Tapentadol (CG5503)

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

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).

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.

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.

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".

Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period).

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

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

Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12.

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.

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

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

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

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".

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

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.

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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