A Study to Compare the Frequency of Constipation Symptoms With Tapentadol Immediate Release (IR) Treatment Versus Oxycodone IR Treatment in Patients With End-stage Joint Disease

Study Overview
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Brief Summary
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The purpose of this study is to compare bowel function/constipation that occurs during tapentadol treatment with that occuring during oxycodone treatment, as measured by the frequency of spontaneous bowel movements per week. The frequency of spontaneous bowel movements will be determined from a Bowel Function Patient Diary completed by the enrolled sujbects.

Detailed Description
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Chronic pain from end-stage degenerative joint disease is often moderate to severe in intensity and results in a relatively constant level of pain requiring continuous pain relief medication. Despite available pain relief medications, 60% to 80% of subjects suffering from chronic pain are currently inadequately treated. Opioid pain medications are central to the effective treatment of moderate to severe pain. However, opioid therapy is frequently complicated by side effects. Constipation is one of the most commonly reported side effects and most debilitating. An opioid medication that provides pain relief with a reduced incidence of constipation symptoms would improve the capability of subjects to stay on medication to achieve the long-term relief they need. This is a randomized, double-blind, placebo- and active-controlled, parallel-arm, multicenter study with 4 treatment groups of subjects who have moderate to severe chronic pain from end-stage degenerative joint disease of the hip or knee and who are candidates for primary total or partial joint replacement. The study consists of 3 periods: a pretreatment period (a 14-day screening for study eligibility and a 7-day washout of any previously taken opioid medication), a double-blind treatment period (a 14-day IR treatment phase followed by a 28-day ER treatment phase), and a follow-up period (1 study-site visit within 4 days after the last dose of study drug is taken and 1 telephone contact within 10 to 14 days after the last dose of study drug is taken). On Day 1 of the IR treatment phase, patients will be randomly assigned to 1 of 4 possible treatment groups to receive 50 mg CG5503 IR, 75 mg CG5503 IR, 10 mg oxycodone IR, or placebo daily every 4 to 6 hours. At the beginning of the ER treatment phase, patients' study drugs will be transitioned to the ER form (by conversion from the IR to approximate equivalent total daily doses of the ER form) of their randomly assigned study drug of tapentadol ER, oxycodone CR, or placebo. The ER study drugs will be taken every 12 hours b.i.d. Dosages will be adjustable, with the study site personnel oversight, to ensure adequate pain relief is provided. Beginning with the washout period, patients will be given hand-held computer diaries in which to record their pain intensity, pain relief, bowel movement information, and answer questions on any nausea or vomiting that may occur. In addition, patients will write down the times and dosages of all medications they take during the study in a medication diary. Safety and tolerability will be assessed using physical examination, monitoring of adverse events, clinical and laboratory measures, and 12 lead ECG results. The first study hypothesis is that both tapentadol IR dosages are more effective than placebo in relieving pain based on the SPID score recorded by the patients over the first 5 days of the study. The second study hypothesis is that the Bowel Function Patient Diary results for both tapentadol IR dosages demonstrate improved tolerability compared to oxycodone IR 10 mg, based on the number of spontaneous bowel movements per week over the first 2 weeks of the study. In the IR treatment phase, each patient will take CG5503 IR 50 mg, CG5503 IR 75 mg, oxycodone IR 10 mg, or placebo orally every 4 to 6 hours for 14 days. In the ER treatment phase, dosages of the IR treatment groups will be converted to approximately equivalent dosages of the ER form of the assigned study drug: tapentadol ER, oxycodone CR, or placebo. Dosages may range from 100 to 500 mg/day of tapentadol ER and 20 to 60 mg/day of oxycodone CR taken orally 2x daily for 28 days.

Official Title
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A Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel-Arm, Multicenter Study in Subjects With End-Stage Joint Disease to Compare the Frequency of Constipation Symptoms in SubjectsTreated With Tapentadol IR and Oxycodone IR Using a Bowel Function Patient Diary

Conditions
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Joint Diseases, Arthritis, Osteoarthritis

Intervention / Treatment
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* Drug: oxycodone CR
* Drug: oxycodone IR
* Drug: Tapentadol ER (CG5503)
* Drug: Tapentadol IR (CG5503)
* Drug: Tapentadol IR (CG5503)
* Drug: placebo
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A clinical diagnosis of osteoarthritis of the hip or knee End-stage degenerative joint disease Eligibility for primary unilateral total or partial joint replacement surgery Pain level moderate to severe and at such a level as to require daily doses of an opioid analgesic medication Exclusion Criteria: Has a life-long history of seizure disorder or epilepsy Had any of the following within the preceding 1 year: mild or moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm Had a severe traumatic brain injury within 15 years of screening (consisting of one or more of the following: brain contusion, intracranial hematoma, either unconsciousness or post traumatic amnesia lasting for more than 24 hours) Joint pain not associated with gout, fibromyalgia, rheumatoid arthritis, other autoimmune disease History of alcohol or drug abuse chronic hepatitis B and C or HIV, active hepatitis B and C within 3 months Severely impaired renal function or moderately to severely impaired hepatic function History of cancer within past 2 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>Tapentadol IR (CG5503) 50mg for 14 days | Drug: Tapentadol IR (CG5503)<br>* 50mg for 14 days<br>|
| Experimental: 002<br>Tapentadol IR (CG5503) 75mg for 14 days | Drug: Tapentadol IR (CG5503)<br>* 75mg for 14 days<br>|
| Active Comparator: 003<br>oxycodone IR 10mg for 14 days | Drug: oxycodone IR<br>* 10mg for 14 days<br>|
| Placebo Comparator: 004<br>placebo 1 capsule for 14 days | Drug: placebo<br>* 1 capsule for 14 days<br>|
| Experimental: 005<br>Tapentadol ER (CG5503) flexible dose tablets and capsules 2 x a day for 28 days (100-500mg/day) | Drug: Tapentadol ER (CG5503)<br>* flexible dose tablets and capsules 2 x a day for 28 days (100-500mg/day)<br>|
| Active Comparator: 006<br>oxycodone CR flexible dose tablets and capsules 2 x a day for 28 days (20-60mg/day) | Drug: oxycodone CR<br>* flexible dose tablets and capsules 2 x a day for 28 days (20-60mg/day)<br>|
| Placebo Comparator: 007<br>placebo Tablets and capsules 2 x a day for 28 days | Drug: placebo<br>* Tablets and capsules 2 x a day for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-Day Sum of Pain Intensity Difference (SPID5) | SPID5 was calculated as the weighted (weights is taken as the number of hours elapsed since the previous measurement) sum of the PID collected up to 5 days. Pain intensity (PI) score is calculated as the average PI over the past 12 hours using an 11-point (0 to 10) numerical rating scale (NRS) where 0 is no pain and 10 is pain as bad as you can imagine. The difference between baseline PI at the qualifying period and current PI is pain intensity difference (PID). | Day 1 to Day 5 | 
| Spontaneous Bowel Movements Per Week (SBMs/Week) | The number of SBM over the 14-day IR treatment phase was determined from the Bowel Function Patient Diary and factored to enable a per week value to be used. An SBM is defined as any BM that has occurred without the use of a laxative, enema, suppository, or manual manipulation within the previous 24 hours. | Week 1 to Week 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain medication, Arthritis, Joint pain, Analgesia, Analgesics, tapentadol, CG5503, Nucynta