A Study to Evaluate the Effectiveness and Safety of Tapentadol (CG5503) Extended Release (ER) in Patients With Moderate to Severe Chronic Low Back Pain

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00449176
• Collaborator: Grünenthal GmbH (Industry)
• Enrollment: 981
• Arms: 3
• Duration (Months): 14.9

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Low Back Pain	Drug: tapentadol (CG5503) ER; Drug: oxycodone CR; Drug: placebo	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 100-250 mg twice daily in patients with moderate to severe chronic pain of the lower back. The study is being conducted for registration and approval of tapentadol (CG5503) in the US and outside US. The trial will consist of five periods: screening (to assess eligibility), washout (3-7 days with determination of 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) in 50 mg steps to patient's optimal dose ranging between 100mg and 250mg twice a day; Oxycodone CR (controlled release) 20mg to 50mg twice a day; Placebo (no active ingredients). All doses of trial treatment will be taken orally with or without food, for a maximum timeframe of 15 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 981 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 Subjects With Moderate to Severe Chronic Low Back Pain
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline of the Average Pain Intensity Based on a 11-point Numerical Rating Scale (NRS) Over the Last Week of the Maintenance Period at Week 12. [Baseline and 12 weeks]

   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 Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. [Baseline and 12 week endpoint]

   Total pain score where zero equals "no pain" to ten equals "pain as bad as you can imagine" from 12 week endpoint vs baseline.

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 Questionnaire 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. Number of Participants With Treatment Discontinuation Due to Lack of Efficacy [Baseline and 12 weeks]

   The number of participants who discontinued 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 Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EuroQol-5 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. Responder Analysis 50% Improvement [Baseline and Week 12]

   Defined by the proportion of subjects achieving at least 50% improvement from baseline in the primary endpoint of change from baseline of the average pain intensity based on the 11-point Numerical Rating Scale (NRS) at week 12. The subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point 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: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and non-pregnant, non-lactating women having a diagnosis of Lower Back Pain (LBP) of non-malignant origin present for at least 3 months

• 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 =5 on an 11-point numerical rater 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 Study to Evaluate the Effectiveness and Safety of Tapentadol (R331333) Extended Release (ER) in Patients with Moderate to Severe Chronic Low Back Pain

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00449176
• Other Study ID Numbers: CR013399; R331333PAI3011
• First Posted: Mar 20, 2007
• Last Update Posted: Apr 30, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by , ,: Low Back Pain; Chronic Pain; Pain Assessment; Tapentadol
• Additional relevant MeSH terms: Back Pain; Low Back Pain; Oxycodone; Tapentadol

Study Results

Participant Flow

Recruitment Details	The recruitment period for this out-patient, multicenter study occurred between 21 February 2007 and 12 March 2008.
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 ER	Oxycodone CR	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	318	328	319
COMPLETED	166	133	152
NOT COMPLETED	152	195	167

Baseline Characteristics

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	318	328	319	965
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.4 (13.21)	50.0 (14.21)	50.4 (14.05)	49.9 (13.83)
Sex: Female, Male (Count of Participants)
Female	194 61%	181 55.2%	184 57.7%	559 57.9%
Male	124 39%	147 44.8%	135 42.3%	406 42.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline of the Average Pain Intensity Based on a 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

Outcome Measure Data

Analysis Population Description

Intent To Treat (ITT) analysis set utilizing Last Observation Carried Forward (LOCF) imputation. The ITT analysis set included all randomized patients that took at least one dose of study medication following randomization. 7 patients (3 tapentadol ER, 3 oxycodone CR, 1 placebo) had no baseline pain scores therefore excluded from the analysis.

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	312	323	316
Mean (Standard Deviation) [scores on a scale]	-2.9 (2.66)	-2.9 (2.52)	-2.1 (2.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tapentadol ER, 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	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8
	Confidence Interval	() 95%; -1.22 to -0.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12.
Description	Total pain score where zero equals "no pain" to ten equals "pain as bad as you can imagine" from 12 week endpoint vs baseline.
Time Frame	Baseline and 12 week endpoint

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) analysis set, last observation carried forward (LOCF) imputation. The ITT analysis set included all randomized patients that took at least one dose of study medication following randomization. The patients who didi not have any assessment during the treatment period were excluded from the analysis.

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	314	323	314
Mean (Standard Deviation) [scores on a scale]	-2.3 (2.25)	-2.1 (2.35)	-1.6 (2.11)

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 Questionnaire 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

Intent to Treat population with LOCF imputation. The patients who didi not have any assessment during the treatment period were excluded from the analysis.

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	311	324	312
Mean (Standard Deviation) [hours]	-0.2 (3.08)	-0.2 (2.32)	-0.1 (2.43)

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

Intent to Treat Analysis (ITT) set, Last Observation Carried Forward (LOCF) imputation method. The ITT analysis set included all randomized subjects who took at least one dose of study medication following randomization. The patients who didi not have any assessment during the treatment period were excluded from the analysis.

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	236	210	245
Number [percentage of participants]	55.5 17.5%	60 18.3%	32.7 10.3%

5. Secondary Outcome

Title	Number of Participants With Treatment Discontinuation Due to Lack of Efficacy
Description	The number of participants who discontinued due to lack of efficacy from baseline to endpoint
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis Set

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	315	326	317
Number [participants]	18 5.7%	9 2.7%	64 20.1%

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 Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EuroQol-5 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

Intent to Treat Analysis Set, LOCF imputation method. The patients who didi not have any assessment during the treatment period were excluded from the analysis.

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	315	325	316
Mean (Standard Deviation) [scores on a scale]	0.2 (0.3)	0.2 (0.33)	0.1 (0.33)

7. Secondary Outcome

Title	Responder Analysis 50% Improvement
Description	Defined by the proportion of subjects achieving at least 50% improvement from baseline in the primary endpoint of change from baseline of the average pain intensity based on the 11-point Numerical Rating Scale (NRS) at week 12. The subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point 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

Intent to Treat Analysis Set

Arm/Group Title	Tapentadol ER	Oxycodone CR	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	315	326	317
Number [Percentage of participants]	27.0 8.5%	23.3 7.1%	18.9 5.9%

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 ER		Oxycodone CR		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 ER		Oxycodone CR		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tapentadol ER		Oxycodone CR		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/ (NaN)		11/ (NaN)		3/ (NaN)
Blood and lymphatic system disorders
Anemia	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Cardiac disorders
Angina Pectoris	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Atrial Fibrillation	1/318 (0.3%)		0/328 (0%)		0/319 (0%)
Coronary Artery Occlusion	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Palpitations	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Ear and labyrinth disorders
Tinnitus	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Gastrointestinal disorders
Abdominal Pain	1/318 (0.3%)		0/328 (0%)		0/319 (0%)
Duodenal Ulcer	0/318 (0%)		0/328 (0%)		1/319 (0.3%)
Gastroesophageal Reflux Disease	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
General disorders
Chest Pain	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Non Cardiac Chest Pain	0/318 (0%)		0/328 (0%)		1/319 (0.3%)
Infections and infestations
Clostridial Infection	2/318 (0.6%)		1/328 (0.3%)		1/319 (0.3%)
Gastroenteritis	1/318 (0.3%)		1/328 (0.3%)		0/319 (0%)
Pneumonia	0/318 (0%)		0/328 (0%)		1/319 (0.3%)
Injury, poisoning and procedural complications
Foot Fracture	1/318 (0.3%)		0/328 (0%)		0/319 (0%)
Injury	1/318 (0.3%)		0/328 (0%)		0/319 (0%)
Metabolism and nutrition disorders
Dehydration	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder Cancer Recurrent	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Nervous system disorders
Depressed Level of Consciousness	1/318 (0.3%)		0/328 (0%)		0/319 (0%)
Dizziness	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Transient Ischemic Attack	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Psychiatric disorders
Bipolar Disorder	0/318 (0%)		0/328 (0%)		1/319 (0.3%)
Confusional State	1/318 (0.3%)		0/328 (0%)		0/319 (0%)
Schizoaffective Disorder	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Schizophrenia	0/318 (0%)		0/328 (0%)		1/319 (0.3%)
Suicidal Ideation	0/318 (0%)		0/328 (0%)		1/319 (0.3%)
Surgical and medical procedures
Cardiac Pacemaker Replacement	1/318 (0.3%)		0/328 (0%)		0/319 (0%)
Coronary Artery Bypass	0/318 (0%)		1/328 (0.3%)		0/319 (0%)
Other (Not Including Serious) Adverse Events
	Tapentadol ER		Oxycodone CR		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	192/318 (60.4%)		240/328 (73.2%)		118/319 (37%)
Gastrointestinal disorders
Constipation	44/318 (13.8%)		88/328 (26.8%)		16/319 (5%)
Diarrhea	19/318 (6%)		8/328 (2.4%)		23/319 (7.2%)
Dry Mouth	26/318 (8.2%)		12/328 (3.7%)		7/319 (2.2%)
Dyspepsia	16/318 (5%)		6/328 (1.8%)		8/319 (2.5%)
Nausea	64/318 (20.1%)		113/328 (34.5%)		29/319 (9.1%)
Vomiting	29/318 (9.1%)		63/328 (19.2%)		5/319 (1.6%)
General disorders
Fatigue	21/318 (6.6%)		24/328 (7.3%)		13/319 (4.1%)
Nervous system disorders
Dizziness	38/318 (11.9%)		55/328 (16.8%)		18/319 (5.6%)
Headache	63/318 (19.8%)		55/328 (16.8%)		44/319 (13.8%)
Somnolence	42/318 (13.2%)		53/328 (16.2%)		8/319 (2.5%)
Psychiatric disorders
Insomnia	13/318 (4.1%)		25/328 (7.6%)		9/319 (2.8%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	12/318 (3.8%)		17/328 (5.2%)		0/319 (0%)
Pruritus	23/318 (7.2%)		55/328 (16.8%)		6/319 (1.9%)

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.