A Trial to Evaluate CG5503 Efficacy and Safety in Acute Pain After Bunionectomy

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double-blind, Parallel-group, Multi-center, Active- and Placebo-controlled Trial to Evaluate the Analgesic Efficacy and Safety of Multiple Doses of CG5503 IR for Postoperative Pain Following Bunionectomy

Conditions
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Bunionectomy, Pain, Postoperative Pain, Acute Pain

Intervention / Treatment
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* Drug: CG5503 IR
* Drug: Morphine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>CG5503 IR 75mg 4 to 6 hourly for 72 hours | Drug: CG5503 IR<br>* 75mg IR 4 - 6 hourly Total: 72 hours<br>|
| Active Comparator: 2<br>Morphine IR 30 mg 4 to 6 hourly for 72 hours | Drug: Morphine<br>* Morphine 30 mg IR 4 - 6 hourly Total: 72 hours<br>|
| Placebo Comparator: 3<br>Matching placebo 4 to 6 hourly for 72 hours | Drug: Placebo<br>* Placebo; 4 - 6 hourly; Total: 72 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline value to 48 hours after first study drug intake. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to 72 hours after first study drug intake | 
| 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. | Baseline to 48 hours after first study drug intake | 
| 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). | Baseline to 6 hours after intake of first study drug | 
| 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). | Baseline to 12 hours after first study drug intake | 
| 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). | Baseline to 24 hours after first study drug intake | 
| 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). | Baseline to 72 hours after first intake of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid, Central acting analgesic, CG5503 IR, Postoperative pain, Bunionectomy, Morphine, Placebo