An Open-label Extension Study With Flexible Dosing of Extended-release (ER) Tapentadol (CG5503) to Treat Patients With Moderate to Severe Chronic Pain

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00487435
• Collaborator: Grünenthal GmbH (Industry)
• Enrollment: 1,166
• Locations: 148
• Arm: 1
• Duration (Months): 24
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of the study is to assess the long-term safety profile of Tapentadol (CG5503) extended release (ER) at dosages ranging from 100 to 250 mg twice a day in treating patients with moderate to severe chronic pain over a period of 1 year. The study will also assess dosage requirements over the long term; characterize adverse events and tolerability, sleep quality, and potential symptoms of withdrawal; characterize pain intensity scores and overall impression of change; and characterize patient-related health outcomes.

Condition or Disease	Intervention/Treatment	Phase
Pain; Osteoarthritis; Low Back Pain	Drug: Tapentadol (CG5503) Extended Release (ER)	Phase 3

Detailed Description

All patients who complete the Phase 3 pivotal trials in osteoarthritis (R331333-PAI-3008; KF5503/11) and low back pain (R331333-PAI-3011; KF5503/23) and the Phase 3 safety trial in the non-European sites (R331333-PAI-3007; KF5503/24) will be allowed to continue participation in the program by entering this trial. The trial will consist of three periods (screening, open-label treatment period, and follow-up). In the open-label treatment/maintenance period (1 year), those patients in the safety trial R331333-PAI-3007 (KF5503/24) taking open-label Tapentadol (CG5503) extended release (ER) will continue the dosage they were taking without undergoing titration. All other patients will be titrated to the minimum therapeutic dosage of Tapentadol (CG5503) extended release (ER) over 1 week. The lowest therapeutic dose allowed in the study is 100 mg twice daily, and the maximum upper dosage of Tapentadol (CG5503) extended release (ER) base is 250 mg twice daily. Downward titration (not below the minimum therapeutic dose of 100 mg twice daily) is permitted at any time using the same decrements without any time restriction. Dosages will be assessed at the scheduled (and unscheduled, if any) visits and adjustment under investigator supervision will be made as necessary. Dosage adjustments should be kept to a minimum. Intake of paracetamol/acetaminophen two 500 mg tablets daily is permitted during the titration week, and during the remainder of the open-label treatment/maintenance period up to a maximum of 7 consecutive days but no more than 14 out of 30 days. Following Week 4, all visits will be scheduled at 4-week intervals, through Week 52. The end-of-treatment visit at Week 52 will include both safety and efficacy assessments. Patients will return to the site for a follow-up visit approximately 4 days after their last dose of Tapentadol (CG5503) extended release (ER) for final safety evaluations and completion of the opioid withdrawal assessments (clinical opioid withdrawal scale, or COWS, and subjective opioid withdrawal scale, or SOWS). Patients experiencing withdrawal symptoms prior to the follow-up visit may telephone and request to be seen sooner. Additionally, the research staff at the site will telephone subjects approximately 10 to 14 days after the last dose of Tapentadol (CG5503) extended release (ER) to inquire if any adverse events have occurred since the previous visit. Tapentadol (CG5503) extended release (ER): 50, 100, 150, 200, and 250 mg orally, taken twice daily (morning and evening) for a maximum duration of 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1166 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-Label Extension, Single-Arm, Flexible-Dosing, Phase 3 Trial With CG5503 Extended-Release (ER) in Patients With Moderate to Severe Chronic Pain
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 Tapentadol (CG5503) Extended Release (ER) 100 150 200 250 mg oral tablet twice daily for 52 weeks	Drug: Tapentadol (CG5503) Extended Release (ER); 100, 150, 200, 250 mg oral tablet twice daily for 52 weeks

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Treatment-emergent Adverse Events (TEAE) [52 weeks]

   The number of subjects who reported a TEAE during the treatment period. TEAE was defined as any adverse event that started or worsened on or after the start of the study medication and up to 3 days after the discontinuation of the study medication.

Secondary Outcome Measures

1. Change From Baseline in Average Pain Intensity Scores at Week 52 Using the Numerical Rating Scale (NRS) [Baseline, 52 weeks]

   The subjects indicated the average level of pain experienced, at each study visit, over the previous 24 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: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Non-lactating female subjects (Sexually active women must be postmenopausal, surgically sterile, or practicing an effective method of birth control [e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double barrier method, contraceptive patch, male partner sterilization] before entry and throughout the trial. Female patients of childbearing potential must have a negative pregnancy test at screening.)

• Completion of the expected double-blind treatment period of the pivotal Tapentadol (CG5503) Phase 3 trials in osteoarthritis (R331333-PAI-3008, KF5503/11) or low back pain (R331333-PAI-3011, KF5503/23), or completion of the 1-year treatment period of the safety CG5503 Phase 3 trial in the non-European sites (R331333-PAI-3007, KF5503/24)

• Must be willing to take Tapentadol (CG5503) extended release (ER) and the rescue medication supplied for the duration of the trial

Exclusion Criteria:

• History of alcohol and/or drug abuse, life-long history of seizure disorder or epilepsy, any of the following within the past year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm

• Severe traumatic brain injury within the past 15 years

• Uncontrolled hypertension (repeated systolic blood pressure >160 mmHg or diastolic blood pressure >95 mmHg)

• Severely impaired renal function

• Moderately or severely impaired hepatic function

• Patients taking neuroleptics, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days prior to screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Hoover	Alabama	United States
3		Mobile	Alabama	United States
4		Mesa	Arizona	United States
5		Phoenix	Arizona	United States
6		Tempe	Arizona	United States
7		Tucson	Arizona	United States
8		Jonesboro	Arkansas	United States
9		Little Rock	Arkansas	United States
10		Anaheim	California	United States
11		Carmichael	California	United States
12		Encinitas	California	United States
13		Fresno	California	United States
14		Huntington Park	California	United States
15		Laguna Hills	California	United States
16		Los Gatos	California	United States
17		Pico Rivera	California	United States
18		Pismo Beach	California	United States
19		Sacramento	California	United States
20		San Diego	California	United States
21		Upland	California	United States
22		Westlake Village	California	United States
23		Stamford	Connecticut	United States
24		Trumbull	Connecticut	United States
25		Chiefland	Florida	United States
26		Clearwater	Florida	United States
27		Fort Myers	Florida	United States
28		Hallandale Beach	Florida	United States
29		Hollywood	Florida	United States
30		Jacksonville	Florida	United States
31		Kissimmee	Florida	United States
32		Miami	Florida	United States
33		New Port Richey	Florida	United States
34		Oldsmar	Florida	United States
35		Pembroke Pines	Florida	United States
36		Plantation	Florida	United States
37		Port Orange	Florida	United States
38		Sarasota	Florida	United States
39		Tamarac	Florida	United States
40		Tampa	Florida	United States
41		Athens	Georgia	United States
42		Augusta	Georgia	United States
43		Decatur	Georgia	United States
44		Marietta	Georgia	United States
45		Perry	Georgia	United States
46		Suwanee	Georgia	United States
47		Woodstock	Georgia	United States
48		Honolulu	Hawaii	United States
49		Boise	Idaho	United States
50		Meridian	Idaho	United States
51		Chicago	Illinois	United States
52		Avon	Indiana	United States
53		Evansville	Indiana	United States
54		Indianapolis	Indiana	United States
55		Valparaiso	Indiana	United States
56		West Des Moines	Iowa	United States
57		Overland Park	Kansas	United States
58		Prairie Village	Kansas	United States
59		Topeka	Kansas	United States
60		Madisonville	Kentucky	United States
61		Baton Rouge	Louisiana	United States
62		Lake Charles	Louisiana	United States
63		Mandeville	Louisiana	United States
64		Metairie	Louisiana	United States
65		New Orleans	Louisiana	United States
66		Columbia	Maryland	United States
67		Owings Mills	Maryland	United States
68		Rockville	Maryland	United States
69		Boston	Massachusetts	United States
70		Brighton	Massachusetts	United States
71		Fall River	Massachusetts	United States
72		N Dartmouth	Massachusetts	United States
73		W Yarmouth	Massachusetts	United States
74		Wellesley Hills	Massachusetts	United States
75		East Lansing	Michigan	United States
76		Grand Blanc	Michigan	United States
77		Kalamazoo	Michigan	United States
78		Troy	Michigan	United States
79		Saint Louis	Missouri	United States
80		Omaha	Nebraska	United States
81		Cherry Hill	New Jersey	United States
82		Albuquerque	New Mexico	United States
83		Mamaroneck	New York	United States
84		New York	New York	United States
85		Williamsville	New York	United States
86		Greensboro	North Carolina	United States
87		Raleigh	North Carolina	United States
88		Winston Salem	North Carolina	United States
89		Cincinnati	Ohio	United States
90		Kettering	Ohio	United States
91		Toledo	Ohio	United States
92		Oklahoma City	Oklahoma	United States
93		Medford	Oregon	United States
94		Allentown	Pennsylvania	United States
95		Chester	Pennsylvania	United States
96		Duncansville	Pennsylvania	United States
97		Morrisville	Pennsylvania	United States
98		Philadelphia	Pennsylvania	United States
99		Greenville	South Carolina	United States
100		Prosperity	South Carolina	United States
101		Sioux Falls	South Dakota	United States
102		Clarksville	Tennessee	United States
103		Nashville	Tennessee	United States
104		Amarillo	Texas	United States
105		Austin	Texas	United States
106		Dallas	Texas	United States
107		Houston	Texas	United States
108		Hurst	Texas	United States
109		Lubbock	Texas	United States
110		Odessa	Texas	United States
111		San Antonio	Texas	United States
112		Salt Lake City	Utah	United States
113		Danville	Virginia	United States
114		Roanoke	Virginia	United States
115		Virginia Beach	Virginia	United States
116		Bellevue	Washington	United States
117		Tacoma	Washington	United States
118		Milwaukee	Wisconsin	United States
119		Adelaide		Australia
120		Melbourne		Australia
121		Newcastle		Australia
122		Woodville North		Australia
123		Chilliwack	British Columbia	Canada
124		Kelowna	British Columbia	Canada
125		Penticton	British Columbia	Canada
126		Vancouver	British Columbia	Canada
127		St. John'S	Newfoundland and Labrador	Canada
128		Ajax	Ontario	Canada
129		Brampton	Ontario	Canada
130		Kitchener	Ontario	Canada
131		London	Ontario	Canada
132		Markham	Ontario	Canada
133		Mississauga	Ontario	Canada
134		Ottawa	Ontario	Canada
135		Sarnia	Ontario	Canada
136		Sudbury	Ontario	Canada
137		Toronto	Ontario	Canada
138		Vancouver	Ontario	Canada
139		Charlottetown	Prince Edward Island	Canada
140		Montreal	Quebec	Canada
141		Pointe-Claire	Quebec	Canada
142		Sherbrooke	Quebec	Canada
143		St. Romuald	Quebec	Canada
144		Saskatoon	Saskatchewan	Canada
145		Halifax		Canada
146		Christchurch		New Zealand
147		Tauranga		New Zealand
148		Wellington		New Zealand

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:

• An open-label extension study with flexible dosing of extended-release (ER) Tapentadol (CG5503) to treat patients with moderate to severe chronic pain

Publications

None provided.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT00487435
• Other Study ID Numbers: CR013567; R331333PAI3010; KF18
• First Posted: Jun 18, 2007
• Last Update Posted: May 9, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: CG5503; Tapentadol; chronic non-malignant pain; osteoarthritis; lower back pain; analgesic; opioid
• Additional relevant MeSH terms: Osteoarthritis; Back Pain; Low Back Pain; Chronic Pain; Tapentadol

Study Results

Participant Flow

Recruitment Details	The recruitment period for this out-patient, multicenter study occurred between 4 June 2007 and 29 June 2009.

Arm/Group Title	Tapentadol (CG5503) Extended Release (ER)
Arm/Group Description	Tapentadol (CG5503) extended release (ER) 100 to 250mg oral tablet twice daily (BID) for up to one year
Period Title: Overall Study
STARTED	1154
COMPLETED	669
NOT COMPLETED	485

Baseline Characteristics

Arm/Group Title	Tapentadol (CG5503) Extended Release (ER)
Arm/Group Description	Tapentadol (CG5503) extended release (ER) 100 to 250mg oral tablet twice daily (BID) for up to one year
Overall Participants	1154
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	954 82.7%
>=65 years	200 17.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.3 (11.43)
Sex: Female, Male (Count of Participants)
Female	668 57.9%
Male	486 42.1%
Region Enroll (participants) [Number]
Australia	15 1.3%
Canada	178 15.4%
New Zealand	10 0.9%
United States of America	951 82.4%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Treatment-emergent Adverse Events (TEAE)
Description	The number of subjects who reported a TEAE during the treatment period. TEAE was defined as any adverse event that started or worsened on or after the start of the study medication and up to 3 days after the discontinuation of the study medication.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Safety analysis set (All randomized subjects who took at least one dose of study medication).

Arm/Group Title	Tapentadol (CG5503) Extended Release (ER)
Arm/Group Description	Tapentadol (CG5503) extended release (ER) 100 to 250mg oral tablet twice daily (BID) for up to one year
Measure Participants	1154
Number [participants]	907 78.6%

2. Secondary Outcome

Title	Change From Baseline in Average Pain Intensity Scores at Week 52 Using the Numerical Rating Scale (NRS)
Description	The subjects indicated the average level of pain experienced, at each study visit, over the previous 24 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, 52 weeks

Outcome Measure Data

Analysis Population Description

observed cases

Arm/Group Title	Tapentadol (CG5503) Extended Release (ER)
Arm/Group Description	Tapentadol (CG5503) extended release (ER) 100 to 250mg oral tablet twice daily (BID) for up to one year
Measure Participants	711
Mean (Standard Deviation) [Scores on a Scale]	-0.26 (2.129)

Adverse Events

Adverse Event Reporting Description	Only subjects who had at least one of the TEAEs listed in the Other (non Serious) AE table are included in the Total no. subjects with Non-Serious Adverse Events.
Arm/Group Title	Tapentadol (CG5503) Extended Release (ER)
Arm/Group Description	Tapentadol (CG5503) extended release (ER) 100 to 250mg oral tablet twice daily (BID) for up to one year
All Cause Mortality
	Tapentadol (CG5503) Extended Release (ER)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Tapentadol (CG5503) Extended Release (ER)
	Affected / at Risk (%)	# Events
Total	84/1154 (7.3%)
Cardiac disorders
Acute myocardial infarction	2/1154 (0.2%)
Atrial fibrillation	2/1154 (0.2%)
Cardiac failure congestive	2/1154 (0.2%)
Myocardial infarction	2/1154 (0.2%)
Acute coronary syndrome	1/1154 (0.1%)
Angina pectoris	1/1154 (0.1%)
Angina unstable	1/1154 (0.1%)
Atrial flutter	1/1154 (0.1%)
Cardiac arrest	1/1154 (0.1%)
Cor pulmonale	1/1154 (0.1%)
Coronary artery disease	1/1154 (0.1%)
Gastrointestinal disorders
Abdominal pain	2/1154 (0.2%)
Vomiting	2/1154 (0.2%)
Colitis ischaemic	1/1154 (0.1%)
Diarrhoea	1/1154 (0.1%)
Nausea	1/1154 (0.1%)
General disorders
Chest pain	2/1154 (0.2%)
Non-cardiac chest pain	2/1154 (0.2%)
Asthenia	1/1154 (0.1%)
Chest discomfort	1/1154 (0.1%)
Drug withdrawal syndrome	1/1154 (0.1%)
Hernia obstructive	1/1154 (0.1%)
Influenza like illness	1/1154 (0.1%)
Hepatobiliary disorders
Cholecystitis	1/1154 (0.1%)
Cholecystitis acute	1/1154 (0.1%)
Infections and infestations
Gastroenteritis viral	2/1154 (0.2%)
Bronchitis	1/1154 (0.1%)
Bursitis infective	1/1154 (0.1%)
Diverticulitis	1/1154 (0.1%)
Mastitis	1/1154 (0.1%)
Pneumonia	1/1154 (0.1%)
Pyelonephritis	1/1154 (0.1%)
Injury, poisoning and procedural complications
Fall	3/1154 (0.3%)
Abdominal injury	1/1154 (0.1%)
Foot fracture	1/1154 (0.1%)
Joint injury	1/1154 (0.1%)
Muscle rupture	1/1154 (0.1%)
Road traffic accident	1/1154 (0.1%)
Investigations
Lipase increased	1/1154 (0.1%)
Platelet count decreased	1/1154 (0.1%)
Metabolism and nutrition disorders
Dehydration	2/1154 (0.2%)
Hypocalcaemia	1/1154 (0.1%)
Hypomagnesaemia	1/1154 (0.1%)
Malnutrition	1/1154 (0.1%)
Obesity	1/1154 (0.1%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	7/1154 (0.6%)
Arthralgia	1/1154 (0.1%)
Arthropathy	1/1154 (0.1%)
Back pain	1/1154 (0.1%)
Chest wall mass	1/1154 (0.1%)
Intervertebral disc protrusion	1/1154 (0.1%)
Muscular weakness	1/1154 (0.1%)
Musculoskeletal chest pain	1/1154 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/1154 (0.1%)
Endometrial cancer	1/1154 (0.1%)
Laryngeal cancer	1/1154 (0.1%)
Lung adenocarcinoma metastatic	1/1154 (0.1%)
Small cell lung cancer stage unspecified	1/1154 (0.1%)
Uterine leiomyoma	1/1154 (0.1%)
Nervous system disorders
Coma	2/1154 (0.2%)
Syncope	2/1154 (0.2%)
Altered state of consciousness	1/1154 (0.1%)
Cerebrovascular accident	1/1154 (0.1%)
Cervicobrachial syndrome	1/1154 (0.1%)
Hypoaesthesia	1/1154 (0.1%)
Intraventricular haemorrhage	1/1154 (0.1%)
Psychiatric disorders
Suicidal ideation	2/1154 (0.2%)
Withdrawal syndrome	2/1154 (0.2%)
Completed suicide	1/1154 (0.1%)
Psychotic disorder	1/1154 (0.1%)
Suicidal behaviour	1/1154 (0.1%)
Renal and urinary disorders
Nephrolithiasis	1/1154 (0.1%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/1154 (0.2%)
Cystocele	1/1154 (0.1%)
Menometrorrhagia	1/1154 (0.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/1154 (0.1%)
Surgical and medical procedures
Colectomy	1/1154 (0.1%)
Vascular disorders
Deep vein thrombosis	1/1154 (0.1%)
Haematoma	1/1154 (0.1%)
Other (Not Including Serious) Adverse Events
	Tapentadol (CG5503) Extended Release (ER)
	Affected / at Risk (%)	# Events
Total	659/1154 (57.1%)
Gastrointestinal disorders
Nausea	135/1154 (11.7%)
Constipation	128/1154 (11.1%)
Diarrhoea	110/1154 (9.5%)
Vomiting	71/1154 (6.2%)
General disorders
Fatigue	77/1154 (6.7%)
Infections and infestations
Nasopharyngitis	77/1154 (6.7%)
Upper respiratory tract infection	71/1154 (6.2%)
Sinusitis	63/1154 (5.5%)
Urinary tract infection	63/1154 (5.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	63/1154 (5.5%)
Nervous system disorders
Headache	151/1154 (13.1%)
Dizziness	98/1154 (8.5%)
Somnolence	61/1154 (5.3%)
Psychiatric disorders
Insomnia	100/1154 (8.7%)
Anxiety	61/1154 (5.3%)

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.