Conditions: Chronic Pain
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: no

Brief summary:
This is an open-label, single Dose, randomised, cross-over study to confirm the bioequivalence (BE) of OTR tablet 10 mg and OXYCONTIN tablet 10 mg in a fasted state in Chinese subjects with chronic pain

Detailed description:
The investigation is designed as an open-label, single dose, randomized, and cross-over study to determine the PK profile of oxycodone from OTR tablet 10 mg and OXYCONTIN tablet 10 mg in Chinese subjects with chronic pain in a fasted state.

the China regulations for drug registration require that controlled medicine (opioid is categorized to be a controlled medicine) should not be applied in healthy volunteers in clinical studies. 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. The subjects with abnormal liver and kidney functions, which may affect the metabolism of oxycodone.

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 period

open label design is applied since the plasma concentration of oxycodone is to be objectively tested and analysed and randomization will be applied to reduce selection bias.

Arms:
arm 1: Oxycodone Tamper Resistant (OTR) Tablet 10 mg arm 2: OXYCONTIN® Tablet 10 mg

Interventions: intervention 1: Oxycodone Tamper Resistant intervention 2: OXYCONTIN®
Intervention descriptions: intervention 1: Orally administered Oxycodone Tamper Resistant 10mg intervention 2: Orally administered OXYCONTIN® Tablet 10 mg

Protocol document:
Prot_000.pdf: 
                                                                                           ONF16-CN-101 
 
 
 
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SIGNATURE PAGE FOR PROTOCOL ONF16-CN-101 
Protocol Number: 
ONF16-CN-101 
Title: 
 
 
An Open-label, Single Dose, Randomized, Cross-over Study to 
Determine the Fasted State pharmacokinetics of Oxycodone from 
Oxycodone Tamper Resistant (OTR) Tablet 10 mg and 
OXYCONTIN® Tablet 10 mg in Chinese Subjects with Chronic Pain 
Test Drug: 
OTR tablet 10 mg 
Medical Writer 
Zoe Chen 
Mundipharma (China) Co., Ltd Beijing, China 
 
Signature 
Date 
Study Physician 
Dongsheng Wang 
Mundipharma (China) Co., Ltd Beijing, China 
 
Signature 
Date 
Drug Safety Manager 
Rachel Gao 
Mundipharma (China) Co., Ltd Beijing, China 
 
Signature 
Date 
Statistician 
Reiner Uhl 
Mundipharma Research GmbH & Co. KG 
Limburg, Germany 
 
Signature: 
 
Date 
Clinical Pharmacologist  
Kevin J Smith  
Mundipharma Research Ltd. Cambridge, UK 
 
Signature 
Date 
Medical Scientist 
Michael Hopp 
Mundipharma Research GmbH & Co. KG 
Limburg, Germany 
 
Signature 
 
Date 
Regulatory Affairs Manager 
Rainbow Bai 
Mundipharma (China) Co., Ltd  Beijing, China 
 
Signature 
Date 
Medical Director, Greater China 
Jane Zhang 
Mundipharma (China) Co., Ltd Beijing, China 
 
Signature 
Date 
 
 
 


 
 
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SIGNATURE PAGE FOR INVESTIGATORS 
Protocol Number: 
ONF16-CN-101 
 
 
Title: 
 
 
 
 
 
An Open-label, Single Dose, Randomised, Cross-over Study to 
Determine the Fasted State pharmacokinetics of Oxycodone from 
Oxycodone Tamper Resistant (OTR) Tablet 10 mg and 
OXYCONTIN® Tablet 10 mg in Chinese Subjects with Chronic Pain 
 
 
Test Drug: 
OTR tablet 10 mg 
 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and China Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki and all its accepted 
amendments to date. 
 
 
 
 
 
 
 
Investigators 
 
Signature 
 
Date 
 
 
 


 
 
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1. TITLE PAGE 
Protocol Number: 
ONF16-CN-101 
 
 
Title: 
An Open-label, Single Dose, Randomised, Cross-over Study to 
Determine the Fasted State pharmacokinetics of Oxycodone from 
Oxycodone Tamper Resistant (OTR) Tablet 10 mg and 
OXYCONTIN® Tablet 10 mg in Chinese Subjects with Chronic Pain 
 
 
 
 
Sponsor: 
Mundipharma (China) Pharmaceutical Co. LTD. 
18F, Tower D, Central International Trade Center 
6A Jianguomenwai Avenue 
Chaoyang District 
Beijing, China  
100022 
 
 
 
 
Test Drug: 
OTR tablet 10 mg 
 
 
Indication: 
Moderate to Severe Pain 
 
 
Phase: 
Phase 1 
 
 
Release Date: 
16-May-2016 
 
 
GCP Statement: 
This study is to be performed in full compliance with ICH and all 
applicable local GCP and regulations. All required study 
documentation will be archived as required by Competent Authorities 
(CA). 
 
 
 
 
 
 
 
 


 
 
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2. CLINICAL PROTOCOL SUMMARY 
Name of Sponsor: 
Mundipharma (China) Pharmaceutical Co. Ltd. 
Name of Generic Product: 
Oxycodone Hydrochloride Controlled-release 
Tablets 
Name of Active Ingredient: 
Oxycodone hydrochloride 
Protocol No.: ONF16-CN-101 
<EUDRACT><IND> No.: NA 
Short Title of the Study: OTR Tablet 10 mg Fasted-state Bioequivalence Study 
Full Title of the Study: An Open-label, Single Dose, Randomised, Cross-over Study to 
Determine the Fasted State Pharmacokinetics of Oxycodone from Oxycodone Tamper 
Resistant (OTR) Tablet 10 mg and OXYCONTIN® Tablet 10 mg in Chinese Subjects with 
Chronic Pain 
Investigators(s)/Centre(s): 1-2 Sites in China 
Study Initiation:  
Planned [Q4-2016] 
Phase of Development:                
Phase 1 
Objectives: 
Primary 
 
To confirm the bioequivalence (BE) of OTR tablet 10 mg and OXYCONTIN tablet 10 
mg in a fasted state. 
Secondary 
 
To assess the safety of OTR tablet 10 mg and OXYCONTIN tablet 10 mg, when given 
to Chinese subjects with chronic pain in a fasted state. 
Study Design (Methodology): 
Open-label, single dose, randomised, cross-over study. 
Study Design Graphic: 


 
 
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Number of Subjects: A total of 24 subjects with histories of chronic pain will be 
randomized to receive the study drug to achieve 18 subjects (9 subjects per treatment 
sequence) to complete the study with valid pharmacokinetic (PK) data. 
Criteria for Inclusion/Exclusion:  
Inclusion Criteria: 
Subjects who are to be included in the study, are those who meet all of the following 
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: 
Subjects who are to be excluded from the study are those who meet any of the following 
criteria: 


 
 
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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 


 
 
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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 
Test Treatment, Dose, and Mode of Administration: 
OTR tablet 10 mg. Oxycodone Hydrochloride Controlled-release Tablets containing 10 mg 
oxycodone hydrochloride, manufactured by Purdue Pharma L.P., U.S. 
 
The OTR tablet 10 mg will be administered orally once on the morning of Day 1 of each 
period, in a fasted state. 
Reference Treatment, Dose, and Mode of Administration: 
OXYCONTIN tablet 10 mg. Oxycodone Hydrochloride Prolonged-release (PR) Tablets 
containing 10 mg oxycodone hydrochloride manufactured by Bard Pharmaceuticals Ltd., 
U.K. 
 
The OXYCONTIN tablet 10 mg will be administered orally once on the morning of Day 1 
of each period, in a fasted state. 
Concomitant Medication Including Rescue:  
Naltrexone Cover: Naltrexone hydrochloride will be administered orally with the study 
treatments to reduce opioid-related adverse events (AEs). Naltrexone tablets 25 mg will be 
administered 13 hours, 1 hour before, and 11 hours after each dosing with the study 
treatment respectively (3 occasions for each period). 
 
Ondansetron will be permitted for the treatment of nausea or vomiting based on the clinical 
judgement by the Investigators. 
 
Paracetamol or ibuprofen will be used as rescue medicine for subjects who need the 
analgesic for pain relief. The maximum allowed daily doses of paracetamol and ibuprofen 
are 2.0 g and 1.2 g respectively. 
 
Administration of medications (including vitamins, herbal and/or mineral supplements, 
CYP3A4 inhibitors and inducers, CYP2D6 inhibitors and inducers) other than the study 
drug will be prohibited from the start to the completion of the study, with the exception of 
Vitamin D, calcium supplements, and drug therapy for any AE that might develop.  
 
In case other medications were taken by the subject during the study, the Investigators 
should record that on the case report form (CRF), including the name(s) of drug(s), dosage 


 
 
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and administration, the duration of administration, and the reason for administration. 
 
During the study period, smoking, alcohol, caffeine drinks, and grapefruit juice will be 
prohibited. Acute exercise will also be prohibited during the study period. Study restrictions 
(food, beverages, alcohol, caffeine, smoking, etc.) are detailed in Section 10.6. 
Duration of Treatment and Study Duration: 
Screening should be within 21 days before the randomization. The randomized subjects will 
be administered the test and reference treatments in a randomized order. There will be two 
study periods, with a minimum of 6 days washout between the two doses. Subjects will 
cross over to receive the alternative study drug upon completing Period 1. 
 
PK blood sampling will continue for up to 32 hours after dosing with the study treatment in 
each period. Subjects will stay in the unit for safety monitoring until 72 hours after each 
dosing of the study drug in each period. Subjects will have a safety follow-up visit via 
telephone at 7±1  days after the last dose of study drug in the case of completion or early 
discontinuation from the study. 
 
Total duration of the study is up to 35 days. 
Treatment Schedule (Procedure): 
A single dose of study drug is administered to subjects in each period with a minimum of 6 
days washout between two doses according to a RAS system. Each dose of study drug is 
given with 200 mL water to subjects in a standing position. 
 
Eligible subjects will be randomized into one of the treatment sequences as below: 
Treatment Sequence (n) 
Period 1 
 
Washout 
Period 2 
1 (n=12) 
OTR tablet 10 mg 
OXYCONTIN tablet 10 mg 
2 (n=12) 
OXYCONTIN tablet 10 
mg 
OTR tablet 10 mg 
 
Naltrexone tablets (5 x 5mg) will be administered with 150 mL water to subjects in a 
standing position. 
 
Subjects will fast from food (only water is permitted) for at least 10 hours prior to and at 
least 4 hours after dosing. Subjects will also have restricted fluid for one hour prior to and 
one hour after dosing. 
Criteria for Evaluation: 
Analysis Populations: 
The enrolled population is defined as all subjects who signed ICF. 
 
The intent to treat (ITT) population is defined as all randomised subjects. 
 
The safety population is defined as all randomised subjects who receive at least one dose 
of Investigational Medicinal Product (IMP). 
 
The PK population is defined as all subjects who received IMP and have at least one PK 


 
 
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concentration measurement.  
Efficacy Assessment(s): NA 
Drug Concentration Measurements: 
Blood samples for determining oxycodone plasma concentration will be obtained for each 
patient at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, and 32 
hours post each study drug administration. 
 
For each sample, 4 mL of blood sample will be collected at the above time points. The total 
volume of blood to be collected from each patient for PK analysis will be approximately 
152 mL. 
 
If subjects experience vomiting within 12 hours after dosing of the study treatment, no 
further PK blood sampling will be undertaken for the rest of the study period. 
 
Blood samples, 4 mL each, will be drawn into tubes containing K2EDTA anticoagulant. 
After procurement, samples should be kept in a cool environment, preferably in a container 
of ice water, until processing. Samples must be centrifuged within 30 minutes of collection. 
Following centrifugation (1500 g, 4℃, 15 minutes), the plasma will be transferred, via 
pipettes, into two labelled polypropylene tubes, and stored at -20℃ within one hour of 
collection. 
Bioanalytical Methods: 
The plasma samples will be analysed by a validated bioanalytical assay for oxycodone. 
PK Parameters:  
AUCt, Area under the plasma concentration-time curve calculated from the time of dosing 
to infinity (AUCINF), terminal phase rate constant (LambdaZ), apparent terminal phase 
half-life (t1/2Z), Cmax, and time from dosing to the maximum observed concentration 
(tmax) for oxycodone. 
 
AUCt will be calculated using the linear trapezoidal method. Where possible, LambdaZ 
will be estimated using those points determined to be in the terminal log-linear phase. 
T1/2Z will be determined from the ratio of ln 2 to LambdaZ. The areas under the plasma 
concentration-time curve between the last measured point and infinity will be calculated 
from the ratio of the final observed plasma concentration (Clast) to LambdaZ. This will be 
added to the AUCt to yield AUCINF. 
 
Cmax and tmax will be obtained directly from the reported data. 
 
PK parameters will be determined using actual sampling times. All PK parameters 
calculations will be conducted using the Phoenix WinNonlin, Version 6.2 or later.  
Pharmacodynamic Measurements: NA 


 
 
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Safety Assessments: 
Safety will be assessed by AEs, clinical laboratory results, vital signs (systolic blood 
pressure, diastolic blood pressure, pulse rate, respiration rate, and axillary temperature), 
physical examination, and electrocardiogram (ECGs) in the safety populations.  
 
AEs will be recorded through spontaneous reporting from the time subjects provide their 
informed consent at screening until 7±1 days after the last dose of study drug, and through 
open questioning at each study visit. The subject’s AEs will be categorized into Preferred 
Term (PT) and associated System Organ Class (SOC) using the Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment-emergent AEs (TEAE) will be defined as AEs 
that start or increase in severity after the administration of OTR tablet 10 mg or 
OXYCONTIN tablet 10 mg. When the Investigators identify a serious adverse event (SAE), 
a completed SAE data form signed and dated must be forwarded to Mundipharma China 
within 24 hours. 
Statistical Methods: 
Efficacy Analyses: NA 
Interim Analyses: NA 
PK Analyses:  
Plasma concentration data and PK parameters will be listed for subjects in the enrolled 
population. 
 
Plasma concentration data for the analyte oxycodone will be summarised descriptively by 
nominal time-point and treatment for subjects in the PK population. Individual and mean 
plasma concentrations for the analyte oxycodone will also be plotted over time for each 
treatment. 
 
PK parameters (AUCt, AUCINF, Cmax, tmax, LambdaZ, and t1/2Z) for analyte oxycodone 
will be summarised descriptively by treatment for subjects in the PK population. 
 
The comparison will be OTR tablet 10 mg in a fasted state (test) vs. OXYCONTIN tablet 
10 mg in a fasted state (reference). 
 
Primary Analysis: 
The primary analysis will be for PK parameters AUCt and Cmax and 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) will be used to 
compare the test and the reference treatments. BE of test and reference will be concluded 
for a PK parameter of analyte oxycodone if the 90% Confidence Interval (CI) for the ratio 
(test/reference) falls completely within the BE acceptance range of 80.00% to 125.00%. BE 
of test and reference will be declared at all if it can be concluded for AUCt and Cmax, 
respectively. 
 
Secondary Analysis: 
The primary analysis will be repeated for the PK parameter AUCINF and for analyte 
oxycodone. 
 


 
 
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The statistical analyses will exclude PK parameters for which any of the following criteria 
apply: vomiting within 12 hours after dosing, incorrect dosing, incomplete plasma profile 
which cannot adequately detail the parameter, pre-dose concentration > 5% of Cmax, R2 < 
0.85.The validity of PK data will be discussed further and evaluated during the data review 
meeting at the end of the study. In accordance with BE guidelines, only subjects that 
provide valid PK data for both the test and reference treatments will be included in the 
statistical analysis. 
Safety Analyses: 
All safety summaries will be based on the safety population. 
AEs will be classified into standardised terminology from the verbatim description 
(Investigators term) according to MedDRA Coding Dictionary to give a SOC and PT for 
each event. 
An overall summary of TEAEs will be provided by treatment group. The number and 
percentage of subjects reporting TEAEs will be summarised by the PT nested within the 
SOC. In addition, the number of reported TEAEs will be summarised.  
TEAEs will be summarised by worst severity and relationship to IMP. In addition, severe 
TEAEs, TEAEs leading to death, SAEs, and TEAEs requiring additional therapy will be 
summarised.   
Clinical laboratory parameters and vital signs will be summarised descriptively by 
treatment and time point. The frequency of clinical laboratory and vital sign results with 
respect to normal ranges will be presented. Results of clinical laboratory evaluations that lie 
outside the normal range will be flagged on the listings as high or low. 
The frequency of clinically significant ECG results will be presented. 
Sample Size Rationale: 
The study is designed to have a power of ≥95% to demonstrate a BE (e.g. AUCt and 
Cmax) of OTR tablet 10 mg, in terms of oxycodone, with OXYCONTIN tablet 10 mg in a 
fasted state.  
 
The null hypothesis is that the two treatments are not bioequivalent. The alternative 
hypothesis is that both treatments are bioequivalent. BE between both treatments will be 
concluded if the 90.00% CI for the ratio lies within 80.00% to 125.00% for both AUCt and 
Cmax for the oxycodone analyte. 
 
A total of 24 subjects will be randomised to receive study drug (12 subjects per treatment 
sequence) with the aim that 18 subjects will provide valid PK data (9 subjects per treatment 
sequence) and PK parameters (Cmax and AUCt). This will provide ≥ 95% power to show 
BE simultaneously in both parameters, Cmax and AUCt, between test and reference 
formulation, assuming a true ratio of 1, a within standard deviation (SD) of the period 
differences of 0.24 on the log scale for AUCt and 0.20 on the log scale for Cmax, both PK 
parameters are not anti-correlated, and 90% CI for the ratios of the population means within 
the BE limits of 80.00% and 125.00%. The within SD of the period differences was based 
on Purdue Pharma BE study OTR1003 in healthy volunteers taking oxycodone8.  
 
The sample size was estimated using NQuery t-tests (TOST of equivalence in ratio of means 
for crossover design (natural log scale).   


 
 
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3. TABLE OF CONTENTS 
 
 
Page No 
1. TITLE PAGE ........................................................................................................ 3 
2. CLINICAL PROTOCOL SUMMARY .................................................................... 4 
3. TABLE OF CONTENTS .................................................................................... 12 
4. LIST OF ABBREVIATIONS ............................................................................... 17 
5. STUDY CONDUCT AND OVERSIGHT ............................................................. 19 
5.1 Sponsor .......................................................................................................... 19 
5.2 Declaration of Ethical Conduct ..................................................................... 19 
5.3 Investigators and Study Personnel .............................................................. 19 
5.4 Randomisation ............................................................................................... 19 
5.5 Data Management .......................................................................................... 19 
5.6 Monitoring....................................................................................................... 19 
5.7 Medical Monitoring & Safety ......................................................................... 19 
5.8 Bioanalytical Laboratory ............................................................................... 19 
6. INTRODUCTION ................................................................................................ 20 
6.1 Investigational Drug/Background ................................................................. 20 
6.2 Design Rationale ............................................................................................ 20 
6.3 Risk/Benefit Assessment .............................................................................. 21 
7. STUDY OBJECTIVES ....................................................................................... 21 
7.1 Aim of the study ............................................................................................. 21 
7.2 Primary Objectives ......................................................................................... 22 
7.3 Secondary Objectives .................................................................................... 22 
8. STUDY SUMMARY AND GRAPHIC ................................................................. 22 
8.1 Overall Study Design and Plan ..................................................................... 22 


 
 
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8.2 Study diagram ................................................................................................ 22 
8.3 Efficacy Parameters ....................................................................................... 23 
8.4 PK Measurements .......................................................................................... 23 
8.4.1 Drug Concentration Measurements .............................................................. 23 
8.4.2 PK Parameters: ............................................................................................. 23 
9. SELECTION OF SUBJECTS ............................................................................. 24 
9.1 Number of Subjects ....................................................................................... 24 
9.2 Inclusion Criteria ............................................................................................ 24 
9.3 Exclusion Criteria: ......................................................................................... 24 
10. ASSESSMENTS AND PROCEDURES ........................................................... 25 
10.1 Schedule Overview ...................................................................................... 25 
10.2 Screening Phase (V1) .................................................................................. 28 
10.3 Treatment and Sampling Phase (V2 and V3) ............................................. 28 
10.3.1 Period 1 (V2) ............................................................................................... 29 
10.3.1.1 Day -1....................................................................................................... 29 
10.3.1.2 Day 1 ........................................................................................................ 29 
10.3.1.3 Day 2 ........................................................................................................ 30 
10.3.1.4 Day 4 ........................................................................................................ 30 
10.3.2 Period 2 (V3) ............................................................................................... 31 
10.3.2.1 Day -1, Period 2 ....................................................................................... 31 
10.3.2.2 Day 1, Period 2 ........................................................................................ 31 
10.3.2.3 Day 2, Period 2 ........................................................................................ 32 
10.3.2.4 Day 4, Period 2 ........................................................................................ 32 
10.4 Safety Follow-up (V4) ................................................................................... 33 
10.5 Early Discontinuation/Withdrawal/Loss to Follow-up ............................... 33 
10.6 Study Restrictions ....................................................................................... 33 
10.6.1 Food and Beverages ................................................................................... 33 
10.6.2 Alcohol, Caffeine, and Smoking Restrictions ............................................... 34 
11. STUDY TREATMENTS AND CONCOMITANT THERAPIES .......................... 34 
11.1 Treatment administration ............................................................................ 34 


 
 
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11.1.1 Definitions ................................................................................................... 34 
11.1.2 Test IMPs, Dose, and Mode of Administration ............................................ 35 
11.1.3 NIMP, Dose, and Mode of Administration ................................................... 35 
11.1.4 Other Medications, Dose, and Mode of Administration ............................... 35 
11.2 Identity of Investigational Products and Study Treatments Supply ........ 36 
11.3 Dosing Schedule .......................................................................................... 36 
11.4 Dose Modification ........................................................................................ 36 
11.5 Method of Administration ............................................................................ 36 
11.6 Treatment Assignment ................................................................................ 37 
11.7 Blinding ......................................................................................................... 37 
11.8 Treatment Compliance/Drug Accountability .............................................. 37 
11.9 Concomitant Therapies (Permitted and Prohibited) ................................. 38 
11.10 Shipping, Handling, Storage, and Destruction/Return............................ 38 
11.11 Retention of IMP Samples ......................................................................... 39 
12. REFERENCE VALUES ................................................................................... 39 
12.1 Physical/Vital Sign Assessments ............................................................... 39 
12.2 Laboratory Assessments ............................................................................ 39 
13. SAFETY ASSESSMENTS ............................................................................... 40 
13.1 AEs and SAEs .............................................................................................. 40 
13.2 Reporting of AEs .......................................................................................... 42 
13.3 Causality/Expectedness Assessment ........................................................ 43 
13.4 Severity Assessment ................................................................................... 43 
13.5 Pregnancy ..................................................................................................... 44 
13.6 Laboratory Abnormalities ............................................................................ 44 
13.7 Vital Signs and Physical Examinations ...................................................... 45 
13.8 ECG TEAE ..................................................................................................... 45 
13.9 Other Safety Considerations/Risk Management ....................................... 45 


 
 
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14. STATISTICAL ANALYSES ............................................................................. 46 
14.1 Statistical Methodology and Analytical Plans ........................................... 46 
14.2 Statistical Considerations ........................................................................... 46 
14.3 Analysis Populations ................................................................................... 46 
14.4 Protocol Deviations ..................................................................................... 46 
14.5 Sample Size and Power Considerations .................................................... 47 
14.6 Primary Outcome/Efficacy Variable(s) ....................................................... 47 
14.7 Secondary Outcome/Efficacy Variable(s) .................................................. 48 
14.8 Exploratory Efficacy Variables .................................................................... 48 
14.9 Subject Disposition ...................................................................................... 48 
14.10 Demographic/Baseline Analyses .............................................................. 48 
14.11 IMP Analyses .............................................................................................. 48 
14.12 Concomitant Medications Analyses ......................................................... 49 
14.13 Safety Analyses .......................................................................................... 49 
14.14 Analysis of TEAEs ..................................................................................... 50 
14.14.1 Laboratory Values ..................................................................................... 50 
14.14.2 Vital Signs ................................................................................................. 50 
14.14.3 ECG .......................................................................................................... 51 
14.15 Other Special Tests .................................................................................... 51 
14.16 PK Measurements and Analyses .............................................................. 51 
15. ETHICS & REGULATORY .............................................................................. 52 
15.1 Declaration of Ethical Conduct ................................................................... 52 
15.2 Ethical and Regulatory Review ................................................................... 52 
15.3 Subject Information and Consent ............................................................... 53 
15.4 Data Protection and Human Tissue Sampling ........................................... 54 
15.5 Quality Assurance & Inspection Requirements ........................................ 54 


 
 
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16. STUDY MANAGEMENT RECORDS & PUBLICATION .................................. 55 
16.1 Protocol Amendments ................................................................................. 55 
16.2 Record Maintenance and Retention ........................................................... 55 
16.3 Adherence to the Protocol .......................................................................... 56 
16.4 Discontinuation of Study ............................................................................. 57 
16.5 Retention of Tissue Samples ...................................................................... 57 
16.6 Registration and Publication of Study Summary and Results ................. 57 
17. REFERENCE LIST .......................................................................................... 59 
18. APPENDICES .................................................................................................. 61 
18.1 Sample Processing and Shipment ............................................................. 61 
18.1.1 PK Sample Handling and Shipping ............................................................. 61 
18.1.2 Sample Procurement and Processing ......................................................... 61 
18.1.3 Sample Shipment ........................................................................................ 61 
18.2 REFERENCE VALUES ................................................................................. 61 
18.2.1 Physical/Vital Sign Assessments ................................................................ 61 
18.2.2 Laboratory Assessments ............................................................................. 62 
18.3 Numeric Rating Scale .................................................................................. 63 
18.4 Karnofsky Score of Performance Status.................................................... 64 
LIST OF TABLES                                                                                                          Page No. 
Table 1 Schedule of Visits and Procedures................................................................................ 26 
Table 2: PK Blood Sampling Schedule ..................................................................................... 27 
Table 3 Investigational Drug ................................................................................................... 35 
Table 4 Reference Investigational Drug .................................................................................... 35 
Table 5 NIMP ....................................................................................................................... 35 
Table 6 Normal Ranges for Vital Signs .................................................................................... 61 
Table 7  Criteria Used to Identify Clinically Notable Vital Sign Abnormalities ............................. 62 
Table 8 Clinical Laboratory Tests ............................................................................................ 62 
Table 9 Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values .................... 63 
LIST OF FIGURES                                                                                                       Page No. 
Figure 1 Study Diagram ...........................................................................................................22 


 
 
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4. LIST OF ABBREVIATIONS 
AE                      
ALT             
ANOVA             
AST                     
ATC                   
AUC                
AUCINF                      
AUCt 
Adverse Event                                                                            
Alanine aminotransferase                                                         
Analysis of Variance                                                               
Aspartate aminotransferase                                                
Anatomical-Therapeutic-Chemical                                                 
Area under the plasma concentration-time curve                           
Area under the plasma concentration-time curve calculated from the 
time of dosing to infinity                                                                
Area under the plasma concentration-time curve calculated from the 
time of dosing to the last measurable concentration 
BE                                
BMI                          
bpm                         
CA                    
Bioequivalence                                                                               
Body Mass Index                                                                            
beats per minute                                                                            
Competent Authorities                                                                    
CI                       
Clast 
Confidence Interval                                                                                 
the final observed plasma concentration 
Cmax 
Maximum observed concentration 
CRF                     
CRO 
Case Report Form                                                                     
Contract Research Organisation 
CYP2D6      
CYP3A4       
Cytochrome P450 2D6                                                       
Cytochrome P450 3A4                                                        
EC 
Ethics Committee 
ECG                    
EDC 
Electrocardiogram                                                                   
Electronic data capture system 
FDA                     
Food and Drug Administration                                                   
GCP                   
GGT 
Good Clinical Practice                                                               
gamma-glutamyl-transferase 
H 
Laboratory value above the reference range 
HBsAg                
hCG                    
HCO3
-                          
Hepatitis B Surface Antigen                                                       
Human chorionic gonadotropin                                         
Biocarbonate                                            
HCV 
Hepatitis C Virus 
HIV                              
IB 
Human Immunodeficiency Virus                                                             
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IMP                      
ITT                               
IUD 
Investigational Medicinal Product                                                   
The intent to treat                                                                            
Intrauterine Device 
Kg 
Kilogram 
L 
Laboratory value below the reference range 
LambdaZ             
LC-MS/MS 
Terminal phase rate constant                                                       
Liquid Chromatography - Tandem Mass Spectrometry 
LLN 
Lower limit of normal 
 
 


 
 
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LNH 
Classification according to whether the Laboratory test result was 
below (L), within (N), or above (H) the reference range 
MedDRA              
mg 
Medical Dictionary for Regulatory Activities                        
Milligram 
mL 
Millilitre 
N 
Laboratory value within the reference range 
NIMP                  
NRS                    
OTR 
Non-Investigational Medicinal Product                                   
Numeric Rating Scale                                                            
Oxycontin Tamper Resistant 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetic 
PT                                
QA 
Preferred Term                                                                                         
Quality Assurance 
RAS                    
RBC 
Random Allocation Schedule                                                           
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP                       
SD 
Statistical Analysis Plan                                                           
Standard Deviation 
SOC 
System Organ Class 
SOPs 
Standard Operating Procedures 
t1/2Z                
TEAE 
Apparent terminal phase half-life                                           
Treatment emergent adverse event 
tmax 
Time from dosing to the maximum observed concentration 
ULN 
Upper limit of normal 
UK                               
WBC 
United Kingdom                                                                                       
White Blood Cell 
WHO 
World Health Organisation 
 


 
 
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5. STUDY CONDUCT AND OVERSIGHT 
5.1 Sponsor 
This study will be conducted by qualified Investigators under the sponsorship of Mundipharma 
(China) Pharmaceutical Co. Ltd. 
5.2 Declaration of Ethical Conduct 
This study will be conducted in accordance with the standard operating procedures (SOPs) of the 
Sponsor and Contract Research Organisation (CRO), which are designed to ensure adherence to 
GCP (ICH and China, GCP means both ICH and China hereinafter.) guidelines as described in 
Section15 of this protocol. 
5.3 Investigators and Study Personnel 
The study will be conducted at 1-2 Sites in China. 
5.4 Randomisation 
Randomisation will be completed using a RAS system by the sponsor in a 1:1 ratio.    
5.5 Data Management 
Data management will be the responsibility of the Data Management team from CRO. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. The Monitoring Plan and Data Management Plan (DMP) will detail the data 
entry, cleaning, clarification, and validation procedures to be followed by all relevant study staff. 
Data will be collected by an electronic data capture (EDC) system.  
5.6 Monitoring 
The study will be monitored by qualified personnel from CRO. The Monitoring Plan for the 
study will detail this process. The Investigators will allow monitoring, audit, and inspection of 
the clinical, laboratory, and pharmacy facilities as required, to assure compliance with GCP. The 
CRFs and subject’s corresponding original medical records (source documents) are to be fully 
available for review by the Sponsor’s representatives at regular intervals. These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations and GCP. All 
records at the Sites are subject to inspection by the local CA. 
5.7 Medical Monitoring & Safety 
The name of the Study Physician and Drug Safety Responsible Person along with the telephone 
and fax numbers of the other contact persons are listed in the study site file. 
5.8 Bioanalytical Laboratory 
A central bioanalytical laboratory will be employed to process all bioanalytical data. 


 
 
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6. INTRODUCTION 
6.1 Investigational Drug/Background 
Oxycodone, the derivative of the opium alkaloid analgesic, is a strong, semi-synthetic opioid 
analgesic, effective in the relief of mild to severe malignant and non-malignant pain1-5. As a mu- 
and kappa- opioid receptor agonist3, oxycodone exerts its agonist activity similar to that of 
morphine and other opioid analgesics. 
Oxycodone was launched in the United Kingdom (U.K.) in January 2000 as a prolonged release 
oral preparation (OXYCONTIN tablets) for the treatment of moderate to severe continuous pain. 
These OXYCONTIN tablets, manufactured and marketed by Bard Pharmaceuticals Ltd. and 
Napp Pharmaceuticals Limited respectively, are currently available as 5, 10, 20, 40, and 80 mg 
strengths.  
In China, starting from 2004, the 5, 10, 20, 40, and 80 mg of OXYCONTIN tablets have been 
marketed. These preparations have since been authorized for the treatment of moderate to severe 
around-the-clock pain. OXYCONTIN tablets are for 12-hourly administration. 
A new formulation, OTR, developed by Purdue Pharma L.P., provides improvements in the 
tamper resistant characteristics to make the tablet more difficult to manipulate for misuse and 
abuse. There is an increase in the ability of OTR to resist crushing, breaking, and dissolution 
using a variety of tools and solvents, which makes misuse more difficult and therefore safer for 
patients. The physicochemical properties make abuse via injection difficult. When subjected to 
an aqueous environment, OTR gradually forms a viscous hydrogel, i.e. a gelatinous mass, which 
resists passage through a needle. Clinical studies also suggest that OTR has physicochemical 
properties that are expected to reduce abuse via the intranasal route6. 
The goal of this study is to demonstrate that the new formulation, OTR, is bioequivalent to the 
marketed available OXYCONTIN in 10 mg dosage in a fasted state. 
6.2 Design Rationale 
OTR tablet 10 mg contains the same amount of active ingredient oxycodone as OXYCONTIN 
tablet 10 mg, which is market available. The BE of OTR tablet 10 mg to OXYCONTIN tablet 10 
mg will be examined.  
 
The investigation is designed as an open-label, single dose, randomized, and cross-over study to 
determine the PK profile of oxycodone from OTR tablet 10 mg and OXYCONTIN tablet 10 mg 
in Chinese subjects with chronic pain in a fasted state due to the reasons addressed in the 
following paragraphs. 
 
First of all, the China regulations for drug registration require that controlled medicine (opioid is 
categorized to be a controlled medicine) should not be applied in healthy volunteers in clinical 
studies. In this BE study, subjects with histories of chronic pain are chosen as the target 
population. Per guideline, in this situation, Sponsor should attempt to enrol subjects whose 
disease process is expected to be stable for the duration of the study9. 
 


 
 
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Inclusion/exclusion criteria are strictly defined to reduce the potential variation of the PK data. 
The subjects with abnormal liver and kidney functions, which may affect the metabolism of 
oxycodone, or with recent histories of taking medications which are classified as inducers or 
inhibitors of CYP3A4 and CYP2D6 will be excluded from the study. The eligible subjects will 
generate more valid PK data for the study analysis.   
 
Single dose design is chosen per Food and Drug Administration (FDA)/WHO guideline on 
bioavailability (BA)/BE studies for modified-release products, i.e., "single dose studies are 
preferred to multiple-dose studies as single-dose studies are considered to provide more sensitive 
measurements of the release of active pharmaceutical ingredient (API) from the pharmaceutical 
product into the systemic circulation."  
 
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 hours6, and a 6-day washout period is 
sufficient to achieve the aim.  
 
Finally, open label design is applied since the plasma concentration of oxycodone is to be 
objectively tested and analysed and randomization will be applied to reduce selection bias. 
Naltrexone cover is used to reduce opioid-related AEs and increase tolerance to the study 
treatment.  
 
6.3 Risk/Benefit Assessment 
Opioid misuse and abuse is always the focus of attention from the regulatory authorities and 
clinical practisers. Compared with OXYCONTIN, OTR provides improvements in the tamper 
resistant characteristics which make the tablet more difficult to manipulate for misuse and abuse. 
The available data from clinical studies demonstrated that OTR has physicochemical properties 
that are expected to make abuse difficult and therefore reduce abuse.  
 
Subjects will get study treatment with close monitoring by the Investigators in a medical 
surveillance environment. Naltrexone cover will be applied in the study to reduce opioid-related 
AEs since naltrexone can block the effect of oxycodone effectively as an opioid antagonist. 
Common side effects, such as nausea and emesis, will be targeted by ondansetron. Also, in case 
of flare ups of pain during the study, rescue drugs paracetamol or ibuprofen can be used at the 
discretion of the Investigators.  
 
7. STUDY OBJECTIVES 
7.1 Aim of the study 
This open-label, single dose, randomised, cross-over study aims to determine the fasted-state PK 
of oxycodone from OTR tablet 10 mg and OXYCONTIN tablet 10 mg in Chinese subjects with 
chronic pain. 


 
 
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7.2 Primary Objectives 
To confirm the BE of OTR tablet 10 mg and OXYCONTIN tablet 10 mg in a fasted state. 
7.3 Secondary Objectives 
To assess the safety of OTR tablet 10 mg and OXYCONTIN tablet 10 mg, when given to 
Chinese subjects with chronic pain in a fasted state. 
 
8. STUDY SUMMARY AND GRAPHIC 
8.1 Overall Study Design and Plan 
Protocol ONF16-CN-101 is an open-label, single dose, randomised, cross-over study to 
determine the fasted-state PK of oxycodone from OTR tablet 10 mg and OXYCONTIN tablet 10 
mg in Chinese subjects with chronic pain.  
The study consists of a Screening Phase, a Treatment and Sampling Phase, and a Safety Follow-
up Phase. The Screening Phase aims to check the eligibility of all subjects and will be completed 
within 21 days. The Treatment and Sampling Phase includes Period 1 and Period 2. Eligible 
subjects will report to the Sites one day before Period 1 for the reconfirmation of I/E criteria and 
will be randomized following a RAS system for the single-dose administration of either test or 
reference treatment. The randomized subjects will be administered with a single dose of the study 
drug on Day 1 of each Period at a fasted state. In Period 2, subjects will cross over to receive the 
single-dose administration of alternative study drug following a minimum 6-day washout 
between the 2 doses administration. Naltrexone tablets 25 mg will be administered at 13 hours, 1 
hour before and at 11 hours after each dosing with the study drug respectively to reduce opioid-
related AEs. Blood samples for PK analysis will be collected per each study drug dosing until 32 
hours after as described in Table 1and Table 2. Subjects will remain in the study unit for 72 hours 
after each study drug administration and will be contacted by phone calls for a safety follow-up 
on 7±1 days after the last study  drug dosing in the case of completion or early discontinuation 
from the study. 
Subjects will be fasted (only water is permitted) from at least 10 hours prior to and at least 4 
hours after each dosing. Subjects will also have restricted fluid for one hour preceding and one 
hour after each dosing.  
AEs and concomitant medication will be recorded throughout the study. Vital signs will be 
periodically monitored as described in Table 1 and Table 2. 
8.2 Study diagram 
Fig.1 study diagram  
 


 
 
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8.3 Efficacy Parameters 
Not investigated. 
 
8.4 PK Measurements 
8.4.1 Drug Concentration Measurements 
Blood samples for determining oxycodone plasma concentration will be collected within 5 
minutes pre dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, and 32 hours 
post each study drug administration. For each sample, 4 mL blood sample will be drawn from a 
forearm vein into a tube containing K2EDTA anticoagulant. The total volume of blood to be 
collected from each subject will be approximately 152 mL. If subjects experience vomiting 
within 12 hours after dosing of the study treatment, no further PK blood sampling will be 
undertaken for the rest of the study period. After procurement, samples should be kept in a cool 
environment, preferably in a container of ice water, until processing. Samples must be 
centrifuged within 30 minutes of collection. Following centrifugation (1500 g, 4℃, 15 minutes), 
the plasma will be equally transferred, via pipettes, into two labelled polypropylene tubes, and 
stored at -20℃ within one hour of collection. 
 
Plasma concentration of oxycodone will be quantified by Liquid Chromatography - Tandem 
Mass Spectrometry (LC-MS/MS) methodology using a previously validated assay.  
8.4.2 PK Parameters:  
AUCt, AUCINF, LambdaZ, t1/2Z, Cmax, and tmax for oxycodone will be calculated. 
 
AUCt will be calculated using the linear trapezoidal method. Where possible, LambdaZ will be 
estimated using those points determined to be in the terminal log-linear phase. And t1/2Z will be 
determined from the ratio of ln 2 to LambdaZ. The areas under the plasma concentration-time 
curve between the last measured point and infinity will be calculated from the ratio of Clast to 
LambdaZ. This will be added to the AUCt to yield AUCINF. 
 


 
 
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Cmax and tmax will be obtained directly from the reported data. 
 
PK parameters will be determined using actual sampling times. All PK calculations will be 
conducted using the Phoenix WinNonlin, Version 6.2 or later.  
 
9. SELECTION OF SUBJECTS 
9.1 Number of Subjects 
A total of 24 subjects with histories of chronic pain will be randomized to receive the study drug 
to achieve 18 subjects (9 subjects per treatment sequence) to complete the study with valid PK 
data. 
9.2 Inclusion Criteria 
Subjects to be included in the study are those who meet all of the following criteria: 
1. Chinese male or female subjects with histories of chronic pain regardless of the aetiology, 
aged 18-55 years inclusive 
2. The average pain over the last 24 hours should be scored < 4 assessed with NRS, when not 
receiving analgesics. And the 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 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 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 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. 
9.3 Exclusion Criteria: 
Subjects who are to be excluded from the study are those who meet any of the following 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 or related compounds or any contraindications 
as detailed in the OXYCONTIN and OTR 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 region 
5. Subjects with biliary tract diseases, pancreatitis, prostatic hypertrophy, or corticoadrenal 
insufficiency 


 
 
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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 ULN for ALT, 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 inhibitor 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 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 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 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 HBsAg, anti-HCV, anti-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 
10. ASSESSMENTS AND PROCEDURES 
10.1 Schedule Overview 
Table 1 and Table 2 present the detailed procedures to be carried out at each study visit. 


 
 
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Table 1 Schedule of Visits and Procedures 
Phase 
Pre-treatment 
Treatment and Sampling 
Visit Name and Number 
Screening (V1) 
Period 1 and Washout (V2) 
 
Period 2 (V3)1 
Safety Follow-up2 (V4) 
Day 
≤20 
-1 
1 
2 
4 
-13 
13 
23 
43 
7±1 2 
Hours 
NA 
-13 
-1 
0 
11 
24 
72 
-13 
-1 
0 
11 
24 
72 
 
Report to Study Site 
x 
x4 
 
 
 
 
 
x 
 
 
 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRS Score 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc. /Exc. Criteria 
x 
x5 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs6 and BMI 
x 
x 
x 
See Table 2 for VS 
testing 
x 
x 
x 
See Table 2 for VS testing 
x 
 
Physical Examination 
x 
x 
 
 
 
 
x 
x 
 
 
 
 
x 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Hematology, Blood Chemistry, Urinalysis  
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
HBsAg, anti-HCV, anti-HIV, Syphilis 
Antibody 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen and Alcohol Test 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
β-HCG Test (Female only)7 
x8 
x9 
 
 
 
 
 
x9 
 
 
 
 
x9 
 
Study Restriction Check 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
Naltrexone Dosing10 
 
x 
x 
 
x 
 
 
x 
x 
 
x 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing11 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
PK Blood Sampling  
 
See Table 2 for Blood Sampling Schedule 
 
Concomitant Medication and Non-
pharmacological Therapies 
x 
Concomitant medication will be recorded continuously. 
x 
AE 
x 
AE will be monitored continuously. 
x 
Discharge from Site12 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
1. 
A minimum washout period of 6 days starting between the 1st study drug dosing and the 2nd.  
2. 
Safety Follow-up visit will be 7±1 days after the last dose of study drug in the case of completion/discontinuation from the study. 
3. 
Referring to the day in Period 1. 
4. 
Eligible subjects will report the Sites 24 hours before the 1st study drug dosing for each period.  
5. 
Inclusion/exclusion criteria will be verified to note any changes. 


 
 
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6. 
Vital signs include pulse rate, respiration rate, supine blood pressure, and axillary temperature. Axillary temperature will be measured only at screening, 13, 1 hours before each study drug dosing 
and 24, 72 hours after each study drug dosing. Vital signs will be tested within 10 minutes before naltrexone dosing. The BMI will be measured only at screening.  
7. 
Including women up to less than one year post-menopause. Women with more than one year post-menopause, hysterectomy, and sterilization will not be applied. 
8. 
A blood β-HCG test will be tested.  
9. 
A urine β-HCG test will be performed. 
10. Naltrexone tablets 25 mg will be administered at 13, 1 hours before and 11 hours after each dosing respectively (dosing is defined as 0 hours). 
11. OTR tablet 10 mg or OXYCONTIN tablet 10 mg administered orally with 200 mL water in a fasted state on the morning of Day 1 in each period. 
12. The subjects will not be discharged from the Sites till 72 hours after the study drug administration in each period.  
 
Table 2: PK Blood Sampling Schedule 
PK Blood Sampling 
Visit Name &  
Number 
Period 1 (V2) and Period 2 (V3) 
Day 
1 
2 
Hours Post-dose 
Pre-dose 
0.5 
1 
1.5 
2 
2.5 
3 
3.5 
4 
4.5 
5 
6 
8 
10 
12 
16 
24 
28 
32 
4 mL blood sample 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs 
 
 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
Notes: Time window for the blood sampling and vital sign: 
 
Pre-dose blood sampling will be drawn within 5 minutes before the dosing of the study drug. 
 
For all other blood sampling except the pre-dose sampling: blood sample collection will be within ± 2 minutes of scheduled time for within the first 5 hours after study drug dosing and within ± 
5 minutes thereafter. Every effort should be made to ensure accurate sampling time and deviations should be minimal. 
 
Vital sign will be tested within 10 minutes before the corresponding blood sampling time. 


 
 
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10.2 Screening Phase (V1) 
The Screening Phase (up to 20 days before the study treatment at Day -1) aims to 
evaluate if the subjects are eligible for the study according to inclusion/exclusion 
criteria. The reasons for screening failures will be documented. Subjects will perform 
the following procedures in the Screening Phase: 
 
 The ICF (subjects will sign an ICF prior to executing all other activities.) 
 Demography 
 Medical history collection 
 Physical examination 
 Vital signs and BMI: pulse rate, respiration rate, supine blood pressure, and axillary 
temperature will be examined. Height and weight will be only performed at 
Screening Phase. It will be repeated if any vital sign falls outside the normal range 
and is considered potentially clinically significant.  
 NRS score (‹ 4) 
 ECG 
 Haematology, blood chemistry, and urinalysis 
 Serology testing (HBsAg, anti-HIV, anti-HCV, and syphilis antibody) 
 Urine drug screen (opioids, barbiturates, amphetamines, cocaine metabolites, 
methadone, benzodiazepines, phencyclidine, methamphetamine, or cannabinoids) 
and alcohol test  
 Blood β-HCG test for female subjects up to less than one year post-menopause  
 AEs collection after the ICF acquisition 
 Collection of concomitant medication and non-pharmacological therapies 
 Inclusion/Exclusion criteria list will be checked when all the results of 
examinations are available. 
Subjects who do not meet the inclusion/exclusion criteria are not permitted to attend 
the study. Eligible subjects also need to be instructed not to take alcohol 48 hours 
prior to the study drug dosing. Throughout the study, subjects will be reminded to 
immediately report AEs experienced to the medical staff. These will be recorded in 
the AE section of EDC and reported according to Section 13.2. 
10.3 Treatment and Sampling Phase (V2 and V3) 
Treatment and Sampling Phase includes Period 1 and Period 2. Eligible subjects will 
report to the Sites at Day -1 of each study period and remain to the unit till 72 hours 
after each study drug dosing. Subjects will take either a test (OTR tablet 10 mg) or a 


 
 
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reference treatment (OXYCONTIN tablet 10 mg) in accordance with a RAS system in 
Period 1. After that, subjects will cross over to take the alternative study treatment in 
Period 2 following a washout period of 6 minimum days between the 2 doses 
administrations. Naltrexone cover with a total of 3 occasions will be administered at 
each study period. And 4 mL of blood sample will be drawn for PK analysis from pre-
dose to 32 hours post study drug dosing for each study period as described below. 
 
10.3.1 Period 1 (V2) 
10.3.1.1 Day -1 
 
Subjects will report to the study unit on the day 24 hours before the scheduled 
study drug dosing. 
 
Physical examination 
 
Subjects will be asked how they have been felt since their last visit, whether they 
have collected spontaneous AEs, whether they have taken any prescribed or over 
the-counter medications, or any vitamins or mineral supplements or herbal 
products since their last visit, and whether they have abstained from alcohol 
during the previous 2 days. 
 
Urine drug screen for opioids related drugs and alcohol test will be checked the 
second time and the results must be negative before subjects taking the first dose 
of naltrexone. 
 
Urine β-HCG test with female subjects before menopause and less than one year 
after menopause prior to taking the first dose of naltrexone 
 
Inclusion/exclusion criteria will be verified the second time to notice any changes 
compared to the first time. 
 
Vital signs (including axillary temperature) will be executed within 10 minutes 
before taking naltrexone. 
 
At 13 hours (±5 minutes) before the study drug dosing, 25 mg of naltrexone tablet 
will be administered with 150 mL water in a standing position. 
 
Subjects will be randomized into either OTR or OXYCONTIN group following a 
RAS system and randomization numbers will be assigned.  
 
AE collection 
 
Collection of concomitant medication and non-pharmacological therapies 
including rescue medicine 
10.3.1.2 Day 1 
 
Vital signs (including axillary temperature) will be executed within 10 minutes 
before taking naltrexone.  


 
 
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 
At 1 hour (±2 minutes) before the study drug dosing, 25 mg of naltrexone tablet 
will be administered with 150 mL water in a standing position.  
 
A blood sample (4 mL) drawn at 5 minutes before the study drug administration.   
 
Based on the randomization schedule, either a tablet of OTR 10 mg or 
OXYCONTIN 10 mg will be administered with 200 mL water in a standing 
position. 
 
A blood sample (4 mL) will be drawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 
10, 12, and 16 hours post study drug administration. Blood sample collection will 
be within ± 2 minutes of scheduled time for within the first 5 hours after study 
drug dosing and within ± 5 minutes thereafter. For all the blood sampling, every 
effort should be made to ensure accurate sampling time and deviations should be 
kept to a minimum. 
 
Vital signs (excluding axillary temperature) will be executed at 1, 2, 4, 8, and 12 
hours after study drug administration and will be performed within 10 minutes 
before the corresponding blood sampling time.  
 
At 11 hours (±5 minutes) after the study drug dosing, 25 mg of naltrexone tablet 
will be administered with 150 mL water in a standing position. 
 
AE collection 
 
Collection of concomitant medication and non-pharmacological therapies 
including rescue medicine 
10.3.1.3 Day 2 
 
Vital signs will be executed at 24 (including axillary temperature) and 32 hours 
(excluding axillary temperature) after study drug administration and will be 
performed within 10 minutes before the corresponding blood sampling time. 
 
A blood sample (4 mL) will be drawn for PK analysis at 24, 28, and 32 hours post 
study drug administration. Blood sample collection will be within ± 5 minutes of 
the scheduled time.  
 
AEs collection 
 
Collection of concomitant medication and non-pharmacological therapies 
including rescue medicine 
10.3.1.4 Day 4 
 
Physical examination examined at 72 hours after study drug dosing 
 
Vital signs (including axillary temperature) will be executed at 72 hours (± 10 
minutes) after study drug administration. 
 
AE collection 


 
 
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 
Collection of concomitant medication and non-pharmacological therapies 
including rescue medicine 
 
Subject will be discharged from the unit around 72 hours post study drug dosing. 
Before their discharge, Subjects need to be instructed that they must abstain from 
alcohol during the previous 2 days (within 48 hours) before the scheduled study 
drug dosing in the Period 2. And any vitamins or mineral supplements or herbal 
products will be prohibited until the end of the study. 
10.3.2 Period 2 (V3) 
10.3.2.1 Day -1, Period 2 
 
Subjects will report to the study unit on the day 24 hours before the last scheduled 
study drug dosing. 
 
Physical examination 
 
Subjects will be asked how they have been felt since their last visit, whether they 
have collected spontaneous AEs, whether they have taken any prescribed or over 
the-counter medications, or any vitamins or mineral supplements or herbal 
products since their last visit, and whether they have abstained from alcohol 
during the previous 2 days (within 48 hours before the scheduled study drug 
dosing).  
 
Urine drug screen for opioids related drugs and alcohol test will be checked again 
and the results must be negative before subjects taking naltrexone at Period 2. 
 
Urine β-HCG test with female subjects before menopause and less than one year 
after menopause prior to taking the first dose of naltrexone at Period 2 
 
Vital signs (including axillary temperature) will be executed within 10 minutes 
before taking naltrexone. 
 
At 13 hours (±5 minutes) before the last study drug dosing, 25 mg of naltrexone 
tablet will be administered with 150 mL water in a standing position. 
 
AE collection 
 
Collection of concomitant medication and non-pharmacological therapies 
including rescue medicine 
10.3.2.2 Day 1, Period 2 
 
Vital signs (including axillary temperature) will be executed within 10 minutes 
before taking naltrexone  
 
At 1 hour (±5 minutes) before the study drug dosing, 25 mg of naltrexone tablet 
will be administered with 150 mL water in a standing position. 


 
 
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 
A blood sample (4 mL) drawn at 5 minutes before the study drug administration. 
 
Following the sequence of study treatment in Period 1, subjects will cross over to 
take an alternative study treatment of either OTR 10 mg or OXYCONTIN 10 mg 
with 200 mL water in a standing position. 
 
A blood sample (4 mL) will be drawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 
10, 12, and 16 hours post the study drug administration. Blood sample collection 
will be within ± 2 minutes of scheduled time for within the first 5 hours after 
study drug dosing and within ± 5 minutes thereafter.  
 
Vital signs (excluding axillary temperature) will be executed at 1, 2, 4, 8, and 12 
hours after study drug administration and will be performed within 10 minutes 
before the corresponding blood sampling time.  
 
At 11 hours (±5 minutes) after the study drug dosing, 25 mg of naltrexone tablet 
will be administered with 150 mL water in a standing position. 
 
AE collection 
 
Collection of concomitant medication and non-pharmacological therapies 
including rescue medicine 
10.3.2.3 Day 2, Period 2 
 
Vital signs will be executed at 24 (including axillary temperature) and 32 hours 
(excluding axillary temperature) after the study drug administration and will be 
performed within 10 minutes before the corresponding blood sampling time. 
 
A blood sample (4 mL) will be drawn at 24, 28, and 32 hours (± 5 minutes ) post 
the study drug administration.   
 
AEs collection 
 
Collection of concomitant medication and non-pharmacological therapies  
including rescue medicine 
10.3.2.4 Day 4, Period 2 
 
Physical examination 
 
Vital signs (including axillary temperature) will be executed at 72 hours (± 10 
minutes) after last study drug administration. 
 
ECG will be examined at 72 hours after study drug dosing. 
 
Hematology, blood chemistry, and urinalysis 
 
Urine β-HCG test with female subjects before menopause and less than one year 
after menopause before subjects are discharged from the unit 
 
AE collection 
 
Collection of concomitant medication and non-pharmacological therapies 
including rescue medicine 


 
 
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 
Subject will be discharged from the unit around 72 hours post study drug dosing. 
Before the discharge, Subjects need to be instructed to report AEs experienced to 
Sites until the telephone visit. 
10.4 Safety Follow-up (V4) 
 
The safety follow-up phase will be 7 ±1 days post last study drug dosing, the 
Investigators or a designee will call subjects to collect AEs and concomitant 
medication after being discharged from the unit, and every effort will be given to 
complete the safety follow-up. 
 
During this period, subject may contact Investigators for any AE occurred after 
being discharged from the unit.  
 
Subjects will complete the study. 
10.5 Early Discontinuation/Withdrawal/Loss to Follow-up 
The Investigators(s) or subjects themselves may stop study treatment at any time for 
safety or personal reasons. Subjects will continue to finish the 3 occasions of 
naltrexone dosing if he or she already takes the study treatment when withdrawing 
from the study from the consideration of safety purpose. Whenever possible, the 
subjects will be instructed to remain at the unit to complete the above treatment and 
safety monitoring. Otherwise, subjects will be instructed the timing, dosage, and 
administration method of taking naltrexone. 
Whenever possible, the Investigators or a designee will give phone contacts to the 
withdrawal/discontinued subjects to complete the safety follow-up as described in 
10.4.  
10.6 Study Restrictions 
10.6.1 Food and Beverages 
Menus will be standardised while subjects are resident in the study unit. The menus 
should be kept the same for each study period. However, the menus for each day will 
not be identical. Subjects must consume only the food given to them while in the unit. 
All the meals provided by the Sites will be low fat (<30% fat). Food and water will be 
restricted as follows: 
 


 
 
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 Day -1 (Period 1 and 2)-Subjects will be given a lunch and dinner following 
check-in to the study unit. Subjects will fast (only water is permitted) for at 
least 10 hours prior to each dosing. There will be free access to drinking water 
throughout the day, except within 30 minutes before vital sign measurements. 
 Day 1 (Period 1 and 2)-Subjects will fast (only water is permitted) for at least 
4 hours after each dosing. No fluid will be allowed from one hour prior to and 
one hour after each dosing. A lunch, dinner, and evening snack will be 
provided at 4, 10, and 14 hours after the dosing of study drug. From 1 hour 
after dosing there will be free access to drinking water throughout the day, 
except within 30 minutes before vital sign measurement. 
 Day 2-3 (Period 1 and 2)-A breakfast, lunch, dinner, and evening snack will be 
provided from the Sites. There will be free access to drinking water 
throughout the day, except within 30 minutes before vital sign measurements. 
 Days 4 (Period 1 and 2)-A breakfast will be provided from the Sites. There 
will be free access to drinking water throughout the day, except within 30 
minutes before vital sign measurements. 
10.6.2 Alcohol, Caffeine, and Smoking Restrictions 
Subjects must abstain from alcohol during the study period. Grapefruit juice, caffeine- 
and xanthine-containing food or beverages will not be permitted while subjects are in 
the study unit. Smoking is not permitted at any time during the study. Acute exercise 
will also be prohibited during the study period. 
11. Study treatments and concomitant therapies 
11.1 Treatment administration 
11.1.1 Definitions 
The IMP is defined as a pharmaceutical form of an active substance or placebo being 
tested or used as a reference in a clinical trial, including products already with a 
marketing authorisation but used or assembled (formulated or packaged) in a way 
different from the authorised form, or when used for an unauthorised indication, or 
when used to gain further information about the authorised form. IMP for this study 
consists of the test treatment (OTR tablet 10 mg) and the reference treatment 
(OXYCONTIN tablet 10 mg). 
 
The non-IMP (NIMP) is defined as any medicinal products intended for research and 
development trials, which does not fall within the definition of an IMP. NIMP for this 
study is composed of naltrexone and other medications as the followings. 


 
 
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The other medications used for this study include ondansetron, paracetamol, and 
ibuprofen. They will be used per Investigators’ discretion. These medicines will be 
supplied by Sites directly, and reimbursement will be provided by Sponsor. 
11.1.2 Test IMPs, Dose, and Mode of Administration 
Table 3 Investigational Drug 
Investigational 
Drug 
Dosage 
Form 
Unit 
Strength 
Trade 
Name 
Active 
Ingredients 
Mode of 
Administration 
Oxycodone  
Hydrochloride 
Controlled-
release Tablets 
Tablet 
10 mg 
OTR 
Oxycodone 
hydrochloride 
Oral 
 
The OTR tablet 10 mg is manufactured by Purdue Pharma L.P., U.S. 
Table 4 Reference Investigational Drug 
Reference Drug 
Dosage 
Form 
Unit 
Strength 
Trade Name 
Active 
Ingredients 
Mode of 
Administration 
Oxycodone 
Hydrochloride 
Prolonged-
release Tablets 
Tablet 
10 mg 
OXYCONTIN 
Oxycodone 
hydrochloride 
Oral 
 
The OXYCONTIN tablet 10 mg is manufactured by Bard Pharmaceutical Ltd., U.K. 
11.1.3 NIMP, Dose, and Mode of Administration 
Table 5 NIMP 
 
NIMP 
Dosage 
Form 
Unit Strength 
Trade Name 
Active 
Ingredients 
Mode of 
Administration 
Naltrexone 
hydrochloride 
Tablet 
5 mg 
NuoXinSheng® 
Naltrexone 
Oral 
Naltrexone hydrochloride is manufactured by Wellso Pharmaceutical Co., Ltd.  
11.1.4 Other Medications, Dose, and Mode of Administration 
Ondansetron will be permitted for the treatment of nausea or vomiting based on the 
clinical judgement by the Investigators. Paracetamol or Ibuprofen will be used as 
rescue medicine for subjects who need the analgesic for pain relief. The maximum 
allowed daily doses of paracetamol and ibuprofen are 2.0 g and 1.2 g respectively. 


 
 
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11.2 Identity of Investigational Products and Study 
Treatments Supply 
OTR 10 mg Tablets are film-coated, round, white-colored, bi-convex tablets debossed 
with OP on one side and 10 on the other. OTR should be stored at 25°C (77° F)  and 
excursions are permitted between 15° to 30°C (59° -86°F). Tablets should be 
dispensed in a tight and light-resistant container. OTR Tablets are supplied as 2 tablets 
per blister. 
 
OXYCONTIN Tablets are white, round, convex tablets marked OC on one side and 
10 on the other. OXYCONTIN Tablets cannot be stored above 25°C.  OXYCONTIN 
Tablets are supplied as 2 tablets per blister. 
  
Nuoxinsheng (naltrexone) is a white or off-white tablet. 5 mg tablets are contained in 
plastic bottles with 100 tablets per bottle. Nuoxinsheng (naltrexone) should be tightly 
sealed and kept away from light. 
 
The Sponsor will supply IMPs and NIMP. The Product Release Certificates for the 
IMPs will be included in the clinical study report for this protocol. The study products 
will be supplied in packs labelled to meet the national requirements and will include a 
unique pack identifying number, including generic name, strengths, storage 
requirements etc. 
11.3 Dosing Schedule 
Table 1 presents details of the dosing schedule for each subject in the study. 
11.4 Dose Modification 
IMP is a single dose application and will not be modified. Naltrexone application 
consists of a total of 3 occasions. Any change due to intolerance will be judged by the 
Investigators in consultation with the Sponsor and will be recorded in EDC. 
11.5 Method of Administration 
For oxycodone dosing, subjects will be dosed in a standing position. Subjects will 
swallow a sip of water immediately before dosing. Subjects will then swallow their 
dose, whole, with the remainder of the water (total volume of water 200 mL). The oral 
cavity will be checked by study site personnel to ensure that the dose is swallowed. 
 


 
 
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For naltrexone dosing, subjects will be dosed in a standing position. Subjects will 
swallow a sip of water immediately before dosing. Subjects will then swallow their 
dose, whole, with the remainder of the water. The naltrexone dosing (5 tablets for 25 
mg) will be given with 150 mL water. The oral cavity will be checked by study site 
personnel to ensure that the dose is swallowed. 
11.6 Treatment Assignment 
Randomisation will be performed using a RAS system that automates the random 
assignment of treatment groups to randomisation numbers. The randomisation scheme 
will be reviewed by the Data Management and Statistics Department and locked after 
approval. 
11.7 Blinding 
Not applicable. 
11.8 Treatment Compliance/Drug Accountability 
The Investigators and study staff will be responsible for the accountability and 
management of all clinical supplies (dispensing, inventory, record keeping, return, 
etc.) following Sponsor instructions and adhere to GCP guidelines. 
 
Under no circumstances will the Investigators allow the study medication to be used 
other than as directed by this protocol. Clinical supplies will not be dispensed to any 
individual who is not enrolled in the study. 
 
An accurate and timely record of the receipt of all clinical supplies and dispensing of 
study medication to the subject must be maintained. This includes, but may not be 
limited to: (a) documentation of receipt of clinical supplies, (b) study medication 
dispensing/return reconciliation log, (c) study medication accountability log, and (d) 
all shipping service receipts. All forms will be provided by the Sponsor. Any 
comparable forms that the Sites wish to use must be approved by the Sponsor.  
 
The supplies and inventory records must be made available, upon request, for 
inspection by the designated representative of the Sponsor, or CA. Upon completion 
of drug accountability and reconciliation procedures by investigational site personnel 
and documentation procedures by Sponsor personnel, study drug that is to be returned 
to the Sponsor/Sponsor designated warehouse must be sealed with tamper-evident 
seals and shipped back to the Sponsor/warehouse following all China regulatory and 
shipment laws. 
 


 
 
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11.9 Concomitant Therapies (Permitted and Prohibited) 
Administration of medications (including vitamins, herbal and/or mineral 
supplements, CYP3A4 inhibitors and inducers, and CYP2D6 inhibitors and inducers) 
other than the study drug will be prohibited from the start to the completion of the 
study, with the exceptions of Vitamin D, calcium supplements, and any drug therapy 
for AEs developed during study.  
 
For subjects who receive study drug, any concomitant medications and therapies that 
are ongoing as of the date of informed consent will be recorded on the Concomitant 
Therapy section of EDC and must be approved by the Sponsor. The Investigators will 
record all concomitant medications, including over-the-counter medications, on the 
Concomitant Therapy section of EDC. The use of such concomitant medications 
should be approved in advance by the Sponsor, when possible. The Investigators will 
record the AE for which the concomitant medication was administered on the AE 
section of EDC. 
 
Paracetamol or ibuprofen will be used as rescue medicine for subjects who need the 
analgesic for pain relief. Nausea and vomiting may be treated with Ondansetron as 
deemed appropriate. 
 
Monoamine oxidase inhibitors cannot be used during this trial period or time lapses 
less than 2 weeks since drug withdrawal prior to the study drug administration. 
Tricyclic antidepressants cannot be administered during the trial or have been used 
within 4 weeks prior to the study drug administration. CYP3A4 and CYP2D6 
inhibitors and inducers cannot be applied within 4 weeks prior to the study drug 
administration. Other concomitant treatments should be agreed upon in advance by 
the Sponsor, where possible. 
11.10 Shipping, Handling, Storage, and 
Destruction/Return 
IMPs and NIMP (naltrexone) will be supplied to the Principal Investigators or the 
delegated staff by the Sponsor directly. The other medications including ondansetron, 
paracetamol, or ibuprofen will be supplied by the Sites. Drug supplies must be kept in 
an appropriate secure area (e.g. locked cabinet/pharmacy) and stored according to the 
conditions specified on the drug labels. Specific laws relating to the handling and 
storage of narcotics must be followed, and this will be the responsibility of the 
Investigators. 


 
 
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The investigational site personnel must not destroy any study treatment labels or any 
partly used or unused study treatment supply until directed by the Sponsor or designee 
following accountability checks. Upon completion of drug accountability and 
reconciliation procedures by investigational site personnel and documentation 
procedures by Sponsor personnel, study treatment that is to be returned to the Sponsor 
or Sponsor designated warehouse must be sealed with tamper-evident seals and 
shipped back to the Sponsor or Sponsor designated warehouse following all China 
local regulatory and shipment laws. 
11.11 Retention of IMP Samples 
The samples of IMP must be retained for two years after the drug is approved for 
marketing7. 
12. Reference Values 
12.1 Physical/Vital Sign Assessments 
Vital signs (pulse rate, respiration rate, supine blood pressure, and axillary 
temperature) and weight measurements will be obtained at the visits designated on 
Table 1 and Table 2. Blood pressure and pulse rate will be measured after the subject 
has been supine for 3 minutes. 
Normal ranges for vital signs are shown in Appendix 18.2.1 Table 6.  
Each clinically notable vital sign abnormality has to be recorded on the AE section of 
the EDC. Table 7 in Appendix 18.2.1 describes parameters for clinically notable vital 
signs. Additionally, if the change in vital signs qualifies as an SAE it has to be 
reported to the Sponsor using the SAE data form (Section 13). 
12.2 Laboratory Assessments 
Local Site laboratories will perform tests to qualify subjects for entry into the study. 
Table 1 shows the time points when clinical laboratory tests will be performed. Table 
8 in Appendix 18.2.2 presents the clinical laboratory tests to be performed. 
A laboratory abnormality may qualify as an AE or SAE as described in Section 13.1. 
Additionally, if the abnormality qualifies as an SAE it must be reported to the 
Sponsor using the SAE data form (Section 13). Table 9 in Appendix 18.2.2 presents 


 
 
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the criteria, i.e. upper limit, lower limit criteria for each laboratory parameter, which 
will be used to identify subjects with markedly abnormal laboratory values. 
Values out of the lower normal range do not automatically lead to an exclusion of the 
subject from the study. The decision to discontinue a subject from the study due to 
bilirubin or creatinine levels below the lower limit of normal should be based on the 
medical judgement of the Investigators. Microscopic urinalysis will only be 
performed when certain parameters of the macroscopic urinalysis show abnormal 
results. 
 
13. SAFETY ASSESSMENTS 
Safety assessments will be recorded from the point at which the ICF is signed. These 
will consist of: 
 Monitoring and recording all AEs and SAEs, observed or volunteered, 
regardless of suspected causal relationship to the IMP. This includes reactions, 
interactions, accidents, illnesses, misuse, and abuse.  
 Please refer to Table 1 section 10 for schedule visit arrangement including AE 
collection.  
The obligations and responsibilities with regards to collection, distribution, and 
onward reporting of AEs and reactions to the appropriate regulatory bodies, 
committees, and other Investigators will be carried out in accordance with local and 
international regulations and are documented in a separate Safety Plan. 
13.1 AEs and SAEs 
An AE is any untoward medical occurrence in a patient or a clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
An AE can be:   
 Any unfavourable and unintended sign (including reactions from overdose, 
abuse, or incorrect use of any treatment, or interaction) 
 Any new disease or exacerbation of an existing disease (e.g. increase in 
frequency or worsening in nature) 
 Any deterioration in measurements of laboratory values or other clinical tests 
(e.g. ECG, vital signs, or X-ray) that results in symptoms, a change in 
treatment, or discontinuation from the IMPs 


 
 
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 Recurrence of an intermittent medical condition (e.g. headache) not present at 
baseline 
 Other medical events regardless of their relationship to the IMPs, such as 
accidents, falls, and any injuries resulting from them. 
An SAE is any AE that: 
 results in death 
 is life-threatening (i.e. the subject was at immediate risk of death from the AE 
as it occurred) 
 requires inpatient hospitalisation or prolongation of existing hospitalisation  
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect (in the child of a subject who was exposed 
to the IMPs) 
 is a medically important event or reaction. 
Assessment of medically important events: 
The Investigators must check the list of Important Medical Events (supplied in the 
Investigators Site File) to determine whether criteria for an SAE is met. Additionally, 
any event not on this list, but that the Investigators determine is medically important 
(e.g. if it jeopardises the patient or requires intervention to prevent a serious outcome) 
should be reported as an SAE. 
An SAE must be reported immediately (within 24 hours), independent of the 
circumstances or suspected cause, if it occurs or comes to the attention of the 
Investigators at any time during the study period. Any SAE with a suspected causal 
relationship to the IMP occurring at any other time after completion of the study must 
be promptly reported. 
The following mandatory information must be provided to the Sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
- Protocol number 
- Site number 
- Subject number/Screening number 
- SAE 
- IMPs 
- Serious Criteria 
- Investigators' name and contact details 
- Causality assessment. 
A succinct medical summary narrative should be provided as soon as possible. 


 
 
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Follow-up information should be actively sought until the SAE has resolved or 
sequelae have stabilised. Additional information e.g. hospital reports or death 
certificates, may be requested by the Sponsor and should be 
anonymised/pseudonymised before transmission and subsequently filed in the 
Investigators Site File. 
The medical safety of the subject is of paramount importance when discussing study 
continuation. Not all SAEs will require the subject to be discontinued from the study. 
13.2 Reporting of AEs 
Reporting period – Events will be recorded from the point at which the ICF is signed 
until 7±1  days after last oxycodone dose in the case of completion/discontinuation 
from the study. This includes new AEs that are reported within 7±1  days after last 
oxycodone dosing after the subject’s completion/discontinuation visit. Any AE that is 
still ongoing 7±1  days after the last oxycodone dose will have an outcome of ‘ongoing’ 
in the EDC, however the Investigators will continue to follow up ongoing AEs and 
record information in the source documents. SAEs will be followed until the event 
resolves or the event or sequelae stabilise and this information will be reported to the 
Sponsor using the SAE Data Form. 
Medical conditions that are diagnosed at the screening visit will only be documented 
as AEs if they are known to have started or are suspected to have started after the 
subject has signed the ICF. All other medical findings at the medical examination at 
the screening visit will be documented as medical history. Medical judgement should 
be exercised to estimate if a condition is likely to have started between the signing of 
ICF and the date/time of the physical examination. 
If the Investigators become aware of an SAE after the completion of the study, which 
may have been caused by IMPs or NIMP used in the study, they should report it to the 
Sponsor by phone, fax, or e-mail. 
Screen failures - For subjects who are screen failures, AEs that occurred from the date 
of consent to the date of screen failure will be recorded on the AE section of EDC.  
For subjects who receive study treatment- All AEs will be collected on the AE section 
of EDC. In addition, a note should be made in the source documentation of the subject.   
SAEs- All SAEs will be collected on the AE section of EDC and flagged as serious. A 
separate paper SAE Data Form is supplied for immediate reporting. 
Reporting term - A cluster of signs and symptoms that results from a single cause or 
that could form a diagnosis should be reported as a single AE (e.g. fever, elevated 


 
 
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white blood cell (WBC), cough, abnormal chest x-ray, etc. can all be reported as 
“pneumonia.”). 
Contact - The sponsor drug safety contact phone number/fax number and email 
address will be stored in the Investigators Site File. Questions relating to Drug Safety 
and Pharmacovigilance should be addressed to the numbers or e-mailed.  
13.3 Causality/Expectedness Assessment 
The relationship of an AE to the IMPs should be determined by the Investigators after 
thorough consideration of all facts that are available. 
Assessment of causality- This is based on considering associative connections (time 
or place), pharmacological explanations, previous knowledge of the drug, presence of 
characteristic clinical or pathological phenomena, underlying conditions in the study 
population, exclusion of other causes, and/or absence of alternative explanations. 
The Investigators will be asked if a reasonable possibility of a causal relationship 
to the IMPs is suspected. 
 “Yes” should be selected if there are facts (evidence) or arguments to suggest 
a causal relationship.  
 “No” should be selected if there are no facts (evidence) or arguments to 
suggest a causal relationship. 
If an AE is related to a non-investigational medicinal product, e.g. concomitant 
therapy only, and not an interaction or effect of the IMP, or to a study procedure, the 
causality assessment will be “No” (no reasonable possibility of a causal relationship 
to IMP). The suspected drug or procedure should be indicated in the narrative in such 
cases. 
Assessment of Expectedness - The expectedness of an AE is determined by the 
Sponsor in the reference safety information. The reference safety document used for 
assessing expectedness of AEs in this study is: the current Investigator’s Brochure (IB) 
for OTR and OXYCONTIN. The reference safety information is included in the safety 
section of the IB. 
 
13.4 Severity Assessment 
The Investigators (or medically qualified designee) will evaluate the comments of the 
subject and the response to treatment to judge the severity of the AE. Severity refers 


 
 
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to the accumulated intensity of discomfort/impairment of health and will be assessed 
according to the following criteria: 
Mild:  Awareness of sign, symptom, or event, but easily tolerated. 
Moderate: Discomfort enough to cause interference with usual activity and may 
warrant intervention. 
Severe: Incapacitating with inability to do usual activities or significantly affects 
clinical status and warrants intervention. 
Note: A severe AE will not necessarily be an SAE. 
Any medication necessary for the treatment of an AE must be recorded on the 
Concomitant Therapy Section of the EDC. 
13.5 Pregnancy 
Pregnancy occurring in a male subject’s female partner or in a female subject during a 
clinical study must be reported to the Sponsor using the Pregnancy Notification Form. 
The Sponsor will contact the Investigators to confirm significant pregnancy 
information, i.e. AEs during pregnancy, the pregnancy outcome, and any events to 3 
months post-partum. 
13.6 Laboratory Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the 
following apply: 
 They result in a change in IMP schedule of administration (change in 
dosage, delay in administration, IMP discontinuation, or other medical or 
treatment intervention (e.g. anaemia requiring transfusions or 
hyperglycaemia requiring potassium supplement)) 
 They are considered as clinically significant by the Investigators. 
Where possible, the AE description should be the diagnosis rather than the abnormal 
laboratory value. The same is true if abnormal values reflect a worsening of an 
underlying condition. Abnormal laboratory values that are present at Screening Phase 
are not AEs (unless they are a consequence of a screening procedure). Where an 
Investigator does not deem an abnormal (or markedly abnormal) laboratory value to 
be clinically significant, the reason must be clearly documented in the source notes 
(e.g. normal fluctuation of the disease). 


 
 
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13.7 Vital Signs and Physical Examinations 
AEs from vital sign or physical examination assessments include any changes, values, 
or findings (abnormalities): 
 Which result in medical intervention  
 And/or is deemed by the Investigators as clinically significant 
 And/or meets the clinically notable abnormal criteria (see Table 7 in section 
18). 
13.8 ECG TEAE 
A simultaneous 12-lead resting ECG will be obtained at V1 and V3 will be performed 
during study only if clinically indicated. For consistency, the same physician should 
read all ECGs from one subject whenever possible. Abnormal test findings as judged 
by the Investigators as clinically significant should be recorded as AEs. 
13.9 Other Safety Considerations/Risk Management 
Preventable medication administration errors with an IMP are a potential safety issue 
and must be reported immediately to the Sponsor as a protocol deviation.  Examples 
of these include: 
 Overdose - This must always be reported, and may additionally (but not always) 
meet the criteria for an AE/SAE.   
 Drug Abuse - Defined as intentional excessive and persistent or sporadic use of 
a medicinal product which is accompanied by harmful physical or 
psychological effects. Drug abuse is always a medically important event and 
subject to immediate SAE reporting.   
 Drug Diversion - Defined as study treatment that is sold or given to other 
persons either deliberately or accidentally. This may include accidental 
misdirection of study supply into mainstream hospital supplies. AEs in persons 
other than the subject after drug diversion will be processed in the Sponsor’s 
drug safety database. 
Any packaging or labelling that has been identified as causing potential risk (e.g. due 
to similarity with other products or unclear instruction) must be immediately reported 
to the Sponsor. 
 


 
 
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14. STATISTICAL ANALYSES 
14.1 Statistical Methodology and Analytical Plans 
The statistical analyses described in this section will be performed as further outlined 
in the Statistical Analysis Plan (SAP), which will be finalised prior to database lock 
and will be included in the clinical study report for this protocol. The final SAP will 
take into account any amendment to the protocol. 
14.2 Statistical Considerations 
All data will be listed by treatment groups. 
 
In general, continuous data will be summarised by treatment group using the 
following descriptive statistics: n, mean, SD, median, minimum, and maximum.  
Categorical data will be summarised by treatment group as the number and percentage 
of subjects in each category. 
 
Further details of statistical methods and analyses will be documented in the SAP. 
14.3 Analysis Populations 
Enrolled Population 
The enrolled population is defined as all subjects who signed ICF. 
 
ITT Population 
The ITT population is defined as all randomised subjects. 
 
Safety Population 
The safety population is defined as all randomised subjects who received at least one 
dose of IMP. 
 
PK Population  
The PK population is defined as all subjects who receive IMP and have at least one 
PK concentration measurement.  
14.4 Protocol Deviations 
The following major protocol deviations may exclude a subject from the PK analysis: 


 
 
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1) Failure to comply with the inclusion/exclusion criteria 
2) Received incorrect study treatment 
3) Received study prohibited concomitant drugs 
4) Failure to collect data for the primary endpoint as detailed in the protocol. 
Further details will be documented in the SAP. Additional factors excluding subjects 
from analysis populations may be included in the SAP for the study.  
Major protocol deviations will be agreed at the Data Review Meeting (DRM) prior to 
database lock.  
14.5 Sample Size and Power Considerations 
The study is designed to have a power of ≥ 95% to demonstrate BE (AUCt and Cmax) 
of OTR tablet 10 mg, in terms of oxycodone, with OXYCONTIN tablet 10 mg in a 
fasted state.  
The null hypothesis is that the two treatments are not bioequivalent. The alternative 
hypothesis is that both treatments are bioequivalent. BE between both treatments will 
be concluded if the 90% CI for the ratio lies within 80.00% to 125.00% for both 
AUCt and Cmax for the oxycodone analyte. 
A total of 24 subjects will be randomised to receive study drug (12 subjects per 
treatment sequence) with the aim that 18 subjects will provide valid PK data (9 
subjects per treatment sequence) and PK parameters (Cmax and AUCt). This will 
provide ≥ 95% power to show BE simultaneously in both parameters, Cmax and 
AUCt, between test and reference formulations, assuming a true ratio of 1, a within 
SD of the period differences of 0.24 on the log scale for AUCt and 0.20 on the log 
scale for Cmax, both PK parameters are not anti-correlated, and 90% CI for the ratios 
of the population means within the BE limits of 80.00% and 125.00%. The within SD 
of the period differences was based on Purdue Pharma BE study OTR1003 in healthy 
volunteers taking oxycodone.8 
The sample size was estimated using NQuery t-tests (TOST of equivalence in ratio of 
means for cross-over design (natural log scale). 
14.6 Primary Outcome/Efficacy Variable(s) 
Not applicable. 


 
 
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14.7 Secondary Outcome/Efficacy Variable(s) 
Not applicable. 
14.8 Exploratory Efficacy Variables 
Not applicable. 
 
14.9 Subject Disposition 
The number and percentage of subjects in each population will be summarised by 
treatment group and overall for subjects in the enrolled set.  
 
The number and percentage of subjects enrolled and the primary reason for screen 
failure will be summarised for subjects in the enrolled population. 
 
The number and percentage of subjects that complete the study and the primary 
reason for discontinuation will be summarised for subjects in the enrolled population. 
 
14.10 Demographic/Baseline Analyses 
Demographic and baseline variables will be summarised by treatment groups and 
overall for subjects in the safety population. 
 
Age, weight, height, and BMI will be summarised as continuous data. Gender and 
ethnicity will be summarised as categorical data. 
 
Current medical conditions will be summarised by SOC and PT. 
14.11 IMP Analyses 
IMP will be summarised as treatment exposure. 
Treatment exposure will be defined and calculated as the dose of IMP taken by 
subjects. Treatment exposure will be summarised by treatment group as continuous 
data. 
Treatment exposure will be summarised by treatment group and overall for subjects in 
the safety population. 
 


 
 
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14.12 Concomitant Medications Analyses 
Concomitant medications will be assigned an 11-digit code using the WHO Drug 
Dictionary Enhanced (WHO-DDE) drug codes. Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code 
indicating therapeutic classification.  
The number and percentage of subjects taking concomitant medications will be 
summarised by ATC anatomical class, pharmacological class, pharmacological sub-
class, and treatment group for subjects in the enrolled population. 
14.13 Safety Analyses 
All safety summaries will be based on the safety population. 
AEs will be classified into standardised terminology from the verbatim description 
(Investigators term) according to MedDRA Coding Dictionary to give an SOC and PT 
for each event. 
An overall summary of AEs will be provided by treatment groups. The number and 
percentage of subjects reporting AEs will be summarised by the PT nested within the 
SOC. In addition the number of reported AEs will be summarised.  
TEAE will be summarised. A TEAE will be defined as any AE with an onset date on 
or after IMP dosing if the AE was absent before IMP dosing, or worsened after IMP 
dosing. TEAEs/SAEs collected from dosing of IMP till the last visit will be 
summarized. AEs with an onset data before IMP dosing will be listed.  
TEAEs will be summarised by worst severity and relationship to IMP. In addition, 
severe TEAEs, TEAEs leading to death, SAEs, and TEAEs requiring additional 
therapy, TEAEs leading to discontinuation from study, TEAEs requiring additional 
therapy, TEAEs leading to dose reduction, and TEAEs leading to dose interruption 
will be summarised.   
The most frequent TEAEs will be summarised for the treatment period. These will 
also be presented graphically using a dot plot and a caterpillar plot within which the 
percentage of subjects reporting each of the most common TEAEs will be presented 
alongside the odds ratio (and associated 95% CI) for comparing the incidence of AEs. 
Clinical laboratory parameters and vital signs will be summarised descriptively. The 
frequency of vital sign results with respect to normal ranges will be presented. The 
frequency of clinically significant ECG results will be presented. 


 
 
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14.14 Analysis of TEAEs 
14.14.1 Laboratory Values 
Clinical laboratory data to be summarised includes haematology, blood chemistry, 
and urinalysis. Clinical laboratory results recorded at V1 and V3 and change from 
baseline to V3 will be summarised as continuous data for each parameter. 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). 
Clinical laboratory values after IMP dosing will be evaluated for markedly abnormal 
values. The number and percentage of subjects reporting markedly abnormal values 
will be summarised for each parameter by treatment groups. Each subject can be 
counted once in the parameter high and the parameter low categories, as applicable. 
Scatter plots will be produced for each laboratory parameter comparing baseline and 
end of study values. In addition, clinically laboratory parameters will be plotted over 
time using a box and whisker plot. 
14.14.2 Vital Signs 
Vital sign parameters to be summarised include systolic blood pressure, diastolic 
blood pressure, pulse rate, respiration rate, and axillary temperature.  
Vital sign results recorded at each visit and change from baseline to each test will be 
summarised as continuous data for each parameter. Table 7 of Section 18.2.1 lists the 
abnormal ranges applied for this study. 
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). 
Vital sign values after IMP dosing will be evaluated for clinically notable 
abnormalities. The number and percentage of subjects reporting clinically notable 
abnormalities will be summarised for each parameter by treatment groups. Each 
subject can be counted once in the parameter high and the parameter low categories, 
as applicable.  


 
 
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Scatter plots will be produced for each vital sign parameter comparing baseline and 
end of study values. In addition, vital signs will be plotted over time using a box and 
whisker plot. 
14.14.3 ECG 
ECG results will be recorded at V1 and V3. Clinically significant ECG findings as 
determined by the Investigators will be reported. 
14.15 Other Special Tests 
None planned. All analyses, including any further analyses not yet described in this 
study protocol, will be pre-specified and described in the SAP. 
14.16 PK Measurements and Analyses 
PK Analyses:  
Plasma concentration data and PK parameters will be listed for subjects in the 
enrolled population. 
Plasma concentration data for analyte oxycodone will be summarised descriptively by 
nominal time-point and treatment for subjects in the PK population. Individual and 
mean plasma concentrations for analyte oxycodone will also be plotted over time for 
each treatment. 
PK parameters (AUCt, AUCINF, Cmax, tmax, LambdaZ, and t1/2Z) for analyte 
oxycodone will be summarised descriptively by treatment for subjects in the PK 
population. 
The comparison will be OTR tablet 10 mg in fasted state (test) vs. OXYCONTIN 
tablet 10 mg in fasted state (reference). 
Primary Analysis: 
The primary analysis will be for PK parameters AUCt and Cmax and for analyte 
oxycodone. ANOVA with fixed effect terms for treatment, period, sequence, and 
subject within sequence for ratio of means (using log scale) will be used to compare 
the test and the reference treatments. BE of test and reference will be confirmed for a 
PK parameter of analyte oxycodone if the 90% CI for the ratio (test/reference) falls 
completely within the BE acceptance range of 80.00% to 125.00%. BE of test and 
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Secondary Analysis: 
The primary analysis will be repeated for the PK parameter AUCINF and for analyte 
oxycodone. 
The statistical analyses will exclude PK parameters for which any of the following 
criteria apply: vomiting within 12 hours after dosing, incorrect dosing, incomplete 
plasma profile which cannot adequately detail the parameter, pre-dose concentration > 
5% of Cmax, R2 < 0.85.The validity of PK data will be discussed further and 
evaluated during the data review meeting at the end of the study. In accordance with 
BE guidelines, only subjects that provide valid PK data for both the test and reference 
treatments will be included in the statistical analysis. 
Further details will be specified in the SAP.  
 
15. ETHICS & Regulatory 
15.1 Declaration of Ethical Conduct 
This study will be conducted in accordance with the SOPs of the Sponsor and CRO, 
which are designed to ensure adherence to GCP guidelines as required by the 
following: 
1. Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in 
Biomedical Research Involving Human Patients”), and all its accepted 
amendments to date concerning medical research in humans. 
2. GCP and relevant regulations. 
This study will be conducted in accordance with the regulation of narcotic drugs and 
psychotropic drugs in China. 
The Investigators agree, when signing the protocol, to adhere to the instructions and 
procedures described in the protocol and to adhere to the principles of GCP to which 
the protocol conforms as well as all governing local regulations and principles for 
medical research. 
15.2 Ethical and Regulatory Review 
The protocol, any protocol amendments, the patient information sheet (PIS), ICF and 
any study related information or documents issued to subjects for recruitment, data 
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by the study site’s local Ethics Committee (EC) before subjects are screened for entry. 
The ECs should be constituted and functioning in accordance with ICH E6, Section 
3.2, and any local regulations. 
A signed letter of positive opinion regarding the study from the EC Chairman must be 
sent to the Investigators who will provide the Sponsor with a copy prior to study start 
and the release of any study treatment to the Site by the Sponsor (ICH E6). The 
Investigators or Sponsor will submit, depending on local regulations, periodic reports 
and inform the EC of any reportable AEs per ICH guidelines and local EC standards 
of practice. SAEs should be reported to the EC in accordance with local regulatory 
requirements. 
In the case of early termination/temporary halt of the study, the Investigators should 
notify the EC and CA within 15 days and a detailed written explanation of the reasons 
for the termination/halt should be given. If the EC decides to suspend or terminate the 
study, the Investigators will immediately send the notice of study suspension or 
termination by the EC to the Sponsor. 
The end of the study will be the date of the last scheduled study visit for the last 
subject in the study. The Sponsor will always also provide the EC/CA with a 
summary of the study’s outcome. 
15.3 Subject Information and Consent 
Informed consent should be obtained by means of PIS and ICF, prepared in 
accordance with ICH E6 Section 4.8.10 and applicable local regulations, written in 
non-technical language. All subjects and/or legally authorised representatives will be 
provided with oral and written information describing the nature and duration of the 
study and the procedures to be performed. The subject will be asked to sign and date 
an ICF prior to any study-specific procedures being performed. No subject can enter 
the study before his informed consent has been obtained. A sample subject ICF used 
in the study will be included in the clinical study report for this protocol. 
As part of administering the informed consent document, the Investigators must 
explain to all subjects and/or their legally authorised representative the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved, and any potential discomfort. Each subject must be informed 
that participation in the study is voluntary and that he may withdraw from the study at 
any time and that withdrawal of consent will not affect his subsequent medical 
treatment or relationship with the treating physician. The subject should understand 
the PIS and ICF before signing and dating the ICF. The Investigators or person 


 
 
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obtaining consent must also sign and date the form. Each subject will be given a copy 
of the signed ICF and written information.  
The original signed ICF for each subject will be verified by the Clinical Research 
Associates (CRAs) from designated CRO and kept in the study centre investigational 
site files. This applies for any additional ICFs signed (e.g. for re-consent). 
15.4 Data Protection and Human Tissue Sampling 
Data protection will be carried out in accordance with the Principles of the Data 
Protection Act (1998) 95/46/EC. This will apply to all study data in whatever format 
it is collected and recorded.   
Any ECGs etc. collected for the trial will be retained in the patient’s notes held with 
the Investigators.  
Samples collected for the purpose of bioanalytical analysis will not be retained after 
analysis.  
15.5 Quality Assurance & Inspection Requirements 
This study will be organised, performed, and reported in compliance with the protocol, 
SOPs of the Sponsor and CRO. ICH E6 defines Quality Assurance (QA) as ‘all those 
planned and systemic actions that are established to ensure that the trial is performed 
and the data are generated, documented (recorded) and reported in compliance with 
GCP and the applicable regulatory requirements’. Sponsor QA activity will be 
undertaken as outlined in the study audit plan. Section 5.19.3 (b) of ICH E6 states that 
the audit plan and procedures for a trial audit should be guided by the importance of 
the trial to submissions to CA, the number of subjects in the trial, the type and 
complexity of the trial, the level of risks to the trial subjects, and any identified 
problem(s). The Investigators are required to support audit activities, to be available 
to the auditors upon requests, and to permit the auditor direct access to source 
data/documents. 
A CA/authorised third party may also wish to conduct an inspection (during the study 
or after its completion). If an inspection is requested by a CA, the Investigators must 
inform the Sponsor immediately that this request has been made. 
 


 
 
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16. Study management Records & Publication 
16.1 Protocol Amendments 
The Investigators should not implement any deviation from, or changes to the 
protocol without agreement by the Sponsor and prior review and documented 
approval from the EC (ICH E6 4.5.2). 
Any change to the protocol requires a written substantial or non-substantial protocol 
amendment. Substantial protocol amendments specifically affecting the safety of 
subjects, the scope of the investigation, or the scientific quality of the study require 
approval by site EC and related organizations. These requirements should in no way 
prevent any immediate action from being taken by the Investigators, or by the 
Sponsor, in the interest of preserving the safety of all subjects included in the study. If 
an immediate change to the protocol is felt by the Investigators to be necessary for 
safety reasons, the Study Physician must be notified promptly and the EC for the Sites 
must be informed in accordance with the policy of the EC approving the study, local 
regulations and policies. Changes affecting only administrative aspects of the study do 
not require substantial protocol amendments or EC approval, but the EC must be kept 
informed of such changes. In these cases, the Sponsor will send a letter to the EC 
detailing such changes. 
16.2 Record Maintenance and Retention 
In order to provide the Sponsor with accurate, complete, and legible case reports, the 
following criteria are to be maintained in all study related and source documentation: 
 All entries are to be typed or printed using a ballpoint pen. 
 There are to be no erasures, write-overs, and use of correction fluid or tape. 
And the original entry must remain legible. 
 Errors are to be corrected by placing one line through the error. The correct 
entry should appear next to the error, dated, and initialled by the responsible 
person making the change.  The name of anyone making corrections must 
appear on the Site Signature Log collected at the beginning of the study and as 
study assignments change throughout the conduct of the study.  Each error is 
to be corrected separately. 
 The Investigators (Principal Investigators or Sub Investigators) must sign and 
date the CRF.  
 Changes to any study document that has been previously signed by the 
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is made. Changes made to CRFs issued by the Sponsor must likewise be 
traced and signed by the Investigators. 
Neither a subject’s name nor initials are to appear on documents transmitted to the 
Sponsor in order to maintain confidentiality.  
In order to provide the Sponsor/CRO with accurate, complete, and legible data, the 
following criteria are to be maintained: 
 Source documents will be completed according to a source document 
agreement outlining all the data that is to be collected in the source documents 
throughout the study. 
The circumstances of completion or termination of the study notwithstanding, the 
Investigators have the responsibility to retain all study documents, including but not 
limited to the protocol, copies of CRF, IB, regulatory agency registration documents, 
ICFs, and EC correspondence. 
The Sites should plan on retaining study documents for approximately 15 years after 
completion of the study. This will include copies of CRF. 
It is requested that at the completion of the required retention period, or should the 
Investigators retire or relocate, the Investigators contact the Sponsor, allowing the 
Sponsor the option of permanently retaining the study records. Records retained will 
be stored independently of the Sponsor, and the Sponsor will not be permitted direct 
access to this data. 
16.3 Adherence to the Protocol 
The Investigators will conduct the study in strict accordance with the protocol, which 
has been written to enable the Investigators’ compliance with ICH E6, Section 4. 
There are to be no waivers to the Inclusion/Exclusion criteria and no Investigators-led 
deviations from the schedules and procedures set out within this protocol. Any subject 
whose treatment deviates from the protocol or who is not qualified for study 
participation may be ineligible for analysis and may compromise the study. 
Any unintentional deviation or violation that is discovered should be reported to the 
Sponsor immediately. Any deviation or violation that may have an impact upon 
subject’s safety or suitability for the study should be reported to EC, and discussed 
with the Study Physician. 
Subjects who have not signed an EC-approved ICF cannot receive study medication. 


 
 
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The Investigators and research team must comply with the 13 principles of ICH GCP 
and all applicable local regulatory laws and regulations. 
16.4 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative 
reasons at any time, however not without good cause. Reimbursement for expenses 
covering subjects, use of live-in facilities, laboratory tests, and other professional fees 
will be made. The Investigators will refund the excess of payments made in advance. 
The Investigators reserve the right to discontinue the study should his/her judgement 
so dictate.  In such an event, final settlement of the grant-in-aid will be adjusted pro 
rata, and the Investigators will refund the excess of payments made in advance. The 
Investigators will notify the EC in case of study discontinuation.  Study records must 
be retained as noted above. 
16.5 Retention of Tissue Samples 
The blood samples will be kept for 2 years after the marketing approval per clinical 
trial approval of the product. 
16.6 Registration and Publication of Study Summary and 
Results 
The investigational site may publish or present the results of this protocol subject to 
the protection of any patentable rights of the Sponsor or its nominees and subject to 
the protection of the Sponsor’s confidential information. The Sponsor has the ultimate 
control over any decision to publish. The Sponsor will be furnished with a copy of 
any proposed publication or presentation at least 60 days prior to submission for 
review of confidential of patentable information. Upon notice by the Sponsor, 
however, that the Sponsor reasonably believes that a patent application claiming an 
invention relating to the study drug made during the performance of the study will be 
filed prior to such publication, such publication may be delayed for an additional 30 
days or until any patent application or applications have been filed, whichever will 
first occur. 
For multicenter studies, it is mandatory that the first publication be based on data 
obtained from all analysed subjects; therefore Investigators participating in 
multicentre studies must agree not to present data gathered individually or by a 
subgroup of centres prior to the full, initial publication, unless this has been agreed to 


 
 
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by all other Investigators and the Sponsor. Authorship of communications arising 
from pooled data will be determined by both contribution to the scientific design, 
conduct, and interpretation of the study and by mutual agreement and will include 
selected members from investigational sites as well as Sponsor personnel.  
 
 
 
 


 
 
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17. REFERENCE LIST 
 
1. Kalso E, Pöyhiä R, Onnela P, Linko K, Tigerstedt I, Tammisto T. 
Intravenous morphine and oxycodone for pain after abdominal surgery. 
Acta Anaesthesiol Scand. 1991 Oct; 35(7):642-646. 
2. Nuutinen LS, Wuolijoki E, Pentikainen IT. Diclofenac and oxycodone in 
treatment of post-operative pain: a double-blind study. Acta Anaesthesiol 
Scand. 1986 Nov; 30(8):620-624. 
3. Coluzzi F, Mattia C. Oxycodone. Pharmacological profile and clinical data 
in chronic pain management. Minerva Anestesiol. 2005 Jul; 71(7):451-460. 
4. Leow KP, Smith MT, Williams B, Cramond T. Single dose and steady-state 
PKs and pharmacodynamics of oxycodone in patients with cancer. Clin 
Pharmacol Ther. 1992 Nov; 52(5):487-495. 
5. Glare PA, Walsh TD. Dose-ranging study of oxycodone for chronic pain in 
advanced cancer. J Clin Oncol. 1993 May; 11(5):973-978. 
6. Investigator’s Brochure of OxyContin®, Purdue Pharma, released date 
Oct/2012, Edition Number 15. 
7. Technical Guidelines for Human Bioequivalence Studies with 
Pharmacokinetic Endpoints for Chemical Generic Drugs, Draft for 
Comment, November 2015  
8. A Randomized, Open-Label, Single-Center, Single-Dose, Two-Way 
Crossover Study in Healthy Subjects to Determine the Fasting 
Bioequivalence of Oxycodone Tamper Resistant (OTR) 10 mg Tablets to 
OxyContin® 10 mg Tablets, Protocol number: OTR1003, by Purdue 
Pharma L.P.   
9. Guideline for industry, Bioavailability and bioequivalence studies 
submitted in NDAs or INDs-general considerations, US department of 
health and human services, food and drug administration, center for drug 
evaluation and research, March, 2014 
10. Oldenmenger WH, de Raaf PJ, de Klerk C, van der Rijt CC. Cut points on 
0-10 numeric rating scales for symptoms included in the Edmonton 
Symptom Assessment Scale in cancer patients: a systematic review. J Pain 
Symptom Manage. 2013 Jun; 45(6):1083-93. 
11. Crooks V, Waller S, Smith T, Hahn TJ. The use of the Karnofsky 


 
 
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Performance Scale in determining outcomes and risk in geriatric outpatients. 
J Gerontol. 1991 Jul; 46(4): M139-44.


 
 
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18. APPENDICES 
18.1 Sample Processing and Shipment 
18.1.1 PK Sample Handling and Shipping 
Samples and Sample Log Forms will be shipped by the Investigators to the Bioanalytical central 
laboratory. Analysis will be performed by means of LC-MS/MS. Details on the analytical 
methodology, the method of validation, and the analytical within-study quality control 
procedures will be included in the clinical study report for this protocol. 
18.1.2 Sample Procurement and Processing 
For each sample, 4 mL of blood sample will be collected at the defined time points. The total 
volume of blood to be collected from each patient for PK analysis will be approximately 152 mL. 
Blood samples, 4 mL each, will be drawn into tubes containing K2EDTA anticoagulant. After 
procurement, samples should be kept in a cool environment, preferably in a container of ice water, 
until processing. Samples must be centrifuged within 30 minutes of collection. Following 
centrifugation (1500 g, 4℃, 15 minutes), the plasma will be transferred equally into two labelled 
polypropylene tubes via pipettes, and stored at -20℃within one hour of collection. 
18.1.3 Sample Shipment 
Samples will be shipped in accordance with the standard shipping procedures provided by a 
central lab.  
18.2 REFERENCE VALUES 
18.2.1 Physical/Vital Sign Assessments 
Normal ranges for vital signs are shown in Table 6 below.  
Table 6 Normal Ranges for Vital Signs 
 
Adult Subjects ( ≥18 yrs) 
Systolic blood pressure 
90-140 mmHg 
Diastolic blood pressure 
60-90 mmHg 
Pulse rate 
60-100 bpm 
Respiration rate 
12-20 breaths per minute 
axillary Temperature  
36.0 - 37.5°C  
Table 7 describes parameters for clinically notable vital signs. 


 
 
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Table 7 Criteria Used to Identify Clinically Notable Vital Sign Abnormalities 
Vital Sign Parameter 
Value 
Change From Baselinea 
Systolic blood pressure 
155 mmHg 
Increase of 20 mmHg 
 
<80 mmHg 
Decrease of 20 mmHg 
Diastolic blood pressure 
95 mmHg 
Increase of 15 mmHg 
 
50 mmHg 
Decrease of 15 mmHg 
Pulse rate 
120 bpm 
Increase of 15 bpm 
 
<50 bpm 
Decrease of 15 bpm 
Respiration rate 
>24 breaths/minute  
- 
 
<8 breaths/minute  
- 
Axillary temperature 
>38°C  
 
 
<36°C  
 
aBoth value and change from baseline  criteria must be met to qualify as a clinically notable vital 
sign abnormality. 
18.2.2 Laboratory Assessments 
Table 8 presents the clinical laboratory tests to be performed. 
Table 8 Clinical Laboratory Tests 
Category 
Parameters 
Haematology 
Red blood cell (RBC), haemoglobin, haematocrit, platelets, and 
WBC with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
Chemistry 
 
Electrolytes 
sodium, potassium, chloride, biocarbonate (HCO3
-)  
Liver function tests 
alkaline phosphatase, AST, ALT, gamma-glutamyl-transferase 
(GGT), total bilirubin, direct bilirubin 
Renal function parameters 
blood urea nitrogen, creatinine 
Other 
glucose, calcium, albumin, cholesterol, triglycerides, phosphorus 
(inorganic phosphate), lactate dehydrogenase (LDH), total protein, 
globulin, uric acid 
 
 
Urinalysis 
pH, protein, glucose, ketone, occult blood, RBC, WBC, epithelial 
cells, bacteria, casts, crystals, specific gravity 
Table 9 presents the criteria (i.e. upper limit, lower limit criteria for each laboratory parameter) 
that will be used to identify subjects with markedly abnormal laboratory values.   


 
 
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Table 9 Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values 
 
Units 
Laboratory Parameter 
Lower Limit 
Upper Limit 
Haematology 
 
 
Haemoglobin 
Male <11 g/dL (110 g/L) 
Male >17.5 g/dL (175 g/L) 
Female <10 g/dL (100 g/L) 
Female >16.5 g/dL (165 g/L) 
Platelets 
70.0  109/L  
>400.0  109/L 
Leukocytes 
3.5  109/L  
>10.5  109/L 
Lymphocytes 
1.2  109/L  
>4.5  109/L 
Neutrophils 
2.0  109/L  
>7.0  109/L 
Clinical Chemistry 
Electrolytes 
 
 
Na+ 
130 mmol/L  
150 mmol/L 
K+ 
3.2 mmol/L  
5.7 mmol/L 
HCO3
- 
27.3 mmol/L 
21.4 mmol/L 
Liver Function Tests  
 
 
Alkaline phosphatase 
—–– 
3  ULN  
AST 
—–– 
3  ULN 
ALT 
—–– 
3  ULN 
GGT (gamma glutamyl 
transpeptidase, GGTP) 
—–– 
3  ULN 
Total bilirubin 
—–– 
1.5  ULN 
Renal Function Tests 
 
 
Creatinine 
—–– 
1.5  ULN 
Other Chemistry 
 
 
Calcium 
2.0 mmol/L 
3.0 mmol/L 
Phosphorous (inorganic 
phosphate) 
0.8 mmol/L 
— 
Glucose 
3.2 mmol/L 
7.0 mmol/L 
Uric acid 
Male <180 μmol/L 
Male 440 μmol/L 
Female <120 μmol/L 
Female >320 μmol/L 
Cholesterol 
<2.3 mmol/L 
6.0 mmol/L 
Triglycerides 
<0.3 mmol/L 
2.5 mmol/L 
Albumin 
3.2 g/dL 
>5.5 g/dL 
LLN: Lower limit of the laboratory reference (normal) range    
ULN: Upper limit of the laboratory reference (normal) range 
 
 
18.3 Numeric Rating Scale 
On a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable, how would 
you rate your pain over the last 24 hours. 
 
0              1                 2                3              4              5             6            7             8             9              10 
No Pain                                                                                                                                Worst Pain Imaginable  
 
 
 


 
 
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Pain will be categorized as none (0), mild (1-4), moderate (5-7), and severe (8-10)10. 
 
18.4 Karnofsky Score of Performance Status 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA 
 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed 
70 
Cares for self; unable to carry on normal activity or 
to do active work. 
60 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
50 
Requires considerable assistance and frequent 
medical care. 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 
The Karnofsky score of performance is categorized as addressed in the table11. 

SAP_001.pdf: 
                Protocol：ONF16-CN-101                      Statistical Analysis Plan  
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Statistical Analysis Plan 
 
 
An Open-label, Single Dose, Randomized, Cross-over 
Study to Determine the Fasted State pharmacokinetics of 
Oxycodone from Oxycodone Tamper Resistant (OTR) 
Tablet 10 mg and OXYCONTIN® Tablet 10 mg in Chinese 
Subjects with Chronic Pain 
 
 
 
 
 
 
 
 
Sponsor: 
MundiPharma (China) Pharmaceutical Co. Ltd 
Protocol No: 
ONF16-CN-101  
Version Date: 
January 30, 2018 
Version Number: 
V1.0 
 
 
 


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Approvals 
 
Signature 
Date 
Name：Feng Xue 
Position：Biostatistician II 
Company：WuXi Clinical Development Services (Shanghai) Co. Ltd 
 
Signature 
Date 
Name：Shelly Luo 
Position：Director of Biostatistics 
Company：WuXi Clinical Development Services (Shanghai) Co. Ltd 
 
Signature 
Date 
Name：Minjun Zhou 
Position：Project Manager 
Company：WuXi Clinical Development Services (Shanghai) Co. Ltd 
 
Signature 
Date 
Name：Rongna A 
Position：Phase I Study Lead 
Company：Mundipharma (China) Co., Ltd Beijing, China 
 
Signature 
Date 
Name：Martin Kontek 
Position：Senior Statistical Programmer 
Company：Mundipharma Research GmbH & Co. KG Limburg, Germany 
 
Signature 
Date 
Name：Reiner Uhl 
Position：Senior Statistician 
Company：Mundipharma Research GmbH & Co. KG Limburg, Germany 
 
Signature 
Date 
Name：Rolf Tiemann 
Position：Head of Biostatistics & Clinical Data Science 
Company：Mundipharma Research GmbH & Co. KG Limburg, Germany 
 
Signature 
Date 
Name：Rachel Gao 
Position：Senior Drug Safety Manager 
Company：Mundipharma (China) Co., Ltd Beijing, China 
 
Signature 
Date 
Name：Chunxiao Cai 
Position：Clinical Lead 
Company：Mundipharma (China) Co., Ltd Beijing, China 
 
 
 


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Signature 
Date 
Name：Yang Cui 
Position：Group Clinical Lead  
Company：Mundipharma (China) Co., Ltd Beijing, China 
 
 


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Version History 
 
Version 
Date 
Reason for Change 
0.1 
2017-05-04 
First version 
0.2 
2017-06-23 
1. Added PK Sampling deviation time window 
2. Medical history and current medical conditions definition 
added 
3. Added for detail PK parameter examined criteria 
0.3 
2017-08-02 
1. Updated sample SAS codes used for BE analysis 
2. TOST procedure modified as per D J Schuirmann, Vol. 15, 
No. 6, 1987 
0.4 
2017-11-21 
1. 
Added the definition of significant adverse events. 
2. 
Deleted AE figures 
3. Fisher’s exact replaced by McNemar test for Adverse 
Events and Exposure tables 
0.5 
2017-12-06 
1. Updated wording of PK population definition and 
bioequivalence analysis population 
0.6 
2017-12-30 
1. Added additional criteria to protocol deviation 
2. Updated definition of prior and concomitant to be 
consistent with protocol. 
0.7 
2018-01-16 
1. Updated signature page 
1.0 
2018-01-30 
Finalization 
 
 


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Table of Content 
1. 
Introduction ................................................................................................................................... 6 
2. 
Study Objectives ............................................................................................................................ 6 
3. 
Study Design .................................................................................................................................. 6 
3.1 
Sample Size Consideration ................................................................................................ 8 
3.2 
Randomization .................................................................................................................. 8 
4. 
Study Variables ............................................................................................................................... 8 
4.1 
Pharmacokinetic Parameters ............................................................................................ 8 
4.2 
Safety Variables ................................................................................................................. 8 
5. 
Definitions ...................................................................................................................................... 8 
6. 
Analysis Set .................................................................................................................................... 9 
7. 
Interim Analysis .............................................................................................................................. 9 
8. 
Data Review ................................................................................................................................... 9 
8.1 
Data Handling and Transfer .............................................................................................. 9 
8.2 
Data Screening .................................................................................................................. 9 
9. 
Statistical Methods ...................................................................................................................... 10 
9.1 
General Consideration .................................................................................................... 10 
9.1.1 
General Guideline ........................................................................................................... 10 
9.1.2 
Missing Data or Missing Date ......................................................................................... 10 
9.1.2.1 
Handling of Missing Dates .......................................................................................... 10 
9.1.2.2 
Handling of Missing Values ......................................................................................... 10 
9.1.2.3 
Assessment Windows ................................................................................................. 10 
9.1.3 
Software Version ............................................................................................................. 11 
9.2 
Disposition ...................................................................................................................... 11 
9.3 
Demographic and Baseline Characteristics ..................................................................... 11 
9.3.1 
Demographics ................................................................................................................. 11 
9.3.2 
Protocol Deviations ......................................................................................................... 11 
9.3.3 
Medical History and Current Medical Conditions ........................................................... 12 
9.3.4 
Prior and Concurrent Therapies...................................................................................... 12 
9.4 
Pharmacokinetic Analysis and Bioequivalence Analysis ................................................. 12 
9.4.1 
Drug Concentration Measurements and Analysis .......................................................... 12 
9.4.2 
Pharmacokinetic Analysis ............................................................................................... 13 
9.4.3 
Bioequivalence Analysis .................................................................................................. 14 
9.5 
Safety Analysis ................................................................................................................ 15 
9.5.1 
Treatment Compliance and Exposure ............................................................................. 15 
9.5.2 
Adverse Events ................................................................................................................ 16 
9.5.3 
Laboratory Data .............................................................................................................. 17 
9.5.4 
Vital Signs ........................................................................................................................ 19 
9.5.5 
ECG .................................................................................................................................. 20 
9.5.6 
Physical Examinations ..................................................................................................... 20 
9.5.7 
Other Observations Related to Safety ............................................................................ 20 
10. 
Validation ..................................................................................................................................... 21 
11. 
Reference ..................................................................................................................................... 21 
Appendix 1 
List of Abbreviations ........................................................................................................... 22 
Appendix 2 TOST Example SAS code ............................................................................................................ 23 
 
  
 


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1. 
Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the report and 
analyses of data collected under MundiPharma (China) Pharmaceutical Co. Ltd. for ONF16-CN-101 study.  
This SAP should be read in conjunction with the study protocol and electronic case report form (CRF). This 
version of the plan has been developed using the protocol dated May 16, 2016 and eCRF version 2.0 dated Feb 7, 
2017. Any further changes to the protocol or eCRF may necessitate updates to the SAP. A final version of this SAP 
will be issued for sponsor approval prior to database lock. 
2. 
Study Objectives  
This open-label, single dose, randomised, cross-over study aims to determine the Fasted-state 
pharmacokinetics (PK) of oxycodone from OTR tablet 10 mg and OXYCONTIN tablet 10 mg in Chinese subjects 
with chronic pain.  
Primary objective is to confirm the BE of OTR tablet 10 mg and OXYCONTIN tablet 10 mg in a Fasted state. 
Secondary objective is to assess the safety of OTR tablet 10 mg and OXYCONTIN tablet 10 mg, when given 
to Chinese subjects with chronic pain in a Fasted state. 
3. 
Study Design 
Study Design 
Open-label, single dose, randomised, cross-over study 
Study Population 
Subjects with histories of chronic pain 
Geographic Regions 
1-2 sites in China 
Investigational Medical 
Product(s)  
Test Group:  
OTR tablet 10 mg. Oxycodone Hydrochloride Controlled-release Tablets 
containing 10 mg oxycodone hydrochloride, manufactured by Purdue Pharma 
L.P., U.S.  
The OTR tablet 10 mg will be administered orally once on the morning of Day 1 of 
each period, in a Fasted state.  
 
Reference Group:  
OXYCONTIN tablet 10 mg. Oxycodone Hydrochloride Prolonged-release (PR) 
Tablets containing 10 mg oxycodone hydrochloride manufactured by Bard 
Pharmaceuticals Ltd., U.K.  
The OXYCONTIN tablet 10 mg will be administered orally once on the morning of 
Day 1 of each period, in a Fasted state.  
Treatment and Study 
Duration 
Screening should be performed within 21 days before the randomization. The 
randomized subjects will be administered the test and reference treatments in a 
randomized order. There will be two study periods (Period 1 and Period 2), with a 
minimum of 6 days washout between the two doses. Subjects will cross over to 
receive the alternative study drug upon completing Period 1. 
PK blood sampling will continue for up to 32 hours after dosing with the study 
treatment in each period. Subjects will stay in the unit for safety monitoring until 
72 hours after each dosing of the study drug in each period. Subjects will have a 
safety follow-up visit via telephone at 7±1 days after the last dose of study drug in 
the case of completion or early discontinuation from the study. 
Total duration of the study is up to 35 days. 
Planned Number of 
Subjects 
A total of 24 subjects with histories of chronic pain will be randomized to receive 
the study drug to achieve 18 subjects (9 subjects per treatment sequence) to 
complete the study with valid pharmacokinetic (PK) data. 
Randomisation and 
Blinding 
Subjects will be randomized into either the treatment sequence of 
OTR-OXYXONTIN or OXYCONTIN-OTR group in a 1:1 ratio at Day -1 of Period 
1. 
This is an open-label study, and thus blinding not applicable. 
Other Features (as 
NA 


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appropriate) 
 
 Figure 1: Study Flowchart 
 
Protocol Amendment Version History 
Version 
Date 
Reason for Change 
1.0 
2016-05-16 
NA 
 
 


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3.1 Sample Size Consideration 
The study is designed to have a power of ≥95% to demonstrate a bioequivalence (BE) (AUCt and Cmax) of 
OTR tablet 10 mg, in terms of oxycodone, with OXYCONTIN tablet 10 mg in a fasted state. 
The null hypothesis is that the two treatments are not bioequivalent. The alternative hypothesis is that both 
treatments are bioequivalent. BE between both treatments will be concluded if the 90.00% CI for the ratio lies 
within 80.00% to 125.00% for both AUCt and Cmax for the oxycodone analyte. 
A total of 24 subjects was randomised to receive study drug (12 subjects per treatment sequence) with the 
aim that 18 subjects will provide valid PK data (9 subjects per treatment sequence) and PK parameters (Cmax 
and AUCt). This will provide ≥ 95% power to show BE simultaneously in both parameters, Cmax and AUCt, 
between test and reference formulation, assuming a true ratio of 1, a within standard deviation (SD) of the period 
differences of 0.24 on the log scale for AUCt and 0.20 on the log scale for Cmax, both PK parameters are not 
anti-correlated, and 90% CI for the ratios of the population means within the BE limits of 80.00% and 125.00%. 
The within SD of the period differences was based on Purdue Pharma BE study OTR1003 in healthy volunteers 
taking oxycodone. 
The sample size was estimated using nQuery t-tests (TOST of equivalence in ratio of means for crossover 
design (natural log scale). 
3.2 Randomization 
Twenty-four subjects will be enrolled and randomly assigned to two sequences of treatments (receiving OTR 
10 mg before OXYCONTIN 10 mg or receiving OXYCONTIN 10 mg before OTR 10 mg) in a 1:1 sequence ratio. 
Every 4 subjects will be grouped as a block. Subjects in every block will be randomized with a 1:1 sequence ratio 
into receiving OTR 10mg before OXYCONTIN 10mg or into receiving OXYCONTIN 10mg before receiving OTR 
10mg. 
4. 
Study Variables 
4.1 Pharmacokinetic Parameters 
- Maximum concentration（Cmax） 
- Area under the concentration-time curve from time 0 to last quantifiable concentration (AUCt) 
- AUC from time 0 to infinity (AUCINF) 
- Terminal rate constant（LambdaZ） 
- Time to maximum concentration（tmax） 
- Terminal half-life（t1/2z） 
4.2 Safety Variables 
- Adverse events (AEs), Serious adverse events (SAEs) 
- Laboratory values 
- Vital signs 
- Electrocardiogram (ECG) 
5. 
Definitions 
Baseline is defined as last value prior to first dose of investigational medicinal product (IMP). 
Change from baseline will be calculated as follows:  
 Change from baseline = post-baseline assessment value - the baseline assessment value. 


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Age (in years) is defined as the date of informed consent relative to the date of birth, will be auto-calculated 
during the eCRF collection. 
Body mass index (BMI) will be calculated as follows:   
 BMI (kg/m^2) = (Weight (kg))/〖Height(m)〗^2  
Duration will be calculated as follows:  
 Duration = last observation date – first observation date +1 
Study Day and Treatment Day are defined as follows: 
 Study date: 
 If study date < randomisation date then study day = study date – randomisation date 
 If study date >= randomisation date then study day = study date – randomisation date + 1 
 Treatment Day = treatment date – date of first dose of IMP +1 
6. 
Analysis Set 
Enrolled (ENR) Population 
The enrolled population is defined as all subjects who signed inform consent form (ICF). 
Intention to treat (ITT) Population 
The ITT population is defined as all randomised subjects. 
Safety Population 
The safety population is defined as all randomised subjects who received at least one dose of IMP. 
PK Population 
The PK population is defined as all subjects who receive IMP and have at least one PK concentration 
measurement. 
Exclusions from each population will be agreed at the Data Review Meeting (DRM) meeting. 
Subjects in the safety population will be analysed ‘as treated’. For all other populations, subjects will be 
analysed ‘as randomised’, unless stated otherwise. 
7. 
Interim Analysis 
No interim analysis is planned. 
8. 
Data Review 
Final data for analysis should always be 100% cleaned prior to receipt by Clinical Programming. The purpose 
of this section is to indicate the history of the data and the process used to ensure that the data are acceptable for 
statistical analysis prior to database lock 
8.1  Data Handling and Transfer 
Refer to Data Management Plan.  
8.2  Data Screening 
Beyond the data screening built into the Data Management Plan, the programming of analysis datasets, 
tables, figures, and listings (TFL) provides additional data screening. Presumed data issues will be output into 


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Statistical Analysis Software (SAS) logs identified by the word “Problem” and extracted from the logs by a SAS 
macro and sent to Data Management. 
Review of a pre-freeze TFL run (if included in the study contract) on clean subjects and a post-freeze TFL run 
on the frozen database allow for further data screening prior to lock. The post-freeze TFL will be discussed with 
the sponsor in a data review meeting (DRM) to identify any final data issues and seek corrections prior to 
database lock. The statistician and the sponsor must approve database lock. 
9. 
Statistical Methods 
9.1 General Consideration 
9.1.1 
General Guideline 
In general, all the tables are summarised by treatment sequence or treatment where appropriate. Continuous 
data will be summarised using the following descriptive statistics: n, mean, standard deviation (SD), median, 
minimum and maximum. Categorical data will be summarised as the number and percentage of subjects in each 
category (including the category ‘missing’ if applicable). 
All data will be listed. The data will be sorted by treatment sequence, subject number and date of assessment 
(if applicable). 
9.1.2 
Missing Data or Missing Date 
9.1.2.1 Handling of Missing Dates 
In general, for the subject data listings, no imputation of missing or incomplete dates will be applied. 
Partial Dates for Date of Birth 
The following conventions will be used for imputing partial dates: 
 
If only the day is missing, the 15th will be used to replace the missing day. 
 
If both the day and the month are missing, the 1st July will be used to replace the missing day and month. 
Partial Dates for Adverse Events and Previous/Concomitant Medications 
For completely missing AE (or medication) start dates, the event will be considered as treatment emergent for 
both period 1 and period 2 (for AEs) or concomitant (for medications) unless the end date rules out the possibility.  
For partial missing start dates (month and/or year is missing), AE (or medication) will be assigned the period 
with which the available start and stop dates are consistent. If the partial missing AE (or medication) start dates do 
not allow for identification of ‘treatment-emergent’ (or ‘period 1/period 2 treatment-emergent’ or ‘concomitant’) from 
the month and/or year alone, a conservative approach will be taken to ensure that these AEs (or medications) are 
defined as treatment emergent for period 1, period 2, or both period 1 and period 2 (or as concomitant) unless the 
end date rules out the possibility. 
9.1.2.2 Handling of Missing Values 
No missing data will be imputed. 
9.1.2.3 Assessment Windows 
According to protocol section 10.1, the study visits are scheduled at the exact day during the treatment period, 
and just allow ± 1 day window for follow -up visit.  
No assessment windows will be slotted for this study. In general, only data recorded at the nominal visit will be 
presented for by-visit summaries, data will be assigned using the visit numbers as per the eCRF, and baseline visit 
will be the last non-missing results prior to IMP at Period 1. 
For shift tables (change from baseline to the worst/end of study), a conservative approach will be used where 
the worst/latest post-baseline result including unscheduled visits will be selected. 
All data will be listed. 


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9.1.3 
Software Version 
All analyses will be conducted using SAS version 9.4. 
9.2 
Disposition 
The number and percentage of subjects who were screened and randomized will be presented for ENR, also 
the number and percentage of subjects having failed screening will be presented along with a summary of the 
primary reason of screening failure. For the subjects who were randomised, summaries will be presented for the 
number and percentage of subjects who randomised, completed the study, and withdrew early from the study by 
corresponding reasons for withdrawal by treatment sequence for ITT.  
All disposition information will be listed. 
9.3 
Demographic and Baseline Characteristics 
The summary of demographic and baseline characteristics are based on ITT. 
9.3.1 
Demographics 
Subject demographics and baseline characteristics will be summarized by treatment sequence for the ITT 
with descriptive statistics. Continuous variables will use Wilcoxon rank sum test method to estimate the difference 
between two treatment sequences; Categorical variables will use Fisher-exact method. The results of these tests 
will be provided including p-value for descriptive purposes and will not be used as a formal basis to determine the 
factors to be included in statistical models. Since this is a crossover study for BE analysis, any baseline 
imbalances of factors between treatment sequences will not affect the results in conclusion. Additional analyses 
may be performed to adjust these imbalance baseline differences as an ad-hoc analysis after database lock. 
The following demographics and baseline characteristics will be summarised appropriately for the study: 
 
Age (years)  
 
Gender – Female, Male 
 
Ethnicity – Han, Other  
 
Weight (kg)  
 
Height (cm)  
 
BMI (kg/m2)  
 
Numeric Rating Scale Score: the average pain over the last 24 hours 
 
All demographic and baseline characteristics will be listed. 
9.3.2 
Protocol Deviations 
Protocol deviations are failures to adhere to the inclusion/exclusion criteria if subject successfully passed 
screening and protocol requirements and will be divided into major protocol deviations and minor protocol 
deviations. Major protocol deviations are those that are considered to have a significant effect on the BE analyses 
and hence would exclude the subject from the BE analyses. Minor protocol deviations are those not considered to 
significantly affect the BE analyses and hence do not warrant subjects’ exclusion.  
 
The following criteria might be considered as major protocol deviations: 
(1) Failure to comply with the inclusion or exclusion criteria 
(2) Received incorrect treatment (i.e. actual treatment taken differs from the randomised treatment 
scheduled) 
(3) Received study prohibited concomitant drugs 
(4) Failure to collect data for the primary endpoint as detailed in the protocol 
(5) Failure to comply with study restrictions, including food and beverages restrictions and Alcohol, Caffeine, 
and Smoking Restrictions. 
 
The evaluable subjects set must be finalized at the DRM (or earlier), prior to database lock. 


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The number and percentage of subjects with protocol deviations (major/minor) will be summarised by 
protocol deviation category for each treatment sequence and overall based on the ITT. 
All protocol deviations will be listed. Listings of food and beverages restrictions and Alcohol, Caffeine, and 
Smoking Restrictions will be presented respectively. 
 
9.3.3 
Medical History and Current Medical Conditions 
Medical history and current medical conditions will be defined using the stop date recorded, relative to the 
date of V1-Screening. A medical history will be defined as any medical condition resolved up to, but not including 
the date of V1-Screening. A current medical condition will be defined as any condition going at the date of 
V1-Screening. Medical history and current medical conditions will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) central coding dictionary version 19.1, 
The number and percentage of subjects with medical history/current medical conditions will be summarised 
by system organ class (SOC) and preferred term (PT) for each treatment sequence and overall based on the ITT. 
All medical history and current medical conditions will be listed. 
9.3.4 
Prior and Concurrent Therapies 
Therapies will include medication and non-pharmacological therapies.  
 A prior therapy will be defined as any therapy taken up to, but not including the informed consent date. A 
concomitant therapy will be defined as any therapy either ongoing at the date of informed consent or with an onset 
date time on or after informed consent to the completion of the study. Medications will be assigned an 11-digit 
code using the World Health Organisation Drug Dictionary Enhanced (WHO-DDE) drug codes of the most recent 
version (WHO-DD June 2016), and will be further coded to the appropriate Anatomical-Therapeutic-Chemical 
(ATC) code indicating therapeutic classification. Non-pharmacological therapies will be coded using MedDRA 
version 19.1. 
The number and percentage of subjects taking prior and concomitant medications will be summarised by ATC 
anatomical class (ATC level 1), pharmacological class(ATC level 3), pharmacological sub-class(ATC level 4), and 
preferred term for each treatment sequence and overall based on the ITT. 
A listing of prior and concomitant medications will be provided. A listing of non-pharmacological therapies will 
also be provided. 
9.4 
Pharmacokinetic Analysis and Bioequivalence Analysis  
PK analysis will be performed on the PK population. 
9.4.1 
Drug Concentration Measurements and Analysis 
Plasma concentration for analyte oxycodone will be summarised descriptively by nominal time-point and 
treatment as continuous data (i.e. n, mean, standard deviation, standard error, median, minimum, and maximum) 
for subjects in the PK population. Concentrations that are below the lower limit of quantitation will be assigned a 
value of 0 for the purposes of computing descriptive statistics.  
The following PK sampling window will be used to identify any significant sampling deviation, and significant 
deviations will be discussed at the DRM.  
Table 1.  PK Sampling deviation time window  
Planned PK sampling time 
Sampling deviation without significance 
0 h (predose) 
Within 30 min before administration 
> 0 h and ≤ 1 h 
±1 min  


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> 1 h and ≤ 4 h 
±2 min  
> 4 h and ≤ 8 h 
±5 min  
> 8 h and ≤24 h 
±10 min  
> 24 h  
±20  min 
 
Additionally, plasma concentrations for analyte oxycodone will be presented graphically in the following way 
using both a linear and log linear scales. 
 
The mean plasma concentration data of each treatment will be plotted over time 
 
For each treatment, the mean and individual plasma concentration data for each subject will be 
plotted over time  
 
For each subject, the individual plasma concentration data for each treatment will be plotted over 
time 
All plasma concentrations will be listed for Safety population. 
9.4.2 
Pharmacokinetic Analysis 
PK parameters for oxycodone will be derived using non-compartmental methods with WinNonlin software 
(Pharsight Corporation, v6.3 or above). The following PK parameters will be calculated for each subject.  
 
Cmax：Maximum concentration (ng/mL) obtained directly from the observed concentration versus 
time data for all analytes. 
 
AUCt：Area under the concentration-time curve from time 0 (immediately predose on Day 1) to last 
quantifiable concentration (h*ng/mL), calculated by linear up/log down trapezoidal summation. 
 
AUCINF：AUC from time 0 (immediately predose on Day 1) to infinity (h*ng/mL), calculated by 
linear up/log down trapezoidal summation. 
 
LambdaZ：Apparent terminal rate constant (1/h) estimated by log-linear least-squares regression of 
the terminal part of the concentration-time curve for all analytes (at least 3 timepoints to the last 
quantifiable concentration at this study). 
 
t1/2z：Apparent terminal half-life (h), determined as Ln2/LambdaZ.  
 
tmax：Time to maximum concentration (h) obtained directly from the observed concentration versus 
time data using actual draw times.  
 
R2:  Coefficient of determination from the linear regression used to determine LambdaZ. 
Pharmacokinetic parameters (AUCt, AUCINF, Cmax, tmax, LambdaZ, t1/2Z, and R2) for analyte oxycodone 
will be summarised descriptively by treatment for subjects in the PK population using the following descriptive 
statistics: n, mean, standard deviation, standard error, median, minimum, and maximum. For AUCt, AUCINF, and 
Cmax, the geometric mean, the standard deviation of geometric mean, and the geometric coefficient of variation 
(CV) will also be presented. Non-quantifiable PK parameter values below the limit of quantification (BLQ) will be 
set to equal zero for the analysis and will be set to missing for log-transformed data. 


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9.4.3 
Bioequivalence Analysis 
Only subjects who provide valid PK data for both the test and reference treatment will be included in the BE 
analysis. Subject who have major protocol deviations must be excluded from the BE analysis, when agreed on the 
DRM. 
Primary Analysis  
Log transformed data for oxycodone AUCt, and Cmax will be analysed using an analysis of variance (ANOVA) 
model, with fixed terms for treatment, period, treatment sequence and subject within sequence. Treatment 
population geometric means will be estimated from the exponential of the treatment Least Square (LS) means. 
Ratios of treatment population geometric means will be estimated by exponentiating the difference (test-reference) 
between treatment LS means, and 90% confidence intervals (CI) for the ratios will be calculated. For each 
comparison of interest, the exponentiated LS Mean and ratio will be presented along with its 90% CI for the AUCt, 
and Cmax parameters. Also, intra-subject variablity will be presented for each parameter per China Food and 
Drug Administration (CFDA) requirement. BE of test and reference will be confirmed for a PK parameter of analyte 
oxycodone if the 90% CI for the ratio (test/reference) falls completely within the BE acceptance range of 80.00% to 
125.00%. BE of test and reference will be confirmed in all if it can be confirmed with AUCt and Cmax. 
The sample SAS code as below 
proc mixed data=xxx; 
 
class sequence subject period treat; 
 
model Y = sequence period treat subject(sequence); 
 
estimate ‘Study - Ref’ treat 1 -1 / cl alpha=0.1; 
 
lsmeans treat; 
run; 
Where Y denotes the response measure (e.g., log(AUCt), log(Cmax)) being analyzed. 
 
In additional, with the Mean Squared Error (MSE) estimated from ANOVA model, Schuirmann’s Two 
One-Sided Test (TOST) will be performed for Cmax and AUCt at the alpha of 0.05 level (Donald J. Schuirmann, 
1987). The TOST Procedure, as its name implies, consists of decomposing the interval hypotheses Ho and H1 into 
two sets of one-sided hypotheses. 
 
 
The two sets of one-sided hypotheses can be tested with ordinary one-sided t tests, where 𝑋̅T-𝑋̅R is the  
difference between Cmax (or AUCt)  of products T and R in the log scale, the limits θ1 andθ2 (θ1 <θ2) are the 
pre-defined equivalence interval(ln(0.8) and ln(1.25)), s is the square root of the error mean square (√MSE) from 
the crossover design analysis of variance, t1-α(ν) is the point that isolates probability α in the upper tail of the 
Student's t distribution with ν degrees of freedom, where ν is the number of degrees of freedom associated 
with the error mean square. 


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Example SAS code can be found in Appendix 2. 
Secondary Analysis: 
The primary analysis will be repeated for the PK parameter AUCINF of analyte oxycodone.  
For tmax, with orginial value, nonparametric method (Hodges-Lehmann's median analysis) (Lingling Han, 
2015) will be used to determine the difference between two treatments (study-reference) and its 90% asymptotic 
CI. 
BE Analysis Considerations: 
The statistical summaries and analyses will exclude PK parameters from the relevant subject period for which 
any of the following criteria apply: vomiting within 12 hours after dosing, incorrect dosing, incomplete plasma 
profile which cannot adequately detail the parameter, pre-dose concentration>5% of Cmax.  
Pre-dose concentration>5% of Cmax and AUC % Extrapolation>20% will be summarised for PK population. 
In addition, the PK parameters AUCINF, t1/2Z and LambdaZ will be examined to see if they are evaluable 
based on the following criteria: 
 
Any R2<0.85 will be flagged out in the corresponding listing. If R2 associated with the LambdaZ 
estimate for any subject is <0.85 then the subject’s LambdaZ, and corresponding t1/2Z and AUCINF 
parameter values for that subject’s period will be excluded to perform the sensitivity analysis for the 
primary BE analysis.  
 
If a single non-quantifiable (NQ) value occurs between measurable concentrations in a profile, the 
NQ will be omitted (set to missing) in the derivation of pharmacokinetic parameters, statistical 
analysis, and the individual subject plots. 
These exclusions will be identified in the listings of the PK data.  
The validity of PK data will be discussed further and evaluated during the data review meeting at the end of 
the study. In accordance with BE guidelines, only subjects that provide valid PK data for both the test and 
reference treatments will be included in the statistical analysis. 
9.5 
Safety Analysis 
The summary of safety data will be based on Safety population. Safety data that will be summarised includes 
exposure, adverse events, clinical laboratory assessments, vital signs and ECGs. All safety analyses will be 
based on the safety population and will be summarised by treatment unless otherwise stated. Subjects will be 
assigned to the treatment according to the actual treatment they have received (“as treated”). 
9.5.1 
Treatment Compliance and Exposure 
IMP will be summarised as treatment exposure. Treatment exposure will be defined and calculated as the 
dose of IMP taken by subjects. Treatment exposure will be summarised by treatment. Regarding naltrexone 
dosing, exposure will be summarised by treatment for each nominal time point. Summary statistics of dosing 
exposure includes n, mean, minimum and maximum.  


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Treatment compliance is defined as the subjects who received 10mg study/reference drug at the scheduled 
visit per protocol. Treatment compliance will be summarized by the number and proportion of subjects who 
received treatments in compliance with the study protocol in each treatment of the safety population, the 
difference between the treatments will be tested using Fisher-exact method. P-value will be provided for 
descriptive purpose. Since it is a crossover study and only subjects that provide valid PK data for both the test and 
reference treatments will be included in BE analysis, any imbalance between treatment exposures will not affect 
the results in BE conclusion. 
9.5.2 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system 
(version 19.1) to give a System Organ Class (SOC) and Preferred Term (PT) for each adverse event (AE). 
A treatment emergent AE (TEAE) will be defined as follows: 
A TEAE is defined as any AE with an onset datetime on or after the first dose of IMP if the AE was absent 
before the first dose of IMP, or worsened after the first dose of IMP.  
A TEAE will be assigned to treatment period 1 IMP if it had an onset datetime on or after the first dose of IMP 
in treatment period 1, up to the treatment period 2 IMP given. A TEAE will be assigned to treatment period 2 IMP if 
it had an onset datetime on or after the first dose of IMP in treatment period 2, up to and including the day of the 
follow-up visit. If an AE had an onset datetime on or after the first dose of IMP in treatment period 1, and it was 
ongoing at the start of period 2 and it did not worsen in severity, it will be assigned to treatment period 1. 
TEAEs/SAEs collected from dosing of IMP till the last visit will be will be summarised. All AEs (including AEs 
with an onset data before IMP dosing) will be listed for subjects in the safety population.  
An overall summary of TEAEs will be provided by treatment. The number and percentage of subjects 
reporting TEAEs will be summarised by the PT nested within the SOC. In addition, the number of reported AEs will 
be summarised.  
Overall Summary of Adverse Events 
    An overall summary of AEs will be presented showing the number and percentage of subjects reporting at 
least one of the following:  
• 
Any AE 
• 
Any TEAE  
• 
Any related TEAE  
• 
Any severe TEAE  
• 
Any related severe TEAE  
• 
Any serious TEAE  
• 
Any related serious TEAE 
• 
Any significant AE, which is defined as AEs leading to death, leading to withdrawal from study, 
requiring treatment given, leading to dose reduction, leading to dose interruption and leading to 
dose discontinuation   
   • 
Any TEAE leading to death  
   • 
Any death because of a related serious TEAE 
   • 
Any TEAE leading to discontinuation from study 
   • 
Any TEAE requiring additional therapy 
   • 
Any TEAE leading to dose reduction 
   • 
Any TEAE leading to dose interruption 
   • 
Any TEAE leading to dose discontinuation 


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    Additionally, the number of reported AEs, reported TEAEs, related TEAEs, severe TEAEs, related severe 
TEAEs, serious TEAEs, related serious TEAEs and significant AEs will also be presented. The difference between 
the treatments will be tested using McNemar test. 
 
Analyses of Treatment Emergent Adverse Events  
The number and percentage of subjects reporting TEAEs will be summarized by Preferred Term (PT) nested 
within System Organ Class (SOC). If a System Organ Class (SOC) / Preferred Term (PT) is reported more than 
once for a subject, the subject will only be counted once for this System Organ Class (SOC) / Preferred Term (PT).  
All AE summary tables will be sorted by System Organ Class (SOC) and Preferred Term (PT) within System 
Organ Class (SOC). In addition, the number of reported TEAEs will be summarized in the same manner.  
Moreover, the number and percentage of subjects reporting the most frequent TEAEs (Preferred Term ≥ 10% 
in any treatment) for each treatment period will be summarised by System Organ Class (SOC) and Preferred Term 
(PT). 
 
TEAE by Severity 
The number and percentage of subjects with TEAEs will be summarised by worst severity (mild, moderate, 
and severe) by Preferred Term (PT) nested within System Organ Class (SOC). Worst severity will be counted if an 
AE is reported more than once by the same subject for this System Organ Class (SOC) / Preferred Term (PT).  
 
TEAE by Relationship 
The number and percentage of subjects with TEAEs will be summarised by relationship to IMP (related and 
not related) by Preferred Term (PT) nested within System Organ Class (SOC). The highest relationship to IMP will 
be counted if an AE is reported more than once by the same subject for this System Organ Class (SOC) / 
Preferred Term (PT). 
 
Deaths, Serious Adverse Events and Significant Adverse Events 
The number and percentage of subjects  
 
with TEAEs leading to death,  
 
with any Serious TEAEs,  
 
with any severe TEAEs, 
 
with any TEAE leading to discontinuation from the study  
 
with any significant AEs 
will be summarised by Preferred Term (PT) nested within System Organ Class (SOC).  
 
AE Listings 
The AE dictionary will be listed, presenting the MedDRA system organ class, MedDRA preferred term and 
investigator terms. 
All AEs for enrolled population, AEs leading to death, SAEs, severe AEs, significant AEs and AEs leading to 
discontinuation from study will be listed. All death information will be listed too.   
 
9.5.3 
Laboratory Data 
Clinical laboratory data to be summarised includes haematology, blood chemistry, and urinalysis. 
Haematology:  
red blood cells (RBC), haemoglobin, haematocrit, platelets, and white blood cells 
(WBC) with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Blood Chemistry: 
Electrolytes  
sodium, potassium, chloride, bicarbonate (HCO3
-) 


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Liver function 
alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl-transferase (GGT), total bilirubin, direct 
bilirubin 
Renal function 
blood urea nitrogen, creatinine 
Other  
glucose, calcium, albumin, cholesterol, triglycerides, phosphorus (inorganic 
phosphate), lactate dehydrogenase (LDH), total protein, globulin, uric acid 
Urinalysis:  
pH, protein, glucose, ketone, occult blood, red blood cells, white blood cells, 
epithelial cells, bacteria, casts, crystals, specific gravity 
 
Clinical laboratory results recorded at Baseline and V3-Period 2 Day 4 and change from baseline to 
V3-Period 2 Day 4 will be summarised as continuous data for each parameter by treatment sequence. 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or “> X”, 
i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative summaries, 
but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
Clinical laboratory values for each parameter will be assigned an LNH classification according to whether the 
value is lower (L), within (N) or higher (H) than the reference range for that parameter. The values will be 
summarised using shift tables to evaluate categorical changes from baseline to end of study value with respect to 
reference range values (low, normal, high) for each parameter by treatment sequence. The end of study value is 
defined as the latest value assessed for the subject in the study.  
Clinical laboratory values after first dose of IMP will be evaluated for markedly abnormal values. Table 1 
presents the criteria (i.e. upper limit, lower limit criteria for each laboratory parameter) that will be used to identify 
subjects with markedly abnormal laboratory values. 
 Table 2.  Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values 
 
Laboratory Parameter 
Lower Limit 
Upper Limit 
Haematology 
 
 
Haemoglobin 
Male11 g/dL (110 g/L)  
Male>17.5 g/dL (175 g/L) 
 
Female10 g/dL (100 g/L) 
Female>16.5 g/dL (165 g/L) 
Platelets 
70.0  109/L 
>400  109/L 
Leukocytes 
3.5  109/L  
>10.5  109/L 
Lymphocytes 
1.2  109/L 
>4.5  109/L 
Neutrophils 
2.0  109/L 
>7  109/L 
Clinical Chemistry 
Electrolytes 
 
 
Sodium (Na+) 
130 mmol/L 
150 mmol/L 
Potassium (K+) 
3.2 mmol/L 
5.7 mmol/L 
Bicarbonate (HCO3-) 
21.4 mmol/L 
>27.3 mmol/L 
Liver Function Tests  
 
 
Alkaline phosphatase 
—–– 
3  ULN  
AST 
—–– 
3  ULN 
ALT 
—–– 
3  ULN 
 
 
 
GGT (gamma glutamyl trans peptidase, 
GGTP) 
—–– 
3  ULN 


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Total bilirubin 
—–– 
1.5  ULN 
Renal Function Tests 
 
 
Creatinine 
—–– 
1.5  ULN 
Other Chemistry 
 
 
Calcium 
2.0 mmol/L 
3.0 mmol/L 
Phosphorous (inorganic phosphate) 
0.8 mmol/L 
— 
Glucose 
3.2 mmol/L 
7.0 mmol/L 
Uric acid 
Male 180 µmol/L  
Female 120 µmol/L  
Male 440 µmol/L  
Female 320 µmol/L  
Cholesterol 
2.3 mmol/L 
6.0 mmol/L 
Triglycerides 
0.3 mmol/L 
2.5 mmol/L 
Albumin 
3.2 g/dL 
5.5 g/dL 
Note: There are no markedly abnormal ranges identified for urinalysis. 
 
Scatter plots will be produced for each laboratory parameter comparing baseline and end of study values. In 
addition, clinically laboratory values for each parameter will be plotted over time using a box and whisker plot. 
All clinical laboratory data will also be presented in the data listings, abnormal clinical laboratory values and 
markedly abnormal values will be flagged in the listing. 
9.5.4 
Vital Signs 
Vital sign parameters to be summarised include systolic blood pressure, diastolic blood pressure, respiration 
rate, axillary temperature, and pulse rate and will be assessed at the scheduled time-points at V1, V2-Period 1, 
and V3-Period 2. 
Vital sign variables at each visit, and its change from baseline to each test will be summarised as continuous 
data using descriptive summary statistics for each parameter by treatment sequence. 
Vital sign values 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. The values will be summarised 
using shift tables to evaluate categorical changes from baseline to end of study value with respect to reference 
range values (low than, within, higher than) for each parameter by treatment sequence. The end of study value is 
defined as the latest value assessed for the subject in the study.  
Table 3.  Normal Ranges for Vital Signs  
 
Parameter 
Range  
Systolic blood pressure 
90-140 mmHg 
Diastolic blood pressure 
60-90 mmHg 
Pulse rate 
60-100 bpm 
Respiration rate 
12-20 breaths per minute 
Temperature (where applicable) 
36 – 37.5 °C  
 
Vital sign values after first dose of IMP will be evaluated for clinically notable abnormalities. The number and 
percentage of subjects reporting clinically notable vital sign abnormalities will be summarised for each parameter 


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by time-point and treatment sequence. Each subject can be counted once in the parameter high and the 
parameter low categories per time-point, as applicable. 
Table 4.  Criteria Used to Identify Clinically Notable Vital Sign Abnormalities  
 
Vital Sign Parameter 
Criteria 
Value 
Change From Baselinea 
Systolic blood pressure 
High 
≥155 mmHg 
Increase of ≥20 mmHg 
 
Low 
<80 mmHg 
Decrease of ≥20 mmHg 
Diastolic blood pressure 
High 
≥95 mmHg 
Increase of ≥15 mmHg 
 
Low 
≤50 mmHg 
Decrease of ≥15 mmHg 
Pulse rate 
High 
≥120 bpm 
Increase of ≥15 bpm 
 
Low 
<50 bpm 
Decrease of ≥15 bpm 
Respiration rate 
High 
>24 breaths/minute 
- 
 
Low 
<8 breaths/minute 
- 
Axillary temperature 
High 
>38°C  
- 
 
Low 
<36°C  
 
*Both value and change from baseline criteria must be met to qualify as a clinically notable vital sign abnormality. 
 
Scatter plots will be produced for each vital sign parameter comparing baseline and end of study values. In 
addition, vital sign values for each parameter will be plotted over time using a box and whisker plot. 
All vital sign data will also be presented in the data listings. Abnormal vital signs values and clinically relevant 
vital sign abnormalities will be flagged in the listing.  
9.5.5 
ECG 
ECG will be recorded at Baseline and V3-Period 2 Day 4.  
ECG will be judged by the investigator as clinically significant (yes/no). The number and percentage of 
subjects with worst post-baseline findings will be summarised by treatment sequence. The worst post-baseline 
finding refer to the worst evaluation result observed post-baseline including unscheduled visits, with a severity 
order of abnormal, clinical significant > abnormal, not clinical significant > normal. This will include a summary of 
frequency counts for the number of subjects who had significant changes from baseline, with respect to those who 
had no significant findings at baseline to significant findings post-baseline. 
The description of the clinically significant ECG findings will be listed. 
9.5.6 
 Physical Examinations 
All phyical examination results will be listed. 
9.5.7 
Other Observations Related to Safety 
The following observations will be provided for listing only; 
 
Allergy history 
 
β-HCG test  
 
Urine Drug test 
 
Alcohol test 


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10. Validation 
To ensure that each TFL delivery is submitted to the highest level of quality. Our quality control procedures 
will be documented separately in the study specific quality control plan. 
 
11. Reference 
Donald J. Schuirmann, A Comparison of the Two One-Sided Tests Procedure and the Power Approach for 
Assessing the Equivalence of Average Bioavailability, Journal of Pharmacokinetics and Biopharmaceutics, Vol. 15, 
No. 6, 1987 
Lingling Han, Calculating the point estimate and confidence interval of Hodges-Lehmann's median using SAS® 
software. ST-154 
 


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Appendix 1 
List of Abbreviations 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutical Chemical 
BE 
Bioequivalence 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CFDA 
China Food and Drug Administration 
CI 
Confidence Interval 
CV 
Coefficient of Variation 
DRM 
Data Review Meeting 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
IMP 
Investigational Medicinal Product 
ITT 
Intent-To-Treat 
LLN 
Lower Limit of Normal 
LNH 
Low, Normal, High 
LS 
Least Squares 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
MSE 
Mean Square Error 
NA 
Not Applicable 
NQ 
Non Quantifiable 
PK 
Pharmacokinetic 
PT 
Preferred Term 
RAS 
Random Allocation Schedule 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Tables, Figures, and Listings 
TOST 
Two One-Sided Test 
ULN 
Upper Limit of Normal 
ULQ 
Upper the Limit of Quantification 
WHO-DD 
World Health Organisation Drug Dictionary 
 
 
 


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Appendix 2 TOST Example SAS code 
ANOVA 
TOST.docx