Arthralgia, Bunion, Hallux Valgus, Pain
Conditions
Keywords
Acute pain, bunionectomy, tapentadol
Brief summary
The purpose of this study is to evaluate the effectiveness (level of pain control) and safety of the administration of 2 different dose levels of tapentadol (CG5503) compared with oxycodone and with placebo in subjects who have had a bunionectomy.
Detailed description
Patients undergoing bunionectomy often experience moderate to severe acute pain post-surgery. Normally such pain is controlled when patients receive repeated doses of opioid analgesics. However, opioid therapy is commonly associated with side effects such as nausea, vomiting, sedation, constipation, and less frequently, respiratory depression. Tapentadol (CG5503), a newly synthesized drug with an immediate release (IR) formulation, also acts as a centrally acting analgesic but has a dual mode of action. The aim of this study is to investigate the effectiveness (level of pain control) and safety (side effects) of 2 dose levels of tapentadol (CG5503) IR compared to no drug (placebo) or one dose level of oxycodone (an opioid commonly used to treat post-surgical pain). This study is a randomized, double-blind (neither investigator nor patient will know which treatment is received), active- and placebo-controlled, parallel-group, multicenter study to evaluate treatment of the acute pain from bunionectomy. The study will include a blinded 72 hour inpatient (the patient will stay in the facility where the procedure is done) phase immediately following bunionectomy, during which patients will be treated with either 50- or 75-mg tapentadol (CG5503) IR, a placebo, or 10-mg oxycodone IR, and pain relief will be periodically assessed. Assessments of pain intensity (PI) and pain relief (PAR) are obtained using the numerical rating scale, and the patient global impression of change scale (PGIC) will measure overall patient status. 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 (CG5503) and oxycodone. The study hypotheses are that at least one tapentadol (CG5503) IR dose will be different from placebo in controlling patients pain at 48 hours, followed by establishing that at least one tapentadol (CG5503) IR dose will be non-inferior compared with oxycodone IR (oxycodone IR is not clinically significantly better than a tapentadol (CG5503) IR dose). A comparison of the incidence rate of the adverse events of nausea and/or vomiting, and the incidence rate of the adverse event of constipation, between tapentadol (CG5503) IR and oxycodone IR will also be performed. Tapentadol (CG5503) IR 50 or 75 mg, or oxycodone 10 mg, or placebo, 1 capsule taken by mouth every 4 to 6 hours during the 72-hour postsurgery phase of the study (acetaminophen is also allowed during the first 12 hours on Day 1, if needed for pain). All doses of study treatment will be taken with approximately 120 mL of water with or without food.
Interventions
50mg capsule q4-6 hrs for 3 days
DRUGoxycodone
10mg capsule q4-6 hrs for 3 days
DRUGplacebo
1 capsule q4-6 hrs for 3 days
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients must undergo primary unilateral first metatarsal bunionectomy * Pain intensity must be moderate to severe following removal of a continuous popliteal sciatic block * Female patients must be postmenopausal, surgically sterile, or practicing an effective method of birth control if they are sexually active.
Exclusion criteria
* Patients will be excluded from the study if they have a history of seizure disorder or epilepsy * History of malignancy within the past 2 years before starting the study * History of alcohol or drug abuse * Evidence of active infections that may spread to other areas of the body * Clinical laboratory values reflecting severe renal insufficiency * Moderately or severely impaired hepatic function * Currently treated with anticonvulsants, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), neuroleptics, or serotonin norepinephrine reuptake inhibitor (SNRI).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sum of Pain Intensity Difference Over 48 Hours (SPID48) | 48 hours | The SPID score incorporates the cumulative analgesic effects of tapentadol IR on pain intensity over an extended period (48 hours) allowing for an evaluation of multiple doses of drug, even when dosing frequency may vary. Scoring is derived from the Numerical Rating Scale (NRS) from 0 = No pain to 11 = Pain as bad as you can imagine. A positive difference between the mean SPID48 for an active study drug and placebo would indicate a numerically larger analgesic effect for subjects dosed with active study drug than in the placebo group. A higher value in SPID indicates greater pain relief. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Rescue Pain Medication Use. | 3 days | The effect of tapentadol (CG5503) IR on the time to the first use of rescue pain medication. |
| The SPID at 12 Hours Relative to First Dose. | 12 hours | The SPID score incorporates the cumulative analgesic effects of tapentadol IR on pain intensity over an extended period (12 to 72 hours) allowing for an evaluation of multiple doses of drug, even when dosing frequency may vary. Scoring is derived from the Numerical Rating Scale (NRS) from 0 = No pain to 11 = Pain as bad as you can imagine. A positive difference between the mean SPID12 for an active study drug and placebo would indicate a numerically larger analgesic effect for subjects dosed with active study drug than in the placebo group. A higher value in SPID indicates greater pain relief. |
| SPID at 24 Hours Relative to First Dose | 24 hours | The SPID score incorporates the cumulative analgesic effects of tapentadol IR on pain intensity over an extended period (12 to 72 hours) allowing for an evaluation of multiple doses of drug, even when dosing frequency may vary. Scoring is derived from the Numerical Rating Scale (NRS) from 0 = No pain to 11 = Pain as bad as you can imagine. A positive difference between the mean SPID24 for an active study drug and placebo would indicate a numerically larger analgesic effect for subjects dosed with active study drug than in the placebo group. A higher value in SPID indicates greater pain relief. |
| Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change to Day 3 | Baseline and 3 days | Ordinal measure indicating change from the start of treatment (On a scale of 7 = Very much Worse to 1 = very much improved) to endpoint at Day 3 |
| Total Pain Relief (TOTPAR)at 48 Hours | 48 hours | Total Pain Relief (TOTPAR48) was defined as the weighted sum over all pain relief scores(PAR) from 0.5 hour to Hour 48, with the actual time elapsed from the previous PAR observation as the weight. A higher value in TOTPAR indicates greater pain relief. |
Countries
United States
Participant flow
Recruitment details
The recruitment period for this inpatient, multicenter study occurred between January 28, 2008 and October 3, 2008.
Pre-assignment details
The study consisted of a screening period (duration up to 28 days), and a double blind active treatment period (4 days).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo capsule taken by mouth every 4 to 6 hours for 3 days. | 69 |
| Tapentadol 50mg Fixed Dose Tapentadol 50mg capsule taken by mouth every 4 to 6 hours for 3 days. | 275 |
| Tapentadol 75mg Fixed Dose Tapentadol 75mg capsule taken by mouth every 4 to 6 hours for 3 days. | 278 |
| Oxycodone 10mg Fixed Dose Oxycodone 10mg capsule taken by mouth every 4 to 6 hours for 3 days. | 279 |
| Total | 901 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 | 8 | 5 |
| Overall Study | Lack of Efficacy | 16 | 18 | 5 | 9 |
| Overall Study | Other | 1 | 2 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 4 | 9 | 9 |
Baseline characteristics
| Characteristic | Tapentadol 50mg Fixed Dose | Tapentadol 75mg Fixed Dose | Placebo | Oxycodone 10mg Fixed Dose | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Categorical >=65 years | 10 participants | 10 participants | 1 participants | 13 participants | 34 participants |
| Age, Categorical Between 18 and 65 years | 265 participants | 268 participants | 68 participants | 265 participants | 866 participants |
| Age, Continuous | 42.4 years STANDARD_DEVIATION 13.23 | 43.5 years STANDARD_DEVIATION 12.57 | 42.8 years STANDARD_DEVIATION 13.65 | 43.4 years STANDARD_DEVIATION 13.25 | 43.1 years STANDARD_DEVIATION 13.05 |
| Gender Female | 232 participants | 248 participants | 64 participants | 233 participants | 777 participants |
| Gender Male | 43 participants | 30 participants | 5 participants | 45 participants | 123 participants |
| Region of Enrollment United States | 275 participants | 278 participants | 69 participants | 278 participants | 900 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 69 | 161 / 275 | 192 / 278 | 218 / 279 |
| serious Total, serious adverse events | 0 / 69 | 0 / 275 | 0 / 278 | 1 / 279 |
Outcome results
Primary
Sum of Pain Intensity Difference Over 48 Hours (SPID48)
The SPID score incorporates the cumulative analgesic effects of tapentadol IR on pain intensity over an extended period (48 hours) allowing for an evaluation of multiple doses of drug, even when dosing frequency may vary. Scoring is derived from the Numerical Rating Scale (NRS) from 0 = No pain to 11 = Pain as bad as you can imagine. A positive difference between the mean SPID48 for an active study drug and placebo would indicate a numerically larger analgesic effect for subjects dosed with active study drug than in the placebo group. A higher value in SPID indicates greater pain relief.
Time frame: 48 hours
Population: The primary analysis set was the Intent to Treat (ITT) analysis set that included all subjects who were randomized, received at least one dose of study drug and had a non-missing baseline pain intensity score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Sum of Pain Intensity Difference Over 48 Hours (SPID48) | 54.1 Scores on a scale | Standard Deviation 105.74 |
| Tapentadol 50mg Fixed Dose | Sum of Pain Intensity Difference Over 48 Hours (SPID48) | 122.2 Scores on a scale | Standard Deviation 98.66 |
| Tapentadol 75mg Fixed Dose | Sum of Pain Intensity Difference Over 48 Hours (SPID48) | 143.7 Scores on a scale | Standard Deviation 96.52 |
| Oxycodone 10mg Fixed Dose | Sum of Pain Intensity Difference Over 48 Hours (SPID48) | 140.3 Scores on a scale | Standard Deviation 99.52 |
Comparison: Null hypothesis: There are no differences in pain intensity measured by SPID-48 hours between any of tapentadol dose groups and placebo. ANCOVA model with factors of treatment, center and baseline pain intensity score was used for the primary analysis.p-value: <0.00195% CI: [39.01, 85.73]ANCOVA
Secondary
Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change to Day 3
Ordinal measure indicating change from the start of treatment (On a scale of 7 = Very much Worse to 1 = very much improved) to endpoint at Day 3
Time frame: Baseline and 3 days
Population: The primary analysis set was the Intent to Treat (ITT) analysis set that included all subjects who were randomized, received at least one dose of study drug and had a non-missing baseline pain intensity score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change to Day 3 | 65.2 percentage of participants |
| Tapentadol 50mg Fixed Dose | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change to Day 3 | 83.2 percentage of participants |
| Tapentadol 75mg Fixed Dose | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change to Day 3 | 87.8 percentage of participants |
| Oxycodone 10mg Fixed Dose | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change to Day 3 | 86.0 percentage of participants |
Secondary
SPID at 24 Hours Relative to First Dose
The SPID score incorporates the cumulative analgesic effects of tapentadol IR on pain intensity over an extended period (12 to 72 hours) allowing for an evaluation of multiple doses of drug, even when dosing frequency may vary. Scoring is derived from the Numerical Rating Scale (NRS) from 0 = No pain to 11 = Pain as bad as you can imagine. A positive difference between the mean SPID24 for an active study drug and placebo would indicate a numerically larger analgesic effect for subjects dosed with active study drug than in the placebo group. A higher value in SPID indicates greater pain relief.
Time frame: 24 hours
Population: The primary analysis set was the Intent to Treat (ITT) analysis set that included all subjects who were randomized, received at least one dose of study drug and had a non-missing baseline pain intensity score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | SPID at 24 Hours Relative to First Dose | 12.1 Scores on a scale | Standard Deviation 43.64 |
| Tapentadol 50mg Fixed Dose | SPID at 24 Hours Relative to First Dose | 45.4 Scores on a scale | Standard Deviation 45.73 |
| Tapentadol 75mg Fixed Dose | SPID at 24 Hours Relative to First Dose | 58.1 Scores on a scale | Standard Deviation 45.89 |
| Oxycodone 10mg Fixed Dose | SPID at 24 Hours Relative to First Dose | 53.8 Scores on a scale | Standard Deviation 46.69 |
Secondary
The SPID at 12 Hours Relative to First Dose.
The SPID score incorporates the cumulative analgesic effects of tapentadol IR on pain intensity over an extended period (12 to 72 hours) allowing for an evaluation of multiple doses of drug, even when dosing frequency may vary. Scoring is derived from the Numerical Rating Scale (NRS) from 0 = No pain to 11 = Pain as bad as you can imagine. A positive difference between the mean SPID12 for an active study drug and placebo would indicate a numerically larger analgesic effect for subjects dosed with active study drug than in the placebo group. A higher value in SPID indicates greater pain relief.
Time frame: 12 hours
Population: The primary analysis set was the Intent to Treat (ITT) analysis set that included all subjects who were randomized, received at least one dose of study drug and had a non-missing baseline pain intensity score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The SPID at 12 Hours Relative to First Dose. | 7.5 Scores on a scale | Standard Deviation 20.7 |
| Tapentadol 50mg Fixed Dose | The SPID at 12 Hours Relative to First Dose. | 21.1 Scores on a scale | Standard Deviation 21.89 |
| Tapentadol 75mg Fixed Dose | The SPID at 12 Hours Relative to First Dose. | 26.0 Scores on a scale | Standard Deviation 23.11 |
| Oxycodone 10mg Fixed Dose | The SPID at 12 Hours Relative to First Dose. | 24.9 Scores on a scale | Standard Deviation 22.8 |
Secondary
Time to First Rescue Pain Medication Use.
The effect of tapentadol (CG5503) IR on the time to the first use of rescue pain medication.
Time frame: 3 days
Population: The primary analysis set was the Intent to Treat (ITT) analysis set that included all subjects who were randomized, received at least one dose of study drug and had a non-missing baseline pain intensity score.
Secondary
Total Pain Relief (TOTPAR)at 48 Hours
Total Pain Relief (TOTPAR48) was defined as the weighted sum over all pain relief scores(PAR) from 0.5 hour to Hour 48, with the actual time elapsed from the previous PAR observation as the weight. A higher value in TOTPAR indicates greater pain relief.
Time frame: 48 hours
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Pain Relief (TOTPAR)at 48 Hours | 68.2 scores on a scale | Standard Deviation 39.48 |
| Tapentadol 50mg Fixed Dose | Total Pain Relief (TOTPAR)at 48 Hours | 96.6 scores on a scale | Standard Deviation 37.39 |
| Tapentadol 75mg Fixed Dose | Total Pain Relief (TOTPAR)at 48 Hours | 107.5 scores on a scale | Standard Deviation 35.74 |
| Oxycodone 10mg Fixed Dose | Total Pain Relief (TOTPAR)at 48 Hours | 105.2 scores on a scale | Standard Deviation 37.4 |