Cancer, Chronic Pain, Pain
Conditions
Keywords
analgesia, analgesics, chronic pain, tumour related pain, chronic malignant tumor-related pain
Brief summary
The purpose of this trial is the characterization of the long term safety profile and long-term dose requirements of tapentadol PR (prolonged release) in patients with malignant tumor-related pain. In the United States the prolonged-release formulation is also referred to as the extended-release formulation.
Detailed description
The prevalence of tumor-related pain is high and the treatment of chronic tumor-related pain remains a challenging therapeutic problem. Participants directly entering the KF5503/52 trial from the KF5503/15 trial (i.e., within 7 days of Visit 8 of the KF5503/15 trial) is scheduled: a Transfer Visit, an Open-label Treatment Period and a Follow-up Period. For participants with a gap of more than 7 days and less than 24 weeks, between their full completion of the KF5503/15 trial and entry into the KF5503/52 trial the following is scheduled: an Enrollment Visit, an Entry Visit for assessment of eligibility, an Open-label Treatment Period and a Follow-up Period. This trial was designed to offer patients with chronic malignant tumor-related pain the option of continuing treatment by receiving tapentadol prolonged release (PR). The protocol scheduled visits every 28 days during the open-label treatment period. Unscheduled visits (or at least unscheduled telephone calls) were planned when dose adjustment is required. If a visit is not possible at the time of dose change, it could be done up to 7 days later. Unscheduled visits could also be performed whenever considered necessary (i.e., for evaluation of adverse events).
Interventions
Titration to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerates and wishes to continue treatment.
Sponsors
Grünenthal GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have signed an Informed Consent Form. * At least 18 years of age. * Male and non-pregnant, non-lactating female subjects. Sexually active women must be post menopausal, surgically sterile, or practicing an effective method of birth control before entry and throughout the trial. Female participants of child-bearing potential must have a negative pregnancy test at enrollment. * Within 24 weeks of either full completion or completion of the double-blind treatment period (Visit 8) of KF5503/15 trial performed in participants with moderate to severe chronic malignant tumor related pain. * Participant is, in the opinion of the investigator, expected to continue to have an overall positive benefit/risk ratio from continuing analgesic treatment within this trial. * Participant must be willing to take tapentadol prolonged release (PR) throughout their participation in the trial.
Exclusion criteria
* History of alcohol and/or drug abuse. * The participant has a clinically significant disease other than cancer that in the Investigator's opinion may affect the safety of the participant. * Employees of the investigator or trial center or family members of the employees or the investigator. * Known to or suspected of not being able to comply with the protocol and the use of tapentadol prolonged release (PR). * Concurrent participation in another trial (except for participation in the KF5503/15 trial) or planning to be enrolled in another clinical trial during the course of this trial. * Previous participation in another trial between the end of KF5503/15 and enrollment into the current trial, KF5503/52. * History of seizure disorder, epilepsy, traumatic brain injury, stroke or transient ischemic attack. * Known history and/or presence of cerebral tumors or metastases. * Rapidly escalating pain or pain uncontrolled by therapy and was previously treated with maximum dose level of Investigational Medicinal Product. * Participant is taking any prohibited concomitant medications. * Uncontrolled hypertension. * Known moderate or severe hepatic impairment. * Known severe renal impairment. * Clinically relevant history of hypersensitivity, allergy, or contraindications to tapentadol or its excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time Dependence of Adverse Events | Day 1; 144 weeks | The onset and duration of TEAEs was not evaluated for this trial. |
| Severity of Adverse Events | Day 1; up to 144 weeks | The severity of treatment emergent adverse events was any untoward medical occurrence in a patient administered tapentadol. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of the (investigational) medicinal product whether or not related to the use of tapentadol. The clinical intensity of adverse event were classified as: Mild: signs and symptoms which can be easily tolerated. Symptoms could be ignored and disappeared when the participant is distracted. Moderate: symptoms caused discomfort but were tolerable, they could not be ignored and affect concentration. Severe: symptoms affected the usual daily activity. |
| Relatedness Assessment of Treatment Emergent Adverse Events | Day 1; up to 144 weeks | Participant-based analysis of treatment emergent adverse events (TEAEs) regarding the relationship to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The relationship was rated by the investigator. The categorization of relatedness into one of the two categories was based on the following: Related included possible, probable/likely, and certain; whilst unrelated treatment emergent adverse events include those rated by the investigator as unlikely, conditional/unclassified, un-assessable/unclassifiable, and not related. |
| Countermeasures Taken Due to Treatment Emergent Adverse Events | Day 1; up to 144 weeks | Participant-based analysis of treatment emergent adverse events (TEAEs) regarding countermeasure to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The countermeasure taken by the investigator were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess Consumption of Tapentadol During Long Term Use | Day 1; up to 144 weeks | Summary of the modal total daily dose during the treatment period. The modal dose was based on assessment of the consecutive morning and evening intake amounts on each day and evaluation of the total daily dose. |
| Tapentadol Prolonged Release Exposure | Day 1; up to 144 weeks | The number of days that participants took tapentadol prolonged release. The extent of exposure was categorized into 2 periods, less than 90 days and more than 90 days (up to 144 weeks). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Average Pain Intensity (Over a Twelve-week Period) | Day 1; up to Week 144 | The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Average pain intensity score is the average of pain experienced for previous 24 hours as rated on an 11-point NRS at each visit. Calculations are based on 3 consecutive planned (at 4-weekly intervals) visits. All available data of a participant was used; if a participant dropped-out or had incomplete data during a 12-week period no imputations were performed for the missing values. |
| Average Daily Total Tapentadol Prolonged Release Dose | Day 1; up to 144 weeks | The Total Daily Dose (TDD) on any given day is the sum of the morning and evening intake amounts. The average TDD is an individuals average over the trial period. |
Countries
Bulgaria, Hungary, Moldova, Poland, Romania, Russia, Serbia
Participant flow
Recruitment details
First participant was enrolled on the 03 March 2011 and the last participant completed the trial on the 08 May 2014.
Participants by arm
| Arm | Count |
|---|---|
| Tapentadol Prolonged Release All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 7 |
| Overall Study | Lack of Efficacy | 5 |
| Overall Study | Other | 2 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Sponsor Decision Administrative Reasons | 2 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Tapentadol Prolonged Release |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Age, Continuous | 55.8 years STANDARD_DEVIATION 11.91 |
| Body Mass Index | 23.6 kg/m^2 STANDARD_DEVIATION 4.79 |
| Height | 165.0 centimeters STANDARD_DEVIATION 10.24 |
| Pain type Neuropathic | 23 participants |
| Pain type Nociceptive (somatic) | 26 participants |
| Pain type Visceral | 22 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 31 Participants |
| Region of Enrollment Bulgaria | 2 participants |
| Region of Enrollment Hungary | 4 participants |
| Region of Enrollment Moldova, Republic of | 6 participants |
| Region of Enrollment Poland | 5 participants |
| Region of Enrollment Romania | 5 participants |
| Region of Enrollment Russian Federation | 3 participants |
| Region of Enrollment Serbia | 6 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 15 Participants |
| Weight | 64.6 kilograms STANDARD_DEVIATION 16.45 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 31 |
| serious Total, serious adverse events | 14 / 31 |
Outcome results
Primary
Countermeasures Taken Due to Treatment Emergent Adverse Events
Participant-based analysis of treatment emergent adverse events (TEAEs) regarding countermeasure to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The countermeasure taken by the investigator were reported.
Time frame: Day 1; up to 144 weeks
Population: Safety Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Treatment Emergent Adverse Events | Countermeasures Taken Due to Treatment Emergent Adverse Events | All Treatment Emergent Events | 30 participants |
| Number of Treatment Emergent Adverse Events | Countermeasures Taken Due to Treatment Emergent Adverse Events | No Treatment Emergent Adverse Events | 1 participants |
| Number of Treatment Emergent Adverse Events | Countermeasures Taken Due to Treatment Emergent Adverse Events | No countermeasures taken | 5 participants |
| Number of Treatment Emergent Adverse Events | Countermeasures Taken Due to Treatment Emergent Adverse Events | Countermeasures with Medication | 17 participants |
| Number of Treatment Emergent Adverse Events | Countermeasures Taken Due to Treatment Emergent Adverse Events | Trial Discontinued Countermeasure | 6 participants |
| Number of Treatment Emergent Adverse Events | Countermeasures Taken Due to Treatment Emergent Adverse Events | Other Countermeasure due to Somnolence | 1 participants |
| Number of Treatment Emergent Adverse Events | Countermeasures Taken Due to Treatment Emergent Adverse Events | Other Countermeasure due to Migraine | 1 participants |
Primary
Relatedness Assessment of Treatment Emergent Adverse Events
Participant-based analysis of treatment emergent adverse events (TEAEs) regarding the relationship to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The relationship was rated by the investigator. The categorization of relatedness into one of the two categories was based on the following: Related included possible, probable/likely, and certain; whilst unrelated treatment emergent adverse events include those rated by the investigator as unlikely, conditional/unclassified, un-assessable/unclassifiable, and not related.
Time frame: Day 1; up to 144 weeks
Population: Safety Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Treatment Emergent Adverse Events | Relatedness Assessment of Treatment Emergent Adverse Events | No Treatment Emergent Adverse Events | 1 participants |
| Number of Treatment Emergent Adverse Events | Relatedness Assessment of Treatment Emergent Adverse Events | All Treatment Emergent Adverse Events | 30 participants |
| Number of Treatment Emergent Adverse Events | Relatedness Assessment of Treatment Emergent Adverse Events | Investigator-rated Related | 6 participants |
| Number of Treatment Emergent Adverse Events | Relatedness Assessment of Treatment Emergent Adverse Events | Investigator-rated Not Related | 24 participants |
Primary
Severity of Adverse Events
The severity of treatment emergent adverse events was any untoward medical occurrence in a patient administered tapentadol. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of the (investigational) medicinal product whether or not related to the use of tapentadol. The clinical intensity of adverse event were classified as: Mild: signs and symptoms which can be easily tolerated. Symptoms could be ignored and disappeared when the participant is distracted. Moderate: symptoms caused discomfort but were tolerable, they could not be ignored and affect concentration. Severe: symptoms affected the usual daily activity.
Time frame: Day 1; up to 144 weeks
Population: Safety Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Treatment Emergent Adverse Events | Severity of Adverse Events | mild intensity | 3 participants |
| Number of Treatment Emergent Adverse Events | Severity of Adverse Events | moderate intensity | 15 participants |
| Number of Treatment Emergent Adverse Events | Severity of Adverse Events | severe intensity | 12 participants |
Primary
Time Dependence of Adverse Events
The onset and duration of TEAEs was not evaluated for this trial.
Time frame: Day 1; 144 weeks
Population: No evaluation was performed.
Secondary
Assess Consumption of Tapentadol During Long Term Use
Summary of the modal total daily dose during the treatment period. The modal dose was based on assessment of the consecutive morning and evening intake amounts on each day and evaluation of the total daily dose.
Time frame: Day 1; up to 144 weeks
Population: The modal dose is based on assessment of the consecutive morning and evening intake amounts on each day and evaluation of the total daily dose.~No participant received more than 500 mg per day.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | 450 to less than 500 mg/day | 0 participants |
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | 500 mg/day | 8 participants |
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | less than 200 mg/day | 0 participants |
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | 200 to less than 250 mg/day | 3 participants |
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | 250 to less than 300 mg/day | 1 participants |
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | 300 to less than 350 mg/day | 8 participants |
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | 350 to less than 400 mg/day | 0 participants |
| Number of Treatment Emergent Adverse Events | Assess Consumption of Tapentadol During Long Term Use | 400 to less than 450 mg/day | 11 participants |
Secondary
Tapentadol Prolonged Release Exposure
The number of days that participants took tapentadol prolonged release. The extent of exposure was categorized into 2 periods, less than 90 days and more than 90 days (up to 144 weeks).
Time frame: Day 1; up to 144 weeks
Population: Safety Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Treatment Emergent Adverse Events | Tapentadol Prolonged Release Exposure | 0 to 90 days | 11 participants |
| Number of Treatment Emergent Adverse Events | Tapentadol Prolonged Release Exposure | more than 90 days | 20 participants |
Other Pre-specified
Average Daily Total Tapentadol Prolonged Release Dose
The Total Daily Dose (TDD) on any given day is the sum of the morning and evening intake amounts. The average TDD is an individuals average over the trial period.
Time frame: Day 1; up to 144 weeks
Population: Safety Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Number of Treatment Emergent Adverse Events | Average Daily Total Tapentadol Prolonged Release Dose | 360 mg per day | Standard Deviation 91.21 |
Other Pre-specified
Average Pain Intensity (Over a Twelve-week Period)
The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Average pain intensity score is the average of pain experienced for previous 24 hours as rated on an 11-point NRS at each visit. Calculations are based on 3 consecutive planned (at 4-weekly intervals) visits. All available data of a participant was used; if a participant dropped-out or had incomplete data during a 12-week period no imputations were performed for the missing values.
Time frame: Day 1; up to Week 144
Population: Safety Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 121 to 132 | 1.0 units on a scale | Standard Deviation 0 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Baseline | 3.3 units on a scale | Standard Deviation 1.79 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 1 to 12 | 3.1 units on a scale | Standard Deviation 1.95 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 13 to 24 | 3.1 units on a scale | Standard Deviation 2.51 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 25 to 36 | 2.1 units on a scale | Standard Deviation 1.57 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 37 to 48 | 2.0 units on a scale | Standard Deviation 1.71 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 49 to 60 | 2.0 units on a scale | Standard Deviation 1.78 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 61 to 72 | 2.0 units on a scale | Standard Deviation 1.61 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 73 to 84 | 2.4 units on a scale | Standard Deviation 1.97 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 85 to 96 | 3.1 units on a scale | Standard Deviation 3.16 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 97 to 108 | 3.1 units on a scale | Standard Deviation 3.76 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 109 to 120 | 3.3 units on a scale | Standard Deviation 2.52 |
| Number of Treatment Emergent Adverse Events | Average Pain Intensity (Over a Twelve-week Period) | Week 133 to 144 | 1.0 units on a scale | Standard Deviation 0 |