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

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.

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.

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.

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.