Pain
Conditions
Keywords
Pain, R331333 (JNS024ER, CG5503), tapentadol (NUCYNTA), Opioid analgesic, Oxycodone CR (OXYCONTIN CR), Chronic malignant tumor related cancer pain
Brief summary
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
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.
Interventions
DRUGOxycodone CR
One 5 mg to 40 mg capsule twice daily for 4 weeks.
DRUGR331333 (referred to as JNS024 ER or CG5503)
One 25 mg to 200 mg capsule twice daily for 4 weeks.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, Last 3 Days of Study Drug Administration (4 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Rescue Medication Use for the Double-blind Treatment Period | 4 weeks | 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. |
| Total Daily Dose of Rescue Medication Use for the Double-blind Treatment Period | 4 weeks | 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. |
| Percentage of Patients in Patient Global Impression of Change (PGIC) Score Categories | Baseline, Endpoint of the 4-week Treatment Period | 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. |
| Proportion of Patients Entering the Maintenance Period | 4 weeks | 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. |
| Number of Patients Who Discontinued Due to Lack of Efficacy | 4 weeks | The duration from the date of first study drug intake to treatment discontinuation due to lack of efficacy. |
| Proportion of Patients With Various Levels of Pain Improvement (Responders) | Baseline, Last 3 Days of Study Drug Administration (4 weeks) | 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. |
Countries
Japan, South Korea
Participant flow
Recruitment details
To evaluate the safety and efficacy of tapentadol ER compared with oxycodone CR in Japanese and Korean patients with moderate to severe chronic cancer pain. This study was conducted from 25 Aug 2010 to 16 Aug 2012 at 69 sites in Japan and Korea. A total of 340 patients received at least 1 dose of study drug and were included in the safety analyses.
Participants by arm
| Arm | Count |
|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets Patients received tapentadol (ER) 25 to 200 mg twice daily for 4 weeks. During the titration period, the dose was titrated to the individual's optimal dose balancing efficacy and tolerability until sufficient analgesia was attained. 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. During the maintenance period, patients continued to take their optimized dose of study drug achieved during the titration period. Dosage adjustments of study drug were allowed during the titration and maintenance periods, with the exception of the last 3 days of the maintenance period when the dose was to remain unchanged. | 168 |
| Oxycodone Controlled-release (CR) Oral Tablets Patients received oxycodone controlled-release (CR) 5 to 40 mg twice daily for 4 weeks. During the titration period, the dose was titrated to the individual's optimal dose balancing efficacy and tolerability until sufficient analgesia was attained. 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. During the maintenance period, patients continued to take their optimized dose of study drug achieved during the titration period. Dosage adjustments of study drug were allowed during the titration and maintenance periods, with the exception of the last 3 days of the maintenance period when the dose was to remain unchanged. | 172 |
| Total | 340 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 14 |
| Overall Study | Death | 3 | 4 |
| Overall Study | Lack of Efficacy | 4 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Noncompliance with Study Drug | 1 | 4 |
| Overall Study | Other | 6 | 0 |
| Overall Study | Physician Decision | 8 | 1 |
| Overall Study | Progressive Disease | 10 | 14 |
| Overall Study | Protocol Violation | 6 | 5 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Oxycodone Controlled-release (CR) Oral Tablets | Total | Tapentadol (JNS024) Extended-release (ER) Oral Tablets |
|---|---|---|---|
| Age, Continuous | 64.9 years STANDARD_DEVIATION 11.41 | 65.2 years STANDARD_DEVIATION 11.3 | 65.5 years STANDARD_DEVIATION 11.21 |
| Age Customized <65 years | 79 Participants | 156 Participants | 77 Participants |
| Age Customized >=65 years | 93 Participants | 184 Participants | 91 Participants |
| Region of Enrollment Japan | 110 participants | 221 participants | 111 participants |
| Region of Enrollment Korea | 62 participants | 119 participants | 57 participants |
| Sex: Female, Male Female | 72 Participants | 150 Participants | 78 Participants |
| Sex: Female, Male Male | 100 Participants | 190 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 110 / 168 | 127 / 172 |
| serious Total, serious adverse events | 78 / 168 | 69 / 172 |
Outcome results
Primary
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.
Time frame: Baseline, Last 3 Days of Study Drug Administration (4 weeks)
Population: Per-protocol population included all patients who were randomized, received at least 1 dose of study drug, had post-baseline efficacy data and didn't have major protocol deviations (including use of prohibited concomitant medications, non-compliance, failure to meet selection criteria, violation of regulatory requirements, or treatment deviation).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | 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 | -2.69 Scores on scale | Standard Deviation 2.223 |
| Oxycodone Controlled-release (CR) Oral Tablets | 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 | -2.57 Scores on scale | Standard Deviation 2.027 |
Comparison: The primary hypothesis to be tested for the study was that the JNS024 ER group was not inferior to oxycodone CR as defined by the upper limit of the 95% confidence interval of the difference between JNS024 ER and oxycodone CR on the mean change from baseline of the NRS pain intensity score during the last 3 days of study drug administration. It was to be concluded that JNS024 ER is not inferior to oxycodone CR if the upper 95% confidence limit is less than 1 point.p-value: 0.78695% CI: [-0.506, 0.383]ANCOVA
Secondary
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.
Time frame: 4 weeks
Population: This is a subset of the per-protocol population that included patients who received at least 1 dose of rescue medication. The per-protocol population included all patients who were randomized, received at least 1 dose of study drug, had post-baseline efficacy data and didn't have major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Frequency of Rescue Medication Use for the Double-blind Treatment Period | 1.39 Number of doses per day | Standard Deviation 0.46 |
| Oxycodone Controlled-release (CR) Oral Tablets | Frequency of Rescue Medication Use for the Double-blind Treatment Period | 1.35 Number of doses per day | Standard Deviation 0.431 |
Secondary
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.
Time frame: 4 weeks
Population: Time to discontinuation due to lack of efficacy was not analyzed since there was only 1 patient in the per-protocol set (in the tapentadol group) who discontinued treatment due to lack of efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Number of Patients Who Discontinued Due to Lack of Efficacy | 1 Number of participants |
| Oxycodone Controlled-release (CR) Oral Tablets | Number of Patients Who Discontinued Due to Lack of Efficacy | 0 Number of participants |
Secondary
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.
Time frame: Baseline, Endpoint of the 4-week Treatment Period
Population: Per-protocol population included all patients who were randomized, received at least 1 dose of study drug, had post-baseline efficacy data and didn't have major protocol deviations (including use of prohibited concomitant medications, non-compliance, failure to meet selection criteria, violation of regulatory requirements, or treatment deviation).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Percentage of Patients in Patient Global Impression of Change (PGIC) Score Categories | Percentage much improved or very much improved | 58.7 Percentage of Participants |
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Percentage of Patients in Patient Global Impression of Change (PGIC) Score Categories | Percentage much worse or very much worse | 4.0 Percentage of Participants |
| Oxycodone Controlled-release (CR) Oral Tablets | Percentage of Patients in Patient Global Impression of Change (PGIC) Score Categories | Percentage much improved or very much improved | 50.4 Percentage of Participants |
| Oxycodone Controlled-release (CR) Oral Tablets | Percentage of Patients in Patient Global Impression of Change (PGIC) Score Categories | Percentage much worse or very much worse | 1.4 Percentage of Participants |
Secondary
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.
Time frame: 4 weeks
Population: Per-protocol population included all patients who were randomized, received at least 1 dose of study drug, had post-baseline efficacy data and didn't have major protocol deviations (including use of prohibited concomitant medications, non-compliance, failure to meet selection criteria, violation of regulatory requirements, or treatment deviation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Proportion of Patients Entering the Maintenance Period | 86 Percentage of Participants |
| Oxycodone Controlled-release (CR) Oral Tablets | Proportion of Patients Entering the Maintenance Period | 80 Percentage of Participants |
Secondary
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.
Time frame: Baseline, Last 3 Days of Study Drug Administration (4 weeks)
Population: Per-protocol population included all patients who were randomized, received at least 1 dose of study drug, had post-baseline efficacy data and didn't have major protocol deviations (including use of prohibited concomitant medications, non-compliance, failure to meet selection criteria, violation of regulatory requirements, or treatment deviation).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Proportion of Patients With Various Levels of Pain Improvement (Responders) | Proportion with at least a 30 percent improvement | 63.5 Percentage of Participants |
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Proportion of Patients With Various Levels of Pain Improvement (Responders) | Proportion with at least a 50 percent improvement | 50.0 Percentage of Participants |
| Oxycodone Controlled-release (CR) Oral Tablets | Proportion of Patients With Various Levels of Pain Improvement (Responders) | Proportion with at least a 30 percent improvement | 59.0 Percentage of Participants |
| Oxycodone Controlled-release (CR) Oral Tablets | Proportion of Patients With Various Levels of Pain Improvement (Responders) | Proportion with at least a 50 percent improvement | 42.4 Percentage of Participants |
Secondary
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.
Time frame: 4 weeks
Population: This is a subset of the per-protocol population that included patients who received at least 1 dose of rescue medication. The per-protocol population included all patients who were randomized, received at least 1 dose of study drug, had post-baseline efficacy data and didn't have major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol (JNS024) Extended-release (ER) Oral Tablets | Total Daily Dose of Rescue Medication Use for the Double-blind Treatment Period | 6.95 Milligrams | Standard Deviation 2.302 |
| Oxycodone Controlled-release (CR) Oral Tablets | Total Daily Dose of Rescue Medication Use for the Double-blind Treatment Period | 6.73 Milligrams | Standard Deviation 2.153 |