Chronic Pain
Conditions
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.
Interventions
Orally taking Oxycodone Tamper Resistant 40mg in fast state
DRUGOXYCONTIN®
Orally taking OXYCONTIN® 40mg in fast state
Sponsors
Mundipharma (China) Pharmaceutical Co. Ltd
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Chinese male or female subjects with histories of chronic pain regardless of the aetiology, aged 18-55 years both inclusive 2. 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 3. Body weight ≥45 kg and a body mass index (BMI) ≥18 and ≤28 kg/m2 4. Karnofsky score of Performance Status ≥70 5. Willing to take all the food supplied while the subject is in the study unit 6. Be able to read, understand, and sign written Informed Consent Form (ICF) prior to study participation and be willing to follow the protocol requirements 7. 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 8. 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
1. Subjects who are currently taking opioids or have used opioids in the past 14 days prior to receiving the study drug 2. 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 3. Histories of or any current conditions that might interfere with drug absorption, distribution, metabolism, or excretion 4. Subjects who are likely to have paralytic ileus or acute abdomen or to require an operation on abdominal regions 5. Subjects with biliary tract diseases, pancreatitis, prostatic hypertrophy, or corticoadrenal insufficiency 6. Subjects with respiratory depression, corpulmonale, or chronic bronchial asthma 7. Any history of seizures or symptomatic head trauma 8. 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. 9. Any other significant illness other than the primary disease of chronic pain during the 4 weeks preceding the entry into this study 10. 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 11. Subjects who are currently taking tricyclic antidepressants or have used tricyclic antidepressants within 4 weeks prior to the study drug administration 12. 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 13. 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 14. 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. 15. 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) 16. 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 17. 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 18. Positive Hepatitis B Surface Antigen (HBsAg), anti-Hepatitis C Virus (HCV), anti-Human Immunodeficiency Virus (HIV), or syphilis antibody test result 19. Urine screening before study is positive for opioids, barbiturates, amphetamines, cocaine metabolites, methadone, benzodiazepines, phencyclidine, methamphetamine, or cannabinoids. Or alcohol breath test is positive 20. Any history of frequent nausea or emesis regardless of aetiology 21. 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 22. Subjects who participated in a clinical research study within 30 days of study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | up to 32 hours | 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. |
| AUCt of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | up to 32 hours | 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. |
| AUCINF of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | up to 32 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of AEs Related to ECGs | up to 35 days | Twelve-lead ECG was conducted at screening and on Day 4 of Period 2. |
| Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | up to 35 days | 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. |
| Number of AEs Related to Physical Examination | up to 35 days | Physical examination was conducted at screening, and on Day -1, Day 4 in each Period. |
| Number of Lab Tests With Clinical Significance | up to 35 days | 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). |
| Number of AEs Related to Vital Sign | up to 35 days | 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). |
Countries
China
Participant flow
Recruitment details
38, from Jun2017 to Oct2017, from patient database, medical clinic, advertisement recruitment and etc.
Participants by arm
| Arm | Count |
|---|---|
| OTR 40 Mg-OXYCONTIN 40 mg the treatment sequence is OTR 40 mg dose first and then OXYCONTIN 40 mg dose | 19 |
| OXYCONTIN 40 Mg-OTR 40 mg the treatment sequence is OXYCONTIN 40 mg dose first and then OTR 40 mg dose | 19 |
| Total | 38 |
Baseline characteristics
| Characteristic | OTR 40 Mg-OXYCONTIN 40 mg | OXYCONTIN 40 Mg-OTR 40 mg | Total |
|---|---|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 9.61 | 40.2 years STANDARD_DEVIATION 10.18 | 40.8 years STANDARD_DEVIATION 9.79 |
| BMI | 22.52 kg/m2 STANDARD_DEVIATION 2.419 | 22.16 kg/m2 STANDARD_DEVIATION 2.433 | 22.34 kg/m2 STANDARD_DEVIATION 2.399 |
| Height | 160.4 cm STANDARD_DEVIATION 9.1 | 157.7 cm STANDARD_DEVIATION 8.21 | 159.1 cm STANDARD_DEVIATION 8.67 |
| Race/Ethnicity, Customized HAN | 19 Participants | 19 Participants | 38 Participants |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 25 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 13 Participants |
| Weight | 57.87 kg STANDARD_DEVIATION 7.182 | 55.19 kg STANDARD_DEVIATION 8.088 | 56.57 kg STANDARD_DEVIATION 7.65 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 4 / 35 | 3 / 35 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 |
Outcome results
Primary
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.
Time frame: up to 32 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cmax of OTR 40 mg | AUCINF of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | 610.9314 ng*h/ml |
| Cmax of OXYCONTIN® 40 mg | AUCINF of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | 612.8057 ng*h/ml |
Primary
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.
Time frame: up to 32 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cmax of OTR 40 mg | AUCt of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | 604.5095 ng*h/ml |
| Cmax of OXYCONTIN® 40 mg | AUCt of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | 588.6874 ng*h/ml |
Primary
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.
Time frame: up to 32 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cmax of OTR 40 mg | Cmax of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | 60.98 ng/mL |
| Cmax of OXYCONTIN® 40 mg | Cmax of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State | 52.23 ng/mL |
Secondary
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.
Time frame: up to 35 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cmax of OTR 40 mg | Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | Number of AEs (#) | 23 TEAEs |
| Cmax of OTR 40 mg | Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | Number of TEAEs (#) | 23 TEAEs |
| Cmax of OTR 40 mg | Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | Number of relateda TEAEs | 15 TEAEs |
| Cmax of OXYCONTIN® 40 mg | Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | Number of AEs (#) | 22 TEAEs |
| Cmax of OXYCONTIN® 40 mg | Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | Number of TEAEs (#) | 22 TEAEs |
| Cmax of OXYCONTIN® 40 mg | Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State | Number of relateda TEAEs | 16 TEAEs |
Secondary
Number of AEs Related to ECGs
Twelve-lead ECG was conducted at screening and on Day 4 of Period 2.
Time frame: up to 35 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cmax of OTR 40 mg | Number of AEs Related to ECGs | 0 AEs of ECG related |
| Cmax of OXYCONTIN® 40 mg | Number of AEs Related to ECGs | 0 AEs of ECG related |
Secondary
Number of AEs Related to Physical Examination
Physical examination was conducted at screening, and on Day -1, Day 4 in each Period.
Time frame: up to 35 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cmax of OTR 40 mg | Number of AEs Related to Physical Examination | 0 AEs related to Physical examination |
| Cmax of OXYCONTIN® 40 mg | Number of AEs Related to Physical Examination | 0 AEs related to Physical examination |
Secondary
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).
Time frame: up to 35 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cmax of OTR 40 mg | Number of AEs Related to Vital Sign | 2 AEs of vital signs related |
| Cmax of OXYCONTIN® 40 mg | Number of AEs Related to Vital Sign | 4 AEs of vital signs related |
Secondary
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).
Time frame: up to 35 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cmax of OTR 40 mg | Number of Lab Tests With Clinical Significance | 3 Lab tests with clinical significance |
| Cmax of OXYCONTIN® 40 mg | Number of Lab Tests With Clinical Significance | 3 Lab tests with clinical significance |