Low Back Pain
Conditions
Keywords
Low Back Pain, Chronic Pain, Pain Assessment, Tapentadol
Brief summary
The purpose of this trial is to evaluate the effectiveness (level of pain control) and safety of orally administrated tapentadol (CG5503) Extended Release (ER) (base) at doses of 100-250 mg twice daily in patients with moderate to severe chronic pain of the lower back, in comparison with placebo and Oxycodone Controlled Release (CR).
Detailed description
The primary objective of this randomized (study medication assigned to patients by chance), double-blind (neither patient nor investigator knows the study medication), phase III, placebo and active controlled trial is to evaluate the efficacy and safety of orally administered tapentadol (CG5503) Extended Release (ER) (base) at doses 100-250 mg twice daily in patients with moderate to severe chronic pain of the lower back. The study is being conducted for registration and approval of tapentadol (CG5503) in the US and outside US. The trial will consist of five periods: screening (to assess eligibility), washout (3-7 days with determination of baseline pain intensity), titration (of dose over 3 weeks to the optimal individual level), maintenance (investigational drug intake for 12 weeks with adjustments allowed), and follow-up (2 weeks post treatment discontinuation). The study hypothesis is that the study drug will be more effective than placebo in reducing patients' pain intensity. The Secondary objectives include the collection of pharmacokinetic (related to how the body uses the drug) information for dose verification. The trial objectives will be assessed by comparing the baseline pain level to the level of week 12 of the maintenance phase. This will be done by looking at the patient's pain diary information. Titrate tapentadol (CG5503) ER (extended release) in 50 mg steps to patient's optimal dose ranging between 100mg and 250mg twice a day; Oxycodone CR (controlled release) 20mg to 50mg twice a day; Placebo (no active ingredients). All doses of trial treatment will be taken orally with or without food, for a maximum timeframe of 15 weeks.
Interventions
50, 100, 150, 200, 250 mg twice daily for 15 weeks
DRUGoxycodone CR
10, 20, 30, 40, 50 mg twice daily for 15 weeks
DRUGplacebo
matching placebo twice daily for 15 weeks
Sponsors
Grünenthal GmbH
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and non-pregnant, non-lactating women having a diagnosis of Lower Back Pain (LBP) of non-malignant origin present for at least 3 months * Patients taking analgesic medications for at least 3 months prior to screening and/or dissatisfied with their current therapy * Patients requiring opioid treatment must be taking daily doses of opioid-based analgesic, equivalent to \< 160 mg of oral morphine * Baseline score of =5 on an 11-point numerical rater scale, calculated as the average pain intensity during the last 3 days prior to randomization.
Exclusion criteria
* History of alcohol and/or drug abuse in Investigator's judgement * History of significant liver insufficiency * chronic hepatitis B or C, or HIV, presence of active hepatitis B or C within the past 3 months * Life-long history of seizure disorder or epilepsy * History of malignancy within past 2 years, with exception of basal cell carcinoma that has been successfully treated * Uncontrolled hypertension * Patients with severely impaired renal function * Patients with moderate to severly impaired hepatic function or with laboratory values reflecting inadequate hepatic function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of the Average Pain Intensity Based on a 11-point Numerical Rating Scale (NRS) Over the Last Week of the Maintenance Period at Week 12. | Baseline and 12 weeks | For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. | Baseline and 12 week endpoint | A Sleep Questionnaire addressed the following question: How long after bedtime/lights out did you fall asleep last night (hours)? 12 week endpoint-mean changes from baseline at endpoint for sleep latency. Decrease in time(hours) indicates improvement. |
| Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 | Baseline and 12 week endpoint | Ordinal measure indicating change from start of treatment (On a scale of 7 = Very much Worse to 1 = very much improved) |
| Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. | Baseline and 12 week endpoint | Total pain score where zero equals no pain to ten equals pain as bad as you can imagine from 12 week endpoint vs baseline. |
| Change From Baseline in EuroQol-5® (EQ-5D) Health Status Index to Week 12 | Baseline and 12 week endpoint | Change from baseline to end point in EuroQol-5 Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating full health and 0 representing dead. |
| Responder Analysis 50% Improvement | Baseline and Week 12 | Defined by the proportion of subjects achieving at least 50% improvement from baseline in the primary endpoint of change from baseline of the average pain intensity based on the 11-point Numerical Rating Scale (NRS) at week 12. The subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point NRS where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. |
| Number of Participants With Treatment Discontinuation Due to Lack of Efficacy | Baseline and 12 weeks | The number of participants who discontinued due to lack of efficacy from baseline to endpoint |
Participant flow
Recruitment details
The recruitment period for this out-patient, multicenter study occurred between 21 February 2007 and 12 March 2008.
Pre-assignment details
The study consisted of a screening period (duration up to 14 days), a washout period (duration 3 to 7 days), a double-blind active treatment period with titration period (duration 3 weeks) and maintenance period (duration 12 weeks).
Participants by arm
| Arm | Count |
|---|---|
| Tapentadol ER Tapentadol (CG5503) extended release(ER) 100-250mg twice daily(BID) | 318 |
| Oxycodone CR oxycodone controlled release(CR) 20-50mg twice daily(BID) | 328 |
| Placebo Matching Placebo twice daily(BID) | 319 |
| Total | 965 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 51 | 107 | 15 |
| Overall Study | all other | 22 | 19 | 20 |
| Overall Study | Lack of Efficacy | 13 | 7 | 50 |
| Overall Study | Lost to Follow-up | 13 | 8 | 12 |
| Overall Study | Study drug non-compliant | 14 | 11 | 11 |
| Overall Study | Withdrawal by Subject | 39 | 43 | 59 |
Baseline characteristics
| Characteristic | Tapentadol ER | Oxycodone CR | Placebo | Total |
|---|---|---|---|---|
| Age Continuous | 49.4 years STANDARD_DEVIATION 13.21 | 50.0 years STANDARD_DEVIATION 14.21 | 50.4 years STANDARD_DEVIATION 14.05 | 49.9 years STANDARD_DEVIATION 13.83 |
| Sex: Female, Male Female | 194 Participants | 181 Participants | 184 Participants | 559 Participants |
| Sex: Female, Male Male | 124 Participants | 147 Participants | 135 Participants | 406 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 192 / 318 | 240 / 328 | 118 / 319 |
| serious Total, serious adverse events | 8 / — | 11 / — | 3 / — |
Outcome results
Primary
Change From Baseline of the Average Pain Intensity Based on a 11-point Numerical Rating Scale (NRS) Over the Last Week of the Maintenance Period at Week 12.
For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours 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.
Time frame: Baseline and 12 weeks
Population: Intent To Treat (ITT) analysis set utilizing Last Observation Carried Forward (LOCF) imputation. The ITT analysis set included all randomized patients that took at least one dose of study medication following randomization. 7 patients (3 tapentadol ER, 3 oxycodone CR, 1 placebo) had no baseline pain scores therefore excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline of the Average Pain Intensity Based on a 11-point Numerical Rating Scale (NRS) Over the Last Week of the Maintenance Period at Week 12. | -2.9 scores on a scale | Standard Deviation 2.66 |
| Oxycodone CR | Change From Baseline of the Average Pain Intensity Based on a 11-point Numerical Rating Scale (NRS) Over the Last Week of the Maintenance Period at Week 12. | -2.9 scores on a scale | Standard Deviation 2.52 |
| Placebo | Change From Baseline of the Average Pain Intensity Based on a 11-point Numerical Rating Scale (NRS) Over the Last Week of the Maintenance Period at Week 12. | -2.1 scores on a scale | Standard Deviation 2.33 |
Comparison: The primary null hypothesis to be tested for the study was that the tapentadol ER group was not different from the placebo group for the primary endpoint. Assuming the mean treatment group difference of 0.7 with an SD of 2.7, 314 subjects per treatment group were estimated to provide 90% power to show that the tapentadol ER group was statistically different from placebo at an alpha level of 0.05. The total number of subjects to be randomly assigned to a treatment group for the study was 942.p-value: <0.00195% CI: [-1.22, -0.47]ANCOVA
Secondary
Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12.
Total pain score where zero equals no pain to ten equals pain as bad as you can imagine from 12 week endpoint vs baseline.
Time frame: Baseline and 12 week endpoint
Population: Intent to Treat (ITT) analysis set, last observation carried forward (LOCF) imputation. The ITT analysis set included all randomized patients that took at least one dose of study medication following randomization. The patients who didi not have any assessment during the treatment period were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. | -2.3 scores on a scale | Standard Deviation 2.25 |
| Oxycodone CR | Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. | -2.1 scores on a scale | Standard Deviation 2.35 |
| Placebo | Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. | -1.6 scores on a scale | Standard Deviation 2.11 |
Secondary
Change From Baseline in EuroQol-5® (EQ-5D) Health Status Index to Week 12
Change from baseline to end point in EuroQol-5 Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating full health and 0 representing dead.
Time frame: Baseline and 12 week endpoint
Population: Intent to Treat Analysis Set, LOCF imputation method. The patients who didi not have any assessment during the treatment period were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline in EuroQol-5® (EQ-5D) Health Status Index to Week 12 | 0.2 scores on a scale | Standard Deviation 0.3 |
| Oxycodone CR | Change From Baseline in EuroQol-5® (EQ-5D) Health Status Index to Week 12 | 0.2 scores on a scale | Standard Deviation 0.33 |
| Placebo | Change From Baseline in EuroQol-5® (EQ-5D) Health Status Index to Week 12 | 0.1 scores on a scale | Standard Deviation 0.33 |
Secondary
Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12.
A Sleep Questionnaire addressed the following question: How long after bedtime/lights out did you fall asleep last night (hours)? 12 week endpoint-mean changes from baseline at endpoint for sleep latency. Decrease in time(hours) indicates improvement.
Time frame: Baseline and 12 week endpoint
Population: Intent to Treat population with LOCF imputation. The patients who didi not have any assessment during the treatment period were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. | -0.2 hours | Standard Deviation 3.08 |
| Oxycodone CR | Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. | -0.2 hours | Standard Deviation 2.32 |
| Placebo | Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. | -0.1 hours | Standard Deviation 2.43 |
Secondary
Number of Participants With Treatment Discontinuation Due to Lack of Efficacy
The number of participants who discontinued due to lack of efficacy from baseline to endpoint
Time frame: Baseline and 12 weeks
Population: Intent to Treat Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol ER | Number of Participants With Treatment Discontinuation Due to Lack of Efficacy | 18 participants |
| Oxycodone CR | Number of Participants With Treatment Discontinuation Due to Lack of Efficacy | 9 participants |
| Placebo | Number of Participants With Treatment Discontinuation Due to Lack of Efficacy | 64 participants |
Secondary
Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12
Ordinal measure indicating change from start of treatment (On a scale of 7 = Very much Worse to 1 = very much improved)
Time frame: Baseline and 12 week endpoint
Population: Intent to Treat Analysis (ITT) set, Last Observation Carried Forward (LOCF) imputation method. The ITT analysis set included all randomized subjects who took at least one dose of study medication following randomization. The patients who didi not have any assessment during the treatment period were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol ER | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 | 55.5 percentage of participants |
| Oxycodone CR | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 | 60 percentage of participants |
| Placebo | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 | 32.7 percentage of participants |
Secondary
Responder Analysis 50% Improvement
Defined by the proportion of subjects achieving at least 50% improvement from baseline in the primary endpoint of change from baseline of the average pain intensity based on the 11-point Numerical Rating Scale (NRS) at week 12. The subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point NRS where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine.
Time frame: Baseline and Week 12
Population: Intent to Treat Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol ER | Responder Analysis 50% Improvement | 27.0 Percentage of participants |
| Oxycodone CR | Responder Analysis 50% Improvement | 23.3 Percentage of participants |
| Placebo | Responder Analysis 50% Improvement | 18.9 Percentage of participants |