Tapentadol (CG5503)

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00421928
• Collaborator: Grünenthal GmbH (Industry)
• Enrollment: 1,030
• Arms: 3
• Duration (Months): 23

Study Details

Study Description

Brief Summary

The purpose of this trial is to evaluate the effectiveness (level of pain control) and safety of orally administered tapentadol (CG5503) Extended Release (ER) (base) at doses of 100-250 mg twice daily in patients with moderate to severe chronic pain due to osteoarthritis of the knee, in comparison with placebo and Oxycodone Controlled Release (CR).

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis, Knee; Pain	Drug: oxycodone; Drug: placebo; Drug: tapentadol (CG5503)	Phase 3

Detailed Description

The primary objective of this randomized (study medication assigned to patients by chance), double-blind (neither patient nor investigator knows the study medication) , phase III, placebo and active controlled trial is to evaluate the efficacy and safety of orally administered tapentadol (CG5503) Extended Release (ER) (base) at doses of 100-250 mg twice daily in patients with moderate to severe chronic pain from osteoarthritis (OA) of the knee. The study is being conducted for registration and approval of tapentadol (CG5503) in the US and outside the US. The trial will consist of five periods: screening (to assess eligibility) , washout (3-7 days with determination of a baseline pain intensity), titration (of dose over 3 weeks to the optimal individual level) , maintenance (investigational drug intake for 12 weeks with adjustments allowed), and follow-up (2 weeks post treatment discontinuation). The study hypothesis is that the study drug will be more effective than placebo in reducing patients pain intensity. The Secondary objectives include the collection of pharmacokinetic (related to how the body uses the drug) information for dose verification. The trial objectives will be assessed by comparing the baseline pain level to the level of week 12 of the maintenance phase. This will be done by looking at the patient's pain diary information. Titrate tapentadol (CG5503) ER (extended release) 50mg to patient's optimal dose ranging between 100mg and 250mg twice a day; Oxycodone CR (controlled release) 10mg to 50mg twice a day; Placebo (no active ingredients). All doses of trial treatment will be taken orally with approximately 120 mL of water with or without food for a maximum timeframe of 15 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1030 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-Control, Parallel-arm, Phase III Trial With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of CG5503 Extended-Release (ER) in Patients With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 tapentadol (CG5503) 50 100 150 200 250mg twice a day (BID) during 15 weeks	Drug: tapentadol (CG5503); 50, 100, 150, 200, 250mg twice a day (BID) during 15 weeks
Active Comparator: 002 oxycodone 10 20 30 40 50mg twice a day (BID) during 15 weeks	Drug: oxycodone; 10, 20, 30, 40, 50mg twice a day (BID) during 15 weeks
Placebo Comparator: 003 placebo matching placebo twice a day (BID) during 15 weeks	Drug: placebo; matching placebo twice a day (BID) during 15 weeks

Outcome Measures

Primary Outcome Measures

1. Change From Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale(NRS) Over the Last Week of the Maintenance Period at Week 12. [Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period).]

   For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".

Secondary Outcome Measures

1. Change From Baseline in Western Ontario McMaster Questionnaire (WOMAC) Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week of the Maintenance Period at Week 12 [Baseline and 12 week endpoint]

   Change from baseline to Week 12 of WOMAC Global Score: WOMAC is measure with a Likert ordinal scale from 0-4 with lower scores indicating lower levels of symptoms or physical disability

2. Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. [Baseline and 12 week endpoint]

   A Sleep Questionniare addressed the following question: "How long after bedtime/lights out did you fall asleep last night (hours)?" 12 week endpoint-mean changes from baseline at endpoint for sleep latency. Decrease in time(hours) indicates improvement.

3. Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 [Baseline and 12 week endpoint]

   Ordinal measure indicating change from start of treatment (on a scale of 7 = Very much worse to 1 = Very much improved)

4. Distribution of Time to Treatment Discontinuation Due to Lack of Efficacy [Baseline to 12 weeks]

   The median time to treatment discontinuation due to lack of efficacy from baseline to endpoint

5. Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12 [Baseline and 12 week endpoint]

   Change from baseline to end point in EuroQol-5 (EQ-5D) Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EQ-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead

6. Change From Baseline in Responder Analysis 50% Improvement to Week 12 [Baseline and Week 12]

   Defined by the percentage of subjects achieving at least 50% improvement from baseline in the primary endpoint based on the 11-point NRS at week 12. For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients diagnosed with osteoarthritis of the knee based on the American College of Rheumatology (ACR) criteria and functional capacity class of I-III

• patients taking analgesic medications for at least 3 months prior to screening and/or dissatisfied with their current therapy

• Patients requiring opioid treatment must be taking daily doses of opioid-based analgesic, equivalent to <160 mg of oral morphine

• baseline score of greater than or equal to 5 on an 11-point numerical rating scale, calculated as the average pain intensity during the last 3 days prior to randomization.

Exclusion Criteria:

• History of alcohol and/or drug abuse in Investigator's judgement

• history of significant liver insufficiency

• chronic hepatitis B or C, or HIV, presence of active hepatitis B or C within the past 3 months

• life-long history of seizure disorder or epilepsy

• history of malignancy within past 2 years, with exception of basal cell carcinoma that has been successfully treated

• uncontrolled hypertension

• patients with severely impaired renal function

• patients with moderate to severly impaired hepatic function or with laboratory values reflecting inadequate hepatic function

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

Additional Information:

• A Randomized Double-Blind, Placebo & Active-Control, Parallel-Arm Phase 3 Study With Controlled Dose Adjustment to Evaluate the Efficacy and Safety of Tapentadol Extended-Release (ER) in Subjects With Moderate to Severe Chronic Pain Due to OA of the Knee

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00421928
• Other Study ID Numbers: CR013402; R331333PAI3008; KF11
• First Posted: Jan 15, 2007
• Last Update Posted: Apr 18, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by , ,: Chronic Pain; Osteoarthritis, Knee; tapentadol; Pain Assessment
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Oxycodone; Tapentadol

Study Results

Participant Flow

Recruitment Details	The recruitment period for this out-patient, multicenter study occurred between 07 February 2007 and 15 July 08.
Pre-assignment Detail	The study consisted of a screening period (duration up to 14 days), a washout period (duration 3 to 7 days), a double-blind active treatment period with titration period (duration 3 weeks) and maintenance period (duration 12 weeks)

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Period Title: Overall Study
STARTED	344	342	337
COMPLETED	181	118	203
NOT COMPLETED	163	224	134

Baseline Characteristics

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo	Total
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)	Total of all reporting groups
Overall Participants	344	342	337	1023
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	249 72.4%	249 72.8%	260 77.2%	758 74.1%
>=65 years	95 27.6%	93 27.2%	77 22.8%	265 25.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.4 (10.09)	58.2 (10.29)	58.2 (9.15)	58.3 (9.85)
Sex: Female, Male (Count of Participants)
Female	216 62.8%	202 59.1%	200 59.3%	618 60.4%
Male	128 37.2%	140 40.9%	137 40.7%	405 39.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale(NRS) Over the Last Week of the Maintenance Period at Week 12.
Description	For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
Time Frame	Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period).

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. Last observation carried forward (LOCF) was used to impute pain score after discontinuation

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Measure Participants	344	342	337
Mean (Standard Deviation) [Scores on a scale]	-3.0 (2.39)	-2.6 (2.38)	-2.2 (2.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tapentadol (CG5503), Placebo
	Comments	The primary null hypothesis to be tested for the study was that the tapentadol ER group was not different from the placebo group for the primary endpoint. Assuming the mean treatment group difference of 0.7 with an SD of 2.7, 314 subjects per treatment group were estimated to provide 90% power to show that the tapentadol ER group was statistically different from placebo at an alpha level of 0.05. The total number of subjects to be randomly assigned to a treatment group for the study was 942.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) model was used with treatment and pooled analysis center as factors and baseline pain intensity score as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.7
	Confidence Interval	() 95%; -1.04 to -0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Western Ontario McMaster Questionnaire (WOMAC) Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week of the Maintenance Period at Week 12
Description	Change from baseline to Week 12 of WOMAC Global Score: WOMAC is measure with a Likert ordinal scale from 0-4 with lower scores indicating lower levels of symptoms or physical disability
Time Frame	Baseline and 12 week endpoint

Outcome Measure Data

Analysis Population Description

Intent To Treat (ITT), observed cases analysis conducted, no imputation performed.

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Measure Participants	149	92	158
Mean (Standard Deviation) [Scores on a scale]	-1.2 (0.82)	-1.1 (0.87)	-0.9 (0.84)

3. Secondary Outcome

Title	Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12.
Description	A Sleep Questionniare addressed the following question: "How long after bedtime/lights out did you fall asleep last night (hours)?" 12 week endpoint-mean changes from baseline at endpoint for sleep latency. Decrease in time(hours) indicates improvement.
Time Frame	Baseline and 12 week endpoint

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Measure Participants	339	337	331
Mean (Standard Deviation) [Hours]	0.2 (2.8)	0.1 (1.81)	0.3 (2.72)

4. Secondary Outcome

Title	Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12
Description	Ordinal measure indicating change from start of treatment (on a scale of 7 = Very much worse to 1 = Very much improved)
Time Frame	Baseline and 12 week endpoint

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Measure Participants	317	308	309
Number [percentage of participants]	51.1 14.9%	37.7 11%	32.4 9.6%

5. Secondary Outcome

Title	Distribution of Time to Treatment Discontinuation Due to Lack of Efficacy
Description	The median time to treatment discontinuation due to lack of efficacy from baseline to endpoint
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

ITT: The results for median and interquartile ranges were not estimable because insufficient number of subjects discontinued due to lack of efficacy to estimate the values.

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Measure Participants	0	0	0

6. Secondary Outcome

Title	Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12
Description	Change from baseline to end point in EuroQol-5 (EQ-5D) Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EQ-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead
Time Frame	Baseline and 12 week endpoint

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Measure Participants	344	342	337
Mean (Standard Deviation) [scores on a scale]	0.6 (0.26)	0.5 (0.28)	0.5 (0.29)

7. Secondary Outcome

Title	Change From Baseline in Responder Analysis 50% Improvement to Week 12
Description	Defined by the percentage of subjects achieving at least 50% improvement from baseline in the primary endpoint based on the 11-point NRS at week 12. For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

ITT. Subjects who discontinued from the study were considered non-responders.

Arm/Group Title	Tapentadol (CG5503)	Oxycodone	Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	oxycodone controlled release (CR)20-50mg twice daily (BID)	Matching Placebo twice daily (BID)
Measure Participants	344	342	337
Number [Percentage of participants]	32.0 9.3%	17.3 5.1%	24.3 7.2%

Adverse Events

Time Frame	All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Arm/Group Title	Tapentadol (CG5503)		Oxycodone		Placebo
Arm/Group Description	Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)		oxycodone controlled release (CR)20-50mg twice daily (BID)		Matching Placebo twice daily (BID)
All Cause Mortality
	Tapentadol (CG5503)		Oxycodone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tapentadol (CG5503)		Oxycodone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/344 (1.2%)		10/342 (2.9%)		6/337 (1.8%)
Blood and lymphatic system disorders
Anaemia	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Cardiac disorders
Myocardial Infarction	0/344 (0%)		1/342 (0.3%)		1/337 (0.3%)
Cardiac Failure Congestive	1/344 (0.3%)		0/342 (0%)		0/337 (0%)
Angina Pectoris	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Atrial Flutter	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Ear and labyrinth disorders
Meniere's Disease	1/344 (0.3%)		0/342 (0%)		0/337 (0%)
Gastrointestinal disorders
Abdominal Pain	0/344 (0%)		0/342 (0%)		1/337 (0.3%)
Intestinal Mass	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
General disorders
Drug Withdrawal Syndrome	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Infections and infestations
Pneumonia	1/344 (0.3%)		0/342 (0%)		0/337 (0%)
Influenza	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Pyelonephritis Acute	0/344 (0%)		0/342 (0%)		1/337 (0.3%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/344 (0.3%)		0/342 (0%)		0/337 (0%)
Pain in Extremity	0/344 (0%)		0/342 (0%)		1/337 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung Cancer Metastatic	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Nervous system disorders
Embolic Stroke	0/344 (0%)		0/342 (0%)		1/337 (0.3%)
Psychiatric disorders
Confusional State	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Suicidal Ideation	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Renal and urinary disorders
Renal Failure Acute	0/344 (0%)		2/342 (0.6%)		0/337 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/344 (0%)		0/342 (0%)		1/337 (0.3%)
Surgical and medical procedures
Spinal Fusion Surgery	0/344 (0%)		1/342 (0.3%)		0/337 (0%)
Other (Not Including Serious) Adverse Events
	Tapentadol (CG5503)		Oxycodone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	200/344 (58.1%)		269/342 (78.7%)		134/337 (39.8%)
Gastrointestinal disorders
Nausea	74/344 (21.5%)		125/342 (36.5%)		23/337 (6.8%)
Constipation	65/344 (18.9%)		126/342 (36.8%)		22/337 (6.5%)
Dry Mouth	22/344 (6.4%)		15/342 (4.4%)		8/337 (2.4%)
Vomiting	18/344 (5.2%)		61/342 (17.8%)		11/337 (3.3%)
Diarrhoea	16/344 (4.7%)		17/342 (5%)		20/337 (5.9%)
General disorders
Fatigue	37/344 (10.8%)		35/342 (10.2%)		15/337 (4.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/344 (2.9%)		6/342 (1.8%)		17/337 (5%)
Back Pain	7/344 (2%)		5/342 (1.5%)		22/337 (6.5%)
Nervous system disorders
Dizziness	61/344 (17.7%)		65/342 (19%)		16/337 (4.7%)
Headache	51/344 (14.8%)		50/342 (14.6%)		56/337 (16.6%)
Somnolence	37/344 (10.8%)		67/342 (19.6%)		14/337 (4.2%)
Skin and subcutaneous tissue disorders
Pruritus	24/344 (7%)		43/342 (12.6%)		4/337 (1.2%)

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.