multiplicity.

Adverse Events

Adverse Event Reporting Description	Only participants who had at least one of the TEAEs listed in the Other (non Serious) AE table are included in the Total no. participants with Non-Serious Adverse Events.
Arm/Group Title	Placebo		Tapentadol 50 mg		Tapentadol 75 mg		Oxycodone		Placebo ER		Tapentadol ER		Oxycodone CR
Arm/Group Description	IR Treatment : 1 capsule for 14 days		IR Treatment : 50mg for 14 days		IR Treatment : 75mg for 14 days		IR Treatment : 10mg for 14 days		ER Treatment : Tablets and capsules 2 x a day for 28 days		ER Treatment : flexible dose tablets and capsules 2 x a day for 28 days (100-500mg/day)		ER Treatment : flexible dose tablets and capsules 2 x a day for 28 days (20-60mg/day)
All Cause Mortality
	Placebo		Tapentadol 50 mg		Tapentadol 75 mg		Oxycodone		Placebo ER		Tapentadol ER		Oxycodone CR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Tapentadol 50 mg		Tapentadol 75 mg		Oxycodone		Placebo ER		Tapentadol ER		Oxycodone CR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/148 (0.7%)		1/151 (0.7%)		0/154 (0%)		1/143 (0.7%)		0/122 (0%)		1/250 (0.4%)		0/91 (0%)
Cardiac disorders
Arteriosclerosis coronary artery	1/148 (0.7%)		0/151 (0%)		0/154 (0%)		0/143 (0%)		0/122 (0%)		0/250 (0%)		0/91 (0%)
Myocardial infarction	0/148 (0%)		0/151 (0%)		0/154 (0%)		1/143 (0.7%)		0/122 (0%)		0/250 (0%)		0/91 (0%)
Infections and infestations
Kidney infection	0/148 (0%)		1/151 (0.7%)		0/154 (0%)		0/143 (0%)		0/122 (0%)		0/250 (0%)		0/91 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/148 (0%)		0/151 (0%)		0/154 (0%)		0/143 (0%)		0/122 (0%)		1/250 (0.4%)		0/91 (0%)
Vascular disorders
Deep vein thrombosis	0/148 (0%)		0/151 (0%)		0/154 (0%)		0/143 (0%)		0/122 (0%)		1/250 (0.4%)		0/91 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Tapentadol 50 mg		Tapentadol 75 mg		Oxycodone		Placebo ER		Tapentadol ER		Oxycodone CR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/148 (32.4%)		65/151 (43%)		88/154 (57.1%)		98/143 (68.5%)		23/122 (18.9%)		80/250 (32%)		36/91 (39.6%)
Gastrointestinal disorders
Nausea	11/148 (7.4%)		26/151 (17.2%)		31/154 (20.1%)		57/143 (39.9%)		5/122 (4.1%)		23/250 (9.2%)		12/91 (13.2%)
Constipation	22/148 (14.9%)		21/151 (13.9%)		28/154 (18.2%)		42/143 (29.4%)		10/122 (8.2%)		37/250 (14.8%)		18/91 (19.8%)
Vomiting	1/148 (0.7%)		7/151 (4.6%)		13/154 (8.4%)		34/143 (23.8%)		5/122 (4.1%)		13/250 (5.2%)		6/91 (6.6%)
Diarrhoea	5/148 (3.4%)		4/151 (2.6%)		7/154 (4.5%)		5/143 (3.5%)		5/122 (4.1%)		13/250 (5.2%)		4/91 (4.4%)
Dry mouth	1/148 (0.7%)		4/151 (2.6%)		9/154 (5.8%)		6/143 (4.2%)		1/122 (0.8%)		3/250 (1.2%)		1/91 (1.1%)
Nervous system disorders
Somnolence	5/148 (3.4%)		20/151 (13.2%)		14/154 (9.1%)		17/143 (11.9%)		2/122 (1.6%)		8/250 (3.2%)		2/91 (2.2%)
Dizziness	6/148 (4.1%)		17/151 (11.3%)		35/154 (22.7%)		25/143 (17.5%)		4/122 (3.3%)		5/250 (2%)		3/91 (3.3%)
Headache	12/148 (8.1%)		6/151 (4%)		7/154 (4.5%)		15/143 (10.5%)		7/122 (5.7%)		8/250 (3.2%)		4/91 (4.4%)
Skin and subcutaneous tissue disorders
Pruritus	1/148 (0.7%)		2/151 (1.3%)		4/154 (2.6%)		13/143 (9.1%)		0/122 (0%)		3/250 (1.2%)		2/91 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.