OTR Tablet 40 mg Fasted-state Bioequivalence Study

Study Overview
=================
Brief Summary
-----------------
This is an open-label, single dose, randomised, cross-over study to confirm the bioequivalence (BE) of OTR tablet 40 mg and OXYCONTIN tablet 40 mg in a fasted state in Chinese subjects with chronic pain

Detailed Description
-----------------
In this BE study, subjects with histories of chronic pain are chosen as the target population. Inclusion/exclusion criteria are strictly defined to reduce the potential variation of the PK data. Single dose design is chosen per Food and Drug Administration (FDA)/WHO guideline on bioavailability (BA)/BE studies for modified-release products. As a general rule, cross-over design is applied in the study to decrease the inter-individual variations between the two cohorts. A washout period lasting for at least 7 half-lives of the investigational medicine is needed to eliminate the drug residual from the previous period7. The elimination half-life of oxycodone from OTR is 4.5 hours, and a 6-day washout period is sufficient to achieve the aim.

Official Title
-----------------
An Open-label, Single Dose, Randomised, Cross-over Study to Determine the Fasted State Pharmacokinetics of Oxycodone From Oxycodone Tamper Resistant (OTR) Tablet 40 mg and OXYCONTIN® Tablet 40 mg in Chinese Subjects With Chronic Pain

Conditions
-----------------
Chronic Pain

Intervention / Treatment
-----------------
* Drug: Oxycodone Tamper Resistant
* Drug: OXYCONTIN®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Chinese male or female subjects with histories of chronic pain regardless of the aetiology, aged 18-55 years both inclusive The average pain over the last 24 hours should be scored < 4 assessed with Numeric Rating Scales (NRS), when not receiving analgesics. The pain condition has been kept stable at least in the past 7 days prior to entering into the screening and is expected to be stable during the study duration Body weight ≥45 kg and a body mass index (BMI) ≥18 and ≤28 kg/m2 Karnofsky score of Performance Status ≥70 Willing to take all the food supplied while the subject is in the study unit Be able to read, understand, and sign written Informed Consent Form (ICF) prior to study participation and be willing to follow the protocol requirements Willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, some Intrauterine Device (IUD), sexual abstinence, or vasectomised partner Female subjects, including those up to less than one year post-menopausal, must have a negative serum pregnancy test and be non-lactating Exclusion Criteria: Subjects who are currently taking opioids or have used opioids in the past 14 days prior to receiving the study drug Have hypersensitivity history to any opioids, naltrexone, naloxone, or related compounds or any contraindications as detailed in the OTR and OXYCONTIN tablet Summary of Product Characteristics Histories of or any current conditions that might interfere with drug absorption, distribution, metabolism, or excretion Subjects who are likely to have paralytic ileus or acute abdomen or to require an operation on abdominal regions Subjects with biliary tract diseases, pancreatitis, prostatic hypertrophy, or corticoadrenal insufficiency Subjects with respiratory depression, corpulmonale, or chronic bronchial asthma Any history of seizures or symptomatic head trauma Subjects with abnormal liver function (values exceeding the upper limit of normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin during the Screening Phase) or abnormal renal function (values exceeding the ULN for serum creatinine during the Screening Phase). Note: if the values of ALT, AST or total bilirubin are between 1 to 1.2 times of ULN and confirmed not clinically significant by the Investigators, the subject may be recruited after getting the approval from Sponsor. Any other significant illness other than the primary disease of chronic pain during the 4 weeks preceding the entry into this study Subjects who are unable to stop taking monoamine oxidase inhibitors during this trial period or time lapses less than 2 weeks since drug withdrawal prior to the study drug administration Subjects who are currently taking tricyclic antidepressants or have used tricyclic antidepressants within 4 weeks prior to the study drug administration Subjects who have used any medicinal product which inhibits Cytochrome P450 3A4 (CYP3A4) (e.g. troleandomycin, ketoconazole, gestodene, etc.) or induces CYP3A4 (e.g. glucocorticoids, barbiturates, rifampicin, etc.) within 4 weeks prior to the study drug administration Subjects who have used any medicinal product which inhibits Cytochrome P450 2D6 (CYP2D6) (e.g. fluoxetine, quinidine, ritonavir, etc.) or induces CYP2D6 (e.g. dexamethasone, rifampicin, glutethimide, etc.) within 4 weeks prior to the study drug administration Histories of smoking (being a smoker or an occasional smoker) within 45 days prior to the study drug administration and refusal to abstain from smoking during the study. According to World Health Organization (WHO), a smoker is defined as having smoked at least 1 cigarette per day continuously for more than 6 months and an occasional smoker is defined as having smoked for more than 4 times per week and less than 1 cigarette per day continuously for more than 6 months. Subjects with histories of alcoholism or drug abuse. Alcoholism is defined as regular alcohol consumption exceeding 14 drinks/week (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor) Consumption of alcoholic beverages within 48 hours before study drug administration, and refusal to abstain from alcohol for at least 48 hours after study drug administration Refusal to abstain from food for 10 hours preceding and 4 hours following administration of the study drug and to abstain from caffeine or xanthine entirely during each confinement Positive Hepatitis B Surface Antigen (HBsAg), anti-Hepatitis C Virus (HCV), anti-Human Immunodeficiency Virus (HIV), or syphilis antibody test result Urine screening before study is positive for opioids, barbiturates, amphetamines, cocaine metabolites, methadone, benzodiazepines, phencyclidine, methamphetamine, or cannabinoids. Or alcohol breath test is positive Any history of frequent nausea or emesis regardless of aetiology Blood or blood products donated within 30 days prior to administration of the study drugs or anytime during the study, except as required by this protocol Subjects who participated in a clinical research study within 30 days of study entry

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxycodone Tamper Resistant<br>Oxycodone Tamper Resistant (OTR) Tablet 40 mg | Drug: Oxycodone Tamper Resistant<br>* Orally taking Oxycodone Tamper Resistant 40mg in fast state<br>* Other names: Oxycodone Tamper Resistant (OTR) Tablet 40 mg;|
| Active Comparator: OXYCONTIN®<br>OXYCONTIN® Tablet 40 mg | Drug: OXYCONTIN®<br>* Orally taking OXYCONTIN® 40mg in fast state<br>* Other names: OXYCONTIN® Tablet 40 mg;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | The analysis was for PK parameters Cmax of analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) were used to compare the test and the reference treatments. | up to 32 hours | 
| AUCt of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | The analysis was for PK parameters AUCt of analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) were used to compare the test and the reference treatments. | up to 32 hours | 
| AUCINF of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | The analysis was for PK parameters AUCINF for analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) was used to compare the test and the reference treatments. | up to 32 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | An overall summary of adverse events will be provided by treatment groups. The number and percentage of subjects reporting adverse events will be summarised by the preferred term nested within the System Organ Classification. In addition the number of reported adverse events will be summarised. | up to 35 days | 
| Number of Lab Tests With Clinical Significance | Clinical laboratory data to be summarised includes haematology, blood chemistry, and urinalysis.Each parameter will be assigned an LNH classification according to whether the value is lower than (L), within (N) or higher than (H) the reference range for that parameter. Results will be summarised using shift tables to evaluate categorical changes from baseline to end of study with respect to reference range values (lower than, within, and higher than). | up to 35 days | 
| Number of AEs Related to Vital Sign | Vital sign parameters to be summarised include systolic blood pressure, diastolic blood pressure, pulse rate, respiration rate, and axillary temperature. Vital sign results for each parameter will be assigned an LNH classification according to whether the value is lower than (L), within (N), or higher than (H) the reference range for that parameter. Vital sign results will be summarised using shift tables to evaluate categorical changes from baseline to end of study with respect to reference range values (lower than, within, and higher than). | up to 35 days | 
| Number of AEs Related to ECGs | Twelve-lead ECG was conducted at screening and on Day 4 of Period 2. | up to 35 days | 
| Number of AEs Related to Physical Examination | Physical examination was conducted at screening, and on Day -1, Day 4 in each Period. | up to 35 days |