Clinical trial NCT02880475
Conditions: Chronic Pain
Keywords: Moderate to severe chronic non-malignant pain
Sponsor: Mundipharma (China) Pharmaceutical Co. Ltd
Start date: 2014-06-01; Completion date: 2015-07-10
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, randomized, single-dose, parallel group study. The objectives of this study are to assess pharmacokinetics of oxycodone and naloxone from oxycodone/naloxone (OXN) prolonged release (PR) tablet 5/2.5 mg (OXN 5/2.5) and 20/10 mg (OXN 20/10) in Chinese patients with moderate to severe chronic non-malignant pain.

Detailed description:
It will be conducted to assess the pharmacokinetics of OXN 5/2.5 and OXN 20/10 tablets. Subjects will be allocated to a sequence of two strength group in accordance with a random allocation schedule (RAS) in a 1:1 ratio.

Subjects will attend a screening visit within 14 days of the first (OXN) dosing day (Day 1).

Eligible subjects will then check into the study unit on the day before OXN dosing (Day -2). Subjects will be administered their OXN dose the next 2 morning (Day 1), following an overnight fast.

Arms: arm 1: The subjects were randomized to receive a single dose of OXN prolonged release tablet 5/2.5mg for one time. arm 2: The subjects were randomized to receive a single dose of OXN prolonged release tablet 20/10 mg for one time.
Interventions: intervention 1: OXN PR tablet
Intervention descriptions: intervention 1: Orally administered OXN PR tablet 5/2.5 mg or OXN PR tablet 20/10 mg

Protocol documents:
Prot_000.pdf: 
 
 
                                                                                                                                          OXN08-CN-101 
1 TITLE PAGE 
Protocol Number: 
 OXN08-CN-101 
 
 
 
Title: 
An open-label, randomized, single-dose, parallel group study to 
investigate the pharmacokinetics of oxycodone and naloxone from 
oxycodone/naloxone (OXN) prolonged release (PR) tablet 5/2.5 mg 
(OXN 5/2.5)and20/10 mg (OXN 20/10) in Chinese patients with 
moderate to severe chronic non-malignant pain. 
 
 
 
 
 
Sponsor: 
Mundipharma (China) Pharmaceutical Co., Ltd 
Room 1808 Tower D CITC, 6A Jianguomen Wai Avenue, Beijing 
100022, China 
[Beijing, China]  [zip code：100022] 
[China] 
 
 
 
Test Drug: 
Oxycodone/naloxone (OXN) prolonged release (PR) tablet 
 
 
 
 
 
Phase: 
Phase I 
 
 
Release Date: 
[25-Sep-2014]  
 
 
GCP Statement: 
This study is to be performed in full compliance with ICH and all 
applicable local Good Clinical Practices (GCP) and regulations.  All 
required study documentation will be archived as required by 
competent authorities. 
 
 
Confidentiality: 
This document is confidential.  It contains proprietary information of 
[Mundipharma (China) Pharmaceutical Co., Ltd].  Any viewing or 
disclosure of such information that is not authorised in writing by the 
Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
 
 
 
 
Final version 1.0, version date: 15 Oct 2013 
 
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                                                                                                                                          OXN08-CN-101 
 
2 SIGNATURE PAGE FOR INVESTIGATOR 
Protocol Number: 
OXN08-CN-101 
 
Title: 
An open-label, randomized, single-dose, parallel group study to 
investigate the pharmacokinetics of oxycodone and naloxone from 
oxycodone/naloxone (OXN) prolonged release (PR) tablet 5/2.5 mg 
(OXN 5/2.5)and20/10 mg (OXN 20/10) in Chinese patients with 
moderate to severe chronic non-malignant pain. 
 
 
 
Test Drug: 
Oxycodone/naloxone prolonged release tablet 5/2.5 (OXN 5/2.5) 
Oxycodone/naloxone prolonged release tablet 20/10 (OXN 20/10) 
 
 
 
 
 
 
 
 
 
 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with Good Clinical Practice guidelines, including the Declaration of 
Helsinki and all its accepted amendments to date. 
 
 
 
Hu Pei 
 
 
 
 
 
                
 
 
 
        
                    
        
 
             
Investigator                                               Signature                                                    Date                               
           
                                                                               
                                                  
 
 
Zeng Xiaofeng 
 
                
 
 
 
        
                    
        
 
             
Investigator                                               Signature                                                    Date                 
 
Final version 1.0, version date: 15 Oct 2013 
 
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                                                                                                                                          OXN08-CN-101 
3 PROTOCOL SYNOPSIS 
 
Name of Company:  
Mundipharma (China) Pharmaceutical Co., Ltd. 
 
 
 
 
 
Name of Finished Product:  
Targin® 
 
Name of Active Ingredient: 
Oxycodone hydrochloride (HCl) and naloxone HCl 
 
Protocol No.: OXN08-CN-101 
 
 
Title of the Study:  
An open-label, randomized, single-dose, parallel group study to investigate the pharmacokinetics of 
oxycodone and naloxone from oxycodone/naloxone (OXN) prolonged release (PR) tablet 5/2.5 mg (OXN 
5/2.5)and20/10 mg (OXN 20/10) in Chinese patients with moderate to severe chronic non-malignant pain. 
 
 
Investigator/Study Center: 
Dr. HU Pei , ,Zeng Xiaofeng/Peking Union Medical College Hospital, more sites might be included as 
necessary. 
 
 
Study Dates: 
4Q 2013– 4Q 2014 
 
 
Study Status: 
Planned 
 
Phase of Development: 
Phase 1 
 
Objectives: 
a. To determine the PK of oxycodone, naloxone and metabolites in Chinese patients. 
b. To assess, in a single dose investigation, the dose-proportionality of OXN. 
 
 
Methodology:   
An open-label, randomized, single-dose, parallel group study. The patients will be enrolled in sequence 
to receive one dose of either OXN 5/2.5, OXN 20/10. 
 
 
Number of Subjects:  
Planned:  
24 subjects, each group (OXN 5/2.5, OXN 20/10) will have 12 subjects receiving OXN active treatment. 
More subjects will be enrolled if the completed subjects are less than 12 subjects in each group. 
 
 
Indication and Criteria for Inclusion: 
Chinese male and female patients with moderate to severe chronic non-malignant pain for OXN 5/2.5, 
OXN 20/10 single-dose study, aged 18 to 65 years. 
 
Final version 1.0, version date: 15 Oct 2013 
 
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Criteria for Inclusion:   
 
1. Adult Chinese patients with moderate to severe chronic non-malignant pain.  
2. Male and female subjects with age range 18 to 65 years (including 18 and 65), body weight ≥ 45kg 
and BMI range 18 to 30 (including 18 and 30).  
3. Patients who should rate their pain (Pain Intensity Scale -“average pain” over the last 24 hours) as ≥4 
on 0-10 scale. 
4. Patients, who are able to read, understand and sign written informed consent prior to study 
participation and are willing to follow the protocol requirements.  
5. Females of childbearing potential and less than one year post-menopausal must have a negative 
serum pregnancy test during screening visit and at check-in and be non-lactating. In addition, they 
must be willing to use adequate and reliable contraception throughout the study. Highly effective 
methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per 
year) when used consistently and correctly such as sterilization, implants, injectables, combined oral 
contraceptives, some IUDs (intrauterine Device, hormonal), sexual abstinence or vasectomised 
partner. 
 
Criteria for exclusion: 
 
1. Females who are pregnant (positive β-human chorionic gonadotrophin [HCG] test) or lactating. 
2. Use of opioid or opioid antagonist-containing medication in the 30 days before the start of the study. 
3. Known sensitivity to oxycodone, naloxone, or related compounds.   
4. Subjects with clinically unstable respiratory disease, dysfunction of the biliary tract, thyroid disease, 
adrenal cortical insufficiency, prostatic hypertrophy requiring intervention (medication or surgical) or 
renal artery stenosis, or any other medical condition, that, in the opinion of the investigator or the 
sub-investigator, precludes entry into this study.   
5. Subject who have a past (within 5 years) history of malignant neoplasm including leukemia and 
lymphoma.   
6. The electrocardiogram examination results are abnormal, in the opinion of the investigator or the 
sub-investigator, and are clinical significance. 
7. Subjects with abnormal liver function (values exceed the upper limit of normal for AST, ALT or total 
bilirubin during the Screening Period) or abnormal renal function (values exceed the upper limit of 
normal for serum creatinine during the Screening Period).   
8. Patients with a contraindication to the study medication. 
9. Subjects who have a psychiatric disorder such that participation in the study may, in the opinion of 
the investigator or the sub-investigator, pose an unacceptable risk to the subject. 
 
Final version 1.0, version date: 15 Oct 2013 
 
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10. Subjects who have a current or past (within 5 years) history of substance or alcohol abuse, or 
subjects who give a positive result in drug abuse test during the Screening Period, or subjects who, 
in the opinion of the investigator or the sub-investigator, have demonstrated addictive orsubstance 
abuse behaviors.   
11. Subjects with uncontrolled seizures or convulsive disorder.   
12. Subjects who will receive any interventional therapy (surgery, paracentesis,etc) for arthritis during 
the study period. 
13. History of or any current conditions that might have interfered with drug absorption, distribution, 
metabolism or excretion. 
14. Any history of frequent nausea or emesis regardless of aetiology. 
15. Participation in any clinical drug study during the 3 months preceding the initial dose in this study. 
16. Use of any medication including vitamins, herbal and/or mineral supplements during the course of 
the study, other than Vitamin D, calcium supplements and continued use by females of 
contraceptive medication or HRT. 
17. Consumption of alcoholic beverages within 48 hours before study drug administration, and refusal to 
abstain from alcohol until at least 48 hours after the last study drug administration. 
18. Blood or blood products donated within 90 days prior to study drug administration or anytime during 
the study, except as required by this protocol.  
19. Positive results of urine drug screen(for opioids, barbiturates, amphetamines, cocaine metabolites, 
methadone, diazepam and cannabinoids), alcohol breath test, hepatitis B surface antigen (HBsAg), 
hepatitis C virus antibody (Ab),  human immunodeficiency virus (HIV) test or qualitative syphilis 
tests. 
20. Patients with moderate to severe hypohemia (HGB<90g/L during the screening). 
 
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Concomitant Therapy: 
Administration of medications (including vitamins, herbal and/or mineral supplements) other than the 
study drug will be prohibited from the start of the study to completion of the study, with the exception of 
Vitamin D, calcium supplements, continued use by females of contraceptive medication or HRT, and drug 
therapy for any adverse events that might develop.  
In case other medication was taken by the subject after during the study, the investigator should record 
that on the case report form, including the name of drug(s), dosage and administration, the duration of 
administration, and the reason for administration. 
Paracetamol or NSAID’s ibuprofen will be used as rescue medicine for patients who need the analgesic 
for pain relief. The maximum of Paracetamol allowed daily dose is 1.3g. The maximum of ibuprofen 
allowed daily dose is 1.2g. Ondansetron can be used before 30 minutes of study treatment, in the opinion 
of the investigator or the sub-investigator. If nausea, Ondansetron can be given at the discretion of the 
investigator after study treatment.Subjects will be withdrawn if they take any medicine affecting 
metabolism. 
 
 
Study Restrictions: 
During the study period, smoking, liquor, caffeine drinks and grapefruit juice will be prohibited. Acute 
exercise will also be prohibited during the study period. Study Restrictions (Food, Beverages, Alcohol, 
Caffeine and Smoking etc.) will be detailed in the full protocol for the study. 
 
Test Treatment, Dose, and Mode of Administration:  
Single dose: Oxycodone/naloxone PR tablet 5/2.5 mg (OXN 5/2.5), a PR combination tablet containing 
5 mg of oxycodone HCl and 2.5 mg of naloxone HCl; oxycodone/naloxone PR tablet 20/10 mg (OXN 
20/10), a PR combination tablet containing 20 mg of oxycodone HCl and 10 mg of naloxone HCl.  
One OXN tablet shall be administered orally, at Day 1 (0 h). 
OXN tablets are manufactured by Bard Pharmaceuticals Limited.  
 
Batch number: PN3787 (5/2.5mg)，PN3952 (20/10mg). 
 
Reference Treatment, Dose, and Mode of Administration: 
 Not applicable. 
 
 
Duration of Treatment:  
Screening is within 14 days before dosing on Day 1. There will be one study period. Subjects will be 
administered the study treatment on Day 1. Pharmacokinetic blood sampling and safety monitoring 
continued for up to 48 hours after dosing on Day 1. Subjects will have a post-study clinical evaluation at 
48 h (±2 h) after their OXN dose. 
Total duration of the study will be up to 17 days. 
Single dose: 
 
Screening and pre-dose examination: Day -14 to Day -2        
 
Treatment duration: Day1 (0 h) 
 
Safety Follow-up: Day 3 (48 h ± 2 h) 
 
 
Treatment Schedule: 
Each dose of OXN 5/2.5, OXN 20/10 will be given with 200 ml water to subjects in a standing position. 
 
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Criteria for Evaluation 
 
Analysis Populations: 
The enrolled population is defined as the group of individuals who provided informed consent. 
The safety population is defined as the group of subjects who received at least one dose of study drug, 
and had at least one post-dose safety assessment. 
The full analysis population for pharmacokinetic parameters is defined as the group of subjects who has 
at least one pharmacokinetic parameter post dose. 
 
Pharmacokinetic Measures:  
Blood samples for pharmacokinetic analysis will be taken as below schedule: 
Single dose: 
Pre-dose, 0.5h, 1.0h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 10h, 12h, 14h, 24h,28h,32h,36h,48h 
post dose. About 6 mL per sample. A total of 126 mL PK blood sample will be collected from each 
patient. 
 
Safety: Safety will be assessed using adverse events (through subject interview and spontaneous 
reporting), clinical laboratory results, vital signs, physical examinations, and ECGs. 
 
 
Bioanalytical Methods:  
The plasma samples will be analysed for oxycodone, noroxycodone, oxymorphone and noroxymorphone, 
and for naloxone, 6β-naloxol, naloxone-3-glucuronide, and 6β-naloxol-3-glucuronide using validated 
bioanalytical assays. 
 
 
Pharmacokinetics:  
Plasma concentrations of oxycodone, noroxycodone, oxymorphone and noroxymorphone, and for 
naloxone, 6β-naloxol, naloxone-3-glucuronide, and 6β-naloxol-3-glucuronide will be analyzed to 
determine the following pharmacokinetic parameters: AUC0-t, AUC0-inf, Cmax, tmax, Lambda_Z and t1/2 
and so on. 
 
 
Safety:   
Safety will be assessed using adverse events (through subject interview and spontaneous reporting), 
clinical laboratory results, vital signs, physical examinations, and ECGs. 
 
The adverse event will be reported according to MCPC procedures which will be mentioned in the full 
protocols. 
 
All SAEs will be reported to MCPC within 24 hours. Medical doctors / research nurses who will be 
involved in the study will be trained on how to report SAEs accordingly. MCPC will report the SAE to MRL 
within the timeline that has been required in PVA between MRL and MCPC. 
 
Final version 1.0, version date: 15 Oct 2013 
 
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Statistical Methods:   
Data will be tabulated, summarized, and plotted against time when appropriate.  
Descriptive statistics of PK parameters AUC0-t, AUC0-inf, Cmax, tmax, Lambda_z and t1/2 of oxycodone, 
noroxycodone, oxymorphone, and noroxymorphone as well as naloxone, 6β-naloxol, naloxone-3-
glucuronide, and 6β-naloxol-3-glucuronide shall be analyzed by treatment group (naloxone-3-glucuronide 
will be the major metabolite of naloxone). The dose-proportionality of oxycodone and naloxone, 
metabolites(AUC0-t, AUC0-INF and Cmax) will be analyzed using the linear mixed effect model (with 
treatment as the fixed term and subject as the random effect). 
 
Safety Analyses: All safety data (ie, adverse events, vital signs, and laboratory tests) will be listed by 
subject and dosage group. Results of the vital signs and laboratory tests that are outside the normal 
range will be identified on the listings. 
 
Sample Size Rationale: No formal sample size calculations will be performed. 24 subjects (12 in each 
dosage group) are regarded as sufficient according to CFDA regulation requirement. If subject withdraw 
from the study, subject replacement is needed. 
 
 
 
 
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                                                                                                                                          OXN08-CN-101 
4 TABLE OF CONTENTS 
 
Page 
1 TITLE PAGE ......................................................................................................... 1 
2 SIGNATURE PAGE FOR INVESTIGATOR.......................................................... 2 
3 PROTOCOL SYNOPSIS....................................................................................... 3 
4 TABLE OF CONTENTS ....................................................................................... 9 
5 LIST OF ABBREVIATIONS ................................................................................ 14 
6 ETHICS ................................................................................................................. 16 
6.1Independent Ethics Committee ........................................................................ 16 
6.2Ethical Conduct of the Study ........................................................................... 16 
6.3Subject Information and Consent .................................................................... 16 
7 INVESTIGATORS AND STUDY PERSONNEL .................................................... 16 
8 INTRODUCTION ................................................................................................. 17 
9 STUDY OBJECTIVES ........................................................................................ 17 
10 INVESTIGATIONAL PLAN ............................................................................... 18 
10.1Overall Study Design and Plan ...................................................................... 18 
10.1.1Screening Period（day-14today-2） ........................................................... 19 
10.1.2Treatment Phase .......................................................................................... 19 
10.1.2.1.Days -2- check-in ...................................................................................... 19 
10.1.2.2. Days -1– the day before OXN dosing ..................................................... 19 
10.1.2.3. Days 1– OXN dosing day ........................................................................ 19 
10.1.2.4. Days 2, 3 ................................................................................................... 19 
10.1.2.5. End-of-Study Procedures ....................................................................... 19 
10.2 Discussion of Study Design, Including Choice of Treatments and 
Appropriateness of Measurements ...................................................................... 19 
10.3 Selection of Study Population ....................................................................... 20 
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10.3.1Inclusion Criteria .......................................................................................... 20 
10.3.2Exclusion Criteria ......................................................................................... 20 
10.4 Study Methods ................................................................................................ 22 
10.4.1.Schedule of Visits and Procedures ........................................................... 22 
Table1. Schedule of Visits and Procedures/ CRF Modules (parameters in 
italics will be collected in the CRF) ....................................................................... 22 
Table 2: PK blood sampling schedule .................................................................. 23 
10.4.1.1Screening Period - Screening Visit (V1, Days -14 to -2) ......................... 24 
10.4.1.2. Days -2 - Day-1(Table1) ........................................................................... 24 
10.4.1.3. Days 1 ....................................................................................................... 24 
10.4.1.4. Days 2-3.................................................................................................... 25 
10.4.1.5. End-of-Study ............................................................................................ 25 
10.4.2 Pharmacokinetic Sample Collection .......................................................... 25 
10.4.3. Study Restrictions ...................................................................................... 25 
10.4.3.1. Food and Beverages ............................................................................... 25 
10.4.3.2. Alcohol, Caffeine, and Smoking Restrictions ....................................... 26 
10.4.4. Efficacy Assessments ............................................................................... 26 
10.4.5. Pharmacokinetic Measurements ............................................................... 26 
10.4.5.1. Drug Concentration Measurements ....................................................... 26 
10.4.5.2. Pharmacokinetic Metrics ........................................................................ 26 
10.4.6.Safety Assessments ................................................................................... 27 
10.4.6.1. Laboratory Measurements ...................................................................... 29 
10.4.6.2. Vital Sign and Weight Measurements .................................................... 29 
10.4.6.3. Medical History and Physical Examinations ......................................... 29 
10.4.6.4. Electrocardiograms (ECGs) .................................................................... 29 
10.4.7. Adverse Events (AEs) and Serious Adverse Events (SAEs) .................. 29 
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10.4.7.1. Reporting of Adverse Events ................................................................. 31 
10.4.7.2. Causality Assessment ............................................................................ 32 
10.4.7.3.Severity Assessment ............................................................................... 32 
10.4.7.4.Pregnancy ................................................................................................. 33 
10.4.7.5.Laboratory Abnormalities ........................................................................ 33 
Table3. Clinical Laboratory Tests ......................................................................... 33 
10.4.7.6.Vital Signs and Physical Examinations .................................................. 34 
Table4 Criteria Used to Identify Clinically Notable Vital Sign Abnormalities .... 34 
10.4.7.7.ECG Adverse Events ................................................................................ 34 
10.4.7.8.Other Safety Considerations/Risk Management .................................... 35 
10.4.8.Product Quality Complaint ......................................................................... 35 
10.4.8.1.Process ..................................................................................................... 35 
10.4.8.2. Contacting the sponsor about the product quality .............................. 36 
10.4.9. Completion/Discontinuation of Subjects ................................................. 36 
10.5. Treatments ..................................................................................................... 36 
10.5.1. Treatments Administered .......................................................................... 36 
10.5.2. Packaging, labeling and re-supply ........................................................... 36 
10.5.3. Drug Accountability ................................................................................... 36 
10.5.4. Method of Assigning Subjects to Treatment Sequences ....................... 37 
10.5.5. Removal of Subjects from Therapy or Assessment ................................ 37 
10.5.6. Dosing Schedule ........................................................................................ 38 
10.5.7. Method of Administration .......................................................................... 38 
10.5.8. Blinding ....................................................................................................... 38 
10.5.9. Concomitant Therapy ................................................................................ 38 
10.5.10. Treatment Compliance ............................................................................. 38 
10.6. Data Quality Assurance ................................................................................ 38 
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10.6.1. Data Collection ........................................................................................... 39 
10.6.2. Clinical Data Management ......................................................................... 39 
10.6.3. Bio-analytical Data Management and Quality Control ............................ 39 
10.7. Statistical Methods ........................................................................................ 39 
10.7.1. Statistical and Analytical Plans ................................................................. 39 
10.7.1.1. Analysis Populations .............................................................................. 39 
10.7.1.1.1. Demographic/Baseline Analyses ........................................................ 40 
10.7.1.1.2. Study Drug ............................................................................................ 40 
10.7.1.1.3. Concomitant Medications .................................................................... 40 
10.7.1.2. Pharmacokinetic Analyses ..................................................................... 40 
10.7.1.3. Safety Analyses ....................................................................................... 41 
10.7.1.3.1. Adverse Events .................................................................................... 41 
10.7.1.3.2. Laboratory Values ................................................................................ 41 
10.7.1.4. Vital Signs ................................................................................................ 41 
Table5. Reference Range for Vital Sign Values ................................................... 42 
10.7.1.5. ECG Changes .......................................................................................... 42 
10.7.2. Sample Size and Power Considerations .................................................. 42 
10.7.3. Interim Analysis .......................................................................................... 42 
11. PROCEDURES AND INSTRUCTIONS ............................................................. 42 
11.1. Ethics and Good Clinical Practice ............................................................... 42 
11.2. Subject Information and Informed Consent ................................................ 43 
11.3. Administrative Procedures ........................................................................... 43 
11.3.1. Changes to the Protocol ............................................................................ 43 
11.3.2. Adherence to the Protocol ......................................................................... 43 
11.3.3. Monitoring Procedures .............................................................................. 44 
11.3.4. Recording of Data ...................................................................................... 44 
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11.3.5. Retention of Records ................................................................................. 45 
11.3.6. Auditing Procedures .................................................................................. 45 
11.3.7. Handling of Study Drug ............................................................................. 45 
11.3.8. Publication of Results ................................................................................ 45 
11.3.9. Discontinuation of Study ........................................................................... 46 
12. APPENDICES .................................................................................................... 46 
12.1. Pharmacokinetic Sample Handling and Shipping ...................................... 46 
12.1.1. Sample Procurement and Processing ...................................................... 46 
12.1.2. Sample Transportation .............................................................................. 46 
13. REFERENCE LIST ............................................................................................ 47 
Figure 1:Flow diagram for AE reporting ............................................................... 49 
Figure2： Brief pain inventory – Short Form (BPI-SF) ........................................ 50 
 
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                                                                                                                                          OXN08-CN-101 
5 LIST OF ABBREVIATIONS 
OA 
Osteoarthritis  
AE 
Adverse Event 
ALT 
Alanine transaminase (also SGPT) 
AST 
Aspartate transaminase (also SGOT) 
MCPC 
Mundipharma (China) Pharmaceutical Co., Ltd. 
PUMCH 
Peking University Medical College Hospital 
AUCt 
Area under the plasma concentration-time curve calculated from the 
time of dosing to the last measurable concentration 
AUCINF 
Area under the plasma concentration-time curve calculated from the 
time of dosing to infinity 
Cmax 
Maximum observed concentration 
LambdaZ 
Terminal phase rate constant 
BMI  
Body mass index 
Bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CRA 
Clinical Research Associate 
CRF 
Case report form 
ECG 
Electrocardiogram 
DCF 
Data Clarification Form 
EDTA 
Ethylenediaminetetraacetic acid 
EC 
Ethics Committee 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl-transferase 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IMP 
Investigational Medicinal Product 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
CI 
Confidence Intervals 
mg 
Milligram 
Ml 
Millilitre 
LLN 
Lower limit of the laboratory reference (normal) range 
LNH 
Classification according to whether the Laboratory test result was 
below (L), within (N), or above (H) the reference range 
PR 
Prolonged Release 
RAS 
Random Allocation Schedule 
RBC 
Red blood cell (count) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimetre mercury 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event  
RBC 
Red blood cell (count) 
SOPs 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
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t1/2Z 
Apparent terminal phase half-life 
tmax 
Time from dosing to the maximum observed concentration 
ULN 
Upper limit of the laboratory reference (normal) range 
WBC 
White blood cell (count) 
WHO 
World Health Organisation 
WHO-DD 
WHO Drug Dictionary 
TEAE 
Treatment Emergent Adverse Events 
MRL 
Mundipharma Research Limited 
PVA 
Phamacovgilance Agreement 
Final version 1.0, version date: 15 Oct 2013 
 
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6 ETHICS 
 
6.1Independent Ethics Committee 
The protocol, any protocol amendments, the informed consent form (ICF) will be reviewed and 
approved by the study site’s local independent ethics committee (IEC) before subjects are 
screened for entry. Verification of the IEC unconditional approval of the protocol will be 
transmitted to the Sponsor or its designee prior to the shipment of drug supplies to the study site. 
6.2Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices of the Sponsor, 
which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required 
by the following: 
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. 
 
ICH Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of 
Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on 
Harmonization of Pharmaceuticals for Human Use. 
 
6.3Subject Information and Consent 
All subjects will be provided with oral and written information describing the nature and duration 
of the study and data protection details. Each subject will be given a copy of the ICF and written 
information, as applicable. The subject will be asked to sign an ICF prior to any study specific 
procedures being performed. A sample subject ICF, and information sheet, will be included in 
the clinical study report (CSR) for this protocol. 
 
This study will be conducted in accordance with national and local laws (e.g. China Regulation 
on the Control of Narcotic Drugs and Psychotropic Drugs). 
 
 
7 INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified Investigators under the sponsorship of Mundipharma 
(China) Pharmaceutical Co., Ltd at a Phase I study unit of Peking Union Medical College 
Hospital, Department of Clinical Pharmacology in China.  
Dr Hu Pei, (Department of Clinical Pharmacology) and Zeng Xiaofeng(Department of 
Rheumatology)will be the Principal Investigator. study management and monitoring will be 
responsible by the sponsor. 
The study will be coordinated and monitored by qualified personnel from Mundipharma (China) 
Pharmaceutical Co., Ltd. Pharmacokinetic analysis, Data management, statistical analyses and 
bioanalytical sample analysis will be the responsibility of Phase I unit, clinical Pharmacology 
researcher center, Peking Union Medical College Hospital. 
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8 INTRODUCTION 
Mundipharma Research GmbH & Co. KG and its independent associate companies (NPRL 
and Purdue Pharma L.P) are developing a novel analgesic in a prolonged release tablet 
dosage form that combines the opioid agonist oxycodone with the opioid antagonist naloxone. 
 
Oxycodone is an opioid analgesic available as a prolonged release formulation with indications 
ranging from moderate to severe pain.  
 
The naloxone component in the fixed combination is added to counteract opioid-induced 
constipation by blocking the action of oxycodone at opioid receptors locally in the gut. In addition, 
due to the presence of the opioid receptor antagonist, naloxone, OXN PR tablets may decrease 
abuse liability versus single-entity modified-release opioids when the tablets are crushed for 
injection, or intranasal administration. Opioid therapy is a mainstay in the management of 
chronic pain. Prolonged release opioids have been shown to be effective agents in pain 
management; however, the ability to properly titrate and treat pain with opioids can be limited by 
adverse events. Opioid-induced constipation, is a frequently occurring and often severe adverse 
event in patients treated for pain with opioid therapy. Current therapy recommends the 
administration of laxatives; however, many patients discontinue opioid therapy because of 
ongoing problems with opioid-induced constipation. It is therefore advantageous to minimize the 
development of constipation or to reduce its severity. In this strategy, the high first-pass effect of 
naloxone is regarded as an advantage: the improvement in bowel function can be accomplished 
through the local action of naloxone in the gut, while the analgesic activity of oxycodone is not 
antagonized due to the low systemic availability of naloxone. The results of all clinical studies 
conducted so far indicated that the administration of prolonged release oxycodone and naloxone 
in combination was not associated with clinically important differences in analgesic efficacy, 
provided a patient benefit in terms of relief of constipation and was well tolerated. 
 
 
A melt extrusion oxycodone/naloxone prolonged release tablet formulation with an oxycodone: 
naloxone ratio of 2:1. The two dose strengths to be used in this study are OXN5/2.5, and OXN 
20/10, in which the number before the slash is the milligram amount of oxycodone hydrochloride 
and the number after the slash is the milligram amount of naloxone hydrochloride. 
 
This study (OXN08-CN101) will investigate pharmacokinetics of oxycodone and naloxone from 
oxycodone/naloxone (OXN) prolonged release (PR) tablet 5/2.5 mg (OXN 5/2.5), 20/10 mg 
(OXN 20/10) in Chinese chronic non-malignant patients with moderate to severe pain. 
Additionally, the pharmacokinetic dose-proportionality of OXN 5/2.5 and OXN 20/10 will be 
investigated. 
 
9 STUDY OBJECTIVES 
The objectives of this study are to assess pharmacokinetics of oxycodone and naloxone from 
oxycodone/naloxone (OXN) prolonged release (PR) tablet 5/2.5 mg (OXN 5/2.5)and20/10 mg 
(OXN 20/10) in Chinese patients with moderate to severe chronic non-malignant pain. 
 
To determine the PK of oxycodone, naloxone and metabolites in chinese patients.  
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To assess, in a single dose investigation, the dose-proportionality of OXN. 
 
10 INVESTIGATIONAL PLAN 
10.1Overall Study Design and Plan 
It will be conducted to assess the pharmacokinetics of OXN 5/2.5 and OXN 20/10 tablets. 
Subjects will be allocated to a sequence of two strength group in accordance with a random 
allocation schedule (RAS) in a 1:1 ratio.  
 
Subjects will attend a screening visit within 14days of the first (OXN) dosing day (Day 1). 
Eligible subjects will then check into the study unit on the day before OXN dosing (Day -2). 
Subjects will be administered their OXN dose the next 2 morning (Day 1), following an overnight 
fast. 
 
There will be 24 subjects with moderate to severe chronic non-malignant pain enrolled in this 
single-dose study, to be comprised of males and females aged 18-65 years. Blood samples will 
be collected in tubes containing the anticoagulant EDTA pre-dose and up to 48 hours after 
administration of OXN. Subjects remain in the study unit up to 48+2 hours after OXN dosing. 
 
Vital signs (pulse, blood pressure, respiration rate) will be monitored pre-dose and then at 1, 2, 4, 
6, 8, 12, 24, 36, 48 hours after OXN dosing. Auxiliary temperature will be monitored pre-dose, 
24, 36, 48 hours after OXN dosing. 
 
AEs will be recorded throughout the study. Subjects will attend a post-study evaluation 48±2 
hours after OXN dosing (in the case of discontinuation from the study). 
 
 
Figure1. Study Diagram 
Single dose： 
 
 
Screening period: -day14 to -day2 
Treatment and sampling period: 2 days 
Group A:  oxycodone/naloxone PR tablet 5/2.5 mg, 1 tablet 
Group B:  oxycodone/naloxone PR tablet 20/10 mg, 1 tablet 
Post-study evaluation: 1 day 
 
-day14 to -day2         2days                   1day               
Screening         Treatment and sampling        Post-study evaluation 
 
R 
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10.1.1Screening Period（day-14today-2） 
Subjects will be screened within14 days before Day 1 of OXN dosing. Safety evaluations, as 
detailed in Section 10.4, will only be carried out after the subject signs the study-specific ICF, 
and eligibility criteria are met. 
 
10.1.2Treatment Phase 
Subjects will receive a single dose of OXN 5/2.5 mg or 20/10mg in this study period in 
accordance with the RAS. 
10.1.2.1.Days -2- check-in 
Subjects will report to the study unit on the day before 2 days of OXN dosing.  
10.1.2.2. Days -1– the day before OXN dosing  
BPI-SF evaluations will be performed in accordance with Table 1. Subjects will undergo drug, 
alcohol screening and safety assessment according to Table 1 and Section 10.4.1.2. (If 
screening visit and treatment day less than 7 days, do not duplicate the assessment completed 
on screening visit.) 
10.1.2.3. Days 1– OXN dosing day 
Subjects will receive a single dose of OXN on the morning of Days 1. Safety assessments and 
blood sampling for pharmacokinetics analysis will occur as detailed in Table 1 and Section 
10.4.1.3. 
10.1.2.4. Days 2, 3 
Subjects will remain in the study unit until the 48-hour procedures have been completed 
(morning of Day 3). They will then be discharged from the study unit. Safety monitoring and 
blood sampling for pharmacokinetic analysis will be carried out according to Table 1 and Section 
10.4.1.4. 
10.1.2.5. End-of-Study Procedures 
Subjects will attend a post-study evaluation 48±2 hours after OXN dosing (in the case of 
discontinuation from the study). Safety evaluations will be performed in accordance with Table 1 
and Sections 10.4.1.5. 
10.2 Discussion of Study Design, Including Choice of Treatments and 
Appropriateness of Measurements 
The blood sampling regimen has been designed in an attempt to adequately detail the 
pharmacokinetic profile of oxycodone, noroxycodone, oxymorphone, noroxymorphone, naloxone, 
6β-naloxol, naloxone-3-glucuronide, and 6β-naloxol-3-glucuronide. Based on earlier studies 
involving OXN, it is unlikely that the plasma concentrations of each of the analytes will be 
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sufficient to enable a quantitative pharmacokinetic analysis. Therefore, the primary focus will 
center on oxycodone and naloxone-3-glucuronide.  
 
The confidence intervals that will be calculated in this study relate to the (dose-corrected) ratios 
of AUC and Cmax (i.e. 20/10 vs 5/2.5 mg strengths).  
 
The study includes all the safety measures expected of a study in chronic non-malignant pain 
subjects. 
10.3 Selection of Study Population 
A total of 24 chronic non-malignant pain subjects, both male and female will be randomized to 
receive study medication with the aim that 24 subjects will complete the study and provide valid 
pharmacokinetic data. More subjects will be enrolled if the completed subjects are less than 12 
subjects in each group. 
 
10.3.1Inclusion Criteria 
Subjects who are to be included in the study are those who meet all of the following screening 
criteria: 
1. Adult Chinese patients with moderate to severe chronic non-malignant pain.  
2. Male and female subjects with age range 18 to 65 years, (including 18 and 65) body weight ≥ 
45kg and BMI range 18 to 30(including 18 and 30).  
3. Paitents who should rate their pain (Pain Intensity Scale -“average pain” over the last 24 
hours) as ≥4on 0-10 scale. 
4. Patients, who are able to read, understand and sign written informed consent prior to study 
participation and are willing to follow the protocol requirements.  
5. Females of childbearing potential and less than one year post-menopausal must have a 
negative serum pregnancy test during screening visit and at check-in and be non-lactating. In 
addition, they must be willing to use adequate and reliable contraception throughout the study. 
Highly effective methods of birth control are defined as those which result in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly such as sterilization, 
implants, injectables, combined oral contraceptives, some IUDs (intrauterine Device, 
hormonal), sexual abstinence or vasectomised partner. 
 
10.3.2Exclusion Criteria 
Subjects to be excluded from the study are those who meet any of the following criteria: 
1. Females who are pregnant (positive β-human chorionic gonadotrophin [HCG] test) or 
lactating. 
2. Use of opioid or opioid antagonist-containing medication in the 30 days before the start of 
the study. 
3. Known sensitivity to oxycodone, naloxone, or related compounds.   
.    
4. Subjects with clinically unstable respiratory disease, dysfunction of the biliary tract, thyroid 
disease, adrenal cortical insufficiency, prostatic hypertrophy requiring intervention 
(medication or surgical) or renal artery stenosis, or any other medical condition, that, in the 
opinion of the investigator or the sub-investigator, precludes entry into this study.   
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5. Subject who have a past (within 5 years) history of malignant neoplasm including leukemia 
and lymphoma.   
6. The electrocardiogram examination results are abnormal. 
7. Subjects with abnormal liver function (values exceed the upper limit of normal for AST, ALT 
or total bilirubin during the Screening Period) or abnormal renal function (values exceed the 
upper limit of normal for serum creatinine during the Screening Period).  
8. Patients with a contraindication to the study medication. 
9. Subjects who have a psychiatric disorder such that participation in the study may, in the 
opinion of the investigator or the sub-investigator, pose an unacceptable risk to the subject. 
10. Subjects who have a current or past (within 5 years) history of substance or alcohol abuse, 
or subjects who give a positive result in drug abuse test during the Screening Period, or 
subjects who, in the opinion of the investigator or the sub-investigator, have demonstrated 
addictive orsubstance abuse behaviors.   
11. Subjects with uncontrolled seizures or convulsive disorder.  
12.  Subjects who will receive any interventional therapy (surgery, paracentesis) for arthritis 
during the study period. 
13. History of or any current conditions that might have interfered with drug absorption, 
distribution, metabolism or excretion. 
14. Any history of frequent nausea or emesis regardless of aetiology. 
15. Participation in any clinical drug study during the 3 months preceding the initial dose in this 
study. 
16. Use of any medication including vitamins, herbal and/or mineral supplements during the 
course of the study, other thanVitamin D, calcium supplements and continued use by 
females of contraceptive medication or HRT. 
17. Consumption of alcoholic beverages within 48 hours before study drug administration, and 
refusal to abstain from alcohol until at least 48 hours after study drug administration. 
18. Blood or blood products donated within 90 days prior to study drug administration or anytime 
during the study, except as required by this protocol.  
19. Positive results of urine drug screen(for opioids, barbiturates, amphetamines, cocaine 
metabolites, methadone, diazepam and cannabinoids), alcohol breath test, hepatitis B 
surface antigen (HBsAg), hepatitis C virus antibody (Ab), human immunodeficiency virus 
(Anti-HIV) test or qualitative syphilis tests. 
20. Patients with moderate to severe hypohemia (HGB<90g/L during the screening). 
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10.4 Study Methods  
10.4.1.Schedule of Visits and Procedures 
Table1. Schedule of Visits and Procedures/ CRF Modules (parameters in italics will be collected in the CRF) 
Phase 
Pre-
treatment
Treatment 
 
Visit Name and Number 
Screening 
Study Period 
Pre-study 
medical1 
Day 
Within 
14days  
Day 
-2 
Day 
-1 
Day1 
Day 
2 
Day 
3 
3 days after 
OXN dosing  
Hours 
within-336  
Check 
-in 
 
 
Pre- 
dose 
 
0 
0.5 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
7 
8 
10 
12 
14 
24 
28 
32 
36 
48 
48±2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography & BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X(weight) 
Inclusion/Exc. Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. history & current Med condition 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Adverse Events3 
X 
x 
X X 
 
X 
X X 
X X 
X X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X-ray(in the opinion of the 
investigator) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Therapy 
X 
x 
X 
X 
 
X 
X X 
X X 
X X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Haematology, Blood, Chemistry, 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Virology5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
β-hCG Pregnancy Test6 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Drug, Alcohol Breath Test 
X 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OXN Dosing 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPI-SF7 
X 
 
 X-X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
X-X 
X 
 
Blood Samples 
 
 
 
See Table 2 for blood sampling schedule 
 
Discharge from study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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1. 
Post-study evaluation 48±2 hours after OXN dosing (in the case of discontinuation from the study). 
2. 
Pulse rate, respiration rate, blood pressure. Axillary temperature will be recorded at pre study screening, pre-dose, at 24, 36, 48 hours post-dose. 
3. 
AEs will be recorded from the time a subject provides their informed consent at screening until 3 days after OXN dosing. Throughout the study, subjects will be asked to volunteer AEs to investigators.  
4. 
Full physical examinations will be carried out at screening and at post-study evaluation. (or new AE happens). 
5. 
Anti-HIV, HBsAg, Hepatitis C antibody,hepatitis B core antigen (anti-HBc), qualitative syphilis test. 
6. 
Serum β-HCG pregnancy test at screening and check-in (Serum FSH for more than one year postmenopausal females), urine pregnancy test at post study(except females who confirmed by 
Serum FSH). (If necessary, in the opinion of the investigator or the sub-investigator, Female using IUDs  will receive a pelvic ultrasound, to confirm the location of the IUDs.) 
7. 
Brief Pain Inventory- Short Form (BPI-SF) (Cleeland, 1991) will be assessed at pre-dose,1h,2h,3h,4h,6h,8h,10h,12h,14h on day1, and BPI-SFwill be assessed at the same time point on day-1 and day2 . 
In addition to the first inquiry of each morning, subjects only need to answer the BPI-SF. 
8. 
If screening visit and treatment day less than 7 days, do not duplicate the assessment completed on screening visit. 
 
 
 
Table 2: PK blood sampling schedule 
Phase  
Treatment 
 
Day 
1 
2 
3 
Hour 
Pre-dose 
0.5 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
7 
8 
10 
12 
14 
24 
28 
32 
36 
48 
Blood Sampling (6 mL) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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10.4.1.1Screening Period - Screening Visit (V1, Days -14 to -2) 
The following evaluations will be performed after the subject signs the study specific informed 
consent form: 
• 
Inclusion/exclusion criteria 
• 
Demography 
• 
Body Mass Index (BMI) 
• 
Medical history 
• 
Physical examination 
• 
12-lead ECG 
• 
X-ray(if any, in the opinion of the investigator or the sub-investigator, X-ray may be arranged 
to confirm the damage of jonit. ) 
• 
Vital signs (supine blood pressure, supine respiration rate, supine pulse rate, axillary 
temperature, height, and weight) 
• 
Urine drug (opioids, barbiturates, amphetamines, cocaine metabolites, methadone, 
diazepam and cannabinoids), alcohol breath test 
• 
Haematology, blood biochemistry, and urinalysis 
• 
Virology (Anti-HIV, HBsAg, Hepatitis C antibody, Anti-syphilis test) 
• 
Serum β-hCG pregnancy test for females of child-bearing potential (Serum FSH for more 
than one year postmenopausal females.If necessary, in the opinion of the investigator or 
the sub-investigator, Female using IUDs  will receive a pelvic ultrasound, to confirm the 
location of the IUDs.) 
• 
Concomitant therapy 
 
10.4.1.2. Days -2 - Day-1(Table1) 
• 
Subjects will be provided with meals and snack, to be eaten. 
• 
Inclusion/exclusion criteria will be verified at check-in. Subjects will be asked how they have 
been feeling since their last visit, whether they have taken any prescribed or over the-
counter medications, or any vitamins or mineral supplements or herbal products since their 
screening visit, and whether they have abstained from alcohol during the previous 2 days 
(within 48 hours before the scheduled study drug dosing). 
• 
Subjects will provide a urine sample for a test of drugs of abuse and a breath test for 
alcohol. The results for all of these tests must be negative prior to study drug dosing. 
• 
Subject will be randomized to treatment. 
• 
BPI-SF 
• 
Subjects must begin fasting >8 hours prior to OXN dosing. 
• 
Subjects must follow the restrictions detailed in Sections 10.4.3 throughout the study. 
 
10.4.1.3. Days 1 
• 
Vital signs will be obtained pre-dose and a brief medical assessment will be performed, as 
applicable. 
• 
A venous blood sample (6mL) will be drawn from each subject pre-dose for the 
determination of baseline oxycodone, naloxone, and metabolites plasma concentrations. 
• 
Study drug will be administered to each subject according to Section 10.5. 
• 
Subjects will remain in a semi-supine position for 4 hours after they have received their 
dose of OXN.(except go to bathroom or other activities related on the study) 
• 
Pharmacokinetic blood samples (6mL) will be obtained as specified in Table 1 and Section 
10.4.2. 
• 
BPI-SF 
• 
Vital signs will be obtained post-dose according to Table 1 and Section 10.4.6.2. 
• 
Safety will be monitored as specified in Table 1 and Section 10.4.6&10.4.7. 
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• 
Food and beverages will be provided in accordance with Section 10.4.3.1. 
 
10.4.1.4. Days 2-3 
• 
Blood samples (6 mL) for pharmacokinetic analysis will be obtained as specified in Table 1 
and Section 10.4.2. 
• 
BPI-SF 
• 
Vital signs will be obtained according to Table 1 and Section 10.4.6.2. 
• 
Safety will be monitored as specified in Table 1 and Section10.4.6&10.4.7. 
• 
Food and beverages will be provided in accordance with Section 10.4.3.1. 
 
10.4.1.5. End-of-Study 
Subjects will attend a post-study evaluation 48±2 hours after OXN dosing, 48±2 hours after OXN 
dosing in the case of discontinuation from the study. The following safety evaluations will be 
carried out: 
• 
review of adverse events  
• 
review of concomitant therapy  
• 
physical examination 
• 
12-lead ECG 
• 
vital signs (supine blood pressure, supine pulse rate, respiration rate, axillary  temperature 
and weight) 
• 
hematology, biochemistry, and urinalysis 
• 
Urine  pregnancy test (female subjects except post menopausal females confirmed by 
Serum FSH) 
• 
Subjects will be discharged after the 48-hour procedures are completed. 
 
10.4.2 Pharmacokinetic Sample Collection 
Beginning on Days 1 serial blood collections (6 mL each) will be obtained at the following times: 
at baseline (0 h; within 30 minutes prior to OXN dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 
6,7,8, 10, 12, 14, 24, 28, 32, 36, 48 hours after OXN dosing. In total there will be 126 mL blood 
taken for pharmacokinetic analysis. 
 
10.4.3. Study Restrictions 
10.4.3.1. Food and Beverages 
Menus will be standardized while subjects are inpatients in the study unit. The menus will follow 
the arrangement of study unit. However, the menus for each day need not be identical. Subjects 
must consume only the food given to them while in the unit. Food and water will be restricted as 
follows: 
 
• 
Days -2 (check-in) - Subjects will be given meals and snack following check-in to the study 
unit on 2 day before OXN dosing. They will fast (only water is permitted) for at least 8 hours 
prior to OXN dosing. 
• 
Days 1(dosing) - Subjects will fast (only water is permitted) for at least 4 hours after OXN 
dosing. Subjects will also have restricted fluid (200 mL water at time of OXN dosing) from 1 
hour before OXN dosing until 1 hour after OXN dosing. From 1 hour after OXN dosing there 
will be free access to drinking water throughout the day, except within 30 minutes before 
vital sign measurements. A low fat lunch (<30% fat), dinner, and an evening snack will be 
provided at 4, 10, and 14 hours after OXN dosing. Drinks of decaffeinated tea or 
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decaffeinated coffee will be supplied with meals (if any). 
• 
Day 2: Breakfast will be provided 24 hours after OXN dosing. Lunch, an evening meal, and 
a snack will be provided 28, 34, and 38 hours after OXN dosing, respectively. There will be 
free access to drinking water throughout the day, except within 30 minutes before vital sign 
measurements. 
• 
Days 3 (discharge) - Breakfast will be optional after all study procedures have been 
completed. 
 
10.4.3.2. Alcohol, Caffeine, and Smoking Restrictions 
Subjects must abstain from alcohol for 48 hours before they check in to the study unit for each 
study period. Caffeine or 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. 
 
10.4.4. Efficacy Assessments 
Not investigated. 
 
10.4.5. Pharmacokinetic Measurements 
10.4.5.1. Drug Concentration Measurements 
Blood samples for determining analyte concentrations will be obtained for each subject during 
the period; pre-dose (within 30 minutes before OXN dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 
6,7, 8, 10, 12, 14, 24, 28, 32, 36, 48 hours (21 blood samples per study period) after OXN 
dosing. Blood will also be drawn, where appropriate, at the first report of a serious or severe 
unexpected adverse event and at its resolution.  
 
At each time of blood sampling, 6mL venous blood will be drawn from a forearm vein into a tube 
containing K2 EDTA anticoagulant. All samples should be processed according to the sample 
handling procedures described in Appendix 12.1.1. 
 
10.4.5.2. Pharmacokinetic Metrics 
In case of no protocol deviation during the trial which affects PK endpoint variables (such as 
AUC and Cmax) (such as missing doses), all subjects will be included in the PK analysis set.  
 
The following PK parameters shall be calculated using the non-compartment analysis method 
within the software Phoenix WinNonlin 6.3 (Pharsight Corp., Mountain View, CA, USA).  
 
Parameters 
Definitions  
Calculation methods  
AUC0-inf 
The area under the plasma 
concentration-time 
curve 
from time 0 to infinity  
AUC0-inf 
=AUC0-t+(Clast/Lambda_z), 
where 
Clast is the corresponding blood concentration 
at the last measurable time point Tlast.  
AUC0-t 
The area under the plasma 
concentration-time 
curve 
from time 0 to the last 
Linear/ log trapezoidal method  
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measurable 
concentration 
(Clast)  
Cmax 
Maximum 
plasma 
concentration  
It shall be obtained directly from observation 
data.  
Lambda_z 
Elimination rate constant [1/ 
hr]  
The 
elimination 
rate 
constant 
shall 
be 
calculated using the linear regression of log-
linear concentration-time curve. The time point 
can be included only if corresponding linearity 
decreases.  
T1/2 
Half-life of elimination [hr]  
T½=ln(2)/Lambda_z. The time point can be 
included 
only 
if 
corresponding 
linearity 
decreases.  
Tmax 
Time 
to 
peak 
blood 
concentration [hr]  
Time to peak blood concentration present for 
the first time on the time axis shall be obtained 
from observation data.  
AUC_%Extrap The 
percentage 
AUC 
extrapolated [%]  
The percentage of area under the plasma 
concentration-time 
curve 
from 
the 
last 
measurable concentration time point after 
dosing t to infinity in AUC0-inf  
 
 
Descriptive statistics of PK parameters of oxycodone and its metabolites (noroxycodone, 
oxymorphone and noroxymorphone), naloxone and its metabolites (naloxone, 6β-naloxol, 
naloxone-3-glucuronide, and 6β-naloxol-3-glucuronide) shall be analysed by dose group. The 
descriptive statistics includes mean, standard deviation, coefficient of variation, minimum and 
maximum (geometric mean shall be indicated, if any).  
 
The mean (Mean ± SD) concentration-time curves of oxycodone and its metabolites 
(noroxycodone, oxymorphone and noroxymorphone), naloxone and its metabolites (naloxone, 
6β-naloxol, naloxone-3-glucuronide, and 6β-naloxol-3-glucuronide) shall be drawn by dose 
group.  
 
The dose-proportionality of oxycodone and naloxone, metabolites (AUC0-t, AUC0-INF and Cmax) 
will be analysed using the linear mixed effect model (with treatment as the fixed term and 
subject as the random effect). 
 
10.4.6.Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs and Serious Adverse 
Events (SAEs); pre-study and post-study haematology, blood chemistry, urine values, and 
ECGs; regular measurement of vital signs, and physical examinations. 
 
During the study period, subjects must be monitored while they are in the study unit, by the 
study unit staff. The Investigator or Co-investigator must remain in the study unit for at least 8 
hours after dosing and during normal working hours, for each study period. 
 
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Throughout the study, subjects will be reminded to immediately report AEs experienced during 
the study to the medical staff. These will be recorded in the CRFs and reported according to 
Sections 10.4.7. 
 
Throughout the study, if any vital sign falls outside the normal range and is considered 
potentially clinically significant or clinically significant, it will be repeated. If the value remains 
outside the normal range and is considered clinically significant by the Investigator, or Co-
investigator, the event will be recorded in the AE section of the CRF. If appropriate, the subject’s 
further participation in the study should be discussed with the CRA or Medical Monitor at the 
Sponsor. As at any time during the study, if the Investigator considers that continuation in the 
study is not in the subject’s best interests, the subject will be discontinued from the study. If the 
Investigator or Co-investigator considers the result not to be of clinical significance, the subject 
may continue in the study and an explanation will be recorded in the source data. 
 
If the subject is discontinued from the study, the full details should be conveyed to the CRA 
immediately (see Section 10.4.7.1 for details relating to the reporting of AEs). 
 
 
Safety assessments will be recorded from the point at which the Informed Consent is signed. 
These will consist of: 
• 
monitoring and recording all adverse events (AEs) and serious adverse events (SAEs), 
observed or volunteered, regardless of treatment group or suspected causal relationship 
to the IMP. This includes reactions, interactions, accidents, illnesses, misuse and abuse.   
Day 1 
• 
Pre-dose vital signs (supine blood pressure, supine pulse rate, respiratory rate, and axillary 
temperature). 
• 
Pre-dose medical evaluation to confirm suitability for dosing. 
• 
Post-dose vital signs (supine blood pressure, supine pulse rate, respiratory rate，and) at 1, 
2, 4, 6, 8 and 12 hours. 
Day 2 
• 
Vital signs (supine blood pressure, supine pulse rate, respiratory rate) at 24, and 36 hours. 
• 
Axillary temperature will be recorded at 24 and 36 hours. 
Day 3 
• 
Vital signs (supine blood pressure, supine pulse rate, respiratory rate) at 48 hours. 
• 
Axillary temperature will be recorded at 48 hours. 
• 
Medical evaluation at 48±2 hours after dosing. 
 See Table 1 for the timing of safety evaluations during the study period: 
 
The obligations and responsibilities with regards to collection, distribution and onward reporting 
of adverse events and reactions to the appropriate regulatory bodies, committees and other 
investigators will be carried out in accordance with local regulations and are documented in a 
separate Safety Plan.   
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10.4.6.1. Laboratory Measurements 
Clinical laboratory tests during the pre-study and post-study will be performed by a local 
laboratory. Laboratory certification as available will be included in the clinical study report for this 
protocol. 
Table 1presents the clinical laboratory tests to be performed. 
 
10.4.6.2. Vital Sign and Weight Measurements 
Vital sign measurements (blood pressure [systolic blood pressure, diastolic blood pressure], 
pulse rate, respiration rate, and axillary temperature) will be obtained at the visits designated on 
the Schedule of Visits and Procedures (Table 1). Blood pressure and pulse will be measured 
after the subject has been supine for 3 minutes. Weight will be recorded pre and post-study. 
 
10.4.6.3. Medical History and Physical Examinations 
Medical history will be taken at screening. Physical examinations will be performed at the pre 
study and post-study. Documentation of the physical examination will be included in the source 
documentation at the investigational site. Significant findings prior to the start of study drug will 
be recorded on the Medical History and Current Medical Conditions CRF. Only changes from 
screening physical examination findings that meet the definition of an adverse event will be 
recorded on the Adverse Events CRF. Medical evaluations will be performed prior to study drug 
administration and 48±2 hours after dosing. 
 
10.4.6.4. Electrocardiograms (ECGs) 
The 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be obtained at the visits designated on 
the Schedule of Visits and Procedures (Table1). ECGs will be performed after the subject has 
been supine for 3 minutes. The ECGs will be evaluated by the study investigator or a designate. 
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional ECGs 
may be collected by the investigator for safety reasons. Clinically relevant abnormal findings will 
be reported as adverse events. 
 
ECG recordings will be made at the following time points: 
• 
At the screening 
• 
At the end-of-study 
 
10.4.7. Adverse Events (AEs) and Serious Adverse Events (SAEs) 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical trial subject 
who is administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment.   
An AE can be:   
• 
Any unfavourable and unintended sign/syptom (including reactions from overdose, 
abuse, incorrect use of any treatment, or interaction) 
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• 
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 IMP 
• 
Recurrence of an intermittent medical condition (e.g. headache) not present at baseline 
• 
Other medical events regardless of their relationship to the IMP, such as accidents, falls 
and any injuries resulting from them. 
 
A Serious Adverse Event (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 IMP) 
 
is a medically important event or reaction. 
Assessment of medically important events: 
The Investigator must check the list of Important Medical Events (supplied in the Investigator 
Site File) to determine whether criteria for a SAE is met.  Additionally, any event not on this list, 
but that the Investigator determines 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 Investigator 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 
- AE 
- IMP(s) 
- Investigator's name and contact details 
Causality assessment should be completed 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 Investigator Site File. 
The medical safety of the subject is of paramount importance when discussing study continuation.   
 
10.4.7.1. Reporting of Adverse Events 
See also SAE flow chart in Appendix Figure1.   
Reporting period – Events will be recorded from the point at which the Informed Consent is 
signed until 7(+3) days after the subject leaves the study.  This includes new AEs that are 
reported in the 7(+3) days following the subject’s completion/discontinuation visit.  Any AE that is 
still ongoing 7(+3) days after the completion/discontinuation visit will have an outcome of 
‘ongoing’ in the CRF, however the Investigator 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 adverse 
events if they are known to have started or are suspected to have started after the subject has 
signed the informed consent form.  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 the informed consent 
and the date/time of the physical examination. 
If the Investigator becomes aware of a SAE after the completion of the study [after the 7(+3) 
days follow up period], which may have been caused by an IMP or NIMP used in the study, they 
should immediately(within 24 hours)report it to the Sponsor by phone, fax or e-mail.  
Screen failures - For subjects who are screen failures, AEs will be recorded on the AE Screen 
Failure Log.  
For subjects who receive at least one dose of study medication - All AEs will be collected on the 
AE section of the CRF.  In addition, a note should be made in the source documentation of the 
subject.   
SAE - All SAEs will be collected on the AE section of the CRF and flagged as serious. The 
invwstigator should complete a seperate paper SAE Data Form and forward to the sponsor 
within 24 hours any information related to onset of SAEs in the subjects participating in the study. 
Investigators should evaluate the relevance of every SAE case with the investigated drug.  
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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. 
Contact - The drug safety commissioner’s contact phone number/fax number and email address 
will be stored in the Investigator Site File.  Questions relating to Drug Safety and 
Pharmacovigilance should be addressed to this number or e-mailed. 
 
10.4.7.2. Causality Assessment 
The question of the relationship of an AE to the IMP should be determined by the Investigator 
after thorough consideration of all facts that are available. 
Assessment of causality is based on 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 Investigator will be asked if a reasonable possibility of a causal relationship to the IMP 
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. 
Please note that the causality assessment of adverse events in the CRF only relates to the 
IMP(s) named in section13.1.  
If an AE is related to a non-investigational medicinal product or concomitant therapy only, and 
not an interaction or effect of the IMP,the causality assessment will be “No” (no reasonable 
possibility of a causal relationship to IMP). 
 
10.4.7.3.Severity Assessment 
The Investigator (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 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. 
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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 adverse event will not necessarily be a serious adverse event. 
Any medication necessary for the treatment of an adverse event must be recorded on the 
Concomitant Therapy Section of the CRF (and, if applicable, on the SAE Data Form). 
 
10.4.7.4.Pregnancy 
Pregnancy occurring in a subject (or his partner) enrolled in the trial must be reported to the 
investigator, who will forward it  to the drug safety specialist of Mundipharma (China) 
Pharmaceutical Co., Ltd. within 24 hours using the paper Pregnancy Notification Form. The 
sponsor will contact the investigator to confirm significant pregnancy-related information (i.e., 
AEs during pregnancy, the pregnancy outcome, and any events to 3 months post-partum). All 
follow up information about the pregnancy will also be reported to the drug safety specialist of 
Mundipharma (China) Pharmaceutical Co., Ltd. within 24 hours. 
  
10.4.7.5.Laboratory Abnormalities 
All clinical laboratory tests will be performed by a local laboratory. 
Table 2 presents the clinical laboratory tests to be performed. 
Table3. Clinical Laboratory Tests 
Category Parameters 
                                                                              
Category                                      Parameters 
                                                                                
Haematology           RBC, hemoglobin, hematocrit, platelets, and WBC with 
differential(neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Chemistry                                      Electrolytes Sodium, potassium, chloride, bicarbonate 
 
Liver function tests                        alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), total bilirubin, direct bilirubin, 
gamma glutamyl transferase (GGT) 
Renal function parameters            blood urea, creatinine 
Other                                             Glucose (fasting), calcium, albumin, cholesterol, 
triglycerides,phosphorus, lactate dehydrogenase (LDH), total 
protein, uric acid 
Urinalysis                                      pH, protein, glucose, ketone, occult blood, specific gravity 
Urine microscopy (if required)      RBC, WBC, casts, crystals 
                                                              
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply: 
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• 
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 Investigator, 
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 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 
document in the source notes (e.g., normal fluctuation of the disease). 
 
10.4.7.6.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 Investigator as clinically significant  
• 
and/or meets the clinically notable abnormal criteria (see table 3 ). 
Table4 Criteria Used to Identify Clinically Notable Vital Sign Abnormalities 
Vital Sign Parameter 
Value 
Change From Baselinea 
Systolic blood pressure 
≥ 180 mmHg 
Increase of ≥ 20 mmHg 
 
≤ 90 mmHg 
Decrease of ≥ 20 mmHg 
Diastolic blood pressure 
≥ 105 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 
< 8 breaths/minute 
- 
 
> 24 breaths/minute 
- 
aBoth value and change from baseline criteria must be met to qualify as a clinically 
notable vital sign abnormality. 
 
10.4.7.7.ECG Adverse Events 
A simultaneous 12-lead resting ECG will be obtained both during the Screening  Phase and the 
end of the study.  For consistency, the same physician should read all ECGs from one subject. 
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Abnormal test findings as judged by the Investigator as clinically significant should be recorded 
as AEs. 
 
10.4.7.8.Other Safety Considerations/Risk Management 
Preventable medication errors related to  an IMP which occur at the time of drug’s 
administration are a potential safety issue and must be reported immediately(within 24 hours) 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 the study supply 
into mainstream hospital supplies.  Adverse events in persons (other than the subjects 
enrolled in the study) after drug diversion will be entered into 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(within 24 
hours) to the Sponsor. 
 
10.4.8.Product Quality Complaint 
Product quality complaint means any suspicion of product fault related to the production, 
labeling or packaging(including dissatisfaction about reliability of product characteristics, quality, 
duration, labeling and package integrity). A product quality complaint may possibly influence 
both product safety and treatment administered to subjects enrolled in the study. Hence,it is of 
great importance to protect subjects, researchers and other involved personnel by reporting and 
analyzing any product quality complaint information in a timely and accurate manner, as 
approved by the world supervision organization.  
 
10.4.8.1.Process 
As long as obtaining product quality complaint events, the investigator should report product 
complaint events information to the sponsor immediately (within 24 hours).  
As for serious product quality complaints caused by product’s fault or serious adverse events, the 
investigators must report them to the sponsor within the timeline of seriously adverse event (please 
refer to section10.4.7.1). If required by the sponsor, a sample of the doubtful product must be saved 
for further investigation. 
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10.4.8.2. Contacting the sponsor about the product quality 
The name (and contact details ) of the sponsor’s representative to be contacted in case of any 
product quality complaint are listed in the contact information page; such information is provided 
as independent document.  
 
10.4.9. Completion/Discontinuation of Subjects 
When a subject completes the study or discontinues from the study, the end-of-study 
procedures will be followed and protocol-specified information will be collected. However, a 
subject may elect to discontinue from the study at any time for safety or personal reasons. The 
Completion/Discontinuation page of the CRF will be completed accordingly. 
 
10.5. Treatments 
10.5.1. Treatments Administered 
The treatments administered in this study are presented below: 
Test treatments 
Oxcodone/Naloxone PR tablets 5/2.5 (OXN 5/2.5) and Oxcodone/Naloxone PR tablets 
20/10(OXN 20/10). 
The randomization for medication numbers will be generated by MCPC. 
Subjects will be randomly assigned to Treatment A or Treatment B before thefirst administration 
of the study drug on Day 1. The treatment will be administered orally as follows: 
Treatment A: one tablet of OXN 5/2.5 in a fasted state 
Treatment B: one tablet of OXN 20/10 in a fasted state 
 
10.5.2. Packaging, labeling and re-supply 
Drug supplies will be provided by MCPC. The clinical trial supply consists of containers with trial- 
and centre identification that hold the trial medication. The study medications will be contained in 
a specific medication pack. Each medication pack will contain an appropriate amount of drug (in 
blister wallet cards) for dosing. The clinical supplies will be labelled with the following as 
appropriate: 
• Study number 
• Name of product and strengths or identification code 
• Pharmaceutical dosage form, quantity of dosage units 
• Directions for use(for clinical trial use only) 
• Caution Statement 
• Sponsor name and address 
• Storage conditions 
• Expiry date 
• Number of batch 
Label examples are given in the Investigator Site File (ISF). 
All drug supply(including unused and partially used study medication )will be fully accounted for. 
Unused study medication will be returned to sponsor for destruction. 
 
10.5.3. Drug Accountability 
The Investigator and study staff will be responsible for the accountability of all clinical supplies 
(dispensing, inventory and record keeping) following Sponsor’s instructions and adherence to 
GCP guidelines as well as China Regulation on the Control of Narcotic Drugs and Psychotropic 
Drugs. 
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Under no circumstances will the Investigator allow the study drug 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, dispensing of study drug to 
the subject, collection of unused supplies returned by the subject, and subsequent return of 
unused study drug to the Sponsor must be maintained. This includes, but may not be limited to: 
(a) documentation of receipt of clinical supplies  
(b) study drug dispensing/return reconciliation log 
(c) study drug accountability log 
(d) all shipping service receipts.  
All forms will be provided by the Sponsor. Any comparable forms that the investigational site 
wishes 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, a 
representative of the CFDA. All unused study drug, including empty containers, are to be 
returned to the Sponsor at the conclusion of the study, unless provision is made to the Sponsor 
for destruction of supplies and containers at the investigational site. 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 must be 
sealed with tamper-evident seals and shipped back to the Sponsor following all local regulatory 
and shipment laws. 
 
PUMCH must retain samples when bioavailability/ bioequivalence testing has been performed 
under contract with a sponsor. Retained samples will retain according to PUMCH’s lab related 
Sops, which states that each reserve test drug and reference standard sample will 
• 
consist of a sufficient quantity to permit CFDA to perform all the release test standards 
required in the application five (5) times, 
• 
 be adequately identified so the reserve samples can be positively identified as having come 
from the same samples as used in the bioavailability/bio-equivalency studies, 
• 
be stored under conditions that will maintain the samples' integrity, identity, strength, quality 
and purity, and be retained for at least five years following the date on which the application 
or supplemental application is approved, or, if the application is not approved, at least five 
years following the date of completion of the bioavailability/bioequivalence study. 
 
10.5.4. Method of Assigning Subjects to Treatment Sequences 
Subjects will be assigned to treatment using a pseudo-random number generator in a computer 
program. The method avoids bias by using a chance mechanism. The randomization scheme 
and identification for each subject will be included in the CSR for this protocol. 
 
10.5.5. Removal of Subjects from Therapy or Assessment 
The Investigator(s) or subjects themselves may decide to stop the study treatment at any time 
for safety or personal reasons. If appropriate, a subject who discontinues from the study 
treatment will be monitored for subsequent protocol-specified safety procedures. A subject that 
discontinues from the study for any reason may be replaced at the discretion of the Sponsor. To 
keep the completed subjects are at leat 12 subjects in each group. 
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10.5.6. Dosing Schedule 
This study is an open-label design, and each subject will receive 1 tablet of OXN 5/2.5 or OXN 
20/10 according to the RAS prepared by a computer program. 
 
10.5.7. Method of Administration 
Each dose of OXN will be given with 200 mL water to subjects in a standing position.  
The oral cavity will be checked by the study site personnel to ensure that the dose has been 
swallowed. 
 
10.5.8. Blinding 
Not applicable. 
 
10.5.9. Concomitant Therapy 
For subjects who receive the study drug, any concomitant medications(including over-the 
counter medications) and therapies that are ongoing as of the date of the informed consent will 
be recorded on the Concomitant Therapy CRFs and must be approved by the sponsor. 
Administration of medications other than the study drug will be prohibited from the start of the 
study to completion of the study, with the exception of Vitamin D, calcium supplements, 
continued use by females of contraceptive medication or HRT.and drug therapy for any adverse 
events that might develop. The Investigator will record the adverse event for which the 
concomitant medication was administered on the Adverse Events CRF. 
 
Paracetamol or NSAID’s ibuprofen will be used as rescue medicine for patients who need the 
analgesic for pain relief. Maximum allowed daily dose of paracetamol is 1.3g. Maximum allowed 
daily dose of ibuprofen is 1.2g. 
 
Ondansetron can be used before 30 minutes of study treatment, in the opinion of the 
investigator or the sub-investigator. If nausea, Ondansetron can be given at the discretion of the 
investigator after study treatment.Subjects will be withdrawn if they take any medicine affecting 
metabolism. 
 
Female subjects who require prescription of HRT or contraceptives will continue their medication, 
in accordance with their primary care physician’s instructions, throughout the study. 
 
10.5.10. Treatment Compliance 
Records of study drug and doses administered will be kept for the whole duration of the study. 
The CRAs will review drug accountability the during investigational site visits and at  when the 
study is completed. 
 
10.6. Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines. Site visit audits may be 
made periodically by the Sponsor’s qualified compliance auditing team, which is an independent 
function from the study conduct team. 
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10.6.1. Data Collection 
Promasys ® system will be used to design electronic CRF and database in accordance with the 
study protocol. Data administrators will responsible for develop data management plans. 
Investigator will enter source data according SOP. There is a one-to-one relationship between 
source data and CRF. Investigator will enter required information source documents. When a 
discrepancy results in corrected source data, data that is corrected will be struck through with a 
single line, initialed, and dated. The completed original CRF researchers will be stored by 
investigator for 5 years and then transfer to the sponsor. 
 
10.6.2. Clinical Data Management 
The internal quality control of entered and collected Source documents will be apply to ensure 
validity and accuracy of the clinical database. Data will be entered using the dual independent 
entry by investigators or authorized investigators, electronic data from the central laboratory will 
be input using SAS® Programming, to ensure the reversibility of source data. CRAs will visit 
investigational site as frequently as documented in the monitoring plan to review the CRFs for 
completeness and accuracy against the source documents, the data administrator will verify the 
validity and accuracy of data after double entry and data input. CRA and data administrator can 
get into a dispute with the data of eCRF, investigator responsible for query answering and /or 
correct data of eCRF or source documents, all changes will be carried out in the Audit Trail 
function. Investigators will explain the reason for modifications in written form; the system will 
save the data information before and after modification. All data query have been clarified or 
resolved, data administrator will lock the database after get the written confirmation investigator 
and the sponsor. 
 
10.6.3. Bio-analytical Data Management and Quality Control 
Samples and sample Log Forms will be sent to Bioassay Lab (East Campous), Phase I Unit 
Clinical Pharmacology Research Center, Peking Union Medical College Hospital by the 
Investigator samples’ analysis. Analyses will be performed by means of validated bioanalytical 
methods. Details on the analytical methodology, method of validation, and the analytical within-
study quality control procedures will be included in the clinical study report. 
 
10.7. Statistical Methods 
Data analyses will be performed by the department of Statistics of PUMCH after the 
studycompletion and database lock. 
 
10.7.1. Statistical and Analytical Plans 
The statistical analyses described in this section will be performed as further outlined in the 
Statistical Analysis Plan, which will be finalized prior database lock,and will be included in the 
clinical study report. 
 
10.7.1.1. Analysis Populations 
The enrolled population is defined as the group of individuals who provided informed consent. 
The safety population is defined as the group of subjects who received at least one dose of 
study drug, and had at least one post-dose safety assessment. The full analysis population for 
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pharmacokinetic parameters is defined as the group of subjects who has at least one 
pharmacokinetic parameter post dose. 
 
10.7.1.1.1. Demographic/Baseline Analyses 
The safety population will be used to summarize and list the demographic and baseline 
variables. 
 
Age, height, weight, and body mass index will be summarized as continuous data. Gender and 
race will be summarized as categorical data. Descriptive summaries will also be done by gender 
if there is a minimum of five subjects for each gender.  
Medical history and concurrent medical conditions will be listed. 
 
10.7.1.1.2. Study Drug 
Drug dosage and levels are fixed in this study. Compliance checks will be carried-out by study 
site staff at the time of dosing. 
The number of subjects taking each study treatment will be summarized in the safety population. 
 
10.7.1.1.3. Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary (WHO-DD) drug codes. A listing of concomitant medications by drug and drug 
class will be included in the clinical study report for this protocol. 
Concomitant medications will be listed for subjects in the safety population. 
 
10.7.1.2. Pharmacokinetic Analyses 
Plasma concentration data and pharmacokinetic metrics will be listed for subjects in the safety 
population.  
 
Plasma concentration data for each analyte will be summarized descriptively by time-point and 
treatment for subjects in the safety population. Individual and mean plasma concentrations for 
each analyte will also be plotted over time for each treatment.  
  
Pharmacokinetic metrics (AUC0-t, AUC0-inf, Cmax, tmax, LambdaZ and t1/2Z) for each analyte 
will be summarized descriptively by treatment and gender for subjects in the full analysis 
population for pharmacokinetic metrics. To have a valid pharmacokinetic metric, a subject must 
not experience emesis within 12 hours after OXN dosing.  
 
The linear relationship between exposure (AUC0-t, AUC0-INF and Cmax) of oxycodone and 
naloxone-3-glucuronic acid and dose shall be analyzed using the linear mixed effect model (with 
treatment as fixed term and subject as random effect) (the specific method will be given in the 
statistical analysis plan).  
 
The primary investigation for the treatments are: 
• The PK of Oxycodone from OXN 5/2.5,OXN 20/10 
• The PK of Naloxone glucuronide from OXN 5/2.5,OXN 20/10 
 
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To assess dose-proportionality of OXN 20/10 vs. OXN 5/2.5 the following secondary 
comparisons will be performed: 
• Oxycodone from OXN 20/10 vs. OXN 5/2.5  
• Naloxone glucuronide from OXN 20/10 vs. OXN 5/2.5  
 
In addition, metabolite: parent ratios of AUCt, and where possible AUCINF will be summarized 
using number, mean, standard deviation, minimum and maximum. 
 
10.7.1.3. Safety Analyses 
Assessment of safety will be performed for all subjects who receive at least one dose of study 
drug and for whom at least one post-dose safety observation is recorded (the safety population). 
Safety data that will be evaluated include adverse events (including changes from baseline in 
physical examination findings), clinical laboratory results, vital signs, and ECGs. All safety data 
will be listed for subjects in the safety population. 
 
10.7.1.3.1. Adverse Events 
Adverse events will be classified into standardized medical terminology from the verbatim 
description (Investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA).Adverse events will be presented by preferred term nested within System Organ 
Class. Verbatim description and all MedDRA level terms, including the lower level terms, for all 
adverse events will be contained in the data listings of the clinical study report for this protocol. 
Adverse events will be summarized by presenting, for each treatment group, the incidence of 
adverse events. The incidence of adverse events will be based on the numbers and 
percentages of subjects with adverse events. Although a MedDRA term may be reported more 
than once time for a subject, that subject will be counted only once in the incidence count for 
that MedDRA term. 
Data for adverse events will be analysed using the treatment emergent signs and symptoms 
(TESS) philosophy. Treatment emergent signs and symptoms are defined as adverse events 
that: 
• emerge during treatment, having been absent at pre-treatment (baseline), or 
• re-emerge during treatment, having been present at baseline but stopped prior to treatment, or 
• worsen in severity during treatment relative to the pre-treatment state, when the adverse event 
is continuous. 
Only treatment emergent adverse events from the study will be summarized. 
 
10.7.1.3.2. Laboratory Values 
Clinical laboratory values will be evaluated for each laboratory parameter by subject. Abnormal 
laboratory values will be identified as those outside (above or below) the normal range. 
Reference (normal) ranges for laboratory parameters will be included in the CSR for this 
protocol. 
 
10.7.1.4. Vital Signs 
Vital sign values will be evaluated on an individual basis by subject. Abnormal vital sign values 
will be identified as those outside (above or below) the reference range. Reference (normal) 
ranges for vital sign parameters will be included in the Clinical Study Report for this protocol. 
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiration rate, and 
Axillary temperature) will be summarized by treatment and time-point for the safety population 
and listed. 
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Table5. Reference Range for Vital Sign Values 
                                                             
Vital Sign Parameter                 Range 
                                                             
Systolic blood pressure 90–140 mmHg 
Diastolic blood pressure 50–90 mmHg 
Pulse rate 60–100bpm 
Respiration rate 12–20 rpm 
Temperature ≤ 37°C 
                                                                  
10.7.1.5. ECG Changes 
ECG data will be obtained in the screening period and at the post-study medical (and, where 
appropriate, if a subject experiences an AE, TEAE, or SAE). ECGs will be classified as clinically 
significant or not clinically significant. 
ECG data will be evaluated on an individual basis for each subject. Clinically significant results 
will be recorded on the CRF and identified on the ECG listing. 
 
10.7.2. Sample Size and Power Considerations 
No formal sample size calculations will be performed. 24 subjects (12 in each dosage group) are 
regarded as sufficient according to CFDA regulation requirement. If subject withdraw from the 
study, subject replacement is needed. 
 
10.7.3. Interim Analysis 
No interim analysis is planned. 
 
11. PROCEDURES AND INSTRUCTIONS 
11.1. Ethics and Good Clinical Practice 
The Investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in the protocol and to adhere to the principles of ICH Good Clinical Practice to which 
the protocol conforms as well as all governing local regulations and principles for medical 
research. The protocol, informed consent, and appropriate related documents must be reviewed 
and approved by an IRB/IEC constituted and functioning in accordance with ICH E6, Section 3, 
and any local regulations eg approvals and notifications as required of the IRB/IEC. 
Documentation of IRB/IEC compliance with the ICH and any local regulations regarding 
constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC Chairman must be sent to the Principal 
Investigator with a copy to the Sponsor prior to study start. If the IRB/IEC decides to suspend or 
terminate the study, the Investigator will immediately send the notice of study suspension or 
termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported by the Sponsor to the IRB/IEC annually (or as required) 
according to local regulatory obligations. SAEs should also be reported by the Sponsor to the 
IRB/IEC in strict accord with local regulatory requirements. 
At the end of the study, the sponsor should notify the IEC within 90 days. The Sponsor should 
also provide the IEC with a summary of the study’s outcome. 
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In the case of early termination/temporary halt of the study, the Investigator should notify the 
IEC within 15 days and a detailed written explanation of the reasons for the termination/halt 
should be given. 
 
11.2. Subject Information and Informed Consent 
As part of providing the informed consent document, the Investigator must explain to each 
subject (or guardian/legally authorized 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/she may withdraw from the study at any time and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language. The subject should understand the statement before signing and dating 
it and will be given a copy of the signed document. No subject can enter the study before his/her 
written informed consent has been obtained. 
An unsigned copy of an IRB/IEC and Sponsor-approved written informed consent must be 
prepared in accordance with ICH E 6, Section 3, and all applicable local regulations and 
provided to the Sponsor. Each subject must sign an approved informed consent prior to study 
participation. The form must be signed and dated by the appropriate parties. The original signed 
ICF for each subject will be verified by the Sponsor and kept in the study center’s investigational 
site files; a signed copy will be given to the subject. 
 
11.3. Administrative Procedures 
11.3.1. Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor. Protocols 
will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the Sponsor before implementation. Amendments specifically affecting the 
safety of subjects, the scope of the investigation, or the scientific quality of the study require 
additional approval by the applicable IRBs/IECs of all investigational sites. These requirements 
should in no way prevent any immediate action from being taken by the Investigator, or by the 
Sponsor, in the interest of preserving the safety of all subjects included in the study. Changes 
affecting only administrative aspects of the study do not require formal protocol amendments or 
IRB/IEC approval, but the IRB/IEC must be kept informed of such changes. In these cases, the 
Sponsor will send a letter to the IRB/IEC detailing such changes. 
 
11.3.2. Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol. There are to be no 
Investigator-initiated deviations from the protocol. Any subject whose treatment deviates from 
the protocol or who is not qualified for study participation maybe ineligible for analysis and may 
compromise the study. On occasion, a subject whose medical condition does not exactly 
conform to the specifications of the protocol but who could potentially benefit from study 
participation may be considered for enrollment by the Sponsor if the Investigator first reviews the 
situation with the Sponsor. In these cases, the potential subject’s participation will be discussed 
with the Sponsor personnel prior to the subject signs the informed consent and the exemption 
for study enrollment will be sent in writing to the investigational site by the Sponsor. The 
investigational site will retain a copy of this document. 
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If the Investigator learns at any time after informed consent that a subject does not meet 
protocol specifications for study participation, he/she will call the Sponsor immediately. Subjects 
who have not signed an IRB/IEC approved ICF cannot receive study drug. The Investigator and 
research team must comply with ICH E6 principles and all applicable local regulatory laws and 
regulations. 
 
11.3.3. Monitoring Procedures 
The Sponsor’s CRA will maintain contact with the Investigator and designated staff by telephone, 
and/or letter, and/or email between study visits. Monitoring visits to each investigational site will 
be conducted by the assigned CRA. The Investigator will allow the CRA to inspect the clinical, 
laboratory, and pharmacy facilities to assure compliance with Good Clinical Practices. 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 ICH regulations. All records 
at the investigational site are subject to inspection by the local regulatory authority.  
In accord with ICH E6, Section 6.10, source documents include, but are not limited to the 
following: 
• Clinic, office, hospital charts; 
• Copies or transcribed health care provider notes which have been certified for accuracy after 
production; 
• Recorded data from automated instruments such as Interactive Voice-response Systems, x-
rays, and other imaging reports, e.g., sonograms, CT scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, Polysomnographys, pulmonary function tests 
(regardless of how these images are stored, including microfiche and photographic negatives); 
• Pain, quality of life, medical history questionnaires completed by subjects; 
• Records of telephone contacts; 
• Diaries or evaluation checklists; 
• Drug distribution and accountability logs maintained in pharmacies or by research personnel; 
• Laboratory results and other laboratory test outputs, e.g., urine pregnancy test result 
documentation; 
• Correspondence regarding a study subject’s treatment between physicians or memoranda sent 
to the IRBs/IECs;  
• CRF components (e.g., questionnaires) that are completed directly by subjects and serve as 
their own source. 
 
11.3.4. Recording of Data 
In order to provide the Sponsor with accurate, complete, and legible case reports, the following 
criteria are to be maintained: 
• All entries are to be typed or printed using a black ink ballpoint pen. 
• There are to be no erasures, write-overs, 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 initialed 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 Investigator must sign and date the CRF where noted. A signature stamp may not be used. 
• Changes to a CRF that has been previously signed by the Investigator must be initialed and 
dated by the Investigator after the change is made. Changes made to CRFs via data 
clarification forms issued by the Sponsor must likewise be signed by the Investigator. Neither 
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a subject’s name nor initials are to appear on documents transmitted to the Sponsor in order 
to maintain confidentiality. 
 
11.3.5. Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the Investigator 
has the responsibility to retain all study documents, including but not limited to the protocol, 
copies of CRFs, Investigator's Brochure, regulatory agency registration documents, eg, ICFs, 
and IRB/IEC correspondence. In addition, the Sponsor will send a list of treatment codes by 
study subject to the Investigator after the clinical database for this study has been secured. The 
investigational site should plan on retaining study documents for approximately 5 years after 
completion of the study according to local regulations. 
It is requested that at the completion of the required retention period, or should the Investigator 
retire or relocate, the Investigator contact the Sponsor, allowing the Sponsor the option of 
permanently retaining the study records. 
 
11.3.6. Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality Assurance 
department may conducts audits of clinical research activities in accordance with the Sponsor’s 
SOPs to evaluate compliance with the principles of ICH Good Clinical Practices and all 
applicable local regulations. A government regulatory authority may also wish to conduct an 
inspection (during the study or after its completion). If an inspection is requested by a regulatory 
authority, the Investigator must inform the Sponsor immediately that this request has been made. 
 
11.3.7. Handling of Study Drug 
All study drugs will be supplied to the Principal Investigator by the Sponsor. Drug supplies must 
be kept in an appropriate secure area (eg, double-locked cabinet) and stored according to the 
conditions specified on the drug labels. The Investigator must maintain an accurate record of the 
shipment and dispensing of the study drug in a drug accountability ledger, a copy of which must 
be given to the Sponsor at the end of the study. An accurate record of the date and amount of 
study drug dispensed to each subject must be available for inspection at any time. 
The assigned CRA will review these documents along with all other study conduct documents at 
appropriate intervals during visits to the investigational site once study drug has been received 
by the investigational site. 
All drug supplies are to be used only for this protocol and not for any other purpose. The 
Investigator must not destroy any drug labels or any partly used or unused drug supply. At the 
conclusion of the study and as appropriate during the course of the study, the Investigator will 
return all used and unused drug containers, drug labels, and a copy of the completed drug 
disposition form to the Sponsor’s CRA and to the Sponsor’s address provided in the Investigator 
folder at each site. 
 
11.3.8. Publication of 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 nominee(s) and subject to the protection 
of the Sponsor’s confidential information. 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 or 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 
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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 analyzed subjects; therefore Investigators participating in multicenter studies must agree not 
to present data gathered individually or by a subgroup of centers prior to the full, initial 
publication, unless this has been agreed to 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. 
 
11.3.9. Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative reasons at 
any time. Reimbursement for expenses covering subjects, use of live-in facilities, laboratory 
tests, and other professional fees will be made. The Investigator will refund the excess of 
payments made in advance. 
The Investigator reserves the right to discontinue the study should his/her judgment so dictate. 
In such an event, final settlement of the grant-in-aid will be adjusted pro rata, and the 
Investigator will refund the excess of payments made in advance. The Investigator will notify the 
IRB/IEC in case of study discontinuation. Study records must be retained as noted above. 
 
12. APPENDICES 
12.1. Pharmacokinetic Sample Handling and Shipping 
12.1.1. Sample Procurement and Processing 
Blood samples, 6 mL each, will be drawn into tubes containing K2 EDTA solution, an 
anticoagulant. It is important for the assay to obtain a full 6-mL blood sample. Samples should 
be centrifuged within 30 minutes of collection. Following centrifugation (1500g, 4°C, 15 min.), 
the harvested plasma will be pipetted equally into two polypropylene labeled tubes and frozen at 
-20°C and below. If the required volume of blood cannot be collected, a minimum of 1.4 mL of 
plasma must be transferred into the first tube and the remaining volume transferred to the 
second tube. Prior to freezing, each plasma sample will be identified by protocol number, 
subject number, specimen matrix (plasma) and nominal time of sampling etc. 
 
12.1.2. Sample Transportation 
At the end of the 48-hour blood collection in the treatment period, one set of samples (primary) 
and second set (back-up samples) packed in sufficient dry ice will be sent to Bioassay Lab (East 
Campus), Phase I Unit clinical Pharmacology researcher center, PUMCH(No1,Shuaifuyuan, 
Dongcheng District, Beijing, 100730 P.R. China). Sample Transportation will performed in 
accordance with bioassay lab’s Sops. 
 
 
 
 
 
 
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13. REFERENCE LIST 
Hussain M, Aungst B, Kearney A, Shefter E. Buccal and oral bioavailability of naloxone and 
naltrexone in rats. Int J of Pharmaceutics. 1987;36:127-30. 
 
Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. 
J Pain Symptom Manage. 2002;23:48-53. 
 
Regenthal R, Krüger M, Richter M, Preiss R. Poisoning with tilidine and naloxone: toxicokinetic 
and clinical observations. Human & Experimental Toxicology.1998; 17:593-7. 
 
Culpepper MJ, Inturrisi CE, Portenoy RK, Foley K, Houde RW, Marsh F et al. Treatment of 
opioid-induced constipation with oral naloxone: a pilot study. Clin.Pharmacol.Ther. 1992; 52 : 
90-5 
 
Hawkes ND, Richardson C, Evans BK, Rhodes J, Lewis SJ, Thomas GAO Effect of an enteric-
release formulation of naloxone on intestinal transit in volunteers taking codeine. Aliment 
Pharmacol Ther. 2001:15; 625-30. 
 
Jurna I, Baldauf J. Retardiert freigesetztes Naloxon oral: Aufhebung der Obstipation durch 
orales Morphin ohne Beseitigung der Analgesie. Der Schmerz. 1993;7: 314- 21. 
 
Latasch L, Zimmermann M, Eberhardt B, Jurna I. Aufhebung einer Morphin-induzierten 
Obstipation durch orales naloxone Anaesthesist.1997; 46: 191-4. 
 
Meissner W, Schmidt U, Hartmann M, Kath R, Reinhard K. Oral naloxone reverses opioid-
associated constipation. Pain. 2000;84:105-9. 
 
Sykes NP. An investigation of the ability of oral naloxone to correct opioid release constipation in 
patients with advanced cancer, Palliativ Medicine. 1996;10:135-44. 
 
Bloomquist ER. The addiction potential of oxycodone (percodan). California Medicine. 
1963;99:127-30. 
 
Freye E. Rezeptorinteraktion von Agonisten, Antagonisten und partiellen Agonisten. In: Opioide 
in der Medizin, Springer Verlag. 1995; 33-44. 
 
Herrmann M. Zum Wirkungsprinzip der Kombination Tilidin plus Naloxon. In: Keup W 
(ed) Biologie der Sucht, Springer Verlag. 1986:202-16. 
 
Senay EC, Clara JR. Impact of Talwin NX. Problems of drug dependence (Harris, LS ed.) 
National Institute of drug abuse research Monograph 55, Washington. 1985:170-7. 
 
Ghodse AH. Analysis of epidemiological data on agonist-antagonist analgesics. Drug Alcohol 
Dependence. 1987;20:375-83. 
Weinhold LL, Preston KL, Farre M, Liebson IA and Bigelow GE. Buprenorphine alone and in 
combination with naloxone in non-dependent humans. Drug Alcohol Depend. 1992;30:263-74. 
 
OXN1016-An open-label, single-dose, 5-treatment, 5-period, randomized crossover study to 
investigate the pharmacokinetics of oxycodone and naloxone from two batch sizes of an 
oxycodone/naloxone prolonged release (PR) tablet 10/5 mg (OXN 10/5) and an 
oxycodone/naloxone PR tablet 40/20 mg (OXN 40/20).Mundipharma, 2006 
 
Final version 1.0, version date: 15 Oct 2013 
 
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OXN1017- An open-label, multiple-dose, parallel group study to compare the steady-state 
pharmacokinetics of oxycodone and naloxone from an oxycodone/naloxone (OXN) prolonged 
release (PR) tablet 10/5 mg in healthy elderly and younger subjects. Mundipharma, 2007 
 
OXN1403-An open-label, single-dose, 4-treatment, 4-period, randomized crossover study in 
healty subjects to assess the pharmacokinetic and bioavailability characteristics of three 
different strengths of a fixed combination OXN and a combination of Oxygesic® plus Nalocion 
CR.Mundipharma, 2005 
 
OXN1018-An open-label, single-dose, 4-treatment, 4-period, randomized crossover study in 
healthy subjects to assess the pharmacokinetics of oxycodone and naloxone after 
administration of an oxycodone/naloxone prolonged release tablet 5/2.5 mg (OXN 5/2.5) in a fed 
and fasted state, an oxycodone hydrochloride prolonged release tablet 5 mg in a fasted state, 
and oxycodone hydrochloride immediate release liquid 5 mg and naloxone hydrochloride liquid 
2.5 mg in a fasted state. Mundipharma, 2007 
 
OXN IB version 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1:Flow diagram for AE reporting 
 
 
 
 
 
 
 
 
 
Adverse Event 
Complete CRF/EDC 
considering the 
following:
Assign severity grade
Does the 
event meet any of the 
following criteria?
•
Results in death
•
Is life threatening
•
Results in persistent or significant disability/incapacity
•
Requires in-patient hospitalisation or prolongs existing hospitalisation
•
Results in a congenital anomaly or birth defect
•
Is an important medical event that may not result in the above
Record outcome
Yes
No
Assess causality
Is the 
event listed in the protocol 
as not requiring immediate 
SAE reporting?
No
Yes
Submit report immediately 
(within 24 hours) with 
outcome/status information 
and follow up until sequalae 
resolved or stabilised
Final version 1.0, version date: 15 Oct 2013 
 
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Figure2： Brief pain inventory – Short Form (BPI-SF)  
Date：                                                                                    Time:                       
Name:                          
 
 
 
 
 
 
 
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SAP_001.pdf: 
Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
1 
 
 
 
Statistical Analysis Plan 
An 
open-label, 
randomized, 
single-dose, 
parallel 
group 
study 
to 
investigate 
the 
pharmacokinetics of oxycodone and naloxone from oxycodone/naloxone (OXN) prolonged 
release (PR) tablet 5/2.5 mg (OXN 5/2.5)and20/10 mg (OXN 20/10) in Chinese patients with 
moderate to severe chronic non-malignant pain. 
 
 
 
 
Product Name: Oxycodone Naloxone Prolonged Release Tablets (OXN PR) 
 
Sponsor: Mundipharma (China) Pharmaceutical Co., Ltd. 
 
 
 
 
 
Version 1.0: Mar 1, 2017 
 


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STATISTICAL ANALYSIS PLAN 
 
Study title: 
An open-label, randomized, single-dose, parallel group study to 
investigate the pharmacokinetics of oxycodone and naloxone from 
oxycodone/naloxone (OXN) prolonged release (PR) tablet 5/2.5 mg 
(OXN 5/2.5)and20/10 mg (OXN 20/10) in Chinese patients with 
moderate to severe chronic non-malignant pain. 
Sponsor: 
Mundipharma (China) Pharmaceutical Co., Ltd. 
Investigator： 
Professor Hu Bei, Peking Union Medical College Hospital 
Professor Zeng Xiao-feng, Peking Union Medical College Hospital 
 
Study doctor:  
Dr. Chen Xia, Peking Union Medical College Hospital 
Clinical trial 
approval number:  
2011L01178,2011L01179,2012L02501,2012L02502 
Protocol number:   OXN08-CN-101 
Sponsor: 
18F, Building D, CITC, A6 Jianguomenwai Street,  
Chaoyang District, Beijing, P. R. China 
Postal Code: 100022 
Telephone: +861065636800 
Fax: +8610 65636700 
Version/Date:      1.0: Mar 1, 2017 
 
Confidentiality Statement 
The information contained in this document, the unpublished data in particular, is owned or 
controlled by Mundipharma (China) Pharmaceutical Co., Ltd. The information is hereby made 
available in a confidential form to you as an investigator, a potential investigator or a consultant for 
reviews by you, your staffs and relevant ethics committee. All information should only be used in 
clinical study of the test drug you are authorized to carry out as described in this protocol. Except 
for the necessity to disclose certain information to the possible subject to certain extent when 
obtaining the informed consent, the information shall not be disclosed to any third parties without 
written permission of Mundipharma (China) Pharmaceutical Co., Ltd. 
 


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Table of Contents 
STATISTICAL ANALYSIS PLAN .............................................................................................................. 2 
Signature page ............................................................................................................................................... 1 
Table of abbreviations .................................................................................................................................. 3 
1. Overview .................................................................................................................................................... 4 
1.1 Study Rationale ............................................................................................................................... 4 
1.2 Study objectives ............................................................................................................................... 4 
1.3 Study design ..................................................................................................................................... 5 
1.3.1 Study design .......................................................................................................................... 5 
1.3.2 Determination of sample size .............................................................................................. 6 
1.3.3 Blinding ................................................................................................................................. 6 
1.4 Guidelines ........................................................................................................................................ 6 
2. Study subjects ............................................................................................................................................ 6 
2.1 Subject arrangement ...................................................................................................................... 6 
2.2 Analytical sets .................................................................................................................................. 6 
2.3 Protocol deviation ........................................................................................................................... 7 
2.4 Demographics and baseline analysis ............................................................................................. 7 
2.4.1 Demographics ....................................................................................................................... 7 
2.4.2 Concomitant Medication ..................................................................................................... 7 
2.5 Determination of treatment compliance ....................................................................................... 7 
3. Pharmacokinetic evaluation ..................................................................................................................... 7 
3.1 Analytical data ................................................................................................................................. 7 
3.2 Pharmacokinetic evaluation ........................................................................................................... 7 
3.2.1 Calculation of PK parameter .............................................................................................. 7 
3.2.2 Evaluation of dose-proportionality ..................................................................................... 9 
3.3.3 Data handling conventions ................................................................................................ 10 
4. Safety assessment .................................................................................................................................... 11 
4.1 Analytical data ............................................................................................................................... 11 
4.2 Exposure data ................................................................................................................................ 11 
4.3 Adverse events ............................................................................................................................... 11 
4.3.1 Serious adverse events ....................................................................................................... 11 
4.4 Evaluation of laboratory tests ...................................................................................................... 11 
4.5 Vital signs ....................................................................................................................................... 12 
4.6 Physical examination .................................................................................................................... 12 
4.7 ECG evaluation ............................................................................................................................. 12 
4.8 Evaluation of pain scores .............................................................................................................. 12 
5. Quality control ........................................................................................................................................ 12 
6. List of Tables............................................................................................................................................ 13 
6.1 List of Tables .................................................................................................................................. 13 
6.2 List of figures ................................................................................................................................. 13 
6.3 Table of listings .............................................................................................................................. 14 
7. References ................................................................................................................................................ 14 
8. Examples of tables .................................................................................................................................. 15 
Tables ........................................................................................................................................... 15 


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Figures .......................................................................................................................................... 24 
Listing .......................................................................................................................................... 25 
 
 


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Signature page 
 
Writer 
Statistician 
 
 
 
 
Yiwen Wu 
 
 
 
 
Clinical Pharmacology Research 
Center of Peking Union Medical 
College Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Reviewer 
Sub-investigator 
 
 
 
 
Xia Chen, Associate Professor 
 
 
 
 
Clinical Pharmacology Research 
Center of Peking Union Medical 
College Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewer 
Bioanalysis investigator  
 
 
 
 
Hongyun Wang, Associate Professor 
 
 
 
 
Clinical Pharmacology Research 
Center of Peking Union Medical 
College Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 


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Reviewer 
Clinical lead 
 
 
 
 
York Peng 
 
 
 
 
Mundipharma (China) Pharmaceutical 
Co., Ltd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
Approver 
Principle investigator 
 
 
 
 
Pei Hu, Professor 
 
 
 
 
Clinical Pharmacology Research 
Center of Peking Union Medical 
College Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of abbreviations 
Abbreviation 
Annotation 
AE 
Adverse events 
AUC0-inf 
Area under plasma drug concentration-time curve from zero time to 
infinity 
AUC0-t 
Area under plasma drug concentration-time curve from zero time to 
the last measurement 
AUC_%Extrap 
Percentage of extrapolated area 
BLQ 
Below Limit of Quantification 
BMI 
Body mass index 
CFDA 
China Food and Drug Administration 
Cmax 
Peak plasma concentration 
CRF 
Case report form  
ECG 
Electrocardiogram 
Lambda_z 
Elimination rate constant 
LLOQ 
Lower Limit of Quantification 
IMP 
Investigational medicinal product 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
Not calculate 
ND 
Not detectable 
OXN PR 
Oxycodone Naloxone Prolonged Release Tablets 
PK 
Pharmacokinetics 
SAE 
Serious adverse events 
Tmax 
Time to peak plasma concentration 
t1/2  
Elimination half-life 


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1. Overview 
1.1 Study Rationale 
Mundipharma Research GmbH & Co. KG and independent affiliates (NPRL and Purdue Pharma 
L.P) have developed a novel compound prolonged-release analgesic tablet composed of an opioid 
agonist oxycodone and an opioid antagonist naloxone. Oxycodone is a sustained-release dosage form 
of opioid analgesics indicated for moderate-severe pain. 
Adding naloxone component to the fixed combination can offset opioid-induced constipation by 
locally blocking the effect of oxycodone on opioid receptors in the intestines. In addition, due to the 
presence of opioid receptor antagonist naloxone, lower abuse rate is expected with Oxycodone 
Naloxone Prolonged Release Tablets (OXN PR) than with single-component sustained-release 
opioids when the tablet is grounded for intravenous or intranasal administration. Opioids are the 
cornerstone of chronic pain management. It has been shown that opioid sustained-release drugs are 
effective for pain management; however, the adverse events (AE) have limited the ability to 
appropriately increase opioid doses to manage the pain. Among patients who receive opioid to 
manage pain, the induced constipation is a frequently occurring severe adverse event (SAE). 
Laxatives are the currently recommended treatment, but many patients frequently discontinue opioid 
therapy because opioid-induced constipation continues to exist with medication. Therefore, it is 
highly beneficial to minimize the occurrence or reduce the severity of constipation. In the current 
compound formulation, the high first-pass effect of naloxone is considered to be an advantage: the 
local action of naloxone in the intestine can improve intestinal function; given the low systemic 
bioavailability of naloxone, however, the analgesic activity of oxycodone is not inhibited. The results 
of all clinical studies conducted so far have shown no significant effect on the analgesic efficacy after 
compound OXN PR formulation is administered, but the patients indeed benefited from relieved 
constipation and tolerated this product very well. 
1.2 Study objectives 
The primary objectives of this study are:  
 
To determine the pharmacokinetic (PK) characteristics of oxycodone, naloxone and its 
metabolites in Chinese patients (with moderate to severe chronic non-malignant pain). 
 
To assess, in a single dose investigation, the dose-proportionality of OXN. 
 


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1.3 Study design 
1.3.1 Study design 
This is an open-label, randomized, single-dose and parallel-group study. A total of 24 subjects 
are expected to be enrolled and randomized at 1:1 ratio into single-dose Oxycodone Naloxone 
Prolonged Release Tablets (OXN PR) 5/2.5 mg group or OXN PR 20/10 mg group, each group 
includes 12 subjects who will orally receive OXN PR active drug. If fewer than 12 subjects in each 
group have completed this study, more subjects will be included. 
Subjects will attend a screening visit within 14days of the first (OXN) dosing day (Day 1). 
Eligible subjects will then check into the study unit on the day before OXN dosing (Day -2). 
Subjects will be administered their OXN dose the next 2 morning (Day 1), following an overnight 
fast. 
There will be 24 subjects with moderate to severe chronic non-malignant pain enrolled in this 
single-dose study, to be comprised of males and females aged 18-65 years. Blood samples will be 
collected in tubes containing the anticoagulant EDTA pre-dose and up to 48 hours after administration 
of OXN. Subjects remain in the study unit up to 48+2 hours after OXN dosing. 
Vital signs (pulse, blood pressure, respiration rate) will be monitored pre-dose and then at 1, 2, 4, 
6, 8, 12, 24, 36, 48 hours after OXN dosing. Auxiliary temperature will be monitored pre-dose, 24, 36, 
48 hours after OXN dosing. 
AEs will be recorded throughout the study. Subjects will attend a post-study evaluation 48±2 
hours after OXN dosing (in the case of discontinuation from the study). 
 
Figure 1: Study Diagram 
Single-dose administration:  
 
Screening period: Day -14 to Day -2 
Treatment and sampling period: 2 days 
Group A: OXN PR 5/2.5 mg, 1 tablet 
Group B: OXN PR 20/10 mg, 1 tablet 
Post-study evaluation: 1 day 
Day -14 to Day -2       2 days                  1 day  
Screening     Treatment and sampling      Post-study evaluation 
Randomization 


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1.3.2 Determination of sample size 
No formal sample size calculations will be performed. 24 subjects (12 in each dosage group) are 
regarded as sufficient according to CFDA regulation requirement. If subject withdraw from the study, 
subject replacement is needed. 
1.3.3 Blinding 
Not applicable. 
1.4 Guidelines 
This statistical plan will follow the SOP of Clinical Pharmacology Research Center of Peking 
Union Medical College Hospital and the requirements of China authority.  
 
2. Study subjects  
2.1 Subject arrangement 
The number and percentage of subjects completed and discontinued from this trial should be 
included in the statistical analysis report; meanwhile, the information of the subjects discontinued 
from the trial, including the reason for discontinuation, should be listed. 
2.2 Analytical sets 
 Intention-to-treat (ITT) population  
ITT population consists of all randomized subjects who meet the inclusion and exclusion criteria. 
 Safety set (SS)  
Safety set is a subset of ITT population and consists of all subjects who receive at least 1 dose 
and have evaluable safety data. 
 PK analysis set (PKS)  
PK analysis set is a subset of ITT population and consists of all subjects who receive at least 1 
dose and have evaluable PK data. It should also be noted: according to the protocol, subjects who 
experience vomiting within 12hr after OXN is administered should not be included in the PKS. 
All the above analysis sets will be determined in data review report. 


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2.3 Protocol deviation  
Primary and secondary protocol deviations should be listed in the statistical analysis report. (Note: 
Major PD will be identified in the data review report.) 
2.4 Demographics and baseline analysis  
2.4.1 Demographics 
Safety set (SS) will be used to summarize and list demographic and baseline variables. Individual 
demographic and baseline characteristic data should be listed in the statistical analysis report. 
Demographic variables such as age, gender, weight, height and ethnicity will be listed by dose 
group and subject; descriptive statistical analysis will be conducted by dose group. The continuous 
variables in the table should list the descriptive statistical results, while the categorical variables 
should list the frequency and percentage. 
Medical History should be listed in the statistical analysis report. 
2.4.2 Concomitant Medication 
The list of Concomitant Medication should include all combined use of drugs in safety sets by 
drug and drug category. 
2.5 Determination of treatment compliance 
The beginning date, ending date and time of administration in these subjects will be listed in the 
statistical analysis report. 
3. Pharmacokinetic evaluation 
3.1 Analytical data 
PK evaluation will be based on the data of all subjects in PKS. 
3.2 Pharmacokinetic evaluation 
3.2.1 Calculation of PK parameter 
If there is no protocol deviation (e.g. failure to take study drug) that may affect PK endpoint 
variables (e.g. AUC, Cmax) during this trial, the subject will be included in PKS. 
Non-compartmental analysis method (Linear Up Log Down) of Phoenix WinNonlin 6.3 


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(Pharsight Corp., Mountain View, CA, USA) software will be used not only to calculate PK 
parameters of oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone), 
and naloxone and its metabolites (6β-naloxol, naloxone-3-glucuronate and 6β-naloxol-3-glucuronate) 
but also to conduct descriptive statistical analysis, including the following parameters:  
 
Parameters 
Definitions  
Calculation methods  
AUC0-inf 
The area under the plasma 
concentration-time curve from 
time 0 to infinity  
AUC0-inf =AUC0-t+(Clast/Lambda_z), where 
Clast is the corresponding blood concentration 
at the last measurable time point Tlast.  
AUC0-t 
The area under the plasma 
concentration-time curve from 
time 0 to the last measurable 
concentration (Clast)  
Linear/ log trapezoidal method  
Cmax 
Maximum plasma concentration  It shall be obtained directly from observation 
data.  
Lambda_z 
Elimination rate constant [1/ hr]  The elimination rate constant shall be 
calculated using the linear regression of 
log-linear concentration-time curve. The time 
point can be included only if corresponding 
linearity decreases.  
T1/2 
Half-life of elimination [hr]  
T½=ln(2)/Lambda_z. The time point can be 
included only if corresponding linearity 
decreases.  
Tmax 
Time to peak blood 
concentration [hr]  
Time to peak blood concentration present for 
the first time on the time axis shall be obtained 
from observation data.  
AUC_%Extrap 
The percentage AUC 
extrapolated [%]  
The percentage of area under the plasma 
concentration-time curve from the last 
measurable concentration time point after 
dosing t to infinity in AUC0-inf  
 
Descriptive statistical analysis of the PK parameters of oxycodone and its metabolites 
(noroxycodone, oxymorphone and noroxymorphone), and naloxone and its metabolites (6β-naloxol, 


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naloxone-3-glucuronate and 6β-naloxol-3-glucuronate) are conducted by dose group. The descriptive 
statistics include mean, standard deviation, coefficient of variation, minimum and maximum. 
The mean concentration-time curve (Mean±SD) for oxycodone and its metabolites 
(noroxycodone, oxymorphone and noroxymorphone), naloxone and its metabolites (6β-naloxol, 
naloxone-3-glucuronate and 6β-naloxol-3-glucuronate) are plotted by dose group. 
3.2.2 Evaluation of dose-proportionality 
The linear mixed effect model (treatment as fixed factor, subject as random effect) will be used 
for exploratory evaluation of the dose-proportionality of for oxycodone, naloxone and metabolites 
(AUC0-48h, AUC0-inf and Cmax). 
Evaluation objectives 
The objective of drug dose-proportionality assessment is to determine whether there is a 
proportional relationship between the dose and exposure level of study drug, which is usually 
evaluated by measuring the relationship between concentration-related PK parameters (e.g. AUC0-48hr, 
AUC0-inf and Cmax) and doses. 
Method for the evaluation of drug dose-proportionality 
Power Model 
Power Model [1,2] is used to find the point estimate and 90% confidence interval (CI) for the 
degree of drug dose-proportionality deviation between the lowest dose and the highest dose during 
this trial; then, the acceptable range after correction by the dose range (see texts below for correction 
method) is used to determine whether the drug demonstrates linearity within this dose range. If 90% 
CI for  falls within (L, U), the drug dose linearly can be established within this dose range; if 90% 
CI for  completely falls outside (L, U), the drug dose linearly cannot be established within this dose 
range; if 90% CI for  partially falls within (L, U), the drug dose linearly cannot be fully established 
within this dose range, but 90% CI for deviation of the drug dose linearly falls within (L, U). 
Correction 
method 
of 
the 
acceptance 
range: 
γ=maximum 
dose/minimum 
dose; 
; 
; L is the lower limit of CI for ; U is the 
upper of CI for . The  estimate and its CI are obtained with the mixed model after logarithmic 
conversion of PK parameters. The  estimate, L and U should be all listed in statistical analysis 
report. 


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3.3.3 Data handling conventions 
3.3.3.1 Basic principles of PK data handling 
The handling of PK concentration data and the calculation of PK parameters in this trial should 
comply with following basic principles:  
1) When calculating PK parameters of data obtained at drug concentration below the lower limit 
of quantitation (BLQ), the value should be replaced with zero if occurring before Tmax and the value 
should be replaced with ND if the BLQ occurs after Tmax; 
2) After Tmax, if measurable concentration appears after two consecutive NDs, it should be 
replaced with ND if there is no measurement error; 
3) When descriptive statistics for concentration at each time point are calculated, all data below 
LLOQ are not brought into the calculation; 
4) When descriptive statistics for concentration at each time point are calculated, if more than 1/3 
of the individual data is not brought into the calculation, the descriptive statistics at that time point 
will not be calculated and are represented with NC; 
5) When the descriptive statistics of concentrations at each time point are calculated, if a subject 
vomits within 12 hours after the administration, then this subject will not be included in the statistical 
analysis of PK, but the plasma drug concentration at the corresponding time point will be provided in 
the listing; 
6) If the extrapolated area of AUC is greater than 20% of AUC0-inf, AUC0-t/AUC0-inf<0.8, then the 
AUC0-inf will neither be included nor be brought into any statistical analysis of AUC0-inf; 
7) The calculation of all PK parameters employs the actual time and measured concentration. 
8) All individual plasma drug concentration retains 3 significant digits, while the descriptive 
statistical results (mean and standard deviation) retain 2 digits after the decimal point; individual PK 
parameters and their descriptive results retain 2 significant digits.  
9)Handling of missing data: 
When missing data is determined, the test results corresponding to this point will not be brought 
into the calculation of relevant statistics. 
3.3.3.2 Statistical method for PK analysis 
Descriptive statistics of PK parameters include the number of cases (N), arithmetic mean (Mean), 
standard deviation (SD), coefficient of variation (CV), minimum (Min), median and maximum (Max). 
The descriptive statistics of PK parameters (mean, standard deviation, coefficient of variation, 
minimum, median and maximum) will be provided by the listing of test drugs. All statistical analysis 
will employ SAS® 9.3. 


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4. Safety assessment 
All statistical analysis will employ SAS® 9.3. 
4.1 Analytical data 
Safety analysis will be based on the data of all subjects in safety set (SS). 
4.2 Exposure data 
The date, time and dose of drugs given to the subjects should be listed in the statistical analysis 
report. 
4.3 Adverse events 
All AE-related information will be provided in the listings of statistical analysis report (including: 
SAE or not, severity, whether concomitant treatment is given, AE outcome and relationship with 
study treatment); each AE will be encoded with MedDRA (preferred term (PT), organ system 
classification (SOC)). The number of AE with different severity and the relationship with study 
treatment will be summarized by dose group; the incidence and percentage of AE will be summarized 
and analyzed with preferred term (PT) and organ system classification (SOC) by different dose groups. 
(AE occurring in all periods is given in the listing, but only TEAE (Treatment Emergent Adverse 
Events) will be statistically analyzed.)  
Double histograms of PK exposure (AUC, Cmax) and AE incidence will be plotted by dose group 
for naloxone and oxycodone, respectively. 
4.3.1 Serious adverse events 
Individual SAE data should be listed in the statistical analysis report. 
4.4 Evaluation of laboratory tests 
For safety set, laboratory examination results of the subjects at the scheduled evaluation point 
will be summarized by different dose group; meanwhile, the relative changes from the baseline will 
be summarized by evaluation point. The table for reference (normal) ranges of laboratory parameters 
will be listed for subjects in each dose group.  
The laboratory test results will be classified and summarized by LNH according to lower than 
(L), equal to (N) or higher than (H) reference range of laboratory parameters. 


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4.5 Vital signs  
All vital sign data will be presented by listing of dose groups and subjects, in which the outliers 
will be marked. Descriptive statistics and listing of various vital signs and their changes from the 
baseline after administration will be provided by dose group. For abnormal data, frequency and 
percentage will be calculated by treatment and abnormality. 
4.6 Physical examination 
Individual data of physical examination should be listed in statistical analysis report, in which the 
outliers will be marked. For abnormal data of physical examination, the frequency and percentage will 
be calculated by treatment and normality. 
4.7 ECG evaluation  
All ECG data will be listed by dose groups and subjects, while the outliers will be marked. 
Descriptive statistics of the changes in examination values of ECG parameters relative to baseline 
after administration will be provided by dose group. For abnormal ECG data, the frequency and 
percentage will be calculated by dose group and clinical significance. 
4.8 Evaluation of pain scores 
The pain scores will be summarized at the scheduled evaluation points by different dose groups. 
5. Quality control 
Statistical analysis and PK analysis should be carried out under the guidance of statisticians and 
PK experts, and reviewed by relevant quality control personnel. 


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6. List of Tables 
6.1 List of Tables 
Table 10.1:1 
Trial completion status 
Table 11.2.1:1 
Demographics results 
Table 11.3 
Descriptive statistical results of plasma concentrations of oxycodone, naloxone and 
their metabolites 
Table 11.4.1.2:1 
Descriptive statistical analysis results (summary) of the PK parameters of oxycodone, 
naloxone and their metabolites 
Table 11.4.1.2:2 
Descriptive statistical analysis results (including individual data) of the PK parameters 
of oxycodone, naloxone and their metabolites 
Table 11.4.1.2:3 
Dose proportionality assessment results  
Table 12.2.3 
Summary on adverse events 
Table 12.2.3:1 
Table for severity of adverse events and treatment-related frequency 
Table 12.2.3:2 
Table for incidence of adverse events (by SOC and PT) 
Table 12.2.3:3 
Table for frequency analysis of serious adverse events 
Table 12.4.1:1 
Descriptive statistical analysis results for haematology 
Table 12.4.1:2 
Descriptive statistical analysis results for changes of haematology relative to the 
baseline 
Table 12.4.1:3 
Table for frequency of haematology results 
Table 12.4.1:4 
Descriptive statistical analysis results for blood chemistry 
Table 12.4.1:5 
Descriptive statistical analysis results for changes of haematology relative to the 
baseline 
Table 12.4.1:6 
Table for frequency of blood chemistry results 
Table 12.4.1:7 
Table for frequency of urinalysis results 
Table 12.5.1:1 
Descriptive statistical analysis results for vital signs 
Table 12.5.1:2 
Descriptive statistical analysis results for changes of vital signs relative to the baseline 
Table 12.5.1:3 
Descriptive statistical analysis results for 12-lead ECG 
Table 12.5.1:4 
Descriptive statistical analysis results for changes of 12-lead ECG relative to the 
baseline 
Table 12.5.1:5 
Table for frequency of 12-lead ECG results 
Table 12.5.1:6 
Table for frequency of physical examination results 
Table 12.5.1:7 
Descriptive statistical analysis results for pain scores 
6.2 List of figures 
Figure 1.1 
Mean plasma drug concentration-time linear curve for oxycodone, naloxone and their 
metabolites 
Figure 1.2 
Mean plasma drug concentration-time semi-logarithmic curve for oxycodone, naloxone 
and their metabolites 
Figure 2.1 
Individual plasma drug concentration-time linear curve for oxycodone, naloxone and 


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their metabolites 
Figure 2.2 
Individual plasma drug concentration-time semi-logarithmic curve for oxycodone, 
naloxone and their metabolites 
6.3 Table of listings 
Listing11.1.1:1 
Listing of trial completion status 
Listing11.1.1:2 
Listing of trial protocol deviation 
Listing11.2.1:1 
Listing of demographics 
Listing11.3:1 
Listing of Concomitant Medication 
Listing11.3:2 
Listing of past medical history 
Listing11.4 
Listing of blood collection 
Listing12.1:1 
Listing of individual medication 
Listing12.2.2:1 
Listing of adverse events 
Listing12.4:1 
Listing of laboratory haematology test results 
Listing12.4:2 
Listing of laboratory haematology test results 
Listing12.4:3 
Listing of laboratory blood biochemistry test results 
Listing12.4:4 
Listing of laboratory blood biochemistry test results 
Listing12.4:5 
Listing of laboratory urinalysis test results 
Listing12.5:1 
Listing of individual vital signs results  
Listing12.5:2 
Listing of individual 12-lead ECG determination results 
Listing12.5:3 
Listing of individual 12-lead ECG examination results  
Listing12.5:4 
Listing of individual physical examination results  
Listing12.5:5 
Listing of individual pain scores results  
 
7. References 
[1] Drug Information Journal, Vol.29, pp. 1039-1048, 1995. Assessment of Dose Proportionality: Report 
 from the Statisticians in the Pharmaceutical Industry/ Pharmacokinetics UK Joint Working Party.  
 
[2] Brian P. Smith, Francois R. Vandenhende, Karl A. DeSante, Nagy A. Farid, Pamela A. Welch, John T. 
Callaghan and S. Thomas Forgue. Confidence Interval Criteria for Assessment of Dose Proportionality; 
Pharmaceutical Research, Vol. 17, No. 10, 2000 


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8. Examples of tables 
Tables 
Table 10.1:1 Study completion status 
 
TreatmentA 
 (N= xx) 
n (%) 
TreatmentB 
 (N= xx) 
n (%) 
Subjects without taking study drug 
xxx 
xxx 
Subjects receiving study drug 
xxx 
xxx 
 
 
 
Study completion status  
xxx(xx,x) 
xxx(xx,x) 
 
 
Withdraw from the trial  
 
 
Reason A 
xxx(xx,x) 
xxx(xx,x) 
Reason B 
xxx(xx,x) 
xxx(xx,x) 
Reason C 
xxx(xx,x) 
xxx(xx,x) 
 
 
N: Number of subjects in each group 
n: Number of subjects with effective data 
%: N-based percentage 
 
Table 10.2.1 Demographics results 
 
TreatmentA 
 (N= xx) 
TreatmentB 
 (N= xx) 
Age(years) 
 
 
Mean(SD) 
xx.x(xx.xx) 
xx.x(xx.xx) 
Median(CV) 
xx(xx.xx) 
xx(xx.xx) 
(Min, Max) 
(xx,xx) 
(xx,xx) 
 
 
 
Height(cm) 
 
 
Mean(SD) 
xx.xx(xx.xx) 
xx.xx(xx.xx) 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
16 
 
TreatmentA 
 (N= xx) 
TreatmentB 
 (N= xx) 
Median(CV) 
xx.xx(xx.xx) 
xx.xx(xx.xx) 
(Min, Max) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
Weight(kg) 
 
 
Mean(SD) 
xx.xx(xx.xx) 
xx.xx(xx.xx) 
Median(CV) 
xx.xx(xx.xx) 
xx.xx(xx.xx) 
(Min, Max) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
BMI(kg/m^2) 
 
 
Mean(SD) 
xx.xx(xx.xx) 
xx.xx(xx.xx) 
Median(CV) 
xx.xx(xx.xx) 
xx.xx(xx.xx) 
(Min, Max) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
Gender 
 
 
Male 
xx(xx.xx%) 
xx.xx(xx.xx) 
Female 
xx(xx.xx%) 
xx.xx(xx.xx) 
 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
17 
Table 11.3 Descriptive statistical results of plasma concentrations of oxycodone, naloxone and their 
metabolites 
 
 
 
Subject 
 
 
1
0
1 
1
0
2 
1
0
3 
1
0
4 
1
0
5 
1
0
6 
1
0
7 
1
0
8 
1
0
9 
1
1
0 
1
1
1 
1
1
2 
N 
M
e
a
n 
S
D 
Tr
eat
me
nt 
Analy
te 
Nomina
l_Time 
(hr)  
conc 
(ng/mL)  
Trea
tme
nt A 
OXN 
PR 
0.0 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
0.
00 
1
2 
0.0
0 
0.
0
0 
 
 
0.5 
49
.6 
78
.6 
2.
19 
18
.3 
23
1 
10
.2 
14
9 
0.
60
1 
36
.5 
13
.4 
11
1 
11
0 
1
2 
67.
5 
7
1.
2 
 
 
1.0 
10
8 
14
7 
64
.6 
24
6 
21
7 
71
.2 
26
1 
40
.8 
12
5 
23
7 
18
0 
18
9 
1
2 
15
7 
7
5.
7 
 
 
1.5 
14
7 
15
1 
13
2 
17
8 
18
9 
98
.8 
15
4 
10
7 
18
7 
17
5 
14
7 
17
6 
1
2 
15
3 
2
9.
7 
 
 
2.0 
12
5 
12
6 
14
0 
17
5 
16
0 
11
9 
12
4 
13
8 
19
3 
13
3 
13
6 
14
1 
1
2 
14
2 
2
2.
5 
 
 
3.0 
12
9 
98
.7 
10
6 
12
9 
11
8 
11
4 
11
4 
84
.9 
14
1 
16
5 
12
0 
12
8 
1
2 
12
1 
2
0.
5 
 
 
4.0 
13
0 
82
.5 
87
.2 
10
6 
10
6 
12
6 
10
6 
10
9 
12
1 
13
9 
89
.3 
10
6 
1
2 
10
9 
1
7.
6 
… 
 
Table 11.4.1.2:1 Descriptive statistical analysis results (summary) of the PK parameters of oxycodone, 
naloxone and their metabolites 
Analyte 
Parameters 
Units 
Treatment A 
OXN PR 
AUC0_48hr 
hr*mg/L 
xx(xx) 
 
AUC_%Extrap_pred 
% 
xx (xx) 
 
AUC0-inf 
 
xx (xx) 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
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Cmax 
ng/mL 
xx (xx) 
 
Tmax 
hr 
xx (xx, xx) 
 
Lambada_z 
1/hr 
xx (xx) 
 
T1/2 
hr 
xx (xx) 
… 
Tmax: Median(Min,Max); Other PK parameters Mean (SD) 
 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
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Table 11.4.1.2:2 Descriptive statistical analysis results (including individual data) of the PK parameters 
of oxycodone, naloxone and their metabolites 
Analy
te 
Treatme
nt 
statisti
cs 
Lambada
_z 
(1/hr)  
T1/
2 
(hr
)  
Tma
x 
(hr)  
Cmax 
(ng/m
L)  
AUC0-inf 
(hr*ng/m
L)  
%AUCextr
ap 
(%)  
AUC0_48
hr 
(hr*mg/L
) 
OXN PR 
Treatment A 
N 
** 
** 
** 
** 
** 
** 
** 
 
 
Mean 
** 
** 
** 
** 
** 
** 
** 
 
 
SD 
** 
** 
** 
** 
** 
** 
** 
 
 
Min 
** 
** 
** 
** 
** 
** 
** 
 
 
Median 
** 
** 
** 
** 
** 
** 
** 
 
 
Max 
** 
** 
** 
** 
** 
** 
** 
 
 
CV% 
** 
** 
** 
** 
** 
** 
** 
… 
 
Table 11.4.1.2:3 Dose proportionality assessment results 
Analyte 
Item 
Confidence 
Level 
Point 
Estimate 
Confidence 
Interval 
Criterion 
OXN PR 
AUC0-48h 
AUC0-inf 
0.1 
0.1 
xx 
xx 
(xx, xx) 
(xx, xx) 
(0.800,1.250) 
(0.800,1.250) 
 
Cmax 
0.1 
xx 
(xx, xx) 
(0.800,1.250) 
… 
 
Table 12.2.3 Summary on adverse events 
Parameter 
Treatment A 
N， N(%) 
Treatment B 
N， N(%) 
Total 
N， N(%) 
All AE 
 
 
 
Study drug-related AE* 
 
 
 
Severe AE** 
 
 
 
Study drug-related severe AE 
 
 
 
Serious adverse events (SAE)  
 
 
 
Study drug-related SAE 
 
 
 
AE leading to study termination 
 
 
 
AE given combined treatment 
 
 
 
AE given other treatment 
 
 
 
AE leading to reduced dose of 
study drug 
 
 
 


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 OXN PR 
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20 
*: Positively related, probably related and possibly related are regarded to be correlated with the study drug 
**: The severity of AE is SAE  
N，N(%)：Nbr of AE, Nbr of Subject(incidence) 
 
Table 12.2.3:1 Table for severity of adverse events and treatment-related frequency 
Treatment 
AE 
Severity 
Definitely 
related 
Probably 
related  
Possibly 
related   
Possibly 
unrelated 
Definitely 
unrelated 
Total 
TreatmentA 
（N=12）n (%) 
Mild 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
 
Moderate 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
 
Severe 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
。。。 
 
N: Number of subjects in each group 
n: Number of subjects with effective data 
%: N-based percentage 
 
Table 12.2.3:2 Table for incidence of adverse events (by SOC and PT) 
System organ classification 
GT 
Standard name of AE  
PT 
Treatment A 
(N=12) 
Treatment B 
(N=12) 
Infection and infectious 
diseases 
Total 
**(**) 
**(**) 
 
Upper respiratory tract 
infection 
**(**) 
**(**) 
Various types of 
examinations 
Total 
**(**) 
**(**) 
 
Elevated alanine 
aminotransferase 
**(**) 
**(**) 
 
Elevated blood myoglobin  
**(**) 
**(**) 
 
Elevated creatine 
phosphokinase 
**(**) 
**(**) 
Various types of nervous 
system diseases 
Total 
**(**) 
**(**) 
 
Head discomfort 
**(**) 
**(**) 
Skin and subcutaneous tissue 
diseases  
Total 
**(**) 
**(**) 
 
Dermatitis 
**(**) 
**(**) 
 
Rash 
**(**) 
**(**) 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
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21 
System organ classification 
GT 
Standard name of AE  
PT 
Treatment A 
(N=12) 
Treatment B 
(N=12) 
Systemic disease and various 
administration site reactions 
Total 
**(**) 
**(**) 
 
Fatigue 
**(**) 
**(**) 
 
Local reaction 
**(**) 
**(**) 
 
Drowsiness 
**(**) 
**(**) 
Kidneys and urinary system 
diseases 
 
Total 
**(**) 
**(**) 
 
Frequent micturition 
**(**) 
**(**) 
Gastrointestinal diseases 
Total 
**(**) 
**(**) 
 
Constipation 
**(**) 
**(**) 
 
Abdominal pain 
**(**) 
**(**) 
 
Diarrhea 
**(**) 
**(**) 
 
Oral ulcer 
**(**) 
**(**) 
Blood and lymphatic system 
diseases 
 
Total 
**(**) 
**(**) 
 
Neutropenia 
**(**) 
**(**) 
Eye diseases 
Total 
**(**) 
**(**) 
 
Conjunctival hyperemia 
**(**) 
**(**) 
 
Table 12.2.3:3 Table for frequency analysis of serious adverse events 
Treatment 
SAE related to 
study drug(%) 
SAE(%) 
** 
** 
** 
* Absence of SAE 
 
Table 12.4.1:1 Descriptive statistical analysis results for haematology 
Treatment 
Item 
Unit 
ExpDelta|(min) 
N 
Mean 
SD 
CV(%) 
Min Median Max 
Treatment A 
Item1 
U/L 
TimePoint1 
** 
** 
** 
** 
** 
** 
** 
 
 
 
TimePoint2 
** 
** 
** 
** 
** 
** 
** 
 
 
 
… 
** 
** 
** 
** 
** 
** 
** 
 
Item2 
U/L 
TimePoint1 
** 
** 
** 
** 
** 
** 
** 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
22 
Treatment 
Item 
Unit 
ExpDelta|(min) 
N 
Mean 
SD 
CV(%) 
Min Median Max 
 
 
 
TimePoint2 
** 
** 
** 
** 
** 
** 
** 
 
 
 
… 
** 
** 
** 
** 
** 
** 
** 
 
Item3 
g/L 
TimePoint1 
** 
** 
** 
** 
** 
** 
** 
 
 
 
TimePoint2 
** 
** 
** 
** 
** 
** 
** 
 
 
 
… 
** 
** 
** 
** 
** 
** 
** 
 
Item4 
mmol/L 
TimePoint1 
** 
** 
** 
** 
** 
** 
** 
 
… 
 
TimePoint2 
** 
** 
** 
** 
** 
** 
** 
 
 
 
… 
** 
** 
** 
** 
** 
** 
** 
… 
Screening:TimePoint**—TimePoint**;Baseline:TimePoint**—TimePoint**;Treatment:TimePoint**—TimeP
oint**; 
Similar tables are as follows 
Table 12.4.1:2 Descriptive statistical analysis results for changes of haematology relative to the baseline 
Table 12.4.1:4 Descriptive statistical analysis results for blood chemistry 
Table 12.4.1:5 Descriptive statistical analysis results for changes of haematology relative to the baseline 
Table 12.5.1:1 Descriptive statistical analysis results for vital signs 
Table 12.5.1:2 Descriptive statistical analysis results for changes of vital signs relative to the baseline 
Table 12.5.1:3 Descriptive statistical analysis results for 12-lead ECG 
Table 12.5.1:4 Descriptive statistical analysis results for changes of 12-lead ECG relative to the baseline 
 
Table 12.4.1:3 Table for frequency of haematology results 
Treatment 
Item 
ExpDelta 
(min) 
Norma
l 
n(%) 
Abnormal, without clinical 
significance n(%) 
Abnormal, with clinical 
significance 
n(%) 
Treatment 
A 
Item
1 
TimePoint
1 
**(**) 
**(**) 
**(**) 
 
 
TimePoint
2 
**(**) 
**(**) 
**(**) 
 
 
… 
**(**) 
**(**) 
**(**) 
 
Item
2 
TimePoint
1 
**(**) 
**(**) 
**(**) 
 
 
TimePoint
2 
**(**) 
**(**) 
**(**) 
 
 
… 
**(**) 
**(**) 
**(**) 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
23 
Treatment 
Item 
ExpDelta 
(min) 
Norma
l 
n(%) 
Abnormal, without clinical 
significance n(%) 
Abnormal, with clinical 
significance 
n(%) 
 
Item
3 
TimePoint
1 
**(**) 
**(**) 
**(**) 
 
 
TimePoint
2 
**(**) 
**(**) 
**(**) 
 
 
… 
**(**) 
**(**) 
**(**) 
 
Item
4 
TimePoint
1 
**(**) 
**(**) 
**(**) 
 
… 
TimePoint
2 
**(**) 
**(**) 
**(**) 
 
 
… 
**(**) 
**(**) 
**(**) 
… 
Screening:TimePoint**—TimePoint**;Baseline:TimePoint**—TimePoint**;Treatment:TimePoint**—TimePoint**
; 
Similar tables are as follows 
Table 12.4.1:6 Table for frequency of blood chemistry results 
Table 12.4.1:7 Table for frequency of urinalysis results 
Table 12.5.1:5 Table for frequency of 12-lead ECG results 
Table 12.5.1:6 Table for frequency of physical examination results 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
24 
Figures 
Figure 1.1 Mean plasma drug concentration-time linear curve for oxycodone, naloxone and their 
metabolites 
 
Similar figures are as follows 
Figure 1.2 Mean plasma drug concentration-time semi-logarithmic curve for oxycodone, naloxone and 
their metabolites 
Figure 2.1 Individual plasma drug concentration-time linear curves for oxycodone, naloxone and their 
metabolites 
 
Similar figures are as follows,  


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
25 
Figure 2.2 Individual plasma drug concentration-time semi-logarithmic curve for oxycodone, naloxone 
and their metabolites 
 
Listing 
Listing11.1.1:1 listing of trial completion status 
Subject 
Treatment 
Completion 
status 
Completion 
date 
Signature of 
Investigator 
(Date) 
1001 
Treatment A 
** 
** 
** 
1002 
Treatment A 
** 
** 
** 
1003 
Treatment A 
** 
** 
** 
1004 
Treatment A 
** 
** 
** 
… 
 
Listing11.1.1:2 Listing of trial protocol deviation 
Treatment 
Occasion 
Subject 
(PI 
endorsed) 
measures 
taken on 
protocol 
deviation 
Actual situation 
of deviation 
events 
Nature 
of 
protocol 
deviation 
Time of protocol 
deviation 
Protocol 
requirements 
for deviation 
event-related 
items 
** 
** 
** 
** 
** 
** 
** 
** 
 
 
** 
** 
** 
** 
** 
** 
… 
 
Listing11.2.1:1 Listing of demographics 
Subject 
Age 
(Years) 
Gen
der 
Race 
Heig
ht 
(m) 
Weit
ht 
(kg) 
BMI 
(kg/m^2) 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
… 
 
Listing11.3:1 Listing of Concomitant Medication 
 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
26 
Treatme
nt 
Occasio
n 
Subje
ct 
Does 
concomita
nt 
medicatio
n or 
treatment 
occur 
before the 
first dose? 
Dru
g 
nam
e 
Dos
e 
unit 
Indicatio
n 
Dosage for 
single-dose 
administrati
on 
Route of 
administrati
on 
Does 
medicatio
n 
continue 
at ending 
of this 
study? 
Dosing 
frequenc
y 
Startin
g time 
Endin
g time 
** 
** 
** 
** 
** ** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** ** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** ** 
** 
** 
** 
** 
** 
** 
** 
… 
 
Listing11.3:2 Listing of past medical history 
Subject 
Preferred 
Term 
PT annotations 
Value 
** 
Admissions 
Past history of hospitalization 
** 
 
Operations 
Past history of surgery/trauma 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
27 
Subject 
Preferred 
Term 
PT annotations 
Value 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
1002 
Admissions 
Past history of hospitalization 
** 
 
Operations 
Past history of surgery/trauma 
** 
 
** 
** 
** 
 
** 
** 
** 
… 
 
Listing11.4 Listing of blood collection 
Subject 
Treatment 
Expected 
delta-time 
(hr) 
Actual 
Time 
(hr) 
BiasTime 
(hr) 
Flag 
status 
** 
** 
0 
** 
** 
** 
** 
 
 
0.5 
** 
** 
** 
** 
 
 
1 
** 
** 
** 
** 
 
 
1.5 
** 
** 
** 
** 
 
 
2 
** 
** 
** 
** 
 
 
… 
 
 
 
 
 
** 
0 
** 
** 
** 
** 
 
 
0.5 
** 
** 
** 
** 
 
 
1 
** 
** 
** 
** 
 
 
1.5 
** 
** 
** 
** 
 
 
2 
** 
** 
** 
** 
 
 
… 
 
 
 
 
… 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
28 
 
Listing12.1:1 Listing of individual medication 
Subject 
Occasion 
Treatment 
Expected 
time 
(min) 
Actual 
delta 
time 
(min) 
Admin time (Day and 
Time) 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
… 
 
Listing12.2.2:1 Listing of adverse events 
Treatment Occasion SubjectNr PT 
System 
organ 
catalog 
AE 
severity
AE 
beginning 
time 
AE 
ending 
time 
Whether 
SAE 
Relationship 
between AE and 
treatment 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
… 
 
Listing12.4:1 Listing of laboratory haematology test results 
Subject 
Treatment 
Occasion 
Time 
(min) 
Item 
Value 
Notes 
** 
** 
** 
** 
LabHae
m 
** 
** 
 
** 
** 
** 
LabHae
m 
** 
** 
 
** 
** 
** 
LabHae
m 
** 
** 
 
** 
** 
** 
LabHae
m 
** 
** 


Mundipharma (China) Pharmaceutical Co., Ltd. 
 OXN PR 
CPRCL-183-OXN/SAP/S 
29 
Subject 
Treatment 
Occasion 
Time 
(min) 
Item 
Value 
Notes 
… 
 
Similar listings are as follows, 
Listing12.4:3 Listing of laboratory blood biochemistry test results 
Listing12.4:5 Listing of laboratory urinalysis test results 
Listing12.5:2 Listing of individual 12-lead ECG determination results 
Listing12.5:4 Listing of individual physical examination results 
 
Listing12.4:2 Listing of laboratory haematology test results 
Subject 
Treatment 
Occasion 
Time 
(min) 
Item 
Unit 
Value 
Lower 
Limit 
Upper 
Limit 
Notes 
Judge 
** 
** 
** 
** 
Item1 
** 
** 
** 
** 
** 
** 
 
 
 
 
Item2 
** 
** 
** 
** 
** 
** 
 
 
 
 
Item3 
** 
** 
** 
** 
** 
** 
 
 
 
 
… 
 
 
 
 
 
 
Similar listings are as follows, 
Listing12.4:4 Listing of laboratory blood biochemistry examination results 
Listing12.5:1 Listing of individual vital signs results 
Listing12.5:3 Listing of individual 12-lead ECG examination results