A Study to Evaluate the Effectiveness and Safety of CG5503 (Tapentadol) in the Treatment of Chronic Tumor Related Pain Compared With Placebo and Morphine

Study Overview
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Brief Summary
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The purpose of this study is to determine whether CG5503 (tapentadol) is effective and safe in the treatment of chronic tumor related pain compared to placebo.

Detailed Description
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Normally chronic tumor related pain is controlled when subjects receive repeated doses of opioid analgesics. However, opioid therapy is commonly associated with side effects such as nausea, vomiting, sedation, constipation, addiction, tolerance, and respiratory depression. Tapentadol, a newly synthesized drug with an Prolonged Release (ER) formulation, also acts as a centrally acting pain reliever but has a dual mode of action. The aim of this trial is to investigate the effectiveness (level of pain control) and safety (side effects) of Tapentadol Prolonged Release (ER) compared to a tablet with no active ingredient drug (placebo) and a corresponding dose of Morphine (an opioid commonly used to treat tumor related pain). This trial is a randomized, double-blind (neither investigator nor patient will know which treatment was received), active- and placebo-controlled, parallel-group, randomized-withdrawal, multicenter trial. To maintain the blind all subjects were re-randomized at the start of the maintenance period. To maintain the blind all tapentadol subjects were re-randomized at the start of the maintenance period. Subjects that received morphine in the titration period continued in the maintenance period on morphine. The trial includes a 2 week titration phase starting with either 45 mg Morphine Sulfate Controlled Release (CR) twice daily or 100 mg tapentadol ER taken twice daily (bid). Based on effectiveness and side effects participants can up-titrate in steps of 50 mg Tapentadol ER or 15 mg Morphine Sulfate CR to a maximal dose of 250 mg Tapentadol ER bid or 90 mg Morphine Sulfate CR twice daily respectively. If subjects meet the stabilization criteria at the end of the titration phase they will be re-randomized to either placebo or active treatment and will continue 4 weeks at the last dose level in the maintenance phase. Assessments of pain relief, defined as a responder include the pain intensity numeric rating scale (NRS). The Patient Global Impression of Change scale (PGIC) will also be used as a secondary efficacy endpoint. Safety evaluations include monitoring of adverse events, physical examinations, and clinical laboratory tests. Venous blood samples will be collected for the determination of serum concentrations of tapentadol.

Official Title
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A Randomized Withdrawal, Active- and Placebo-controlled, Double-blind, Multi-center Phase III Trial Assessing Safety and Efficacy of Oral CG5503 (Tapentadol) Prolonged Release (PR*) in Subjects With Moderate to Severe Chronic Malignant Tumor-related Pain. *Prolonged Release and is the Recommended Nomenclature for Use in the European Union (EU). ER Means Extended Release and is the Recommended Nomenclature for Use in the United States of America (USA). PR is Synonymous With ER and is Interchangeable.

Conditions
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Pain, Neoplasm, Cancer

Intervention / Treatment
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* Drug: Tapentadol in the Titration Phase
* Drug: Morphine in the Maintenance Phase
* Drug: Matching Placebo in the Maintenance Phase after Tapentadol in the Titration Phase
* Drug: Tapentadol in the Maintenance Phase
* Drug: Morphine in the Titration Phase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A signed informed consent document. Male and non-pregnant, non-lactating female subjects. Female subjects must be post menopausal, surgically sterile, or practicing an effective method of birth control and continue to do so throughout the trial. At least 18 years of age. Have chronic malignant tumor-related pain Are opioid-naïve or have been pretreated with an equianalgesic dose range equivalent of up to 160 mg oral morphine per day and are dissatisfied with prior treatment. Have a mean pain intensity of at least 5 points on an 11-point Numeric Rating Scale (where 0 indicates no pain and 10 indicates worst possible pain). Have an expected course of the disease such that the pain that will permit compliance with the trial protocol over the entire trial period. Exclusion Criteria: Have a life-long history of seizure disorder or epilepsy. Have had any of the following within one year: mild/moderate traumatic brain injury, stroke, and transient ischemic attack. Have had severe traumatic brain injury within 15 years (consisting of ≥ 1 of the following: brain contusion, intracranial hematoma, and either unconsciousness or post-traumatic amnesia lasting for more than 24 hours) or residual sequelae suggesting transient changes in consciousness. Have a known history and/or presence of cerebral metastases. Have moderately or severely impaired hepatic function. Have laboratory values reflecting inadequate hepatic function. Have thrombopenia, leucopenia or hypercalcemia Have severely impaired renal function. Having uncontrolled hypertension Having clinically relevant history of hypersensitivity, allergy or contraindications to morphine or any of the excipients. Have chronic hepatitis B or hepatitis C, or Human Immunodeficiency Virus (HIV). Subjects currently undergoing the following concomitant therapy: radiotherapy, pain inducing chemotherapy, anti-parkinsonian drugs, neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine re-uptake inhibitors (SNRI) or any other analgesic therapy than investigational medication or rescue medication during the trial. Selective serotonin re-uptake inhibitor (SSRI) treatments are allowed if taken for at least 30 days before the screening period of the trial at an unchanged dose.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Placebo Comparator: Matching Placebo<br>Oral Tapentadol 100 mg to 250 mg twice daily. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase). | Drug: Matching Placebo in the Maintenance Phase after Tapentadol in the Titration Phase<br>* Participant randomized to placebo in the maintenance phase received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off of the tapentadol dose they had received in the titration period. From the fourth day of the maintenance period onwards they received placebo twice daily.<br>|
| Active Comparator: Morphine Controlled Release<br>Oral Morphine 45 mg to 90 mg twice daily. | Drug: Morphine in the Maintenance Phase<br>* Participant started the trials with 45 mg morphine controlled release twice daily. Upward titration could then occur at a minimum of 3-day intervals in increments of 15 mg morphine twice daily. The maximum dose of morphine controlled release was 90 mg twice daily. Downward titration (but not below 45 mg twice daily) was permitted. In the maintenance phase participants continued on the dose level established in titration phase. Participants randomized to the morphine arm remained on morphine if they qualified for the maintenance phase of the study. The participants were maintained on the dose established at the end of the titration phase. The adverse events listed were documented in the maintenance phase.<br>* Other names: MS Contin overencapsulated for blinding;Drug: Morphine in the Titration Phase<br>* After signing informed consent eligible subjects were randomized to receive morphine controlled release. The oral medication was taken twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses). Participant started the trials with 45 mg morphine controlled release twice daily. Upward titration could then occur at a minimum of 3-day intervals in increments of 15 mg morphine twice daily. The maximum dose of morphine controlled release was 90 mg twice daily. Downward titration (but not below 45 mg twice daily) was permitted.<br>|
| Experimental: Tapentadol Extended Release<br>Oral Tapentadol 100 mg to 250 mg twice daily. | Drug: Tapentadol in the Titration Phase<br> <br> * Other names: Nucynta;Drug: Tapentadol in the Maintenance Phase<br>* The participants re-randomized to receive tapentadol prolonged release in the maintenance phase were maintained on the dose established in the titration phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder Rates in Maintenance Period | A responder is a participant in the study that: completed 28 days of the maintenance phase had a numeric rating scale score below 5 on the 11 point scale (where 0 indicates no pain and 10 indicates worst possible pain. This twice daily current pain score was averaged over Day 18 to Day 43. did not use more than 30 mg of rescue medication per day on average in the 28 day (excluding the first 3 days) maintenance period (from Day 18 to Day 43). A participant that met all 3 of the above-mentioned criteria is counted as a responder, in other words the participant benefited from the assigned drug treatment. A participant that fails to meet at least 1 of the 3 criteria is not counted as a responder. | End of the 4 week Maintenance Phase (Day 43) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Global Impression of Change (PGIC) | The Patient Global Impression of Change (PGIC) is an instrument where the participant indicates their perceived change at the end of a treatment phase. The overall participant status assessed using Patient Global Impression of Change (PGIC) self-assessment questionnaire which was used by participants to report on 7 categories listed as follows; Very Much Improved, Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse and Very Much Worse in tapentadol and morphine at Day 15 (Start of Maintenance Phase) and repeated in participants completing the Maintenance Phase in the Matching Placebo, Tapentadol and Morphine (Day 43). | Day 15 corresponds with PGIC at end of titration phase; Day 43 corresponds with PGIC at end of maintenance phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Tumor Related Pain, Analgesic, Tapentadol Extended Release, Morphine Sulfate Controlled Release, Pain assessment, Placebo