| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033371 |
| E.1.2 | Term | Pain |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to determine the efficacy of CG5503 immediate-release (IR) using the sum of pain intensity difference (SPID) over 5 days compared with placebo, and to assess the safety and tolerability of multiple doses of CG5503 IR in subjects who are eligible for elective primary total or partial joint replacement of the hip or knee due to chronic osteoarthritis.
The null hypothesis is that all CG5503 IR dosage efficacy results are equal to placebo based on 5 day SPID in the treatment of chronic pain from end-stage degenerative joint disease of the hip or knee. The alternative hypothesis is that at least one CG5503 IR dose effect will be different from placebo effect.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives include:
• Compare the effect of CG5503 IR with placebo in time to the first rescue pain medication during the double blind treatment period
• Evaluate the effect of CG5503 IR with the distribution of responder rates based on percent change from baseline in pain intensity (PI) for each of the time point (Day 2, 5, and 10)
• Demonstrate the efficacy of CG5503 IR using total pain relief (TOTPAR) and sum of total pain relief and sum of pain intensity difference (SPRID) over 2, 5, and 10 days; and SPID over 2 and 10 days
• Evaluate patient global impression of change (PGIC) of study treatment at the end of the double blind treatment period
• Evaluate the adverse event rates across treatment groups (especially nausea and vomiting)
• Explore sleep quality and bowel movement using questionnaires
• Explore the efficacy of oxycodone IR in comparison with CG5503 IR and placebo |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria before entering the study:
• Man or woman, between 18 and 80 years of age, inclusive
• Signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study
• In countries where pharmacogenomics testing is allowed, signed an informed consent for genetic testing, indicating whether they do or do not wish to participate in the genetic part of the study. Participation in the genetic testing component is not mandatory for participation in the study
• Able to complete all study-related procedures and requirements throughout the double-blind treatment period
• Clinical diagnosis of osteoarthritis of the hip or the knee based on clinical and radiographic criteria defined by standard accepted guidelines; radiographic evidence of osteoarthritis of the target joint must be recorded within the previous 12 months. NOTE: the same target joint must be evaluated throughout the study
• Subjects with noninflammatory, end-stage degenerative joint disease who should need and be waiting for primary unilateral total or partial joint replacement surgery in the opinion of the investigator. Subjects who were offered joint replacement surgery but declined for reasons not associated with exclusion criteria are allowed. (NOTE: the same target joint must be evaluated throughout the study)
• Require daily doses of analgesic medication for chronic pain that is consistent with or makes them candidates for treatment at Step 2 or higher of the WHO Pain Relief Ladder, including subjects who require daily analgesia but cannot tolerate taking daily nonopioid analgesic medication. The subject should be dissatisfied with their current analgesic treatment.
• Before randomization on Day 1, pain is not adequately controlled with the current stable analgesic regimen based on the following criteria:
– Mean PI is equal or greater than 5 (after rounding 4.5 and above to an integer) on an 11-point (0 to 10) NRS during the last 3 days of pain assessments during the run-in period
– Minimum single assessment PI score is equal or greater than 3 during the last 3 days of pain assessments during the run-in period
• Women must be postmenopausal, surgically sterile, or practicing or agree to practice an effective method of birth control if they are sexually active before entry and throughout the study (effective methods of birth control include prescription hormonal contraceptives, intrauterine devices, double-barrier method, and male partner sterilization). Women of childbearing potential must have a negative serum
ß human chorionic gonadotropin (ß-hCG) pregnancy test at screening and a negative urine pregnancy test at randomization on Day 1
• Subjects must use satisfactory contraception from first dose up to 7 days after last dose of study treatment |
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| E.4 | Principal exclusion criteria |
• History of seizure disorder or epilepsy suggested by the presence of any of the following:
– Mild or moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm within 1 year of screening, or
– Severe traumatic brain injury, episode(s) of unconsciousness of more than 24 hours duration or posttraumatic amnesia of more than 24 hours duration within 15 years of screening
• Received an experimental drug or used an experimental medical device within 28 days before screening or have participated in a previous study of CG5503
• Participated in 3 or more clinical trials of analgesics before this study
• History of alcohol and/or drug abuse in the investigator's judgment based on subject history and physical examination
• Pending litigation due to history of chronic pain or disability
• History of chronic hepatitis B and C or human immunodeficiency virus, or presence of active hepatitis B and C within the past 3 months before screening
• Treated with anticonvulsants, monoamine oxidase inhibitors, tricyclic antidepressant, neuroleptics, or serotonin norepinephrine reuptake inhibitors within two weeks prior to screening (selective serotonin reuptake inhibitors treatments are allowed if taken for at least 28 days before screening at an unchanged dose)
• Received treatment with a controlled-release opioid analgesic (e.g., extended-release) within 28 days before screening
• Received treatment with an IR opioid analgesic taken 5 days or more each week during the previous 28 days before screening. Products containing IR opioid analgesics taken 4 days each week or less are allowed
• Products containing IR opioid analgesics must be discontinued prior to the run-in period. The non-opioid component of combination products may be continued during the study.
• History of malignancy within the past 2 years, with the exception of basal cell carcinoma
• Concomitant autoimmune inflammatory conditions involving the target joint
• Acute crystal-induced arthropathy within the past 6 months before screening
• Systemic steroid therapy, excluding inhalers, within 4 weeks before screening
• Presence of any of the following:
– Major trauma to the target joint in the 6 months preceding study screening
– Infection in the target joint in the 6 months preceding study screening
– Apparent avascular necrosis in the target joint in the 6 months preceding study screening
– Intra-articular injections of corticosteroids or hyaluronan injections in the target joint in the 3 months preceding study entry
• Women who plan to become pregnant during the study, or who are breast feeding
• Laboratory values reflecting moderate or severe renal insufficiency
• Moderately or severely impaired hepatic function, or subjects with alanine aminotransaminase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN)
• Contraindication to, or history of allergy to, or hypersensitivity to CG5503, oxycodone, or their excipients
• Plan to undergo surgery or other procedures during the course of the study
• Has a clinically significant disease that in the investigator's opinion may affect efficacy or safety assessments
• Employees of the investigator or study center, with involvement in the proposed study or other studies under the direction of that investigator or study center, including family members of the employees or the investigator |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The measurements used for the efficacy evaluations in this study include PI, pain relief, and the PGIC. The details are presented below.
• Pain Intensity – 11 Point Numerical Rating Scale
The subject will indicate the current PI on a 11-point (0 to 10) NRS in response to the following question: “What is your pain level for the past 12 hours?”
• Pain Relief – 5-Point Numerical Rating Scale
The subject will indicate their pain relief on a 5-point (0 to 4) NRS at the same time points as PI in response to the following question: “How much relief have you had from your starting pain?”
• Patient Global Impression of Change
The subjects will indicate their response (1 to 7) to the following statement: "Since I began study medication, my overall status is:"
The primary efficacy variable is the 5-day SPID.
• Pain Intensity Difference
The pain intensity difference (PID) will be calculated at each assessment time point, using the following formula: PID=Baseline PI-Current PI, where baseline PI is the mean PI collected during the last 3 days of pain assessments during the run-in period.
• Sum of Pain Intensity Difference
The SPID will be calculated over 5, days using the following formula: SPID=∑Wi*PIDi;
where the sum includes all observations collected from baseline to the end of Day 5 and Wi is the time elapsed from the previous observation (PIDi-1) to the current observation (PIDi). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The study is considered completed with the last visit of the last subject undergoing the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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