A Study to Evaluate the Efficacy and Safety of CG5503 Prolonged Release (PR) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee

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 Prolonged Release (PR) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee.

The purpose of this study is to evaluate whether tapentadol (CG5503) prolonged-release (PR) tablets at doses of 100-250 mg twice daily provide a better pain relief in patients with moderate to severe chronic pain due to osteoarthritis of the knee than a placebo (a medication without active substance). In addition the tolerability of CG5503 PR will be assessed. One third of the patients will receive CG5503 and one third will receive placebo. For further comparison one third of the patients will receive oxycodone controlled release (CR) at doses of 20-50 mg twice daily which is an active approved pain medication. Please note that tapentadol ER (Extended Release) and tapentadol PR (Prolonged Release) are identical and used interchangeably. This is due to United States of America and European naming conventions.

Study Overview

• Status: Completed
• Conditions: Pain; Knee Osteoarthritis
• Intervention / Treatment: Drug: Matching Placebo (twice daily); Drug: Tapentadol ER (100 to 250 mg twice daily); Drug: Oxycodone CR (20 to 50 mg twice daily)

Detailed Description

This is a randomized (study medication assigned to patients by chance), double-blind (neither patient nor investigator knows which patient gets which study medication, i.e. CG5503, placebo, oxycodone), placebo and active control study. The primary objective is to evaluate the efficacy and safety of orally administered tapentadol (CG5503) prolonged-release (PR) at doses of 100-250 mg (base) twice daily in patients with moderate to severe chronic pain from osteoarthritis (OA) of the knee. The study 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 after end of treatment). 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 absorbs, distributes, changes and excretes the drug) information for dose verification. The efficacy objectives will be assessed by comparing the baseline pain level to the pain level during the maintenance period. This will be done by looking at the patients' pain diary information (electronic diaries).

• Study Type: Interventional
• Enrollment (Actual): 990
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • Site 043005
  • Mitterdorf, Austria
    • Site 043006
  • Salzburg, Austria
    • Site 043002
  • Vienna, Austria
    • Site 043001
  • Vienna, Austria
    • Site 043004
  • Wiener Neustadt, Austria
    • Site 043003
• Croatia
  • Karlovac, Croatia
    • Site 385003
  • Osijek, Croatia
    • Site 385001
  • Sisak, Croatia
    • Site 385004
  • Zagreb, Croatia
    • Seite 385005
  • Zagreb, Croatia
    • Site 385002
• Germany
  • Berlin, Germany
    • Site 049002
  • Berlin, Germany
    • Site 049008
  • Berlin, Germany
    • Site 049010
  • Dresden, Germany
    • Site 049003
  • Frankfurt, Germany
    • Site 049004
  • Hamburg, Germany
    • Site 049007
  • Leipzig, Germany
    • Site 049001
  • Magdeburg, Germany
    • Site 049005
  • Schwerin, Germany
    • Site 049009
  • Wiesbaden, Germany
    • Site 049006
• Hungary
  • Budapest, Hungary
    • Site 036003
  • Budapest, Hungary
    • Site 036005
  • Budapest, Hungary
    • Site 036006
  • Budapest, Hungary
    • Site 036009
  • Debrecen, Hungary
    • Site 036008
  • Kecskemet, Hungary
    • Site 036004
  • Kecskemét, Hungary
    • Site 036007
  • Visegrad, Hungary
    • Site 036002
• Italy
  • Chieti, Italy
    • Site 039002
  • Milano, Italy
    • Site 039003
  • Pavia, Italy
    • Site 039004
  • Perugia, Italy
    • Site 039001
• Latvia
  • Bauska, Latvia
    • Site 371002
  • Riga, Latvia
    • Site 371004
  • Riga, Latvia
    • Site 371005
• Netherlands
  • Eindhoven, Netherlands
    • Site 031008
  • Losser, Netherlands
    • Site 031003
  • Oude Pekela, Netherlands
    • Site 031006
  • Spijkenisse, Netherlands
    • Site 031007
  • s'Hertogenbosch, Netherlands
    • Site 031004
• Poland
  • Bielsko-Biala, Poland
    • Site 048007
  • Katowice, Poland
    • Site 048006
  • Konskie, Poland
    • Site 048005
  • Krakow, Poland
    • Site 048004
  • Lublin, Poland
    • Site 048001
  • Mielec, Poland
    • Site 048008
  • Piekary Slaskie, Poland
    • Site 048003
  • Rzeszow, Poland
    • Site 048010
  • Warszawa, Poland
    • Site 048009
  • Wroclaw, Poland
    • Site 048002
  • Wroclaw, Poland
    • Site 048011
• Portugal
  • Coimbra, Portugal
    • Site 351001
  • Faro, Portugal
    • Site 351003
  • Funchal, Portugal
    • Sites 351008
  • Guimaraes, Portugal
    • Site 351005
  • Lisboa, Portugal
    • Site 351004
  • Lisboa, Portugal
    • Site 351009
  • Ponta Delgada, Portugal
    • Site 351002
• Romania
  • Bucharest, Romania
    • Site 040001
  • Bucharest, Romania
    • Site 040002
  • Bucharest, Romania
    • Site 040005
  • Bucharest, Romania
    • Site 040006
  • Bucharest, Romania
    • Site 040007
  • Bucharest, Romania
    • Site 040008
  • Bucharest, Romania
    • Site 040009
  • Bucharest, Romania
    • Site 040011
  • Craiova, Romania
    • Site 040010
  • Câmpulung, Romania
    • Site 040004
• Slovakia
  • Banska Bystrica, Slovakia
    • Site 421005
  • Kosice, Slovakia
    • Site 421001
  • Poprad, Slovakia
    • Site 421003
  • Presov, Slovakia
    • Site 421004
  • Rimavska Sobota, Slovakia
    • Site 421002
• Spain
  • Alicante, Spain
    • Site 034002
  • Benidorm, Spain
    • Site 034009
  • L'Hospitalet de Llobregat, Spain
    • Site 034005
  • La roca del Valles, Spain
    • Site 034007
  • Malaga, Spain
    • Site 034015
  • Mostoles, Spain
    • Site 034008
  • Oviedo, Spain
    • Site 034003
  • Oviedo, Spain
    • Site 034013
  • Sevilla, Spain
    • Site 034016
  • Torrelavega, Spain
    • Site 034001
  • Valencia, Spain
    • Site 034012
  • Vic, Spain
    • Site 034004
• United Kingdom
  • Birmingham, United Kingdom
    • Site 044012
  • Blackpool, United Kingdom
    • Site 044004
  • Bradford, United Kingdom
    • Site 044009
  • Cardiff, United Kingdom
    • Site 044013
  • Chesterfield, United Kingdom
    • Site 044002
  • Chorley, United Kingdom
    • Site 044018
  • Ecclesfield, United Kingdom
    • Site 044005
  • Falkirk, United Kingdom
    • Site 044008
  • Kenton, United Kingdom
    • Site 044001
  • London, United Kingdom
    • Site 044006
  • London, United Kingdom
    • Site 044011
  • Reading, United Kingdom
    • Site 044016
  • Solihull, United Kingdom
    • Site 044003
  • Woolpit, United Kingdom
    • Site 044007

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 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 numeric 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 judgment;
• 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 severely impaired hepatic function or with laboratory values reflecting inadequate hepatic function,
• Treatment with neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, anticonvulsants, or anti-parkinsonian drugs, treatment with any other analgesic therapy than investigational medication or rescue medication during the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Matching Placebo (twice daily); The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Drug: Matching Placebo (twice daily); Matching Placebo during 15 weeks (3 weeks titration and 12 weeks maintenance)
EXPERIMENTAL: Tapentadol ER (100 to 250 mg twice daily); The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions.	Drug: Tapentadol ER (100 to 250 mg twice daily); 50, 100, 150, 200, 250 mg twice a day (BID) during 15 weeks (3 weeks titration and 12 weeks maintenance)
ACTIVE_COMPARATOR: Oxycodone CR (20 to 50 mg twice daily); The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions.	Drug: Oxycodone CR (20 to 50 mg twice daily); 10, 20, 30, 40, 50 mg twice a day (BID) during 15 weeks (3 weeks titration and 12 weeks maintenance)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline of the Average Pain Intensity Overall in the 12-week Maintenance Period of the Daily Pain Intensity on an 11-point Numeric Rating Scale (NRS).	For this twice daily pain assessment, the participants were required to indicate the level of pain experienced over the previous 12 hours on an 11-point Numeric Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The lower the value the less pain in the treatment group. Negative values indicate a reduction in pain.	Change from baseline over the 12 week Maintenance Period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	The twice daily pain assessments were averaged. The participants were to indicate their pain 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". The lower the value the less pain intensity.	Change from Baseline to Week 12 of the Maintenance Period
Patient Global Impression of Change	In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.	Baseline; End of 12 week maintenance period
Change From Baseline in the Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week of the Maintenance Period at Week 12	Change from baseline to week 12 of Western Ontario McMaster Questionnaire (WOMAC) Global Score: WOMAC is measured with a Likert ordinal scale (the participant gives one of 5 possible answers) from 0 to 4. Higher scores indicate that a symptom is bothersome and physically disabling.	Change from baseline to week 12 of the maintenance period
Time to Treatment Discontinuation Due to Lack of Efficacy	The median time to treatment discontinuation due to lack of efficacy from baseline to endpoint.	Baseline to week 12 of the maintenance period
Change in the Health Survey Scores Form (SF-36)	The Scores Form 36 (SF-36) includes several brief board questions on 8 aspects, (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a participant was asked to score over the last week. A higher score indicates an improvement in health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state.	Change From Baseline to Week 12 of the Maintenance Period
EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time	The participant scored the EuroQol-5. This 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. The positive values indicate that during the study the health status improved.	Comparison of Baseline to Week 12 of the Maintenance Period
Sleep Questionnaire: Change From Baseline in Sleep Latency Time in Hours to the Last Week of the Maintenance Period.	The Sleep Questionnaire addressed the following question: "How long after bedtime/lights out did you fall asleep last night(hours)?". The mean change from baseline to 12 weeks was studied. Decrease in time, measured in hours, indicates an improvement.	Week 12 of the maintenance period compared to baseline
Sleep Questionnaire: Amount of Time Slept in Hours	The Sleep Questionnaire addressed the following question: "How long did you sleep last night?". The mean change for the number of hours slept during the night before from baseline to 12 weeks was studied.	Baseline to Week 12 of the maintenance period
Sleep Questionnaire: Number of Awakenings During Sleep	The Sleep Questionnaire addressed the following question: "How many times did you wake up during the night?". Sleep was assessed by the subject once a week during the entire double-blind treatment period. Reported are the baseline and end of maintenance period. Generally the less the number of awakenings the better the sleep.	Week 12 of the maintenance period compared with baseline
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire)	The Sleep Questionnaire addressed the following question: "Please rate the overall quality of your sleep last night?" The quality of sleep at baseline and prior to completion of treatment are reported. The participant can choose one of the following options: Excellent, good, fair and poor.	Week 12 of the maintenance period compared to baseline
Patient Assessment of Constipation Symptoms (PAC-SYM) Over Time	The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assesses the severity of symptoms of constipation. Participants are asked "How severe have each of these symptoms been in the last two weeks?" e.g. "Pain in your stomach". There are 3 subscales: 4 questions on Abdominal symptoms, 3 on rectal symptoms and 5 on stool symptoms. Responses are rated on a 5-point Likert scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). If the changes in the overall or subscale scores are positive then there is a worsening in symptoms associated with constipation.	Change from Baseline to Week 12 of the Maintenance Period

Collaborators and Investigators

• Sponsor: Grünenthal GmbH
• Collaborators: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• Investigators: Principal Investigator: Alain Serrie, Dr., C.E.T.D Hôpital Lariboisière, Paris, France

Publications and helpful links

General Publications

• Etropolski M, Kuperwasser B, Flugel M, Haufel T, Lange B, Rauschkolb C, Laschewski F. Safety and tolerability of tapentadol extended release in moderate to severe chronic osteoarthritis or low back pain management: pooled analysis of randomized controlled trials. Adv Ther. 2014 Jun;31(6):604-20. doi: 10.1007/s12325-014-0128-6. Epub 2014 Jul 2.
• Biondi DM, Xiang J, Etropolski M, Moskovitz B. Evaluation of blood pressure and heart rate in patients with hypertension who received tapentadol extended release for chronic pain: a post hoc, pooled data analysis. Clin Drug Investig. 2014 Aug;34(8):565-76. doi: 10.1007/s40261-014-0209-y.
• Etropolski M, Lange B, Goldberg J, Steup A, Rauschkolb C. A pooled analysis of patient-specific factors and efficacy and tolerability of tapentadol extended release treatment for moderate to severe chronic pain. J Opioid Manag. 2013 Sep-Oct;9(5):343-56. doi: 10.5055/jom.2013.0177.
• Merchant S, Provenzano D, Mody S, Ho KF, Etropolski M. Composite measure to assess efficacy/gastrointestinal tolerability of tapentadol ER versus oxycodone CR for chronic pain: pooled analysis of randomized studies. J Opioid Manag. 2013 Jan-Feb;9(1):51-61. doi: 10.5055/jom.2013.0147.
• Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician. 2013 Jan;16(1):27-40.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (ACTUAL): July 1, 2008
• Study Completion (ACTUAL): July 1, 2008

Study Registration Dates

• First Submitted: June 14, 2007
• First Submitted That Met QC Criteria: June 14, 2007
• First Posted (ESTIMATE): June 15, 2007

Study Record Updates

• Last Update Posted (ACTUAL): October 18, 2019
• Last Update Submitted That Met QC Criteria: October 7, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Osteoarthritis; Knee; Placebo; Tapentadol; Centrally acting analgesic; Oxycodone; Pain Assessment; CG5503 PR; Chronic Pain due to knee Osteoarthritis
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee; Chronic Pain; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Uptake Inhibitors; Oxycodone; Tapentadol
• Other Study ID Numbers: 335862; 2006-005783-67 (EUDRACT_NUMBER)