Hysterectomy, Postoperative
Conditions
Keywords
Opioid, Central acting analgesic, Pain postoperative, Abdomen acute, CG5503 IR, Morphine, Placebo
Brief summary
The main objective of this study is to demonstrate the efficacy and safety of multiple-dose application of three different oral doses of CG5503 IR (tapentadol immediate release) compared to placebo in women undergoing abdominal hysterectomy.
Detailed description
Subjects undergoing abdominal hysterectomy often experience moderate to severe acute pain post-surgery. Normally such pain is controlled when subjects receive repeated doses of opioid analgesics. However, opioid therapy is commonly associated with side effects such as nausea, vomiting, sedation, constipation, addiction, tolerance, and respiratory depression. Tapentadol (CG5503), a newly synthesized drug with an immediate release (IR) formulation, also acts as a centrally acting pain reliever 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 3 dose levels of CG5503 IR compared with no drug (placebo) or one dose level of morphine (an opioid commonly used to treat post-surgical pain). This study is a randomized, double-blind (neither investigator nor patient will know which treatment was received), active- and placebo-controlled, parallel-group, multicenter study to evaluate the treatment of acute pain after abdominal hysterectomy. The study will include a blinded 72 hour in-patient phase immediately following hysterectomy, during which subjects will be treated with either 50-, 75-, or 100-mg CG5503 IR, a matched placebo, or 20-mg morphine, and pain relief will be periodically assessed. Assessments of pain relief include the pain intensity numeric rating scale (PI), pain relief numeric rating scale (PAR), and patient global impression of change scale (PGIC). 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 CG5503 and morphine. The alternative study hypothesis is that at least 1 dose strength of CG5503 will be different from placebo in controlling pain at 24 hours (using the mean SPID at 24 hours).
Interventions
DRUGMorphine
20 mg IR; 4 - 6 hourly; Total 72 hours
DRUGCG5503 IR
50mg; 4 - 6 hourly; Total 72 hours
DRUGPlacebo
4 - 6 hourly; Total 72 hours
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Grünenthal GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Female between 18 and 80 years of age; * Scheduled to undergo an abdominal hysterectomy with or without bilateral salpingo-oophorectomy due to uterine leiomyomas, or dysfunctional uterine bleeding or endometrial hyperplasia; * Anesthesiological and surgical procedures performed according to protocol; * Moderate or severe baseline pain following hysterectomy on a Verbal Rating Scale (VRS) within 6 hours following the last possible application of morphine subcutaneous; * Pain following hysterectomy of at least 4 on an 11-point Numeric Rating Scale (NRS) within 6 hours following the last possible application of morphine subcutaneous; * American Society of Anesthesiologists (ASA) classification I-III.
Exclusion criteria
* Vaginal hysterectomy; * Ongoing or known history of painful endometriosis; * Known or suspected chronic pelvic pain syndrome; * Previous abdominal or pelvic open surgery; * History of seizure disorder or epilepsy; * History of alcohol or drug abuse; * Evidence of active infections that may spread to other areas of the body; * severely impaired renal function, moderately or severely impaired hepatic function, * Allergy or hypersensitivity to oxycodone, morphine, fentanyl hydromorphone, heparin, or any compound planned to be used during the anesthesia; * Serious complication during surgery and up to randomization; * Pre-operative use within 12hours prior to surgery or peri-operative use of non-steroidal anti-inflammatory drugs (NSAIDs); * Treated regularly with opioid analgesic or non-steroidal anti-inflammatory drugs (NSAIDs) within 30 days prior to screening;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | Baseline to 24 hours after first intake of study drug | Pain Intensity assessed at predefined time points over a 24 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates no pain and a score of ten indicates pain as bad as you can imagine. Differences calculated as \[baseline-post baseline\] at each predefined time point. The theoretical maximum range of Sum of pain intensity differences (SPID24) is from -240 (indicative of an increase in pain) to 240 (indicative of a decrease in pain, assuming patients start with a baseline value of 10 and all subsequent values will be 0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity | Baseline value to 48 hours after first study drug intake. | Pain Intensity assessed at predefined time points over a 48 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates no pain and a score of ten indicates pain as bad as you can imagine. Differences calculated as \[baseline-post baseline\] at each predefined time point. The theoretical maximum range of Sum of pain intensity differences (SPID48) is from -480 (indicative of an increase in pain) to 480 (indicative of a decrease in pain, assuming patients start with a baseline value of 10 and all subsequent values will be 0). |
Countries
Hungary, Latvia, Poland, Romania, Russia, Serbia, Slovakia, Slovenia, Ukraine
Participant flow
Recruitment details
The recruitment period for this in-patient, multicenter study occurred between 19 May 2007 and 11 Mar 2008.
Pre-assignment details
This trial consisted of 5 periods: a Screening (Day -28 to Day -4 to the Pre-operative Visit) a Surgical (Day -1 to 1), a Postoperative Qualification, a Double-blind Treatment(Day 1-4) and a Follow-up Period (4-14 days after the double-blind treatment). The results refer to randomized subjects.
Participants by arm
| Arm | Count |
|---|---|
| Morphine Morphine IR 20mg 4-6 hourly | 170 |
| CG5503 50mg CG5503 IR 50mg 4 to 6 hourly | 168 |
| CG5503 75mg CG5503 IR 75mg 4 to 6 hourly | 171 |
| CG5503 100mg CG5503 IR 100mg 4 to 6 hourly | 176 |
| Placebo Matched Placebo 4 to 6 hourly | 169 |
| Total | 854 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 7 | 8 | 14 | 6 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 11 | 10 | 4 | 5 | 41 |
| Overall Study | Lack of pain, Technical difficulties | 7 | 3 | 5 | 6 | 3 |
| Overall Study | Lost to Follow-up | 3 | 1 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 2 | 4 | 5 |
Baseline characteristics
| Characteristic | Morphine | CG5503 50mg | CG5503 75mg | CG5503 100mg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 165 Participants | 166 Participants | 170 Participants | 173 Participants | 166 Participants | 840 Participants |
| Age, Continuous | 48.5 years STANDARD_DEVIATION 6.75 | 47.0 years STANDARD_DEVIATION 5.56 | 47.1 years STANDARD_DEVIATION 5.37 | 47.5 years STANDARD_DEVIATION 6.43 | 47.2 years STANDARD_DEVIATION 5.83 | 47.5 years STANDARD_DEVIATION 6.03 |
| Region of Enrollment Hungary | 5 participants | 6 participants | 5 participants | 5 participants | 4 participants | 25 participants |
| Region of Enrollment Latvia | 20 participants | 21 participants | 22 participants | 21 participants | 20 participants | 104 participants |
| Region of Enrollment Poland | 36 participants | 36 participants | 34 participants | 37 participants | 36 participants | 179 participants |
| Region of Enrollment Romania | 34 participants | 33 participants | 34 participants | 36 participants | 35 participants | 172 participants |
| Region of Enrollment Russian Federation | 21 participants | 21 participants | 21 participants | 22 participants | 22 participants | 107 participants |
| Region of Enrollment Serbia | 15 participants | 15 participants | 16 participants | 16 participants | 15 participants | 77 participants |
| Region of Enrollment Slovakia | 25 participants | 25 participants | 25 participants | 25 participants | 24 participants | 124 participants |
| Region of Enrollment Ukraine | 14 participants | 11 participants | 14 participants | 14 participants | 13 participants | 66 participants |
| Sex/Gender, Customized Female | 170 participants | 168 participants | 171 participants | 176 participants | 169 participants | 854 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 99 / 170 | 84 / 168 | 96 / 171 | 106 / 176 | 88 / 169 |
| serious Total, serious adverse events | 3 / 170 | 0 / 168 | 0 / 171 | 1 / 176 | 0 / 169 |
Outcome results
Primary
Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity.
Pain Intensity assessed at predefined time points over a 24 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates no pain and a score of ten indicates pain as bad as you can imagine. Differences calculated as \[baseline-post baseline\] at each predefined time point. The theoretical maximum range of Sum of pain intensity differences (SPID24) is from -240 (indicative of an increase in pain) to 240 (indicative of a decrease in pain, assuming patients start with a baseline value of 10 and all subsequent values will be 0).
Time frame: Baseline to 24 hours after first intake of study drug
Population: Intention to Treat (ITT) and Last Observation Carried Forward (LOCF), i.e. all randomized subjects who received any amount of Investigational Medicinal Product (IMP = study drug) and had a non missing baseline pain assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | 48.8 units on scale | Standard Deviation 41 |
| CG5503 50mg | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | 49.0 units on scale | Standard Deviation 39.87 |
| CG5503 75mg | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | 52.4 units on scale | Standard Deviation 41.85 |
| CG5503 100mg | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | 52.9 units on scale | Standard Deviation 40.95 |
| Placebo | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | 29.0 units on scale | Standard Deviation 44.98 |
Comparison: Null hypothesis of no treatment difference.p-value: <0.000195% CI: [13.4, 27.8]ANCOVA
Comparison: The null hypothesis is that all CG5503 IR dose groups are equal to the placebo group based on the mean sum of pain intensity difference at 24 hours (SPID24). The alternative hypothesis is that at least one CG5503 IR dose group is different from the placebo group based on the mean SPID24.p-value: <0.000195% CI: [10.9, 25.3]ANCOVA
Comparison: The null hypothesis is that all CG5503 IR dose groups are equal to the placebo group based on the mean sum of pain intensity difference at 24 hours (SPID24). The alternative hypothesis is that at least one CG5503 IR dose group is different from the placebo group based on the mean SPID24.p-value: <0.000195% CI: [13.7, 28]ANCOVA
Comparison: The null hypothesis is that all CG5503 IR dose groups are equal to the placebo group based on the mean sum of pain intensity difference at 24 hours (SPID24). The alternative hypothesis is that at least one CG5503 IR dose group is different from the placebo group based on the mean SPID24.p-value: <0.000195% CI: [16.3, 30.4]ANCOVA
Secondary
Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity
Pain Intensity assessed at predefined time points over a 48 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates no pain and a score of ten indicates pain as bad as you can imagine. Differences calculated as \[baseline-post baseline\] at each predefined time point. The theoretical maximum range of Sum of pain intensity differences (SPID48) is from -480 (indicative of an increase in pain) to 480 (indicative of a decrease in pain, assuming patients start with a baseline value of 10 and all subsequent values will be 0).
Time frame: Baseline value to 48 hours after first study drug intake.
Population: Intention to treat (ITT) and Last Observation Carried Forward (LOCF), i.e. all randomized subjects who received any amount of Investigational Medicinal Product (IMP = study drug) and had a non missing baseline pain assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity | 116.6 units on scale | Standard Deviation 87.1 |
| CG5503 50mg | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity | 112.4 units on scale | Standard Deviation 87.32 |
| CG5503 75mg | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity | 120.6 units on scale | Standard Deviation 87.35 |
| CG5503 100mg | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity | 123.5 units on scale | Standard Deviation 83.5 |
| Placebo | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity | 71.1 units on scale | Standard Deviation 101.17 |
Comparison: The null hypothesis is that all CG5503 IR dose groups are equal to the placebo group based on the mean sum of pain intensity difference at 48 hours (SPID48). The alternative hypothesis is that at least one CG5503 IR dose group is different from the placebo group based on the mean SPID48.p-value: <0.000195% CI: [21.6, 52.6]ANCOVA
Comparison: The null hypothesis is that all CG5503 IR dose groups are equal to the placebo group based on the mean sum of pain intensity difference at 48 hours (SPID48). The alternative hypothesis is that at least one CG5503 IR dose group is different from the placebo group based on the mean SPID48.p-value: <0.000195% CI: [28.6, 59.5]ANCOVA
Comparison: The null hypothesis is that all CG5503 IR dose groups are equal to the placebo group based on the mean sum of pain intensity difference at 48 hours (SPID48). The alternative hypothesis is that at least one CG5503 IR dose group is different from the placebo group based on the mean SPID48.p-value: <0.000195% CI: [36.1, 66.7]ANCOVA
Comparison: Null hypothesis of no treatment difference.p-value: <0.000195% CI: [31.4, 62.4]ANCOVA