Acute Pain, Bunionectomy, Pain, Postoperative Pain
Conditions
Keywords
Opioid, Central acting analgesic, CG5503 IR, Postoperative pain, Bunionectomy, Morphine, Placebo
Brief summary
The main objective of this trial is to demonstrate the efficacy and safety of multiple-dose application of oral application of CG5503 IR 75mg compared to placebo and to assess safety and tolerability of CG5503 IR 75mg in subjects following bunionectomy. This trial was performed based on a previously performed double-blind, placebo-controlled, multiple-dose trial in the same indication investigating 3 dose strengths CG5503 IR (50, 75 and 100 mg) published under PMID: 18851776.
Detailed description
Subjects undergoing bunionectomy 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. 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 trial is to investigate the effectiveness (level of pain control) and safety (side effects) of CG5503 IR 75mg compared with no drug (placebo) or one dose of morphine (an opioid commonly used to treat post-surgical pain). This trial is a randomized, double-blind (neither investigator nor patient will know which treatment was received), active- and placebo-controlled, parallel-group, multicenter trial to evaluate the treatment of acute pain after bunionectomy. The trial will include a blinded 72 hour inpatient phase immediately following bunionectomy, during which subjects will be treated with either 75-mg CG5503 IR, a placebo, or 30-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 trial hypothesis is that at least 1 dose strength of CG5503 will be different from placebo in controlling pain at 48 hours.
Interventions
DRUGCG5503 IR
75mg IR 4 - 6 hourly Total: 72 hours
DRUGMorphine
Morphine 30 mg IR 4 - 6 hourly Total: 72 hours
DRUGPlacebo
Placebo; 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
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male and female subjects between 18 and 80 years of age; * Scheduled to undergo primary unilateral first metatarsal bunionectomy; * Anesthesiological and surgical procedures performed according to protocol; * Moderate or severe baseline pain following bunionectomy on a VRS within 9 hours of termination of the continuous popliteal sciatic block or systemic analgesia; * Pain following bunionectomy of at least 4 on an 11-point NRS within 9 hours of termination of the continuous popliteal sciatic block or systemic analgesia; American Society of Anesthesiologists (ASA) classification I-III.
Exclusion criteria
* History of seizure disorder; * History of alcohol, medication or drug dependency, unstable psychological personality requiring intermittent or permanent treatment; severely impaired renal function, moderately or severely impaired hepatic function; * Contraindications to, or history of allergy or hypersensitivity to CG5503, oxycodone, morphine, fentanyl hydrocodone, acetaminophen, heparin, or any compound planned to be used during the anesthesia, or their excipients; * Pre-operative use within 12h prior to surgery or peri-operative use of non- steroidal anti-inflammatory drugs (NSAIDs); * Treated regularly with opioid analgesic or 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 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Pain Relief (TOTPAR) | Baseline to 48 hours after first study drug intake | Total pain relief (TOTPAR) in the 48 hour period from the first dose of study drug. The subject was to indicate pain relief at rest in response to the following question: How much relief have you had from your starting pain? None = 0, A little = 1, Some = 2, A lot = 3 and Complete = 4. The theoretical maximum range of Total pain relief (TOTPAR)48 is from 0 (indicative of no pain relief) to 192. The higher the value the better the pain relief. |
| Sum of Pain Intensity Differences Over 6 Hours (SPID6) Relative to the Baseline Pain Intensity | Baseline to 6 hours after intake of first study drug | Pain Intensity assessed at predefined time points over a 6 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 (SPID6) is from -60 (indicative of an increase in pain) to 60 (indicative of a decrease in pain). |
| Number of Participants Using Rescue Medication | Baseline up to 72 hours after first study drug intake | Number of participants who used at least one dose of rescue medication during the 72 hour double blind period. |
| Sum of Pain Intensity Differences Over 24 Hours (SPID24) Relative to the Baseline Pain Intensity | Baseline to 24 hours after first study drug intake | 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). |
| Sum of Pain Intensity Differences Over 72 Hours (SPID72) Relative to the Baseline Pain Intensity | Baseline to 72 hours after first intake of study drug | Pain Intensity assessed at predefined time points over a 72 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 (SPID72) is from -720 (indicative of an increase in pain) to 720 (indicative of a decrease in pain). |
| Sum of Pain Intensity Differences Over 12 Hours (SPID12) Relative to the Baseline Pain Intensity | Baseline to 12 hours after first study drug intake | Pain Intensity assessed at predefined time points over a 12 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 (SPID12) is from -120 (indicative of an increase in pain) to 120 (indicative of a decrease in pain). |
Countries
United States
Participant flow
Recruitment details
The recruitment period for this in-patient, multicenter study occurred between 04 September 2007 and 11 December 2007.
Pre-assignment details
The trial consisted of a Screening Period (Day -28 up to the first surgical incision on Day -1), a Surgical Period (Day -1 to Day 1 at approximately 03:00 h.), a Qualification Period (Day 1), a Double-Blind Treatment Period (Day 1 up to Day 4), and a Follow-up Period (Day 8 up to Day 18).
Participants by arm
| Arm | Count |
|---|---|
| CG5503 CG5503 IR 75mg 4-6 hourly | 96 |
| Morphine Morphine IR 30mg 4 to 6 hourly | 96 |
| Placebo Matching Placebo 4 to 6 hourly | 99 |
| Total | 291 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 1 |
| Overall Study | Lack of Efficacy | 0 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Morphine | Placebo | CG5503 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 7 Participants | 8 Participants | 2 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 88 Participants | 90 Participants | 94 Participants | 272 Participants |
| Age Continuous | 43.7 years STANDARD_DEVIATION 14.19 | 43.8 years STANDARD_DEVIATION 13.93 | 44.6 years STANDARD_DEVIATION 12.58 | 44.0 years STANDARD_DEVIATION 13.55 |
| Region of Enrollment United States | 96 participants | 99 participants | 96 participants | 291 participants |
| Sex: Female, Male Female | 73 Participants | 88 Participants | 83 Participants | 244 Participants |
| Sex: Female, Male Male | 23 Participants | 11 Participants | 13 Participants | 47 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 | 69 / — | 85 / — | 47 / — |
| serious Total, serious adverse events | 0 / — | 1 / — | 0 / — |
Outcome results
Primary
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).
Time frame: Baseline value to 48 hours after first study drug intake.
Population: Intention to Treat - randomized subjects who were dosed and had a baseline pain intensity assessment. Last observation carried forward was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CG5503 | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | 46.2 units | Standard Deviation 130.83 |
| Morphine | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | 102.5 units | Standard Deviation 153.26 |
| Placebo | Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | -17.5 units | Standard Deviation 111.27 |
Comparison: Null hypothesis of no treatment difference.p-value: <0.000195% CI: [35.9, 105.6]ANCOVA
Secondary
Number of Participants Using Rescue Medication
Number of participants who used at least one dose of rescue medication during the 72 hour double blind period.
Time frame: Baseline up to 72 hours after first study drug intake
Population: Intention to treat (ITT) and Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CG5503 | Number of Participants Using Rescue Medication | 62 participants |
| Morphine | Number of Participants Using Rescue Medication | 46 participants |
| Placebo | Number of Participants Using Rescue Medication | 82 participants |
p-value: <0.0001Log Rank
Secondary
Sum of Pain Intensity Differences Over 12 Hours (SPID12) Relative to the Baseline Pain Intensity
Pain Intensity assessed at predefined time points over a 12 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 (SPID12) is from -120 (indicative of an increase in pain) to 120 (indicative of a decrease in pain).
Time frame: Baseline to 12 hours after first study drug intake
Population: Intention to treat (ITT) and Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CG5503 | Sum of Pain Intensity Differences Over 12 Hours (SPID12) Relative to the Baseline Pain Intensity | 14.4 units | Standard Deviation 28.89 |
| Morphine | Sum of Pain Intensity Differences Over 12 Hours (SPID12) Relative to the Baseline Pain Intensity | 17.9 units | Standard Deviation 32.12 |
| Placebo | Sum of Pain Intensity Differences Over 12 Hours (SPID12) Relative to the Baseline Pain Intensity | -4.7 units | Standard Deviation 24.82 |
Comparison: Null hypothesis of no treatment difference.p-value: <0.000195% CI: [13.2, 28]ANCOVA
Secondary
Sum of Pain Intensity Differences Over 24 Hours (SPID24) 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).
Time frame: Baseline to 24 hours after first study drug intake
Population: Intention to treat (ITT)and Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CG5503 | Sum of Pain Intensity Differences Over 24 Hours (SPID24) Relative to the Baseline Pain Intensity | 22.3 units | Standard Deviation 60.17 |
| Morphine | Sum of Pain Intensity Differences Over 24 Hours (SPID24) Relative to the Baseline Pain Intensity | 41.3 units | Standard Deviation 68.96 |
| Placebo | Sum of Pain Intensity Differences Over 24 Hours (SPID24) Relative to the Baseline Pain Intensity | -10.7 units | Standard Deviation 51.28 |
Comparison: Null hypothesis of no treatment difference.p-value: <0.000195% CI: [20.7, 52]ANCOVA
Secondary
Sum of Pain Intensity Differences Over 6 Hours (SPID6) Relative to the Baseline Pain Intensity
Pain Intensity assessed at predefined time points over a 6 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 (SPID6) is from -60 (indicative of an increase in pain) to 60 (indicative of a decrease in pain).
Time frame: Baseline to 6 hours after intake of first study drug
Population: Intention to treat(ITT) and Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CG5503 | Sum of Pain Intensity Differences Over 6 Hours (SPID6) Relative to the Baseline Pain Intensity | 8.0 units | Standard Deviation 13.51 |
| Morphine | Sum of Pain Intensity Differences Over 6 Hours (SPID6) Relative to the Baseline Pain Intensity | 8.0 units | Standard Deviation 15.59 |
| Placebo | Sum of Pain Intensity Differences Over 6 Hours (SPID6) Relative to the Baseline Pain Intensity | -1.2 units | Standard Deviation 13.1 |
Comparison: Null hypothesis of no treatment difference.p-value: <0.000195% CI: [6.2, 13.6]ANCOVA
Secondary
Sum of Pain Intensity Differences Over 72 Hours (SPID72) Relative to the Baseline Pain Intensity
Pain Intensity assessed at predefined time points over a 72 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 (SPID72) is from -720 (indicative of an increase in pain) to 720 (indicative of a decrease in pain).
Time frame: Baseline to 72 hours after first intake of study drug
Population: Intention to treat (ITT) and Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CG5503 | Sum of Pain Intensity Differences Over 72 Hours (SPID72) Relative to the Baseline Pain Intensity | 78.4 units | Standard Deviation 212.05 |
| Morphine | Sum of Pain Intensity Differences Over 72 Hours (SPID72) Relative to the Baseline Pain Intensity | 174.1 units | Standard Deviation 242 |
| Placebo | Sum of Pain Intensity Differences Over 72 Hours (SPID72) Relative to the Baseline Pain Intensity | -19.1 units | Standard Deviation 179.48 |
Comparison: Null hypothesis of no treatment difference.p-value: 0.000295% CI: [51.9, 164.5]ANCOVA
Secondary
Total Pain Relief (TOTPAR)
Total pain relief (TOTPAR) in the 48 hour period from the first dose of study drug. The subject was to indicate pain relief at rest in response to the following question: How much relief have you had from your starting pain? None = 0, A little = 1, Some = 2, A lot = 3 and Complete = 4. The theoretical maximum range of Total pain relief (TOTPAR)48 is from 0 (indicative of no pain relief) to 192. The higher the value the better the pain relief.
Time frame: Baseline to 48 hours after first study drug intake
Population: Intention to treat(ITT)and Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CG5503 | Total Pain Relief (TOTPAR) | 79.2 units | Standard Deviation 49.63 |
| Morphine | Total Pain Relief (TOTPAR) | 81.6 units | Standard Deviation 56.3 |
| Placebo | Total Pain Relief (TOTPAR) | 41.8 units | Standard Deviation 50.88 |
Comparison: Null hypothesis of no treatment difference.p-value: <0.000195% CI: [22.7, 52.2]ANCOVA