A Safety and Efficacy Study of JNS024 Extended Release (ER) in Japanese and Korean Patients With Chronic Malignant Tumor-Related Cancer Pain

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of R331333 (referred to as JNS024 Extended-Release (ER) or CG5503) compared with an active comparator (oxycodone Controlled Release (CR)) in Japanese and Korean patients with chronic, malignant, tumor-related cancer pain.

Detailed Description
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This is a randomized (study drug assigned by chance), double-blind (neither the patient nor the study staff will know the identity of the study drug assigned to each patient), multicenter study to evaluate the safety and efficacy of orally (by mouth) administered R331333 (referred to as JNS024 extended release [ER] capsules or CG5503) in dosages of 25 mg to 200 mg twice daily compared with orally administered capsules of oxycodone controlled release (CR) in dosages of 5 mg to 40 mg twice daily over 4 weeks in Japanese and Korean patients with moderate to severe chronic malignant tumor-related cancer pain who require around-the-clock opioid therapy (treatment with narcotic analgesics or pain relievers) and are dissatisfied with the pain relief they are experiencing from current treatment. The active control, oxycodone CR, is being used in this study because it is an opioid analgesic approved for the treatment of moderate to severe pain. Approximately 212 Japanese patients and approximately 100 Korean patients who meet screening criteria for the study will be enrolled in the study and will enter the titration period of the study where they will receive a starting dosage of either JNS024 ER 25 mg twice daily or oxycodone CR 5 mg twice daily. The dose of study drug for each patient will be titrated (increased) to the optimal dose until sufficient analgesia (pain relief) is achieved (ie, up to a maximum dose of JNS024 ER 200 mg twice daily or Oxycodone CR 40 mg twice daily). When the dosage of study drug is increased, the safety will be confirmed at the study visit or by telephone on the day after the dose is increased. Once an optimal dose of study drug is determined, the patient will continue to receive that dose during the maintenance period in the study. Patients will participate in the study for total of approximately 6 weeks; during this time patients will receive study drug for 4 weeks (titration and maintenance periods combined). During the study, if a patient experiences breakthrough pain (pain that occurs for short periods of time between doses of study drug), treatment with rescue medication (morphine immediate release [IR] 5 mg) will be given. In addition, patients will be allowed to continue to take stable doses of non-opioid analgesics (non-narcotic pain medications for mild to moderate pain) that they were taking at the time of study entry and may reduce the dosage or discontinue their use during the study. During the study, blood samples will be collected from patients at protocol-specified time points to determine the concentration of study drug after administration. The safety of patients will be monitored during the study by evaluating adverse events and findings from clinical laboratory tests, physical examinations, vital signs measurements, and electrocardiogram (ECG) measurements reported. The primary outcome measure in the study will be the change from baseline to the last 3 days of study drug administration in the average pain intensity score using an 11 point numerical rating scale (NRS). Patients will receive R331333 (referred to as JNS024 ER or CG5503) by mouth with or without food at a starting dose of 25 mg twice daily to be increased if necessary to a maximum dose of 200 mg twice daily for a total of 4 weeks (titration and maintenance periods combined) OR double-blind oxycodone CR by mouth with or without food at a starting dose of 5 mg twice daily to be increased if necessary to a maximum dose of 40 mg twice daily for a total of 4 weeks.

Official Title
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A Randomized, Double-Blind, Active Controlled, Optimal Dose Titration, Multicenter Study to Evaluate the Safety and Efficacy of Oral JNS024 Extended Release (ER) in Japanese and Korean Subjects With Moderate to Severe Chronic Malignant Tumor Related Cancer Pain

Conditions
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Pain

Intervention / Treatment
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* Drug: Oxycodone CR
* Drug: R331333 (referred to as JNS024 ER or CG5503)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented clinical diagnosis of any type of cancer Diagnosis of chronic malignant tumor-related cancer pain with an average score for pain intensity in the past 24 hours of >=4 on the 11-point numerical rating scale (NRS) on the day of randomization (Day -1) Have not received treatment with opioid analgesics within 28 days before screening (Note: codeine phosphate [<=60 mg/d] or dihydrocodeine phosphate [<=30 mg/d] for antitussive use are allowed) Dissatisfied with pain relief by the current treatment and for whom the investigator or designee judges that treatment with opioid analgesics is required Exclusion Criteria: Have complicated with uncontrolled/clinically significant arrhythmia Have previous or concurrent presence of any disease which may develop increased intracranial pressure, disturbance of consciousness, lethargy, or respiratory problems such as traumatic encephalopathy with cerebral contusion, intracranial hematoma, disturbance of consciousness, brain tumor, cerebral infarction, transient ischemic attack, epilepsy or convulsive diseases Have history of alcohol and/or drug abuse Have any disease for which opioids are contraindicated such as serious respiratory depression of serious chronic obstructive pulmonary disease, bronchial asthma attack, cardiac failure secondary to chronic pulmonary disease, paralytic ileus, status epileptics, tetanus, strychnine poisoning, acute alcohol poisoning, hypersensitivity to opium alkaloid, hemorrhagic colitis, or bacterial diarrhea

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 99 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>R331333 (referred to as JNS024 ER or CG5503) One 25 mg to 200 mg capsule twice daily for 4 weeks. | Drug: R331333 (referred to as JNS024 ER or CG5503)<br>* One 25 mg to 200 mg capsule twice daily for 4 weeks.<br>|
| Active Comparator: 002<br>Oxycodone CR One 5 mg to 40 mg capsule twice daily for 4 weeks. | Drug: Oxycodone CR<br>* One 5 mg to 40 mg capsule twice daily for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to the Last 3 Days of Study Drug Administration (Last Observation Carried Forward) in the Score for Average Pain Intensity on an 11-point Numerical Rating Scale | The patients recorded their average pain intensity over the past 24 hours once daily in the evening and at the same time as much as possible (eg, 10:00 PM) throughout the study in response to the following question: What has your average pain level been for the past 24 hours, where 0=no pain and 10=pain as bad as you can imagine. The score at 3 days before the completion of study drug administration was defined as the average pain intensity score averaged over the last 3 days before completion of study drug administration. | Baseline, Last 3 Days of Study Drug Administration (4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients in Patient Global Impression of Change (PGIC) Score Categories | The PGIC was rated by the patient and was based on the single question Since the start of this treatment, my cancer-related pain overall is, where 1=very much improved, 2=much improved, 3=minimally improved, 4=not changed, 5=minimally worse, 6=much worse, 7=very much worse. | Baseline, Endpoint of the 4-week Treatment Period | 
| Frequency of Rescue Medication Use for the Double-blind Treatment Period | During the study, if a patient experienced breakthrough pain (pain that occurs for short periods of time between doses of study drug), treatment with rescue medication (morphine immediate release [IR] 5 mg) was to be given. The average number of doses of Morphine IR taken per day was assessed. | 4 weeks | 
| Total Daily Dose of Rescue Medication Use for the Double-blind Treatment Period | During the study, if a patient experienced breakthrough pain (pain that occurs for short periods of time between doses of study drug), treatment with rescue medication (morphine immediate release [IR] 5 mg) was to be given. The average total daily dose of Morphine IR taken (mg) was assessed. | 4 weeks | 
| Proportion of Patients With Various Levels of Pain Improvement (Responders) | The proportion of patients with at least a 30 percentage improvement based on the percent change from baseline in Numerical Rating Scale score during the last 3 days of the double-blind treatment period. | Baseline, Last 3 Days of Study Drug Administration (4 weeks) | 
| Proportion of Patients Entering the Maintenance Period | Patients were eligible to formally enter the maintenance period if they had a pain intensity score of <=3 and did not take rescue medication more than twice daily while they were taking a stable regimen of study drug (6 identical consecutive doses) over a 3-day period. | 4 weeks | 
| Number of Patients Who Discontinued Due to Lack of Efficacy | The duration from the date of first study drug intake to treatment discontinuation due to lack of efficacy. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, R331333 (JNS024ER, CG5503), tapentadol (NUCYNTA), Opioid analgesic, Oxycodone CR (OXYCONTIN CR), Chronic malignant tumor related cancer pain