Conditions: Cancer Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 232
Healthy volunteers: no

Brief summary:
To Determine the Safety and Efficacy of Oxycodone / Naloxone Prolonged Release Tablets compared to Oxycodone PR in Subjects with Moderate to Severe, Chronic Cancer Pain

Detailed description:
This is a randomised, double-blind, double-dummy, parallel group study using OXN and OXY PR to treat moderate to severe, chronic cancer pain. Subjects with documented history of cancer pain that requires around the clock opioid therapy will be included. Subjects must have a medical history of constipation that was induced by, or worsened by their opioid therapy.

Arms:
arm 1: 5/2.5mg, 10/5mg, 20/10mg or 40/20mg arm 2: 5mg, 10mg, 20mg or 40mg

Interventions: intervention 1: Oxycodone/Naloxone intervention 2: Oxycodone
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 


 
 
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Version Date: 13 March. 2013  
 
 
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SIGNATURE PAGE FOR INVESTIGATORS 
Protocol Number: 
OXN10-CN-303 
 
 
Title: 
 
 
 
 
 
A Phase III, Randomized, Double-blind, Double-dummy, Parallel Group 
Study to Determine the Safety and Efficacy of Oxycodone / Naloxone 
Prolonged Release Tablets 5/2.5mg, 10/5mg, 20/10mg or 40/20mg 
compared to Oxycodone PR 5mg, 10mg, 20mg or 40mg in Subjects with 
Moderate to Severe, Chronic Cancer Pain 
 
 
Test Drug: 
Oxycodone/naloxone prolonged release tablets (OXN) 
 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with ICH and China Good Clinical Practice guidelines, including the 
Declaration of Helsinki and all its accepted amendments to date. 
 
 
 
 
 
 
 
Investigator 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Version Date: 13 March. 2013  
 
 
Page 3 of 72 
 
1 TITLE PAGE 
Protocol Number: 
 OXN10-CN-303 
 
 
 
Title: 
A Phase III, Randomized, Double-blind, Double-dummy, Parallel 
Group Study to Determine the Safety and Efficacy of Oxycodone / 
Naloxone Prolonged Release Tablets 5/2.5mg, 10/5mg, 20/10mg or 
40/20mg compared to Oxycodone PR 5mg, 10mg, 20mg or 40mg in 
Subjects with Moderate to Severe, Chronic Cancer Pain 
 
 
 
Sponsor: 
Mundipharma (China) Pharmaceutical Co.LTD 
18F, Tower D Central International Trade Center 
6A Jianguomenwai Avenue 
Chaoyang District 
Beijing, China 100022 
 
 
 
Test Drug: 
Oxycodone/naloxone prolonged release tablets   
 
 
Indication: 
Chronic Cancer Pain 
 
 
Phase: 
Phase 3 
 
 
Release Date: 
13 Mar. 2013 
 
 
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. 
 


 
 
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2 CLINICAL PROTOCOL SUMMARY 
Name of company：Mundipharma(China) Pharmaceutical Co., Ltd. 
Name of Finished Product:：Oxycodone/naloxone 
prolonged release tablets (OXN 5/2.5mg, 10/5mg, 
20/10mg and 40/20mg) 
Name of Active Ingredient:  
Oxycodone/naloxone combination 
Short Title of the Study: OXN in Moderate to Severe, Chronic Cancer Pain
Full Title of the Study: A Phase III, Randomized, Double-blind, Double-dummy, Parallel Group Study to 
Determine the Safety and Efficacy of Oxycodone / Naloxone Prolonged Release Tablets 5/2.5mg, 10/5mg, 
20/10mg or 40/20mg compared to Oxycodone PR 5mg, 10mg, 20mg or 40mg in Subjects with Moderate to 
Severe, Chronic Cancer Pain 
Protocol No.：OXN10-CN-303 
Investigators/study sites：About 25 study sites in China 
Study Initiation Plan: May 2013 
Phase of Development: Phase III 
Main Objectives: 
 
To determine the improvement in symptoms of constipation in subjects receiving treatment with 
oxycodone/naloxone prolonged release tablets (OXN) compared to oxycodone prolonged release 
tablets(OXY) based on the Bowel Function Index (BFI). 
 
To demonstrate the non-inferiority (comparability) of oxycodone / naloxone prolonged release tablets 
(OXN) compared to oxycodone prolonged release tablets (OXY PR) for the management of chronic cancer 
pain as assessed by the average pain of the Brief Pain Inventory (BPI) recorded by subjects. 
Other objectives: 
 
To compare the improvement in symptoms of constipation in subjects receiving treatment with OXN 
compared to OXY PR based on laxative use. 
 
To demonstrate the comparability of OXN compared to OXY PR for the management of chronic cancer 
pain as assessed by rescue medication use recorded by subjects. 
 
To assess safety of treatment with OXN compared with OXYPR based on the Modified Subjective Opiate 
Withdrawal Scale (SOWS), Adverse Events (AEs), Electrocardiograms (ECG) and laboratory tests. 
 
To assess quality of life based on  EQ-5D 
Study Design (Methodology): 
This is a randomised, double-blind, double-dummy, parallel group study using OXN and OXY PR to treat 
moderate to severe, chronic cancer pain. Subjects with documented history of cancer pain that requires around-
the-clock opioid therapy will be included. Subjects must have a medical history of constipation that was induced 
by, or worsened by their opioid therapy. 
Screening: Subjects who sign informed consent will be screened for entry in to the study. The 
Inclusion/exclusion criteria will be assessed based on medical history, physical examination and lab test results.  
Subjects will be registered into the IRT system. After subjects have been qualified for the study during the initial 
screening visit (V1), they will return to visit the Investigator to be randomised and to enter the double-blind 
treatment phase of the study (V2). 
Double-blind Treatment Phase: Subjects will receive either OXN or OXY at V2. At V2 subjects will stop their 
pre study opioid and laxative medication. Subjects will receive the double-blind medication for 
a period of 4 weeks. Investigators will change the subject’s dose of pre study opioid to a dose of 
oxycodone prolonged release (PR). The starting dose of oxycodone PR will be based on the subject’s 
prior dose of opioid and whether subjects need an increase in opioid dose to control their pain. During 
the double-blind treatment phase study medication will be titrated up to a maximum of 120 mg/day of 
oxycodone PR.  
Open label Morphine Sulfate Tablets will be available to subjects as rescue medication throughout the double-
blind treatment phase. Morphine Sulfate Tablets will be taken  at a dose according to the table 5 and will be 
taken as required by subjects to treat breakthrough pain. A maximum of 6 doses of Morphine Sulfate Tablets 
can be taken in 24 hours. If a subject regularlyrequires more than 2 uses of rescue medication per day, the 
investigator should increase the subject’s 
dose of double-blind medication by 10 mg/day or 20mg/day of OXN/OXY PR in a double-blind, double-dummy 
manner. If a subject requires greater than 120 mg OXY/OXN PR or 120 mg OXY/OXN PR and more than the 
maximum Morphine Sulfate Tablets allowed by the protocol e.g. regularly requires more than six rescue doses 
of Morphine Sulfate Tablets, then the subject must be withdrawn from the study (see section on Concomitant 
Medication Including Rescue - Analgesics). 


 
 
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Throughout the double-blind treatment phase subjects will be given bisacodyl tablets to take as a laxative 
medication. On the day of randomisation pre study laxatives should be discontinued. If no bowel 
movement occurs within 3 days after the start of the double-blind phase, bisacodyl laxative intake will be 
commenced, which means that a laxative should be taken at that time. However investigators can 
instruct their subjects that if they exhibit discomfort during this period they can take oral bisacodyl as a 
laxative earlier than after 3 days as required to treat constipation. After that first 3 day period, bisacodyl 
tablets may be used no sooner than 72 h after the subjects’ most recent bowel movement. However 
investigators can instruct their subjects that if they exhibit discomfort during the 72 hour period they can 
take oral bisacodyl as a laxative earlier than 72 hours after their most recent bowel movement as 
required to treat constipation. The maximum allowed number of bisacodyl intakes is 5 dosages within 7 
consecutive days. 
The double-blind phase is 4 weeks in duration. Following screening and randomisation subjects will 
attend 4 clinic visits (V5, V6, V7, V8) and 3 additional telephone visits (V3, V4, and V9) during the treatment 
period. Visits 3, 4, are scheduled as a telephone visits however at the discretion of the investigator these may be 
completed as clinic visits and the same assessments as scheduled will be 
completed. At each clinic visit, assessments will be carried out to assess the subjects pain control (Brief 
Pain Inventory), use of rescue medication, bowel function (Bowel Function Index), and use of laxative 
medication (last 7 days). Subjects will also be asked for the number of bowel movements they have had 
in the last 7 days before the study visit and the number of days that they had a bowel movement in the 
last 7 days before the study visit. At Visits 3 and 4 , subject will be checked about the pain control to determine 
whether need to be titrated to a higher/lower dose study medication., use of rescue medication and SOWS(on 
V3). Throughout the study adverse events and concomitant medication will be recorded. Other measures 
including  EuroQol EQ-5D will 
be completed at Visit 1 and Visit 8.. 
Number of Subjects:  
Approximately 280 patients may be screened to obtain 230 pateints who will be randomised in a 1:1 ratio to 
OXN / OXY PR. Each group will have 115 subjects.  
Screening Phase Inclusion Criteria: 
1. 
Males and females, at least 18 years or older with a diagnosis of cancer. 
2. 
Females less than one year post-menopausal must have a negative urine pregnancy test recorded prior 
to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective 
method of 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 consistenly and correctly 
such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (hormonal), sexual 
abstinence or vasoectomised partner. 
3. 
Subjects who are receiving WHO step II or Step III analgesic medication who have constipation induced, 
or worsened by their opioid medication, as shown by 
a) 
the subject’s medical need of regular intake of laxatives to have at least 3 bowel evacuations per 
week, or having less than 3 bowel evacuations when not taking a laxative, respectively. 
b) 
the subject’s self-assessment that their constipation was induced or worsened by their current pre-
study opioid medication. 
4. Documented history of moderate to severe, chronic cancer pain that requires around the-clock opioid 
therapy (starting dose of oxycodone PR between 20 -80 mg/day) and are likely to benefit from WHO step III 
opioid therapy for the duration of the study. Subjects must be willing to discontinue their current opioid 
analgesic routine. 
5. Subjects are willing to discontinue pre study laxative medication and take study specific laxative 
medication. 
6. Subjects taking daily fibre supplementation or bulking agents are eligible if they can be maintained on a 
stable dose and regimen throughout the study, and in the investigators opinion are willing and able to 
maintain adequate hydration. 
7. Subjects willing and able (e.g. mental and physical condition) to participate in all aspects of the study, 
including use of medication, completion of subjective evaluations, attending scheduled clinic visits, 
completing telephone contacts, and compliance with protocol requirements as evidenced by providing 
written, informed consent. 
8. Subjects already taking non-opioid analgesics and all other concomitant medications (including those for the 
treatment of depression) are eligible to take part in the study. However, all concomitant medications that are 
considered necessary for the subject’s welfare should be continued at a stable dose throughout the double-
blind phase of the study and under the supervision of the investigator.  


 
 
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9. Expected survival time > 3 months. 
10. With capability of reading, understanding and signing inform consent form and compliance with protocol 
requirements. 
 
Exclusion Criteria: 
1. 
Subjects that require a dose >80 mg/day oxycodone PR at the start of the double-blind phase. 
2. 
Any history of hypersensitivity to oxycodone, naloxone, morphine  , bisacodyl, related products, and 
other ingredients. 
3. 
Subjects with any situation in which opioids are contra-indicated, severe respiratory depression with 
hypoxia and/or hypercapnia, severe chronic obstructive pulmonary disease, cor pulmonale, severe 
bronchial asthma, paralytic ileus. 
4. 
Subjects with evidence of clinically significant gastrointestinal disease (e.g. paralytic ileus, peritnoneal 
carcinosis), significant structural abnormalities of the gastrointestinal tract (e.g. scarring, obstruction 
etc) either related or not related to the underlying cancer or disease progression. 
5. 
Evidence of clinically significant cardiovascular, renal, hepatic or psychiatric disease, as determined 
by medical history, clinical laboratory tests, ECG results, and physical examination, that would place 
the subject at risk upon exposure to the study medication or that may confound the analysis and/or 
interpretation of the study results. 
6. 
Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), r-
glutamyltransferase (GGT) or alkaline phosphatase levels (>3 times the upper limit of normal) or an 
abnormal total bilirubin and/or creatinine level(s) (greater than 1.5 times the upper limit of normal). 
7. 
Cyclic chemotherapy in the two weeks before the screening visit or planned during the core study that 
has shown in the past to influence bowel function. If subjects are having their first cycle of 
chemotherapy during the 2 weeks before the screening visit or during the double-blind phase of the 
study they should be excluded from the study. 
8. 
Radiotherapy that, in the investigators opinion, would influence bowel function or pain during the 
double-blind phase of the study. 
9. 
Subjects with known or suspected unstable brain metastases or spinal cord compression that may 
require changes in steroid treatment throughout the duration of the study. 
10. Subjects with uncontrolled seizures. 
11. Subjects with increased intracranial pressure. 
12. In the investigator’s opinion, subjects who are receiving hypnotics or other central nervoussystem 
(CNS) depressants that may pose a risk of additional CNS depression with opioid study medication.
13. Subjects with myxodema, not adequately treated hypothyroidism or Addisons disease.  
14. Subjects who have a confirmed diagnosis of ongoing irritable bowel syndrome(IBS). 
15. Surgery completed within 4 weeks prior to the start of the Screening Period, or planned surgery 
during the study that would influence pain or bowel function during the study or preclude completion 
of the study. 
16. Subjects receiving opioid substitution therapy for opioid addiction (e.g. methadone or buprenorphine).
17. Active alcohol or drug abuse and/or history of opioid abuse. 
18. Subjects suffering from diarrhoea and/or opioid withdrawal. 
19. Subjects presently taking, or who have taken, naloxone ≤30 days prior to the start of the Screening 
Period. 
20. Subjects who participated in a clinical research study involving a new chemical entity or an 
experimental drug within 30 days of study entry (defined as the start of the Screening Period), unless 
the subject is on data collection phase for Overall Survival. 
 
Criteria for entry to the Double-Blind phase   
 
Subjects continue to comply with the Screening Inclusion/Exclusion criteria. 
 
Withdrawal Criteria: 
1. If the subject demonstrates opioid withdrawal defined as a Modified Subject Opiate Withdrawal 
Scale (SOWS) score >26.  
2. If a subject has a serious adverse event due to an opioid withdrawal syndrome. 


 
 
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3. If a subject meets at least one parameter of the Markedly Abnormal Laboratory values fulfilling at 
least one SAE criteria. 
4. If a subject exceeds/falls below the normal ranges for vital signs fulfilling at least one SAE 
criteria. 
5. If a subject requires greater than 120 mg OxyPR/OXN or 120 mg OxyPR/OXN plus more than 
the maximum Morphine Sulfate Tablets  allowed by the protocol e.g. requires more than six 
rescue doses of Morphine Sulfate Tablets. 
6. Regarding discontinuation criteria with respect to laxative use, overall the maximum allowed 
amount of bisacodyl should not exceed 5 dosages bisacodyl within 7 consecutive days. At the 
discretion of the investigator, the bisacodyl dose may be lowered. If there is no BM within 24 
hours following the 72 h period after the most recent BM bisacodyl use may be repeated. If there 
is still no BM within 24 hours following the use of bisacodyl, an enema may be used. If there is 
still no BM following the use of the enema, the subject will be discontinued from the study. 
7. If as subject demonstrates a clinically relevant reduction in vigilance fulfilling at least one SAE 
criteria. 
 


 
 
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Concomitant Medication Including Rescue: 
All investigational drugs and devices are prohibited unless otherwise specified in the clinical protocol 
or directed by the Investigator, only after having received prior authorization from sponsor. 
All other medication not prohibited by the protocol and considered necessary for the subject’s welfare 
may be administered and/or continued under the supervision of the investigator. 
Analgesics 
Study Medication 
Dosage 
Form 
Unit 
Strength 
Dosing 
Frequency 
Mode of 
administra
tion 
Morphine Sulfate Tablets 
Tablets 
10 mg  
q4-6h PRN 
Oral 
 
During the double-blind treatment phase, all subjects can receive Morphine Sulfate Tablets as rescue 
medication up to 6 times a day at a dose according to table 5 as recommendation. 
At the discretion of the investigator, the rescue dose may be lowered if the subject experience side 
effects from the recommended dose or if after taking the recommended dose, the investigator/subject 
feels that the dose is higher than what may be required to provide adequate analgesia. 
Stable doses of pre-study, non-opioid analgesics may be continued during the study. Any analgesic 
dosing during the double-blind treatment phase should remain stable. Opioid analgesics other than 
the study medication (i.e. OXN, OxyPR) and rescue medication (Morphine Sulfate Tablets) are not 
permitted. 
 
6 rescue doses of Morphine Sulfate Tablets are the total maximum amount of rescue medication 
per day. Subjects who, on more than two consecutive days take >6 rescue doses should be 
discontinued. Note: 1 dose = 1 time rescue is taken and not 1 tablet if multiple tablets are taken 
(i.e. 3 tablets of 10 mg for a 30 mg dose). 
 
During the double-blind treatment phase, subjects, who consistently require 2 rescue doses of 
Morphine Sulfate Tablets per day should have their dose of OXN/OXYPR increased. 
 
During the double-blind phase subjects who are on the maximum daily dose of 120 mg Oxy 
PR/OXN and who regularly require more than 2 rescue doses per day should be discontinued. 
 
The maximum possible Oxycodone dose and equivalent morphine dose during the study is 120 
mg Oxycodone PR per day plus 6 rescue doses of 180mg Morphine Sulfate Tablets  per day, 
i.e. 120 Oxycodone PR plus180mg Morphine Sulfate Tablets per day.  
In case other medication is taken by the subject after administration of the study drug, 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. 
 
 
 


 
 
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Laxatives, Anti-diarrhoeal Agents 
 
Study 
Medication 
Dosage Form 
Unit Strength 
Dosing 
Frequency 
Mode of 
administration 
Bisacodyl 
Tablets 
5 mg 
q3d prn* 
(10 mg/day)# 
Oral 
# At the discretion of the investigator the bisacodyl dose may be lowered (5mg) if the 
investigator/subject feels that the dose is higher than what may be required to provide an adequate 
bowel movement. If the dose is lowered to 5 mg, the lowered dose will be counted as a full single 
dose for this subject. 
* Throughout the double-blind treatment phase subjects will be given bisacodyl tablets to take as a laxative 
medication. On the day of randomization pre-study laxatives should be discontinued. If no bowel movement 
occurs within 3 days after the start of the double-blind phase, bisacodyl laxative intake will be commenced, 
which means that a laxative should be taken at that time. However, investigators can instruct their subjects that 
if they exhibit discomfort during this period they can take oral bisacodyl as a laxative earlier than after 3 days as 
required to treat constipation. After that first 3 day period, biscodyl tablets may be used no sooner than 72 h 
after the subjects’ most recent bowel movement. However investigators can instruct their subjects that if they 
exhibit discomfort during the 72 hour period they can take oral bisacodyl as a laxative earlier than 72 hours after 
their most recent bowel movement as required to treat constipation. The maximum allowed number of bisacodyl 
intakes is 5 dosages within 7 consecutive days. 
Overall the maximum allowed amount of bisacodyl should not exceed 5 dosages bisacodyl within 7 consecutive 
days. At the discretion of the investigator, the bisacodyl dose may be lowered. If there is no BM within 24 hours 
following the 72 h period after the most recent BM bisacodyl use may be repeated. If there is still no BM within 
24 hours following the use of bisacodyl, an enema may be used. If there is still no BM following the use of the 
enema, the subject will be discontinued from the study. 
Anti-diarrhoeals may be used throughout the study. 
 
Test Treatment, Dose, and Mode of Administration:  
Study Medication 
Dosage 
Form 
Unit Strength 
Dosing 
Frequency 
Mode of 
administra
tion 
Oxycodone/naloxone 
prolonged-release 
(OXN) 
Tablets 
5/2.5, 10/5, 20/10 and 
40/20 mg OXN  
Q12h 
Oral 
Matched placebo for 
OxyPR 
Tablets 
Matched placebos for 
5,10,20 and 40 mg Oxy 
PR  
Q12h 
Oral 
During the double-blind treatment phase, subjects randomized to OXN treatment will receive blinded 
OXN and matched OXYPR placebo. Dosing is fixed and symmetrical (20, 30, 40, 60, 80, 100, and 
120 mg/day Oxycodone prolonged release). 
Reference Treatment, Dose, and Mode of Administration: 
Study Medication 
Dosage 
Form 
Unit Strength 
Dosing 
Frequency 
Mode of 
administra
tion 
Oxycodone 
prolonged-release 
(OxyPR) 
Tablets 
5,10,20mg and 40 mg 
Oxy PR 
Q12h 
Oral 
Matched placebo for 
OXN 
Tablets 
Matched placebos for 
5/2.5,10/5,20/10 and 
40/20mg OXN 
Q12h 
Oral 


 
 
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During the double blind treatment phase, subjects randomized to OxyPR treatment will receive 
blinded OxyPR and matched OXN placebo. Dosing is fixed and symmetrical (20,30,40,60,80,100, 
and 120 mg/day Oxycodone prolonged release) 
 
Duration of Treatment:  
Pre-randomization Phase:  
Screening Period: Prospective Assessment: ≤ 7 days 
Double-Blind Phase:  
Treatment Period: 4 weeks. 
Safety Phase: 
Safety follow up: 1 week 
 
Flow Scheme for Treatment plan 
 
 
 
 
 
 
 
 
 
 
 
   ↑              ↑  ↑   ↑           ↑          ↑          ↑        ↑              ↑ 
V1            V2V3 V4        V5       V6       V7      V8           V9      
 
 
Treatment Schedule: 
Pre-randomization Screening Phase (up to 7 days): 
At Visit 1, after written informed consent is obtained, subjects undergo complete evaluation for study 
eligibility (i.e., all inclusion/exclusion criteria). Subjects who meet the Prospective Assessment 
Criteria can be randomized and enter the double-blind treatment phase of the study at visit 2. 
Double-blind Phase (4 weeks): 
At Visit 2, subjects who qualify for entry into the Double-blind Phase of the study will be randomized 
to Oxycodone/naloxone (OXN) or Oxycodone PR (OXYPR) (1:1). At the point of entry into the 
double-blind treatment phase, Investigators will change the subject’s dose of pre-study opioid to a 
dose of Oxycodone PR. This change will be based on the subject’s prior dose of opioid and whether 
subjects need an increase in opioid dose to control their pain. The subject’s pre-study laxatives will 
be changed to study laxatives.Titration of study medication throughout the 4 week double-blind 
phase, if needed, is allowed by 10mg/day or 20mg/day Oxycodone PR. Subjects will receive double-
blind study medication for up to 4 weeks. 
Morphine sulphate tablets will be available as rescue medication. If subjects require 2 use of rescue 
medication per day, the investigator should increase the subject’s dose of OXN/OxyPR up to a 
maximum of 120 mg Oxycodone PR per day. 
Safety Phase (1 week) 
Within one week following completion/discontinuation of the study (V8), the subjects will be followed 
up by telephone for assessment of any ongoing or new adverse events. 
 
The Schedule of Visits and Procedures is presented in TABLE 1 of the protocol. 
Criteria for Evaluation: Analysis Populations 
The following data sets will be analyzed: 
Enrolled Population 
The enrolled population is defined as all subjects who signed informed consent. 
OXY PR 
    Screening 
Double blind Treatment Period 
Safety Phase 
OXN  
≤ 7days 
4 weeks 
1 week 
R 


 
 
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Randomised Population 
The randomised population is defined as all randomised subjects. 
 
Full Analysis Population (FAP) 
The full analysis population is defined as all randomised subjects who receive at least one dose of 
study medication (IMP) and have at least one post-baseline primary efficacy endpoint. 
 
Per Protocol Population (PPP) 
The Per Protocol Population is defined as all FAP subjects without major protocol violations.  Major 
protocol violations will be agreed at the Determination of Subject Evaluability (DOSEA) meeting prior 
to database lock. 
 
 
Safety Population 
The safety population is defined as all randomised subjects who receive at least one dose of IMP and 
with at least one post-baseline safety assessment .  
 
For the superiority test (bowel function) the Full-analysis population will be the primary analysis and 
the PP analysis will be performed for sensitivity reasons. For the non-inferiority test (pain) the PP 
population analysis will  be the primary analysis and the FAS analysis will be the sensitivity analysis. 
All secondary endpoint will be analysed with the FAS population only, all safety analysis will use the 
DB safety population. 
Efficacy Assessments: 
Primary Efficacy Assessments: 
 
Bowel Function Index (BFI), recorded in the Case Report Form (CRF) at each assessment visit. 
The Bowel Function Index is the mean value of the 3 single items included in the BFI. Ease of 
defecation (numerical analogue scale [NAS], 0=easy/no difficulty; 100=severe difficulty); Feeling 
of incomplete bowel evacuation (NAS, 0=not at all, 100=very strong); Personal judgment of 
constipation (NAS, 0=not at all, 100=very strong).  
 
Brief Pain Inventory Short-Form (BPI-SF) (Cleeland, 1991) recorded at each visit assesses 
subject’s’ pain (worst, least, average, right now), pain relief from medication and pain 
interference over the last 24 Hours. 
• 
Secondary efficacy assessments: 
 
Amount of laxative medication use recorded at each assessment visit. Total number of bisacodyl 
tablets used per week, and the number of Bisacodyl tablets used per day will be recorded in the 
CRF. 
 
Amount (mg) of rescue medication used per day (24 hours) recorded on the OXY IR wallet. 
 
Modified Subjective Opiate Withdrawal Scale (SOWS) will be administered at Visits 1,  3, and 9..
 
EQ-5D assessment at Visit 1 and 8.  
 
Number of bowel movements the subject has had in the last 7 days before the study visit and 
number of days the subject had a bowel movement in the last 7 days before the study visit. 
Safety Assessments: 
 
Adverse events (collected via spontaneous reports, subject interview) 
 
Vital signs (at Visits 1, 2, 5, 6, 7 and 8) 
 
Clinical laboratory test results (at Visits 1,and 8) 
 
ECG (at Visits 1 and 8) 
 
Physical examination (at Visits 1 and 8) 
 
Statistical Methods 
Sample Size and Power Considerations  
Approximately 280 patients may be screened to obtain 230 pateints who will be randomised in a 1:1 ratio to 
OXN / OXY PR. Each group will have 115 subjects randomized to ensure 105 patients in the FAS per group. 


 
 
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With 105 subjects in the FAS per treatment group  the study has a power of 90% to detect a treatment difference 
of 12 on the BFI on a two-sided level of significance of α=0.05 assuming a common standard deviation of 26.  
EFFICACY ANALYSES  
 
 
 
 


 
 
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3 TABLE OF CONTENTS 
 
Page 
1  TITLE PAGE ......................................................................................................... 3 
2  CLINICAL PROTOCOL SUMMARY ..................................................................... 4 
3  TABLE OF CONTENTS ..................................................................................... 13 
4  LIST OF ABBREVIATIONS ................................................................................ 18 
5  STUDY CONDUCT AND OVERSIGHT .............................................................. 19 
5.1 Sponsor ............................................................................................................. 19 
5.2 Declaration of Ethical Conduct ....................................................................... 19 
5.3 Investigators and Study Personnel ................................................................ 19 
5.4 Randomisation ................................................................................................. 19 
5.5 Data Management ............................................................................................. 19 
5.6 Monitoring ......................................................................................................... 19 
5.7 Medical Monitoring & Safety ........................................................................... 20 
5.8 Central Review/Central Laboratory/Bioanalytical Laboratory ...................... 20 
6  INTRODUCTION ................................................................................................. 20 
6.1 Therapeutic Area/Background ........................................................................ 20 
6.2 Investigational Drug ......................................................................................... 20 
6.3 Study Rationale ................................................................................................ 21 
7  STUDY OBJECTIVES ........................................................................................ 22 
7.1 Aim of the study ............................................................................................... 22 
7.2 Main Objectives ................................................................................................ 22 
7.3 Other Objectives ............................................................................................... 23 


 
 
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8  STUDY SUMMARY AND GRAPHIC .................................................................. 23 
8.1 Overall Study Design and Plan ....................................................................... 23 
8.2 Study Diagram .................................................................................................. 24 
8.3 Efficacy Parameters ......................................................................................... 25 
8.3.1 Primary Efficacy Variable(s) ............................................................................ 25 
8.3.2 Secondary Efficacy Variable(s) ....................................................................... 25 
9  SELECTION OF SUBJECTS .............................................................................. 25 
9.1 Number of Subjects ......................................................................................... 25 
9.2 Inclusion Criteria .............................................................................................. 26 
9.3 Exclusion Criteria ............................................................................................. 27 
9.4 Criteria for Entry into the Double-blind Phase（the end of screening） .... 28 
10  ASSESSMENTS AND PROCEDURES ............................................................ 29 
10.1 Schedule Overview ........................................................................................ 29 
10.2 Screening/Baseline Period ............................................................................ 30 
10.3 Randomisation-Visit 2 .................................................................................... 31 
10.4 Treatment Period- Visit 3, 4, 5, 6, 7 and 8 ..................................................... 32 
10.5 Follow-Up Period-Visit 9 ................................................................................ 34 
10.6 End of Study ................................................................................................... 34 
10.7 Early Discontinue/Withdrawal from Study ................................................... 34 
11  STUDY TREATMENTS AND CONCOMITANT THERAPIES ........................... 35 
11.1 Study Treatments (IMPs and NIMPs) ............................................................ 35 
11.1.1 Test Investigational Medicinal Product(s), Dose and Mode of 
Administration .......................................................................................................... 35 
11.1.2 Reference Investigational Drug, Dose and Mode of Administration .............. 35 
11.1.3 Non-Investigational Medicinal Product (NIMP), Dose and Mode of 
Administration .......................................................................................................... 35 


 
 
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11.2 Study Treatments to be Supplied ................................................................. 38 
11.3 Dosing Schedule ............................................................................................ 39 
11.3.1 Starting dose of IMP ...................................................................................... 39 
11.3.2 Titration and Maintain dose of IMP ................................................................ 39 
11.4 Dose Modification/Discontinuation of NIMP ................................................ 40 
11.5 Method of Administration .............................................................................. 41 
11.6 Treatment Assignment .................................................................................. 41 
11.7 Blinding ........................................................................................................... 42 
11.8 Treatment Compliance/Drug Accountability ................................................ 42 
11.9 Concomitant Therapies (Permitted and Prohibited) .................................... 42 
11.10 Shipping, Handling, Storage, and Destruction/Return .............................. 43 
12  REFERENCE VALUES .................................................................................... 43 
12.1 Physical/Vital Sign Assessments ................................................................. 44 
12.2 Laboratory Assessments .............................................................................. 44 
12.3 Additional Assessments Reference Ranges................................................ 45 
13  SAFETY ASSESSMENTS ................................................................................ 45 
13.1 Adverse Events (AEs) and Serious Adverse Events (SAEs) ...................... 45 
13.2 Reporting of Adverse Events ........................................................................ 47 
13.3 Causality Assessment ................................................................................... 48 
13.4 Severity Assessment ..................................................................................... 48 
13.5 Outcome Evaluation ....................................................................................... 49 
13.6 Pregnancy ....................................................................................................... 49 
13.7 Laboratory Abnormalities .............................................................................. 49 
13.8 Vital Signs and Physical Examinations ........................................................ 50 
13.9 ECG Adverse Events ...................................................................................... 50 


 
 
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13.10 Other Safety Considerations/Risk Management ........................................ 50 
13.11 Product Quality Complaint .......................................................................... 50 
13.11.1 Process ....................................................................................................... 51 
13.11.2 Contacting the sponsor about the product quality ....................................... 51 
13.12 Overdose ....................................................................................................... 51 
14  STATISTICAL ANALYSES .............................................................................. 52 
14.1 Statistical Methodology and Analytical Plans ............................................. 52 
14.2 Statistical Considerations ............................................................................. 52 
14.3 Analysis Populations ..................................................................................... 52 
14.4 Protocol Violations and Deviations .............................................................. 53 
14.5 Sample Size and Power Considerations ...................................................... 53 
14.6 EFFICACY ANALYSES ................................................................................... 54 
14.7 Subject Disposition ........................................................................................ 54 
14.8 Demographic/Baseline Analyses .................................................................. 55 
14.9 IMP Analyses .................................................................................................. 55 
14.10 Concomitant Medications Analyses ........................................................... 55 
14.11 Safety Analyses/Adverse Outcomes .......................................................... 55 
14.12 Analysis of Adverse Events ........................................................................ 55 
14.13 Analysis of other Safety Parameters .......................................................... 56 
14.14 Other Special Tests ...................................................................................... 57 
15  ETHICS & REGULATORY ............................................................................... 57 
15.1 Declaration of Ethical Conduct ..................................................................... 57 
15.2 Ethical and Regulatory Review ..................................................................... 58 
15.3 Subject Information and Consent ................................................................. 58 
15.4 Data Protection and Human Tissue Sampling ............................................. 59 


 
 
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15.5 Quality Assurance & Inspection Requirements ........................................... 59 
16  STUDY MANAGEMENT RECORDS & PUBLICATION ................................... 59 
16.1 Protocol Amendments ................................................................................... 60 
16.2 Record Maintenance and Retention ............................................................. 60 
16.3 Adherence to the Protocol ............................................................................ 61 
16.4 Discontinuation of Study ............................................................................... 61 
16.5 Retention of Tissue Samples ........................................................................ 61 
16.6 Registration and Publication of Study Summary and Results ................... 61 
17  REFERENCE LIST ........................................................................................... 63 
18  APPENDICES ................................................................................................... 64 
Appendix 1 BPI-SF ................................................................................................. 64 
Appendix 2 BFI ....................................................................................................... 66 
Appendix 3 Modified Subjective Opiate Withdrawal Scale (SOWS) ................... 67 
Appendix 4 EQ-5D .................................................................................................. 68 
Appendix 5 Guidance table for identifying the starting dose of oxycodone 
PR based on pre study opioid use. ....................................................................... 70 
Appendix 6 Flow diagram for AE reporting ......................................................... 71 
Appendix 7  Criteria Used to Identify Clinically Notable Vital Sign 
Abnormalities ............................................................... Error! Bookmark not defined. 
 
 


 
 
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4 LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine transaminase 
ANOVA 
Analysis of variance 
AST 
Aspartate transaminase 
BM 
Bowel Movement 
BFI 
Bowel Functional Index 
BPI-SF 
Brief Pain Intensity-Short Form 
BUN 
Blood urea nitrogen 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DCF 
Data Clarification Form 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
ICF 
Inform Consent Form 
ICH 
International Conference on Harmonisation of Pharmaceuticals for Human 
Use
IEC 
Independent Ethical Committee 
IR 
Instant Release 
IVRS/IWRS 
Interactive Voice Response System/ Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NAS 
Numerical Analog Scale 
OXN 
oxycodone / naloxone prolonged release tablet 
Oxy PR 
oxycodone prolonged release tablet 
PI 
Principal Investigator 
PR 
Prolonged Release 
q12h 
Every 12 hours 
RBC 
Red blood cell (count) 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOPs 
Standard operating procedures 
WBC 
White blood cell (count) 
WHO 
World Health Organisation 
 


 
 
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5 STUDY CONDUCT AND OVERSIGHT 
5.1 Sponsor 
This study will be conducted by qualified Investigators under the Sponsorship of Mundipharma 
(China) Pharmaceutical Co.LTD 
5.2 Declaration of Ethical Conduct 
This study will be conducted in accordance with the standard operating practices of the Sponsor 
and Contract Research Organisation (CRO), which are designed to ensure adherence to Good 
Clinical Practice (GCP) guidelines as described in Section 15 of this protocol. 
5.3 Investigators and Study Personnel 
The study will be conducted at approximately 25 sites in China. 
5.4 Randomisation 
Randomisation will be completed using a validated system by the Sponsor in a 1:1 ratio.  An 
interactive response technology (IRT) system will be employed to manage study treatment 
supply.  Refer to Section 11.6 for details of how treatment is assigned.  
5.5 Data Management 
Data management and statistical analyses will be the responsibility of the Data Management 
and Statistics department at the selected CRO. Data collected via an EDC system as well as 
subject diaries, questionnaires and other external data, e.g. laboratory data, will be stored in a 
clinical database as specified in the CRO’s data management plan.  Quality control and data 
validation procedures will be applied to ensure the validity and accuracy of the clinical database.  
The Monitoring Plan and Data Management Plan will detail the data entry, cleaning, clarification, 
and validation procedures to be followed by all relevant study staff. 
All data will be forwarded to the CRO and an electronic copy supplied to the site.  Subjects will 
complete questionnaires and diaries which will be returned to the Investigator as detailed in 
Section 10. Laboratory data, vital signs, ECG and Adverse Events and concomitant medication 
data will be specified in the Data Management Plan. 
5.6 Monitoring 
The study will be monitored by qualified personnel from the CRO.  The Monitoring Plan for the 
study will detail this process.  The Investigator will allow monitoring, audit and inspection of the 
clinical, laboratory, and pharmacy facilities as required, to assure compliance with Good Clinical 
Practice and Good Laboratory Practice.  The EDC system and subject’s corresponding original 
medical records (source documents) are to be fully available for review by the CRO/Sponsor 
representatives at regular intervals.  These reviews verify adherence to study protocol and data 
accuracy in accordance with local regulations and Good Clinical Practice.  All records at the site 
are subject to inspection by the local competent authorities. 


 
 
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5.7 Medical Monitoring & Safety 
The name of the Study Physician along with the telephone and fax numbers of the other contact 
persons at the Sponsor and CRO are listed in the study site file. 
5.8 Central Review/Central Laboratory/Bioanalytical Laboratory There is no central 
review processes employed in the study. Local laboratories will be used for  sample analysis for 
safety assessment. 
  
6 INTRODUCTION 
 
6.1 Therapeutic Area/Background  
According to WHO's latest data show that it is estimated that by 2020, the global new cancer 
cases every year will reach about 15 million people, about a quarter of newly diagnosed patients, 
a third are treated patients and three-quarters of patients may be with pain. However, due to 
various reasons, thousands of pain patients did not receive regular treatment, suffering from 
severe pain. 
 
Pain is a common symptom of cancer patients. The incidence rate of pain for cancer patients is 
about 60%~80%, where 1/3 for patients with severe pain. Cancer pain patients may survive for 
months or years, if without appropriate analgesic treatment, cancer pain can cause extremely 
serious influence on the quality of life of patients and their families. For example, cancer pain 
can lead to depression, fatigue, anxiety, insomnia, general condition deteriorated, and also a 
serious interference implementation of anticancer therapy.  
  
6.2 Investigational Drug 
Oxycodone prolonged release  
Oxycodone prolonged release (OxyPR) is marketed by Purdue/Mundipharma/Napp and 
independent associated companies as OxyContin® /Oxygesic® in more than 50 countries for 
the treatment of moderate to severe pain (severe to most severe pain in Germany and 
concerned member states, but indication is country-specific) requiring around-the-clock opioid 
analgesia. Oxycodone was first introduced in the market as a prolonged release tablet at the 
end of 1995 in the US. Since then, the exposure in humans can be estimated as being 
approximately 50  million subject months. Oxycodone has been introduced into the market as a 
prolonged release formulation (Oxygesic) in Germany in 1998 and in China in 2004. 
Opioid bowel dysfunction is an adverse drug reaction associated with OxyContin®/Oxygesic® 
and other opioid analgesics that limits the continuous treatment of pain subjects and is therefore 
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Naloxone is a narcotic antagonist used as a solution for injection in the treatment of opioid 
overdose. When administered orally, it can reduce opioid-induced constipation due to a local 
action in the gut. It has a high first-pass metabolism, which is an advantage as the laxative effect 
can be achieved due to the local action in the gut, without significant antagonism of the narcotic 
analgesic effect of the oxycodone. In a clinical investigation in 22 chronic pain subjects with 
opioid-related constipation (Meissner et al., 2000), oral naloxone immediate release was titrated 
individually depending on laxation and withdrawal symptoms up to a daily maximum dose of 36 
mg (12 mg three times daily). In the majority of subjects the days with laxation were significantly 
increased and the days with laxative use significantly decreased. The mean naloxone dose was 
17.5 ± 10.2 mg/day and the mean morphine dose was 232 mg/day. Nausea, restlessness and 
sweating were the most commonly observed side effects during the naloxone treatment. In 
some subjects, localized sensations of mild to moderate abdominal propulsions or cramps 
occurred shortly after naloxone administration. In additional studies, naloxone doses and 
treatment times varied substantially, but clinical findings suggest that oral naloxone doses below 
2-4 mg are generally not effective (Meissner et al., 2000) and that daily naloxone doses of 50% 
of the corresponding morphine dose (including dosages above 100 mg morphine per day) can 
be tolerated (Latasch et al.,1997). 
 Please refer to prescription information of Oxycodone prolonged release  
Oxycodone/naloxone prolonged release (OXN PR)   
Oxycodone/naloxone prolonged release (OXN PR) is a prolonged release tablet consisting of 
oxycodone and naloxone in a 2:1 ratio. This ratio, when given in a prolonged release formulation, 
has been shown in the clinical Phase II study OXN2401 to provide sufficient analgesic activity 
measured by a pain scale (Numerical Analogue Scale (NAS)), similar to that of oxycodone 
combined with placebo naloxone, with an improved safety profile (Mueller-Lissner et al., 2007; 
Meissner et al.; 2008, Meissner et al., 2009). Naloxone prolonged release was well tolerated by 
the subjects in study OXN2401. OXN PR has been shown to provide effective analgesia while 
counteracting constipation (Simpson et al., 2008; Löwenstein et al., 2009; Reimer et al., 2009; 
Meissner et al., 2009; Vondrackowa et al., 2008). OXN PR (Targin®) was introduced into the 
German market in 2006. European regulatory procedures in 26 European countries for four 
dosage strengths (OXN5/2.5 mg PR, OXN10/5 mg PR, OXN20/10 mg PR and OXN40/20 mg 
PR twice daily) up to a maximum daily dose of OXN80/40 mg PR per day has been successfully 
completed. The Indication is: ‘Severe pain which can be adequately managed only with opioid 
analgesics. The opioid antagonist naloxone is added to counteract opioid-induced constipation 
by blocking the action of oxycodone at opioid-receptors locally in the gut’. 
6.3 Study Rationale 
In the UK, OXN PR is available for the treatment of pain under the tradename Targinact® since 
January 2009 (same tradename Targinact also in Cyprus, France, Belgium, Luxemburg, 
Slovenia and the Netherlands). In Norway, Sweden and Finland the tradename is Targiniq®. In 
all other concerned countries the tradename is Targin®. Furthermore OXN PR has also received 
Marketing Authorisation in Australia, Canada, China, Israel, New Zealand and Korea where the 
tradename is Targin®. 
Since the launch of OXN PR as an analgesic into the market the exposure in humans can be 
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established. OXN PR provides an effective pain treatment together with an improved quality of 
life due to a reduced number of patients suffering from impeded bowel function compared to 
treatment with other opioids. OXN PR maintains the systemic opioid effects while naloxone 
counteracts the bowel function disorders that are typical for opioid treatment due to the local 
competitive antagonism of the opioid receptor mediated oxycodone effect by naloxone in the gut. 
The mode of action of OXN PR is based on the particularly low oral bioavailability of naloxone 
(approx. 2%), which prevents that antagonist from having a significant impact on the central, 
analgesic properties of oxycodone. One possible obstacle to the development of higher strength 
OXN PR tablets would arise if the efficient extraction of naloxone by the liver was limited at 
higher strengths. However a single dose study (OXN1019) investigated the absolute 
bioavailability of naloxone following the administration of prolonged release naloxone tablets in 
healthy volunteers. It could be demonstrated that the low absolute bioavailability of naloxone 
was maintained up to a single dose of 120 mg oral naloxone. Therefore study OXN1019 
provided evidence that the administration of OXN PR in daily doses up to OXN180/90 mg PR do 
not point to a specific risk. 
In the clinical Phase III study OXN3401 it could be demonstrated that OXN PR has a superior 
analgesic efficacy compared to placebo and that the addition of naloxone does not negatively 
affect the analgesic efficacy of oxycodone PR (Vondrackova et al., 2008). Based on the clinical 
Phase III studies OXN3001 and OXN3006 it could be illustrated that OXN PR is superior to 
oxycodone PR alone, offering patients effective analgesia while significantly improving opioid-
induced constipation (Simpson et al., 2008; Löwenstein et al., 2009). It was also showed similar 
results in a Phase III study in patients suffering from malignant pain (OXN2001). 
The aim of the present study is to compare the effectiveness of OXN versus OXYPR in the 
management of chronic cancer pain by determining the improvement in symptoms of 
constipation –an adverse effect of opioid treatment, and also by assessing pain relief, safety  
and quality of life.  
 
The study will follow the protocol, ICH- GCP, Chinese GCP and the applicable registration 
requirements 
7 STUDY OBJECTIVES 
 
7.1 Aim of the study 
To assess the investigational drugs’ effectiveness in relieving cancer pain and the improvement 
of adverse reaction of opioid -- symptoms of constipation. 
7.2 Main Objectives 
 
To determine the improvement  in symptoms of constipation in subjects with moderate to 
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(OXN) compared to oxycodone prolonged release tablets(OXY) based on the Bowel 
Function Index (BFI). 
 
To demonstrate the non-inferiority (comparability) of oxycodone / naloxone prolonged 
release tablets (OXN) compared to oxycodone prolonged release tablets (OXY PR) for the 
management of chronic cancer pain as assessed by the average pain of the Brief Pain 
Inventory (BPI). 
7.3 Other Objectives 
 
To compare the improvement in symptoms of constipation in subjects receiving treatment 
with oxycodone/naloxone prolonged release tablets (OXN) to oxycodone prolonged release 
tablets(OXY PR) based on laxative use. 
 
To compare the management of chronic cancer pain of oxycodone / naloxone prolonged 
release tablets (OXN) compared to oxycodone prolonged release tablets (OXY PR) as 
assessed by rescue medication use recorded by subjects. 
 
To compare the management of chronic cancer pain of oxycodone / naloxone prolonged 
release tablets (OXN) compared to oxycodone prolonged release tablets (OXY PR) as 
assessed by Brief Pain Inventory Short-Form (BPI-SF) (Cleeland, 1991) recorded at each 
visit assesses subject’s’ pain (worst, least, right now), pain relief from medication and pain 
interference over the last 24 Hours. BPI will be assessed on V1, V2, V5, V6, V7 and V8.  
 
 
To assess safety of treatment with OXN compared with OXY based on the Modified 
Subjective Opiate Withdrawal Scale (SOWS), Adverse Events (AEs), Electrocardiograms 
(ECG) and laboratory tests. 
 
To assess quality of life based on  EQ-5D 
8 STUDY SUMMARY AND GRAPHIC 
 
8.1 Overall Study Design and Plan 
This is a multiple-center, randomized, double-blind, double-dummy, active-controlled, parallel 
group study using OXN 5/2.5mg, 10/5mg, 20/10mg or 40/20mg and Oxy PR 5mg, 10mg, 20mg 
and 40mg to treat moderate to severe, chronic cancer pain. Subjects with documented history of 
cancer pain that requires around-the clock opioid therapy will be included. Subjects must have a 
medical history of constipation that was induced by, or worsened by their opioid therapy. 
This study is composed of three phases: a screening phase(<7 days) and a 4-week double-blind 
phase and follow up phase(1 week after last dose).  
Following informed consent and screening, eligible subjects will be randomly allocated to one of 
the following treatments (in a ratio of allocation 1:1) via an  IRT system.: 
• 
Active oxycodone prolonged release tablets (OXYPR) and placebo oxycodone / naloxone 
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prolonged release tablets. 
• 
Active oxycodone / naloxone prolonged release tablets (OXN) and placebo oxycodone 
prolonged release tablets (OXYPR). 
At randomisation, the start of the double-blind phase, subjects will discontinue their current (pre 
study) opioid and change to an effective dose of study medication (OXYPR/OXN). Subjects will 
also stop taking any pre study laxatives at the time of randomisation and revert to the study 
laxative regime.  
Approximately 280 patients may be screened to obtain 230 patients who will be randomised in a 
1:1 ratio to OXN / OXY PR. Each group will have 115 subjects. 
 
8.2 Study Diagram 
Figure 1 Study diagram for randomised double-blind study 
 
 
 
Screening 
Maintenance 
Follow up 
7 Days 
Day 0 
28 Days 
7 Days 
R
OXY PR
OXN PR
R = randomisation 
Period 


 
 
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8.3 Efficacy Parameters 
8.3.1 Primary Efficacy Variable(s) 
 
Bowel Function Index (BFI) will be the mean of the following items (assessed at V1, V2, V5, 
V6, V7, V8): 
− Ease of defecation (numerical analogue scale [NAS], 0=easy/no difficulty; 100=severe 
difficulty) 
− Feeling of incomplete bowel evacuation (NAS, 0=not at all, 100=very strong). 
− Personal judgment of constipation (NAS, 0=not at all, 100=very strong). 
Each of the above questions refers to the last 7 days for the subject. 
 
Brief Pain Inventory Short-Form (BPI-SF) (Cleeland, 1991) recorded at each visit assesses 
subject’s’ average pain over the last 24 Hours. BPI will be assessed on V1, V2, V5, V6, V7 
and V8.  
 
 　 
8.3.2 Secondary Efficacy Variable(s) 
 
To compare the improvement in symptoms of constipation in subjects receiving treatment 
with oxycodone/naloxone prolonged release tablets (OXN) to oxycodone prolonged release 
tablets(OXY PR) based on laxative use. 
 
To compare the management of chronic cancer pain of oxycodone / naloxone prolonged 
release tablets (OXN) compared to oxycodone prolonged release tablets (OXY PR) as 
assessed by rescue medication use recorded by subjects. 
 
Brief Pain Inventory Short-Form (BPI-SF) (Cleeland, 1991) recorded at each visit assesses 
subject’s’ pain (worst, least, right now), pain relief from medication and pain interference 
over the last 24 Hours. BPI will be assessed on V1, V2, V5, V6, V7 and V8.   
 
To assess safety of treatment with OXN compared with OXY based on the Modified 
Subjective Opiate Withdrawal Scale (SOWS), Adverse Events (AEs), Electrocardiograms 
(ECG) and laboratory tests. 
 
To assess quality of life based on  EQ-5D 
9 SELECTION OF SUBJECTS 
 
9.1 Number of Subjects 
Approximately 230 subjects will be randomised to achieve 210 evaluable subjects in the Full 
analysis population.  An adequate number of subjects will be screened in the screening period 


 
 
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to achieve this sample size.  All subjects must have supplied written informed consent as per 
Section 15.3 prior to any study assessment or procedure taking place.  
 
9.2 Inclusion Criteria 
Subjects who are to be included in the study, are those who meet all of the following criteria: 
1. Males and females, at least 18 years or older with a diagnosis of cancer. 
2. Females less than one year post-menopausal must have a negative urine pregnancy test 
recorded prior to the first dose of study medication, be non-lactating, and willing to use 
adequate and highly effective method of 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 consistenly and correctly such as sterilisation, implants, injectables, 
combined oral contraceptives, some IUDs (hormonal), sexual abstinence or vasoectomised 
partner. 
3. Subjects who are receiving WHO step II or Step III analgesic medication who have 
constipation induced, or worsened by their opioid medication, as shown by 
 
a. the subject’s medical need of regular intake of laxatives to have at least 3 bowel 
evacuations per week, or having less than 3 bowel evacuations when not taking a 
laxative, respectively. 
b. the subject’s self-assessment that their constipation was induced or worsened by their 
current pre-study opioid medication. 
4. Documented history of moderate to severe, chronic cancer pain that requires aroundthe-
clock opioid therapy (starting dose of oxycodone PR between 20 -80 mg/day) and are likely 
to benefit from WHO step III opioid therapy for the duration of the study.Subjects must be 
willing to discontinue their current opioid analgesic routine. 
5. Opioid medication continue at a stable or nearly stable dose in the investigator's opinion 
during the treatment. 
6. Subjects are willing to discontinue pre study laxative medication and take study specific 
laxative medication. 
7. Subjects taking daily Subjects taking daily fibre supplementation or bulking agents are 
eligible if they can be maintained on a stable dose and regimen throughout the study, and in 
the investigators opinion are willing and able to maintain adequate hydration. 
8. Subjects willing and able (e.g. mental and physical condition) to participate in all aspects of 
the study, including use of medication, completion of subjective evaluations, attending 
scheduled clinic visits, completing telephone contacts, and compliance with protocol 
requirements as evidenced by providing written, informed consent. 
9. Subjects already taking non-opioid analgesics and all other concomitant medications 
(including those for the treatment of depression) are eligible to take part in the study. 
However, all concomitant medications that are considered necessary for the subject’s 
welfare should be continued at a stable dose throughout the double-blind phase of the study 


 
 
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and under the supervision of the investigator. Regarding cyclic chemotherapy please see 
exclusion criteria list. 
10. Subjects expected survived more than 3 months. 
11. Subjects are able to read, understand and sign written informed consent prior to study 
participation and are willing to follow the protocol requirements. 
9.3 Exclusion Criteria 
Subjects to be excluded from the study are those who meet any of the following criteria: 
1. Subjects that require a dose >80 mg/day oxycodone PR at the start of the double-blind 
phase. 
2. Any history of hypersensitivity to oxycodone, naloxone, morphine, bisacodyl, related 
products, and other ingredients. 
3. Subjects with any situation in which opioids are contra-indicated, severe respiratory 
depression with hypoxia and/or hypercapnia, severe chronic obstructive pulmonary disease, 
cor pulmonale, severe bronchial asthma, paralytic ileus. 
4. Subjects with evidence of clinically significant gastrointestinal disease (e.g. paralyticileus, 
peritnoneal carcinosis), significant structural abnormalities of the gastrointestinal tract 
(eg.scarring obstruction etc) either related or not related to the underlying cancer or disease 
progression. 
5. Evidence of clinically significant cardiovascular, renal, hepatic or psychiatric disease, as 
determined by medical history, clinical laboratory tests, ECG results, and physical 
examination, that would place the subject at risk upon exposure to the study medication or 
that may confound the analysis and/or interpretation of the study results. 
6. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), 
r-Glutamltransferase (GGT), or alkaline phosphatase levels (>3 times the upper limit of 
normal) or an abnormal total bilirubin and/or creatinine level(s) (greater than 1.5 times the 
upper limit of normal). 
7. Cyclic chemotherapy in the two weeks before the screening visit or planned during the core 
study that has shown in the past to influence bowel function. If subjects are having their first 
cycle of chemotherapy during the 2 weeks before the screening visit or during the double-
blind phase of the study they should be excluded from the study. 
8. Radiotherapy that, in the investigators opinion, would influence bowel function or pain during 
the double-blind phase of the study. 
9. Subjects with known or suspected unstable brain metastases or spinal cord compression, 
that may require changes in steroid treatment throughout the duration of the study. 
10. Subjects with uncontrolled seizures. 
11. Subjects with increased intracranial pressure. 
12. In the investigator’s opinion, subjects who are receiving hypnotics or other central nervous 
system (CNS) depressants that may pose a risk of additional CNS depression with opioid 
study medication. 


 
 
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13. Subjects with myxodema, not adequately treated hypothyroidism or Addisons disease. 
14. Subjects who have a confirmed diagnosis of ongoing irritable bowel syndrome. 
15. Surgery completed prior to the start of the Screening Period, or planned surgery during the 
study that would influence pain or bowel function during the study or preclude completion of 
the study. 
16. Subjects receiving opioid substitution therapy for opioid addiction (e.g. methadone or 
buprenorphine). 
17. Active alcohol or drug abuse and/or history of opioid abuse. 
18. Subjects suffering from diarrhoea and/or opioid withdrawal. 
19. Subjects presently taking, or who have taken, naloxone, or participated in a clinical research 
study involving a new chemical entity or an experimental drug within 30 days prior to the 
start of the Screening Period (except subject were in follow-up phase of survival data) 
20. Subjects who are incapable of giving informed consent or complying with the protocol. 
9.4 Criteria for Entry into the Double-blind Phase（the end of screening） 
  
Subjects continue to satisfy Screening Inclusion/Exclusion criteria. 
  
The exclusion criteria of Double-blind period are the same as the screening period. 
 


 
 
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10 ASSESSMENTS AND PROCEDURES 
 
10.1 Schedule Overview 
Table 1 Schedule of visits and procedures/ CRF modules for the study. 
Schedule of Visits and Procedures 
Phase 
Period 
Pre-
Randomiz
ation 
Double-blind phase 
Safety 
Phase 
Screening 
period 
Treatment period 
Safety
Phase 
Duration 
<  10 days  
4 weeks 
1 week
Study visit 
V1 
V210 
V3 
V4 
V5 
V6 
V7 
V81 
V9 
Study day2 
-10 to 0 
0  
1 
3 
7± 3 
14± 3 
21± 3 
28± 3 
35+ 3 
Informed consent 
X 
 
 
 
 
 
 
 
 
Assess inclusion/ 
exclusion criteria 
X 
(X) 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
 
 
 
 
 
X 
 
Vital signs 
measurements 
X 
(X) 
 
 
X 
X 
X 
X 
 
Medical history 
X 
(X) 
 
 
 
 
 
 
 
Assess prior and 
current 
medication use 
X 
(X) 
 
 
 
 
 
 
 
Clinical laboratory 
tests 
(hematology, 
chemistry, 
urinalysis) 
X 
 
 
 
 
 
 
X 
 
pregnancy3 
X 
 
 
 
 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
Clinic visit 
X 
(X) 
 
 
X 
X 
X 
X 
 
Telephone visit4 
 
 
X 
X 
 
 
 
 
X 
Laxative 
medication use5 
 
X 
 
 
X 
X 
X 
X 
 
Question on 
bowel movements 
x26 
X 
(X) 
  
  
X 
X 
X 
X 
 
Rescue 
medication use7 
 
daily 
 
Assess 
concomitant 
medication use 
 
X 
 
 
X 
X 
X 
X 
 
Bowel function 
index(BFI)8 
X 
(X) 
 
 
X 
X 
X 
X 
 
Brief pain 
inventory (BPI-
SF) 
X 
(X) 
 
 
X 
X 
X 
X 
 
Modified SOWS 
X 
 
X  
 
 
 
 
 
X 


 
 
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Phase 
Period 
Pre-
Randomiz
ation 
Double-blind phase 
Safety 
Phase 
Screening 
period 
Treatment period 
Safety
Phase 
Duration 
<  10 days  
4 weeks 
1 week
EuroQol EQ-5D 
X 
 
 
 
 
 
 
X 
 
Adverse events 
(Non-elicited 
reporting) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Call IRT to 
enter/update 
subject status 
information 
X 
X 
 
 
X 
X 
X 
X 
 
Study medication 
dosing9 
 
X 
 
 
X 
X 
X 
X 
 
Study medication 
dispensation 
 
X 
 
 
X 
X 
X 
 
 
Drug 
accountability 
 
 
 
 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Discontinuation/ 
end of study 
 
 
 
 
 
 
 
X 
 
1. 
End of the double-blind phase completed at visit 8 or as soon as possible after early discontinuation  
from study medication.  
2. 
The study visit window for Visit 1 ± 3 days  and ± 3 days for Visits 5, 6, 7, 8 , +3 days for visit 9 Further visits to  
the study site will be conducted if considered necessary for the subject’s welfare.  
3. 
Urine test. Women of childbearing potential must have a negative pregnancy test prior to first dose of  
study medication.  
4. 
Visits 3 & 4 are scheduled as telephone visits but can be completed as a clinic visit if required.  
5. 
Laxative use in the last week to be recorded (total number of tablets per week and number of tablets per day)  
6. 
Question 1. Number of bowel movements the subject has had in the last 7 days before the study visit  
Question 2. Number of days the subject had a bowel movement in the last 7 days before the study visit.  
7.   Recorded throughout the day for the rescue medication at the time of occurrence.  
8.   Includes subject assessments; ease of defecation, feeling of incomplete bowel evacuation, and  
personal judgment of constipation over the past 7 days. 
9.   If a subject needs to be titrated for adequate pain control the visit should be documented in the subject’s source notes  
and the change in study medication dose will be recorded on the dosing CRF page at the next clinic visit 
10   If screening visit and visit 2 are on the same day, do not duplicate the assessment completed on visit 1.  
10.2 Screening/Baseline Period 
After confirming the subject’s initial study eligibility, the following procedures/evaluations will be 
performed after the subject signs informed consent. No study procedure will be completed until 
the subject has given written informed consent 
Visit 1  ( 10 days): 
• Informed consent 
• Inclusion/exclusion criteria 
• Demography 
• Physical exam 


 
 
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• Vital signs 
• Medical history 
• Prior and current medication use 
• Clinical laboratory tests (hematology, chemistry, urinalysis) 
• Pregnancy test (urine) if applicable 
• 12-lead ECG 
• Complete 2 questions on bowel movement 
• Bowel Function Index BFI (Appendix 2) 
• Brief Pain Inventory Short Form BPI-SF© (Appendix 1 ) 
• Modified Subjective Opiate Withdrawal Scale SOWS (Appendix 3) 
• EuroQol EQ-5D (Appendix 4) 
Screening failures 
 
For subjects who are screening failures, the visit date should be registered in the IRT System 
and screening failure reason should be also be collected in the IRT system .  
 A subject will be considered a screen failure if the subject signs the ICF but withdraws from the 
study before receiving any study treatment.  Data for screen failures will be collected in the 
source documentation at the site; however, the subject number , date of consent and screen fail 
reason and adverse events will be captured in the EDC system . 
10.3 Randomisation-Visit 2 (Day 0) 
Randomisation will be completed once all inclusion and exclusion criteria are verified. Visit 2 can 
be on the same day of visit 1 or up to 10 days later and will be completed by IRT.  Refer to 
Section 11.6 for further details. 
Visit 2(Day 0) 
• Check Inclusion/exclusion criteria 
• Check medical history unchanged  
•  Vital signs 
• Laxative use 


 
 
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• Complete 2 questions on bowel movement 
• Concomitant medication and therapy 
• Bowel Function Index BFI (Appendix 2) 
• Brief Pain Inventory Short Form BPI-SF© (Appendix 1 ) 
• Modified Subjective Opiate Withdrawal Scale SOWS (Appendix 3) 
• Adverse Events 
Other procedures: 
• Call IRT to update the subject status information 
• Randomisation to double-blind treatment 
Dispense: 
• Double-blind study medications, OXYPR/OXN, rescue medication (morphine sulphate tablet), 
and laxative (bisacodyl) 
• Subject Questionnaires required for Visit 3 and Visit 4 
10.4 Treatment Period- Visit 3, 4, 5, 6, 7 and 8 
Visit 3(Day 1) and Visit 4(Day 3) Telephone Visits (Clinic visits can be performed at the 
discretion of the investigator and the same assessments as scheduled are to be completed) 
The following evaluations will be performed at Visit 3 and 4, which occurs 1 and 3 days after 
Visit 2: 
• Site Study Staff to call the subject to determine whether the subject needs to be titrated to a 
higher/lower dose study medication 
• Record rescue medication use 
• Adverse Events  
Subject Completes: 
• Modified Subjective Opiate Withdrawal Scale SOWS(only on Visit 3) 
V5，V6 和V7 
The following evaluations will be performed at Visit 5, 6, 7 and recorded on the eCRF: 
• 
Call IRT to update subject status information 


 
 
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Vital signs 
　 Complete 2 questions on bowel movement 
—Question 1：number of bowel movements the subject has had in the last 7 days before the 
study visit； 
—Question 2. Number of days the subject had a bowel movement in the last 7 days before the 
study visit. 
　 Laxative use 
　 Record rescue medication use 
　 Concomitant medication and therapy 
　 Bowel Function Index BFI（BFI） 
　 Brief Pain Inventory Short Form BPI-SF©（BPI-SF） 
　 Study Medication Dosing change if needed 
　 Adverse Events　 Study Medication Dispensation 
　 Drug Accountability 
Visit 8( Day 2, at time of study completion or early discontinuation) 
　 Physical exam 
　 Vital signs 
　 Clinical laboratory tests (hematology, chemistry, urinalysis) 
　 Pregnancy test (urine) if applicable 
　 12-lead ECG 
　 Complete 2 questions on bowel movement (see section above for V5-V7 for wording) 
　 Laxative use 
　 Record rescue medication use 
　 Concomitant medication and therapy 


 
 
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　 Bowel Function Index BFI（BFI） 
　 Brief Pain Inventory Short Form BPI-SF©（BPI-SF） 
　 EQ-5D 
 Adverse events 
　 Drug accountability 
　 Call IVRS to update subject status information 
10.5 Follow-Up Period-Visit 9 
Subjects that complete the Treatment Period or who discontinue treatment with IMP(s) early will 
be followed up no earlier than 7 days after the subject’s last dose of IMP.  
 Visit 9(Telephone Visit) 
　 Modified Subjective Opiate Withdrawal Scale（SOWS） 
　 Adverse Events 
10.6 End of Study 
Subjects that complete the treatment Period will carry out Completion/Discontinuation Visit (v8) 
procedures in accordance with Table 1   
10.7 Early Discontinue/Withdrawal from Study 
The Investigator(s) or subjects themselves may stop study treatment at any time for safety or 
personal reasons.  If possible, the subject will attend clinic to complete end-of-study procedures 
(Visit 8). 
Subjects who do not tolerate the study medication will be discontinued from the study. Site study 
staff members will discontinue the subject from the study and the subject will return to the clinic 
to complete Visit 8 and to be provided with appropriate therapy according to standard care. 
For subjects who prematurely stop participation in the study, Investigators will question subjects 
about their primary reason for discontinuing from the study, which will be recorded in the 
electronic Case Report Form. Site study staff members will follow subjects after the last dose of 
study medication for 7 days to collect non-serious adverse events, for 30 days to collect serious 
adverse events and obtain non-serious adverse event outcome information, and for serious 
adverse events, until the event resolves, or the event or sequelae stabilize. 
 


 
 
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11 STUDY TREATMENTS AND CONCOMITANT THERAPIES 
 
11.1 Study Treatments (IMPs and NIMPs) 
11.1.1 Test Investigational Medicinal Product(s), Dose and Mode of Administration 
In double-blind phase, subjects randomized to test treatment group will take OXN and matching 
placebo of OXYPR. The dosage would be fixed and symmetrical (20/10, 30/15, 40/20, 60/30, 
80/40,100/50 or 120/60 mg/day  of oxycodone/naloxone)  
Table 1 Investigational Drug Identity 
Test Treatment,  
Dosage 
Form 
Strength 
Dosing 
Frequency 
Mode of 
Administration 
Oxycodone /naloxone  
prolongedrelease (OXN) 
Tablets 
5/2.5，10/5，20/10 and40/20mg
OXN 
Q12h 
Oral 
Matched placebo 
for OXYPR 
Tablets 
Matching placebos for 5,10, 20 
and 40 mg OXYPR tablets 
Q12h 
Oral 
 
11.1.2 Reference Investigational Drug, Dose and Mode of Administration 
Subjects randomized to reference treatment group will take OXY PR and matching placebo of 
OXN. The dosage would be fixed and symmetrical(20, 30, 40, 60, 80,100 or 120mg/day) 
Table 3 Reference Investigational Drug Identity 
Study Medication 
Dosag
e Form 
Strength 
Dosing 
Frequency 
Mode of 
Administra
tion 
Oxycodone 
Prolonged release (OXY PR) 
Tablet
s 
5，10，20 and 40mg Oxy 
PR 
Q 12 h 
Oral 
Matched placebo 
for OXN 
Tablet
s 
5/2.5，10/5 ，20/10 
and40/20mg OXN placebo 
Q 12 h 
Oral 
 
11.1.3 Non-Investigational Medicinal Product (NIMP), Dose and Mode of 
Administration 
The rescue medications are not Investigational Medicinal Products.  Rescue medications 
include Analgesics and Laxative treatment and will be supplied by the Sponsor.. Table 4 and 6 
listed the analgesics and laxative rescue medication accordingly.  
Table 4 Analgesics Rescue Medication dosage and mode of administration 
 
Rescue 
Medication(Pain) 
Dosa
ge 
Form 
Strength 
Dosage Frequency 
Mode of 
Administratio
n 
Morphine Sulphate 
Tablet 
10 mg 
P.R.N, q4-6h 
Oral 


 
 
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Tablets 
 
During the double-blind treatment phase, all subjects can receive Morphine Sulphate Tablets as 
rescue medication up to 6 times a day at a dose(based on calculation of ratio for morphine and 
oxy IR) according to table 5. 
 
At the discretion of the investigator, the rescue dose may be lowered if the subject experiences 
side effects from the recommended dose, or if after taking the recommended dose the 
investigator/subject feel that the dose is higher than what may be required to provide adequate 
analgesia. 
 
 
• During the double-blind treatment phase, subjects, who consistently require more than 2 rescue 
doses of morphine sulphate tablets per day should have their dose of OXN/OXYPR increased. 
• The maximum possible Oxycodone dose during the study is 120 mg  per day plus 6 rescue doses of 
30mg morphine sulphate tablets per day, i.e. 120 Oxycodone PR plus 180mg morphine sulphate 
tablets per day 
• During the double-blind phase subjects who are on the maximum dose of 120 mg OXYPR/OXN and 
who regularly require more than 2 rescue doses per day should be discontinued. 
• 6 rescue doses of morphine sulphate tablet is the total maximum amount of rescue medication per 
day. Subjects who, on more than two consecutive days take >6 rescue doses should be discontinued. 
Stable doses of pre-study, non-opioid analgesics may be continued during the study. Any 
analgesic dosing during the double-blind treatment phase should remain stable.  
 
Opioid analgesics other than the study medication (i.e. OXN, OXYPR) and rescue medication 
(Morphine Sulphate Tablet) are not permitted during the double-blind phase. 
 
 
 


 
 
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For further information refer to below table for Rescue Dose.  
Table 5 Rescue Dose (based on calculation of ratio for morphine and oxy IR) 
 
Dose Level of daily 
maintenance dose of 
OXN/OXY 
Morphine sulphate tablets 
 Rescue Dose 
(Per Dose) 
L1(20mg) 
10 mg（1 Tablet） 
L2(30mg) 
10 mg（1 Tablet） 
L3(40mg) 
20 mg（2 Tablet） 
L4(60mg) 
20 mg（2 Tablet） 
L5(80mg) 
30 mg（3 Tablet） 
L6(100mg) 
30 mg（3 Tablet） 
L7(120mg)1 
30 mg（3 Tablet） 
1. 
If the daily dose over the  maximum possible oxycodone dose during the study is 120 mg per day plus 6 rescue 
doses of morphine sulphate tablets per day, the subject should discontinued from the study.  
 
Laxatives, Anti diarrhoeal Agents 
Throughout the double-blind treatment phase subjects will be given bisacodyl tablets to take as 
a laxative medication. On the day of randomisation pre study laxatives should be discontinued. If 
no bowel movement occurs within 3 days after the start of the double-blind phase, bisacodyl 
laxative intake will be commenced, which means that a laxative should be taken at that time. 
However investigators can instruct their subjects that if they exhibit discomfort during this period 
they can take oral bisacodyl as a laxative earlier than after 3 days as required to treat 
constipation. After that first 3 day period, bisacodyl tablets may be used no sooner than 72 h 
after the subjects’ most recent bowel movement. However investigators can instruct their 
subjects that if they exhibit discomfort during the 72 hour period they can take oral bisacodyl as 
a laxative earlier than 72 hours after their most recent bowel movement as required to treat 
constipation. The maximum allowed number of bisacodyl intakes is 5 dosages within 7 
consecutive days. 
 
Overall the maximum allowed amount of bisacodyl should not exceed 5 dosages bisacodyl 
within 7 consecutive days. At the discretion of the investigator, the bisacodyl dose may be 
lowered. If there is no BM within 24 hours following the 72 h period after the most recent BM 
bisacodyl use may be repeated. If there is still no BM within 24 hours following the use of 
bisacodyl, an enema may be used. If there is still no BM following the use of the enema, the 
subject will be discontinued from the study.  
 


 
 
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Table 6 Laxatives Rescue Medication dosage and mode of administration 
Rescue 
Medication 
 
Dosage Form 
Unit 
Strength 
Dosing 
 
Dosing 
Frequency 
 
Mode of 
Administrati
on 
 
Bisacodyl  
Tablets 
 
5mg 
q3d PRN
（10mg/day）# 
Oral 
# At the discretion of the investigator the bisacodyl dose may be lowered (5 mg) if the 
investigator/subject feel that the dose is higher than what may be required to provide an 
adequate bowel movement. If the dose is lowered to 5 mg the lowered dose will be counted as 
a full single dose for this subject.  
 
Antidiarrhoeals may be used throughout the study. 
 
11.2 Study Treatments to be Supplied 
The Sponsor will package the study treatments.  Each subject will receive either OXN and 
matched placebo of OXYPR or OXYPR and matched placebo of OXN.  In addition to the IMP 
subjects will also receive rescue medication for analgesia and laxative treatment if needed.  
Investigational and reference drugs will be supplied in labelled containers by the Sponsor.  
IMP 
Dosage form 
strength 
Manufacture site 
OXN PR 
Tablets 
5/2.5mg, 
10/ 5mg, 
20/10mg 
40/20mg 
Bard Pharmaceutical ltd., 
UK 
Matched placebo  
of OXY PR 
Tablets 
5mg, 
10mg, 
20mg 
40 mg 
OXY PR 
Tablet 
5mg, 
10mg, 
20mg 
40 mg 
Matched placebo  
of OXN 
Tablet 
5/2.5mg, 
10/5mg, 
20/10mg 
40/20mg 
The Product Release Certificate(s) for the IMP(s) will be included in the clinical study report for 
this protocol.  The study treatment will be supplied in packs labelled to meet the national 
requirements and will include a unique pack identifying number. 


 
 
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11.3 Dosing Schedule 
11.3.1 Starting dose of IMP 
At Visit 2, qualified subjects with confirmed opioid related constipation will stop their pre study 
opioid and will be randomised in a 1:1 allocation ratio to the double-blind study medication (i.e. 
OXN or OXYPR) taken every 12 hours which will be titrated to an effective analgesic dose.  
 The starting dose of oxycodone PR will be based on the subject’s prior dose of opioid  (see 
Appendix 5 Guidance table for identifying the starting dose of oxycodone PR based on pre-study 
opioid use) and whether subjects need an increase in opioid dose to control their pain.   
The related dose level based on approximately calculation by investigator will be selected as 
starting dosage. Start dose of eligible subjects (in the opinion of the investigator) for treatment is 
at least 20mg/day oxycodone PR to a maximum of 80 mg/day oxycodone PR. 
Subjects requiring a start dose of > 80 mg oxycodone PR should be excluded from the study 
(e.g. >200 mg Morphine). 
. 
11.3.2 Titration and Maintain dose of IMP 
 
Titration 
 
During the double-blind phase study medication will be titrated up to a maximum of 120 mg/day 
of oxycodone PR in a double-blind, double-dummy manner to obtain good pain control. 
 
Open label morphine sulphate tablets will be available to subjects as rescue medication 
throughout the double-blind treatment phase. Morphine sulphate tablets will be taken at a dose 
according to Table 5 as recommendation, and will be taken as required by subjects to treat 
breakthrough pain. A maximum of 6 doses of Morphine sulphate tablets can be taken in 24 
hours (e.g. for a subject on 120 mg/day oxycodone PR then the maximum dose of Morphine 
sulphate tablets would be 180 mg/day). For further information see Appendix 5. 
If a subject regularly requires more than 2 uses of rescue medication per day, the investigator 
should increase the subject’s dose of double-blind medication by 10mg/day or 20mg/day of 
OXN/OXYPR. 
If a subject requires greater than 120 mg/day OXY/OXN or 120 mg/day OXY/OXN plus more 
than the maximum Morphine sulphate tablets allowed by the protocol e.g. regularly requires 
more than two rescue doses of Morphine sulphate tablets, then the subject must be withdrawn 
from the study.  
Daily Maintained dose level 
Dose Level 
Daily maintenance dose of 
OXN  
Daily maintenance dose of 
OXY 
L1  
20/10 mg 
20mg 


 
 
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L2  
30/15 mg  
30mg 
L3  
40/20mg  
40mg 
L4  
60/30 mg  
60mg 
L5  
80/40 mg  
80mg 
L6 
100/50 mg  
100mg 
L71 
120/60  mg  
120mg 
1 Subjects requiring a start dose of > 80 mg oxycodone PR should be excluded from the study (e.g. >200 mg Morphine). 
11.4 Dose Modification/Discontinuation of NIMP 
Analgesia 
During the double-blind treatment phase, all subjects can receive morphine sulphate tablets as 
rescue medication up to 6 times a day at a dose according to Table 5. 
At the discretion of the investigator, the rescue dose may be lowered if the subject experience 
side effects from the recommended dose, or if after taking the recommended dose, the 
investigator/subject feels that the dose is higher than what may be required to provide adequate 
analgesia. 
• 
During the double-blind treatment phase, subjects, who consistently require 2 rescue doses 
of morphine Immediate-release Tablets per day should have their dose of OXN/OXY 
increased.  
• 
The maximum possible Oxycodone dose during the study is 120 mg  per day plus 6 rescue 
doses of 30mg morphine sulphate tablets per day, i.e. 120 Oxycodone PR plus 180mg 
morphine sulphate tablets per day 
• 
6 rescue doses of morphine sulphate tablets are the total maximum amount of rescue 
medication per day. Subjects who, on more than two consecutive days take >6 rescue 
doses should be discontinued. 
• 
During the double-blind phase subjects who are on the maximum daily dose of 120 mg Oxy 
PR/OXN and who regularly require more than 2 rescue doses per day should be 
discontinued. 
 Stable doses of pre-study, non-opioid analgesics may be continued during the study. Any 
analgesic dosing during the double-blind treatment phase should remain stable. Opioid 
analgesics other than the study medication (i.e. OXN, OxyPR) and rescue medication (morphine 
sulfate Tablets) are not permitted. 
• 
 
 
In case other medication is taken by the subject after administration of the study drug, 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. 
Laxatives, Anti-diarrhoeal Agents 


 
 
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1. Throughout the double-blind treatment phase subjects will be given bisacodyl tablets to take 
as a laxative medication. 
2. On the day of randomization pre-study laxatives should be discontinued.  
3. If no bowel movement occurs within 3 days after the start of the double-blind phase, 
bisacodyl laxative intake will be commenced, which means that a laxative should be taken 
at that time.  
However, investigators can instruct their subjects that if they exhibit discomfort during this 
period they can take oral bisacodyl as a laxative earlier than after 3 days as required to treat 
constipation.  
4. After that first 3 day period, biscodyl tablets may be used no sooner than 72 h after the 
subjects’ most recent bowel movement. However investigators can instruct their subjects 
that if they exhibit discomfort during the 72 hour period they can take oral bisacodyl as a 
laxative earlier than 72 hours after their most recent bowel movement as required to treat 
constipation.  
5. The maximum allowed number of bisacodyl intakes is 5 dosages within 7 consecutive days. 
At the discretion of the investigator the bisacodyl dose may be lowered (5mg) if the 
investigator/subject feels that the dose is higher than what may be required to provide an 
adequate bowel movement. If the dose is lowered to 5 mg, the lowered dose will be counted as 
a full single dose for this subject. 
 
Overall the maximum allowed amount of bisacodyl should not exceed 5 dosages bisacodyl 
within 7 consecutive days.  
 
If there is no BM within 24 hours following the 72 h period after the most recent BM bisacodyl 
use may be repeated. If there is still no BM within 24 hours following the use of bisacodyl, an 
enema may be used. If there is still no BM following the use of the enema, the subject will be 
discontinued from the study. 
 
 
Anti-diarrhoeals may be used throughout the study. 
11.5 Method of Administration 
The blinded study medication (i.e. OXN or OXYPR) will be administered orally, prescribed q12h. 
The open-label rescue medication (i.e. morphine sulphate tablets) will be administered orally, 
prescribed q4-6 hours as required for breakthrough pain. The open-label laxative medication (i.e. 
bisacodyl) will be administered orally, prescribed q3 days as needed. Investigators will instruct 
their subjects that if they exhibit discomfort during the 72 hours period they can take oral 
bisacodyl as a laxative earlier than 72 hours after their most recent BM for the treatment of 
constipation. 
11.6 Treatment Assignment 
Treatments are masked in a double-dummy fashion, whereby subjects to receive OXN are given 
OXN and OXYPR placebo, and subjects to receive OXYPR are given OXYPR and OXN placebo. 
 


 
 
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Treatment assignments will be randomised within blocks of fixed size. If possible, no 
stratification will be done.  
 
The randomisation scheme will be reviewed and approved by a statistician at the Sponsor’s site 
and locked after approval. Randomisation data will be kept strictly confidential within the Clinical 
Supplies Department, accessible only to authorised persons until the time of unblinding. The 
randomisation scheme and identification for each subject will be included in the clinical study 
report.  
11.7 Blinding 
The study medication (OXN or OXYPR) will be packaged in a double-blind, double-dummy 
manner, rendering the active tablets indistinguishable from the matched placebo tablets. 
During the double-blind phase, the subject and all personnel involved with the conduct and the 
interpretation of the study, including the Investigators, investigational site personnel, and the 
Sponsor’s and CRO’s staff, will be blinded to the medication codes. Randomisation data will be 
kept strictly confidential, filed securely by the Sponsor, and accessible only to authorized 
persons per Sponsor’s Standard Operating Procedures (SOPs) until the time of unblinding. 
Emergency unblinding will be done via the IRT system. Unblinding is not to be done unless an 
actual emergency occurs and knowledge of the subject’s randomisation code may affect his/her 
medical treatment. If possible, before breaking the blind, the Investigator should consult with the 
Sponsor’s Medical Monitor to ascertain the necessity of breaking the code. A record will be 
made of the date, time and reason for breaking the blind. 
11.8 Treatment Compliance/Drug Accountability 
The Investigator and study staff will be responsible for the accountability and record 
maintenance of all clinical supplies (dispensing, inventory, and returns) following Sponsor 
instructions and will adhere to GCP guidelines as well as applicable country specific regulations.  
Subjects will be asked to return all unused medication and used medication containers at each 
visit of treatment period to evaluate medication compliance.  At each visit the Investigator must 
check and document subjects’ compliance with taking study treatment(s). 
Under no circumstances will the Investigator allow the study treatment(s) to be used other than 
as directed by this protocol.  Clinical supplies will not be dispensed to any individual who is not 
enrolled and currently participating in the study.   
11.9 Concomitant Therapies (Permitted and Prohibited) 
All medications not prohibited by the protocol and considered necessary for the subject’s welfare 
may be administered and/or continued under the supervision of the Investigator. 
For subjects who receive study medication, concomitant medications and therapies, including 
over-the-counter medications and non-pharmacological treatments such as physiotherapy, that 
are ongoing as of the date of informed consent will be recorded on the Concomitant Therapy 
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The Concomitant Therapy CRF will be maintained and updated throughout the subject’s 
participation in the study for any new therapies of changes to existing therapies.  The dose of 
these concomitant medications taken during the double-blind period should be kept constant 
until study completion.  The use of such concomitant medications should be approved in 
advance by the Sponsor, when possible.  The Investigator will record the adverse event for 
which the concomitant medication was administered on the CRF. 
Analgesia and laxative will be permitted for the treatment of breakthrough pain and opiated 
constipation as described in Section 11.4.  
11.10 Shipping, Handling, Storage, and Destruction/Return 
All study treatments will be supplied to the Principal Investigator by the Sponsor via a local 
warehouse contracted by the Sponsor.  Drug supplies must be kept in an appropriate secure 
area (e.g. locked cabinet/pharmacy) and stored according to the conditions specified on the 
drug labels. Specific laws relating to the handling and storage of [narcotics/chemotherapeutics] 
must be followed, and this will be the responsibility of the Investigator [or designee such as 
pharmacist] (e.g.  ). 
Investigational site personnel must maintain an accurate and timely record of the receipt of all 
clinical supplies, dispensing of study treatments to the subject, collection of unused supplies 
returned by the subject and subsequent return of unused or expired study treatment to the 
Sponsor.  This includes, but may not be limited to: (a) documentation of receipt of clinical 
supplies, (b) study treatment dispensing/return reconciliation log, (c) study treatment 
accountability log, and (d) all shipping service receipts.  All forms will be provided by the 
Sponsor’s selected CRO.  Any comparable forms that the site wishes to use must be approved 
by the Sponsor.  A copy of these records must be given to the Sponsor at the end of the 
studyThe supplies and inventory records must be made available, upon request, for inspection 
by the designated representative of the Sponsor, or Competent Authority (CA).   
All unused study treatment(s), including empty containers, are to be returned to the 
investigational site personnel by the subject to the Sponsor designated warehouse termly and 
no later than the conclusion of the study, unless provision is made by the Sponsor for 
destruction of supplies and containers at the investigational site.  The investigational site 
personnel must not destroy any study treatment labels or any partly used or unused study 
treatment supply until directed by the Sponsor or designee following accountability checks.  
Upon completion of drug accountability and reconciliation procedures by investigational site 
personnel and documentation procedures by Sponsor personnel or designee, study treatment 
that is to be returned to the Sponsor designated warehouse must be sealed with tamper-evident 
seals and shipped back to the  Sponsor designated warehouse following [all local regulatory and 
shipment laws/the Pharmacy manual/IRT guidance.  
12 REFERENCE VALUES 
 


 
 
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12.1 Physical/Vital Sign Assessments 
Vital signs (e.g. blood pressure [systolic blood pressure, diastolic blood pressure], pulse rate, 
respiration rate, temperature, and weight measurements will be obtained at the visits designated 
on the Schedule of Visits and Procedures (Table 1).  Blood pressure and pulse rate will be 
measured after the subject has been sitting for 3 minutes. 
 
Each clinically notable vital sign abnormality has to be recorded on the AE section of the eCRF .  
Additionally, if the change in vital signs qualifies as a SAE it has to be reported to the 
CRO/Sponsor using the SAE data form . 
12.2 Laboratory Assessments 
All scheduled clinical laboratory tests will be performed by local laboratories. Local laboratories 
will perform tests to qualify subjects for entry into the study and relative safety assessment. 
Laboratory certification will be included in the clinical study report for this protocol as appendix.  
The Schedule of Visits and Procedures (Section 10.1) shows the time points at which blood and 
urine samples will be collected for clinical laboratory tests.    
 
Items 
Hematology 
RBC， haemoglobin, haematocrit, platelets and WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils). 
Biochemistry 
sodium, potassium, chloride, bicarbonate, Alkaline 
phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl-transferase (GGT), 
total bilirubin, direct bilirubin, blood urea, creatinine, glucose, 
calcium, albumin, cholesterol, triglycerides, phosphorus, lactate 
dehydrogenase (LDH), total protein, globulin, uric acid. 
Urinalysis 
pH, protein, glucose, ketone, occult blood, RBC, WBC, 
epithelial cells, bacteria, casts, crystals, specific gravity 
 
A laboratory abnormality may qualify as an AE or SAE as described in Section 13.7 Additionally, 
if the abnormality qualifies as a SAE it must be reported to the Sponsor using the SAE data form. 
Values out of the lower normal range do not automatically lead to an exclusion of the subject 
from the study. The decision to discontinue a subject from the study due to bilirubin or creatinine 
levels below the lower limit of normal should be based on the medical judgement of the 
Investigator.  Microscopic urinalysis will only be performed when certain parameters of the 
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12.3 Additional Assessments Reference Ranges 
13 SAFETY ASSESSMENTS 
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.   
 
monitoring haematology, blood chemistry, and urine values at visits 1, 8;  
 
periodic measurement of vital signs at visits 1,2,5,6,7,8; 
 
physical examinations at visits 1,8   
 
12-lead ECGs at visits 1,8;  
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.   
13.1 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.   
An AE can be:   
 
Any unfavourable and unintended sign/syptom (including reactions from overdose, 
abuse, incorrect use of any treatment, or interaction) 
 
Any new disease or exacerbation of an existing disease (e.g. increase in frequency or 
worsening in nature) 
 
Any deterioration in measurements of laboratory values or other clinical tests (e.g. ECG, 
vital signs or X-ray) that results in symptoms, a change in treatment, or discontinuation 
from the 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: 


 
 
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 
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. 
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 
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13.2 Reporting of Adverse Events 
See also Appendix Section 6. 
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 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 EDC.  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 EDC in 24 hours after the investigator 
is informed and flagged as serious. All SAEs information shall be collected and recorded in the 
SAE Data Form in the EDC. Investigators should evaluate the relevance of every SAE case with 
the investigated drug.  
Reporting term - A cluster of signs and symptoms that results from a single cause or that could 
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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. 
13.3 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 considering associative connections (time or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic 
clinical or pathological phenomena, underlying conditions in the study population, exclusion of 
other causes, and/or absence of alternative explanations. 
The 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 causality assessment of adverse events in the EDC only relates to the IMP(s) 
named in Chapter 5. 
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). 
13.4 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. 
Moderate:  Discomfort enough to cause interference with usual activity and may warrant 
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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 EDC (and, if applicable, on the SAE Data Form).   
13.5 Outcome Evaluation  
The terms and definitions below are for the evaluation of final AE result:  
 
Ongoing: The AE is continuing at the end of the study (last study visit). 
 
Recovered: the subjects has fully recovered from the adverse event. With no residual 
effects.  
 
Recovered with sequelae: the subject has residual effects of the adverse event. Therapy 
may or may not be given for the adverse event.  
 
Death: Requires a SAE report to the sponsor with all relevant information as to the cause of 
death (within 24 hours from learning of death). 
 
Lost to follow up: All communication with the subject has ceased 
13.6 Pregnancy 
Pregnancy occurring in a subject (or a male subject’s female partner) during a clinical study 
must be reported to the investigator, who will report to the drug safety specialist of Mundipharma 
(China) Pharmaceutical Co., Ltd. in 24 hours using the Pregnancy Notification Form. The CRO 
will contact the investigator to confirm significant pregnancy information i.e. AEs during 
pregnancy, the pregnancy outcome, and any events to 3 months post-partum. All the follow up 
information about the pregnancy will be reported to the drug safety specialist of Mundipharma 
(China) Pharmaceutical Co., Ltd. in 24 hours after being notified.   
13.7 Laboratory Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply: 
 
They result in a change in IMP schedule of administration (change in dosage, delay 
in administration, IMP discontinuation, or other medical or treatment intervention (e.g. 
anaemia requiring transfusions or hyperglycaemia requiring potassium supplement)) 
 
They are considered as clinically significant by the Investigator, 
 
They meet the markedly abnormal criteria 
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 


 
 
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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). 
13.8 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 appendix 7). 
13.9 ECG Adverse Events 
A simultaneous 12-lead resting ECG will be obtained at visit 1 and visit 8.  For consistency, the 
same physician should read all ECGs from one subject.  Abnormal test findings as judged by the 
Investigator as clinically significant should be recorded as AEs. 
13.10 Other Safety Considerations/Risk Management 
Preventable medication administration errors with an IMP are a potential safety issue and must 
be reported immediately to the Sponsor/CRO as a protocol deviation.  Examples of these 
include: 
 Overdose - This must always be reported, and may additionally (but not always) meet 
the criteria for an AE/SAE.   
 Drug Abuse - Defined as intentional excessive and persistent or sporadic use of a 
medicinal product which is accompanied by harmful physical or psychological effects.  Drug 
abuse is always a medically important event and subject to immediate SAE reporting.   
 Drug Diversion - Defined as study treatment that is sold or given to other persons either 
deliberately or accidentally.  This may include accidental misdirection of study supply into 
mainstream hospital supplies.  Adverse events in persons other than the subject after drug 
diversion will be processed in the Sponsor’s drug safety database. 
Any packaging or labelling that has been identified as causing potential risk (e.g. due to 
similarity with other products or unclear instruction) must be immediately reported to the 
Sponsor. 
13.11 Product Quality Complaint  
Product quality complaint means any suspicion of a the product fault related to the production, 
labeling or packaging, including the dissatisfaction about the reliability of product characteristics, 
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influence on the product safety and treatment. It is of great importance to protect the subjects, 
researchers and sponsor by reporting and analyzing any product quality complaint information 
obtained in the clinical research timely and accurately and it is approved by the world 
supervision organization. .  
13.11.1 Process 
As long as obtaining the product quality complaint events, the investigator should report the 
product complaint events information to the sponsor within the shortest time possible.  
As for the serious product quality complaint caused by the product fault or serious adverse 
events, the investigators must report to the sponsor within the timeline of the seriously adverse 
event (please refer to the section about reporting of the seriously adverse events). If required by 
the sponsor, the sample of the doubtful product must be saved for further investigation.  
13.11.2 Contacting the sponsor about the product quality 
The name (and the contact phone) of sponsor to be contacted if any product quality complaint 
have been listed in the contact information page; such information will be provided as 
independent document.  
13.12 Overdose  
Symptoms of oxycodone overdose may include miosis, respiratory depression, somnolence 
progressing to stupor, skeletal muscle flaccidity, bradycardia as well as hypotension. Coma, 
non-cardiogenic pulmonary edema and circulatory failure may occur in more severe cases and 
may lead to fatal outcome. 
Clinical symptoms suggestive of an oxycodone overdose may be treated by the administration 
of opioid antagonists (e.g. naloxone hydrochloride 0.4-2 mg intravenously).  Administration 
should be repeated at 2-3 minute intervals, as clinically necessary.  It is also possible to apply 
an infusion of 2 mg naloxone in 500 ml of 0.9% sodium chloride or 5% dextrose (0.004 mg/ml 
naloxone).  The infusion should run at a rate aligned to the previously administered bolus doses 
and to the patient's response. 
Consideration may be given to gastric lavage. 
Supportive measures (artificial ventilation, oxygen, vasopressors and infusions) should be 
employed, as necessary, to manage the circulatory shock accompanying an overdose.  Cardiac 
arrest or arrhythmias may require cardiac massage or defibrillation.  Artificial ventilation should 
be applied if necessary.  Fluid and electrolyte metabolism should be maintained. 
 
Symptoms of a naloxone overdose alone are unlikely due to the low bioavailability of oral 
naloxone.  Withdrawal symptoms due to an overdose of naloxone should be treated 
symptomatically in a closely-supervised environment. 
 
 
 


 
 
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14 STATISTICAL ANALYSES 
All data analyses will be performed by the CRO after the study is completed and the database is 
released for unblinding. Statistical programming and analyses will be performed using SAS 
and/or other validated statistical software as required. 
14.1 Statistical Methodology and Analytical Plans 
The statistical analyses described in this section will be performed as further outlined in the 
Statistical Analysis Plan (SAP), which will be finalised prior to database lock and will be included 
in the clinical study report for this protocol.  The final SAP will take into account any amendment 
to the protocol. 
14.2 Statistical Considerations 
All data will be listed by treatment group. 
 
In general, continuous data will be summarised by treatment group using the following 
descriptive statistics: n, mean, standard deviation, median, minimum and maximum.  
Categorical data will be summarised by treatment group as the number and percentage of 
subjects in each category. 
The assumptions of the statistical models (e.g. normality) will be assessed. 
Further details of statistical methods and analyses will be documented in the SAP. 
14.3 Analysis Populations 
Enrolled Population 
The enrolled population is defined as all subjects who signed informed consent. 
 
Randomised Population 
The randomised population is defined as all randomised subjects. 
 
Full Analysis Population (FAP) 
The full analysis population is defined as all randomised subjects who receive at least one dose 
of study medication (IMP) and have at least one post-baseline primary efficacy endpoint. 
 
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The Per Protocol Population is defined as all FAP subjects without major protocol violations.  
Major protocol violations will be agreed at the Determination of Subject Evaluability (DOSEA) 
meeting prior to database lock. 
 
 
Safety Population 
The safety population is defined as all randomised subjects who receive at least one dose of 
IMP and with at least one post-baseline safety assessment.  
 
For the superiority test (bowel function) the Full-analysis population will be the primary analysis 
and the PP analysis will be performed for sensitivity reasons. For the non-inferiority test (pain) 
the PP population analysis will be the primary analysis and the FAS analysis will be the 
sensitivity analysis. 
All secondary endpoint will be analysed with the FAS population only, all safety analysis will use 
the DB safety population. 
14.4 Protocol Violations and Deviations 
The following protocol violations may exclude a subject from the  PPP: 
1) Failure to comply with the inclusion/exclusion criteria. 
2) Being non-compliant with study treatments. 
3) Taking any prohibited concomitant therapies. 
Additional factors excluding subjects from inclusion in the PPP may be included in the SAP for 
the study.  Major protocol violations will be agreed at the Determination of Subject Evaluability 
(DOSEA) meeting prior to database lock. Further details will be documented in the SAP. 
14.5 Sample Size and Power Considerations 
Approximately 280 patients may be screened to obtain 230 patients who will be randomised in a 
1:1 ratio to OXN / OXY PR. Each group will have 115 subjects randomized to ensure 105 
patients in the FAS per group. 
With 105 subjects in the FAS per treatment group  the study has a power of 90% to detect a 
treatment difference of 12 on the BFI on a two-sided level of significance of α=0.05 assuming a 
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14.6 EFFICACY ANALYSES  
Summary statistics of efficacy variables will be produced. These will be sorted by treatment 
group (oxycodone, oxycodone/naloxone, combined), visit number where appropriate, and 
country (alphabetically)  where appropriate. Statistics to be reported for continuous variables are: 
sample size, mean, SD, SE, range, median. For categorical variables, counts and percentages 
will be reported. The primary analysis population is the Full Analysis population, secondary 
analyses will use the per-protocol population.   
Primary Efficacy Analyses 
The analysis of the primary endpoint uses an ANCOVA comparing the treatments at final vist 
using LOCF for missing values, adjusted for baseline observation. The full analysis population is 
the primary population for this BFI analysis, the per-protocol population will be analyzed as well. 
Additional sensitivity analyses will be performed. A MMRM model will be used that has fixed 
effects for visit, treatment within visit, baseline; random intercept over subjects; an unstructured 
covariance matrix over the visits. The comparison between treatments at final visit will be 
reported. A similar model will be estimated that assumes a constant treatment effect over visits.  
 
For average pain uses an ANCOVA comparing the treatments at final vist using LOCF for 
missing values, adjusted for baseline observation. The per-protocol  population is the primary 
population for this pain analysis, the Full-Analysis population will be analyzed as well. 
 
Other Efficacy Analyses 
For all other endpoints the summary statistics will be produced as described in section “Efficacy 
Analyses”. Only exploratory statistical comparisons will be made for these endpoints using the 
Full-Analysis population.. 
 
14.7 Subject Disposition 
The number and percentage of subjects in each population will be summarised by treatment 
group and overall for subjects in the enrolled set. Reasons for exclusion from the PPP will also 
be summarised. 
 
The number and percentage of subjects enrolled and the primary reason for screen failure will 
be summarised for subjects in the enrolled population. 
 
The number and percentage of subjects that complete the study and the primary reason for 
discontinuation will be summarised for subjects in the randomised population. 
 
The number and percentage of subjects enrolled from each country and site will be summarised 
for subjects in the randomised population. 


 
 
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14.8 Demographic/Baseline Analyses 
Demographic and baseline variables will be summarised by treatment group and overall for 
subjects in the Full Analysis Population. 
 
Age, weight, height, and body mass index will be summarised as continuous data. Gender and 
race will be summarised as categorical data. 
 
Current medical conditions will be summarised by System Organ Class and Preferred Term. 
14.9 IMP Analyses 
IMP will be summarised as treatment exposure. 
Treatment exposure will be defined as the number of days on IMP. This will be calculated as the 
number of days between the first and last dose of IMP. Treatment exposure will be summarised 
by treatment group as continuous data. 
14.10 Concomitant Medications Analyses 
Concomitant medications will be assigned an 11-digit code using the World Health Organisation 
Drug Dictionary (WHO-DD) drug codes of version Q4/2012.  Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification.  
The number and percentage of subjects taking concomitant medications will be summarised by 
ATC anatomical class, pharmacological class, pharmacological sub-class and treatment group 
for subjects in the FAP. 
14.11 Safety Analyses/Adverse Outcomes 
Safety data that will be evaluated includes adverse events (AEs), laboratory values, vital signs, 
and ECGs.  Safety data will be summarised by treatment group and overall for subjects in the 
safety population.  All safety data will be listed. 
14.12 Analysis of Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
system version 15 and summarized by System Organ Class (SOC) and preferred term for each 
event. 
Only treatment emergent AEs will be summarised.  A treatment emergent AE will be defined as 
any AE with an onset date on or after the first dose of IMP if the AE was absent before the first 
dose of IMP, or worsened after the first dose of IMP.  This will also include AEs with an onset 
date up to and including 7 days after the last dose of IMP. 


 
 
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The number and percentage of subjects reporting any AE will be summarised by the ‘preferred 
term’ nested within the SOC.  In addition, the number of reported AEs will be summarised.  
 
AEs will be summarised by worst severity and relationship to IMP.  In addition, severe AEs, AEs 
leading to death, serious AEs, AEs leading to discontinuation from study, AEs requiring 
additional therapy, AEs leading to dose reduction, and AEs leading to dose interruption will be 
summarised.  
 
The most frequent AEs (preferred term ≥ 5% in any treatment group) will be summarised for the 
double-blind phase. These will also be presented graphically using a dot plot and a caterpillar 
plot within which the percentage of subjects reporting each of the most common AEs will be 
presented alongside the odds ratio (and associated 95% CI) for comparing the incidence of AEs. 
14.13 Analysis of other Safety Parameters 
SOWS Values: SOWS change from baseline to visit 3 and visit 9 will be summarised as 
continuous data. Scatter plots will be produced for SOWS comparing baseline and Visit 3 values. 
 
Laboratory Values: Clinical laboratory data to be summarised includes haematology, blood 
chemistry, and urinalysis.  
 
 
 
 
 
 
 
Clinical laboratory results recorded at each visit and change from baseline to each visit will be 
summarised as continuous data for each parameter.  Each parameter will be assigned an LNH 
classification according to whether the value is lower than (L), within (N) or higher than (H) the 
reference range for that parameter.  Results will be summarised using shift tables to evaluate 
categorical changes from baseline to end of study with respect to reference range values (lower 
than, within, higher than). 
Clinical laboratory values after first dose of IMP will be evaluated for markedly abnormal values. 
The number and percentage of subjects reporting markedly abnormal values will be summarised 
for each parameter by treatment group.  Each subject can be counted once in the parameter 
high and the parameter low categories, as applicable.  Scatter plots will be produced for each 
laboratory parameter comparing baseline and end of study values.  
 
Items 
Hematology 
RBC， haemoglobin, haematocrit, platelets and WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils). 
Biochemistry 
sodium, potassium, chloride, bicarbonate, Alkaline 
phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl-transferase (GGT), 
total bilirubin, direct bilirubin, blood urea, creatinine, glucose, 
calcium, albumin, cholesterol, triglycerides, phosphorus, lactate 
dehydrogenase (LDH), total protein, globulin, uric acid. 
Urinalysis 
pH, protein, glucose, ketone, occult blood, RBC, WBC, 
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Vital Signs: Vital sign parameters to be summarised include systolic blood pressure, diastolic 
blood pressure, pulse rate, respiration rate, and temperature.   
Vital sign results recorded at each visit and change from baseline to each visit will be 
summarised as continuous data for each parameter.   
Vital sign results for each parameter will be assigned an LNH classification according to whether 
the value is lower than (L), within (N) or higher than (H) the reference range for that parameter. 
Vital sign results will be summarised using shift tables to evaluate categorical changes from 
baseline to end of study with respect to reference range values (lower than, within, higher than). 
Vital sign values after first dose of IMP will be evaluated for clinically notable abnormalities. The 
number and percentage of subjects reporting clinically notable abnormalities will be summarised 
for each parameter by treatment group. Each subject can be counted once in the parameter 
high and the parameter low categories, as applicable.  
Scatter plots will be produced for each vital sign parameter comparing baseline and end of study 
values 
ECG: Only Clinically significant ECG findings as determined by the Investigator will be reported.  
14.14 Other Special Tests  
None planned.   
15 ETHICS & REGULATORY 
 
15.1 Declaration of Ethical Conduct 
This study will be conducted in accordance with the standard operating practices of the Sponsor 
and CRO, which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines 
as required by the following: 
1. Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Patients”), and all its accepted amendments to date 
concerning medical research in humans. 
2. ICH E6 Guideline for GCP and subsequent notes for guidance (CPMP/ICH/135/95)  
European Agency for the Evaluation of Medicinal Products, Committee for Proprietary 
Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for 
Human Use. (Note for Guidance on Good Clinical Practice, 2002). 
3. European Union (EU) Clinical Trials Directive 2001/20/EC on the regulation of clinical 
trials in the EU and the implementation of GCP. 
4. GCP Directive 2005/28/EC 
5. Chinese GCP, 2003 
This study will be conducted in accordance with national and local laws (e.g. drug and narcotics 
laws) of the countries where study sites are located. 


 
 
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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. 
15.2 Ethical and Regulatory Review 
The protocol, any protocol amendments, the patient information sheet (PIS), informed consent 
form (ICF) and any study related information or documents issued to subjects for recruitment, 
data recording etc., will be reviewed and approved along with other required documents by the 
central Ethics Committee (EC) and local ethical committee if applicable before subjects are 
screened for entry.  The ECs should be constituted and functioning in accordance with ICH E6, 
Section 3.2, and any local regulations.  A list of the EC(s) that provided a positive opinion for this 
study will be included in the clinical study report for this protocol. 
A signed letter of positive opinion regarding the study from the EC Chairman must be sent to the 
Investigator who will provide the CRO with a copy prior to study start and the release of any 
study treatment to the site by the Sponsor or its designee (ICH E6).  The Investigators or 
Sponsor will submit, depending on local regulations, periodic reports and inform the EC of any 
reportable adverse events (AEs) per ICH guidelines and local EC standards of practice. 
SAEs should be reported to the EC in accordance with local regulatory requirements. 
In the case of early termination/temporary halt of the study, the Investigator should notify the EC 
and CA within 15 days and a detailed written explanation of the reasons for the termination/halt 
should be given.  If the EC decides to suspend or terminate the study, the Investigator will 
immediately send the notice of study suspension or termination by the EC to the Sponsor and 
selcted  CRO. 
At the end of the study, the Sponsor or selected CRO should notify the EC and CA within 90 
days.  The end of the study will be the date of the last scheduled study visit for the last subject in 
the study.  The Sponsor will always also provide the EC/CA with a summary of the study’s 
outcome. 
15.3 Subject Information and Consent 
Informed consent should be obtained by means of a patient information sheet (PIS) and 
Informed Consent Form (ICF), prepared in accordance with ICH E6 Section 4.8.10 and 
applicable local regulations, written in non-technical language. All subjects will be provided with 
oral and written information describing the nature and duration of the study and the procedures 
to be performed.  The subject will be asked to sign and date an ICF prior to any study-specific 
procedures being performed.  No subject can enter the study before his/her informed consent 
has been obtained.  A sample subject ICF used in the study will be included in the clinical study 
report for this protocol. 
As part of administering the informed consent document, the Investigator must explain to each 
subject  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 


 
 
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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.  The subject should understand the patient 
information sheet (PIS) and ICF before signing and dating the ICF.  The Investigator or person 
obtaining consent must also sign and date the form.  Each subject will be given a copy of the 
signed informed consent and written information. 
 The original signed ICF for each subject will be verified by the Sponsor/CRO monitors and kept 
in the study centre investigational site files.  This applies for any additional ICFs signed (e.g. for 
re-consent). 
15.4 Data Protection and Human Tissue Sampling 
Data protection will be carried out in accordance with the Principles of the Data Protection Act 
(1998) 95/46/EC.  This will apply to all study data in whatever format it is collected and recorded.   
Any scan data, imaging, ECGs etc., collected for the trial will be retained in the patient’s notes 
held with the Investigator.  No scans need to be sent for central review. 
Samples collected for the purpose of safety or bioanalytical analysis will not be retained after 
analysis.   
15.5 Quality Assurance & Inspection Requirements 
This study will be organised, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs) of the Sponsor [and CRO].   ICH E6 defines Quality Assurance 
(QA) as ‘all those planned and systemic actions that are established to ensure that the trial is 
performed and the data are generated, documented (recorded) and reported in compliance with 
Good Clinical Practice (GCP) and the applicable regulatory requirements’.  Sponsor QA activity 
will be undertaken as outlined in the study audit plan.  Section 5.19.3(b) of ICH E6 states that 
the audit plan and procedures for a trial audit should be guided by the importance of the trial to 
submissions to competent authorities, the number of subjects in the trial, the type and 
complexity of the trial, the level of risks to the trial subjects and any identified problem(s).  QA 
activities may be outsourced to CROs or independent consultants.  The investigator is required 
to support audit activities, to be available to the auditors upon request and to permit the auditor 
direct access to source data/documents. 
A CA/authorised third party may also wish to conduct an inspection (during the study or after its 
completion).  If an inspection is requested by a CA, the Investigator must inform the Sponsor 
immediately that this request has been made. 
 
16 STUDY MANAGEMENT RECORDS & PUBLICATION 
 


 
 
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16.1 Protocol Amendments 
The Investigator should not implement any deviation from, or changes to the protocol without 
agreement by the Sponsor and prior review and documented approval from the EC (ICH E6 
4.5.2). 
Any change to the protocol requires a written substantial or non-substantial protocol amendment.  
Substantial protocol amendments specifically affecting the safety of subjects, the scope of the 
investigation, or the scientific quality of the study require approval by the applicable ECs of all 
sites and, in some countries, by the CA.  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.  If an immediate change to the 
protocol is felt by the Investigator to be necessary for safety reasons, the [Clinical Leader/Study 
Physician/Medical Monitor] must be notified promptly and the EC for the site must be informed in 
accordance with the policy of the EC approving the study, local regulations and policies.  
Changes affecting only administrative aspects of the study do not require substantial protocol 
amendments or EC approval, but the EC must be kept informed of such changes.  In these 
cases, the Sponsor will send a letter to the EC detailing such changes. 
16.2 Record Maintenance and Retention 
 
 
Neither a subject’s name nor initials are to appear on documents transmitted to the Sponsor in 
order to maintain confidentiality.  Additional anonymisation/pseudonymisation laws as 
applicable by country will also be adhered to. 
Use the following text if an EDC system is being used. 
In order to provide the Sponsor/CRO with accurate, complete, and legible data, the following 
criteria are to be maintained: 
Source documents will be completed according to a source document agreement outlining all 
the data that is to be collected in the source documents throughout the study. 
EDC entries should be made as close to the visit of the subject as possible. 
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 EDC, Investigator's Brochure, regulatory agency registration documents, ICFs, and 
EC correspondence. 
The site should plan on retaining study documents for approximately 15 years after completion 
of the study. This will include copies of the EDC data. 
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 


 
 
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permanently retaining the study records.  Records retained will be stored independently of the 
Sponsor, and the Sponsor will not be permitted direct access to this data. 
16.3 Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol, which has been 
written to enable the Investigator’s compliance with ICH E6, Section 4. 
There are to be no waivers to the Inclusion/Exclusion criteria and no Investigator-led deviations 
from the schedules and procedures set out within this protocol.  Any subject whose treatment 
deviates from the protocol or who is not qualified for study participation may be ineligible for 
analysis and may compromise the study. 
Any unintentional deviation or violation that is discovered should be reported to the 
Sponsor/CRO immediately.  Any deviation of violation that may have an impact upon subject’s 
safety or suitability for the study should be reported to, and discussed with the Medical Monitor. 
Subjects who have not signed an IRB/EC approved ICF cannot receive study medication. 
The Investigator and research team must comply with the 13 principles of ICH GCP and all 
applicable local regulatory laws and regulations. 
16.4 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative reasons at 
any time, however not without good cause.  Reimbursement for expenses covering subjects, 
use of live-in facilities, laboratory tests, and other professional fees will be made.  The 
Investigator will refund the excess of payments made in advance. 
The Investigator reserves the right to discontinue the study should his/her judgement so dictate.  
In such an event, final settlement of the grant-in-aid will be adjusted pro rata, and the 
Investigator will refund the excess of payments made in advance.  The Investigator will notify the 
EC in case of study discontinuation.  Study records must be retained as noted above. 
16.5 Retention of Tissue Samples 
Not Applicable 
16.6 Registration and Publication of Study Summary and Results 
If a study design is of the type required for registration in a public database as detailed in the 
guidance on www.clinicaltrial.gov or www.ClinicalTrialResults.org the study will be registered on 
a public database according to the Sponsor’s SOPs.  As a general guide phase 1, exploratory 
and post marketing studies will not require registration. 
Following the end of the study the results should be published within a year of product approval 
for newly registered products, or within a year of completion of the clinical study report (CSR) if 
the product is already approved.  If results are intended for publication in a peer review scientific 


 
 
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journal, no detailed results will be published on a public database beforehand. 
 
The 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 IMP(s) made during the performance of 
the study will be filed prior to such publication, such publication may be delayed for an additional 
30 days or until any patent application or applications have been filed, whichever will first occur. 
For multi-site studies, it is mandatory that the first publication be based on data obtained from all 
analysed subjects; therefore Investigators participating in multi-site studies must agree not to 
present data gathered individually or by a subgroup of sites prior to the full, initial publication, 
unless this has been agreed to by all other Investigators and the Sponsor.  Publication of clinical 
trial results may include the presentation of such work at national and international congresses, 
symposia, professional meetings, peer-reviewed journals, and via other appropriate channels.  
Named authors and contributors to such publications shall be determined by the Sponsor in 
accordance with both the Company Publication Policy and the criteria as outlined by standard 
authorship guidelines.  Selected Investigators, Consultants and Scientific Advisors may be 
invited to be named authors on such publications by the Sponsor.  If the 
Investigator/Consultant/Scientific Advisor agrees to participate in the publication as an author, 
they will be asked to participate in the creation of all versions of the document(s) in question 
prior to submission or public dissemination.  The Sponsor will ensure that any reasonable 
comments made by the invited author will be incorporated into the publication and that the 
named author will consent to the publication of the final version of the document.  The copyright 
associated with any publication will be and shall remain the sole property of the Sponsor, unless 
or until the copyright of the document is transferred to the scientific peer-reviewed journal prior 
to and as part of the publication process. 


 
 
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17 REFERENCE LIST 
1. 2011 NCCN Cancer pain guideline 
2. OXN IB version 8 
3. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad 
MedSingapore. 1994; 23(2): 129-38. 
4. Frank L, Kleinman L, Farup C, Taylor L and Miner Jr P. Psychometric validation of a 
Constipation Symptom Assessment Questionnaire. Scand J Gastroenerol 1999; 34: 870-877. 
5. Handelsman L, Cochrane KJ, Aronson MJ, et al. Two new rating scales for opiate withdrawal. 
Am J Drug Alcohol Abuse 1987; 13: 293-308. 
6. Xu JG, Yu SY, Narcotic drugs and psychotropic drugs of standardized clinical application and 
management Beijing: People's Medical Publishing House, 2007  


 
 
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18 APPENDICES 
 Appendix 1 BPI-SF 
 


 
 
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Appendix 2 BFI 
 
 


 
 
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Appendix 3 SOWS 
Modified Subjective Opiate Withdrawal Scale (SOWS) 
 
To let us know how you feel at this moment, place an “X” on the line next to the number (0, 1, 2, 3 or 4) 
that best describes how you feel RIGHT NOW. 
 
Not at All A Little Moderately Quite a Bit Extremely 
 
1. I feel anxious. 
 
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
2. I feel like yawning. 
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
3. I'm perspiring. 
 
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
4. My eyes are tearing.  
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
5. My nose is running.  
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
6. I have goose flesh. 
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
7. I am shaking. 
 
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
8. I have hot flashes. 
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
9. I have cold flashes.  
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
10. My bones and muscles ache. 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
11. I feel restless. 
 
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
12. I feel nauseous.  
 
 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
13. I feel like vomiting. 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
14. My muscles twitch. 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
15. I have cramps in my stomach. 
0)____  
1)____  
2)____  
3)____  
4)____ 
 
 
 
(Handelsman et al., 1987) 
 


 
 
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Appendix 4 EQ-5D 
By placing a tick in one box in each group below, please indicate which statements best describe your 
own health state today. 
 
Mobility 
I have no problems in walking about 
 
I have some problems in walking about 
 
I am confined to bed 
 
 
Self-Care 
I have no problems with self-care 
 
I have some problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
I have moderate pain or discomfort 
 
I have extreme pain or discomfort 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 
 


 
 
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To help people say how good or bad a health state is, we have drawn a scale 
(rather like a thermometer) on which the best state you can imagine is marked 
100 and the worst state you can imagine is marked 0. 
 
We would like you to indicate on this scale how good or bad your own health is 
today, in your opinion. Please do this by drawing a line from the box below to 
whichever point on the scale indicates how good or bad your health state is today. 
 
 
Your own 
health state 
today 
9 0
8 0
7 0
6 0
5 0
4 0
3 0
2 0
1 0
100
Worst 
imaginable 
health state
0 
Best  
imaginable 
health state


 
 
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Appendix 5 Guidance table for identifying the starting dose of oxycodone PR 
based on pre study opioid use.  
Opioid Dose 
Range 
 
Guidance  
Pre-Study Opioid  
Examples  
Total Daily Dose 
 
Total Daily Dose 
Study medication 
Start Dose at 
treatment Period3 
Low Dose 
 
Morphine up to 80 mg  
Hydromorphone up to 10 mg 
Dextropropoxyphene 
Dihydrocodeine 
Tramadol 
Fentanyl  25 µg/hour  
Buprenorphine Patch1 35 µg/hour  
Buprenorphine Patch1 52.5  µg/hour 
  
20 - 40 mg OxyPR 
 
 
 
Medium Dose 
Morphine > 80 - 160 mg  
Hydromorphone > 12 mg 
Fentanyl 50 µg/hour  
Buprenorphine Patch1 70 µg/hour 
 
40 - 60 mg OxyPR 
 
 
High Dose2 
 
Morphine 160 - 200 mg  
Hydromorphone > 20 mg  
Fentanyl 75 µg/hour 
 
60 - 80 mg OxyPR  
 
1 Buprenorphine Patch is the 3 day Transtec Patch 
2 Subjects requiring a start dose of > 80 mg oxycodone PR should be excluded from the study (e.g. >200 mg Morphine). 
3 The subjects study medication is to be reviewed the following day (telephone visit) to assess if an increase or decrease in study 
medication is required. 
Please note; this table is for guidance only. 


 
 
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Appendix 6 Flow diagram for AE reporting
 
 
 


 
 
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Appendix 7 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. 
 

SAP_001.pdf: 
Statistical Analysis Plan for OXN10-CN-303 
Version/Date: v1, 30-Dec-2014 
CONFIDENTIAL  
Page 1 of 36 
Statistical Analysis Plan 
Version: V1, 30-Dec-2014 
for 
A Phase III, Randomized, Double-blind, Double-dummy, Parallel 
Group Study to Determine the Safety and Efficacy of Oxycodone / 
Naloxone Prolonged Release Tablets 5/2.5mg, 10/5mg, 
20/10mg or 40/20mg compared to Oxycodone PR 5mg, 10mg, 
20mg or 40mg in Subjects with Moderate to Severe, Chronic 
Cancer Pain 
Sponsor: 
CRO: 
Mundipharma (China) Pharmaceutical Co., Ltd 
Choice Pharma - Taiwan 
+86 1065636798   
+886 2 2722 8755 
18F, Tower D Central International Trade Center 
10F, No. 101, Song Ren Road, 
6A Jianguomenwai Avenue  
 
 
 
 
Taipei 11073, Taiwan 
Chaoyang District 
Beijing, China 100022 
NOTICE: The information contained in this SAP is confidential and proprietary to Choice Pharma and should not be 
disclosed to anyone who is not a recipient or reviewer of this SAP. All rights reserved. No part of this document may 
be reproduced, stored in a retrieval system, or transmitted in any means, electronic, mechanical, photocopying, 
recording, or otherwise without the prior written permission of Choice Pharma.




Statistical Analysis Plan for OXN10-CN-303 
Version/Date: v1, 30-Dec-2014 
CONFIDENTIAL  
Page 3 of 36 
CONTENTS 
ABBREVIATIONS .......................................................................................................................................... 6 
1. SYNOPSIS ................................................................................................................................................... 7
2. OBJECTIVES .............................................................................................................................................. 8
3. STUDY DESIGN ......................................................................................................................................... 9
3.1 GENERAL DESIGN AND PLAN .............................................................................................................................. 9 
3.2 TREATMENT ......................................................................................................................................................... 9 
3.3 SAMPLE SIZE....................................................................................................................................................... 10 
3.4 RANDOMIZATION ............................................................................................................................................... 11 
3.5 BLINDING ............................................................................................................................................................ 11 
3.6 LABORATORY ASSESSMENTS ............................................................................................................................. 11 
4. STUDY POPULATIONS ........................................................................................................................ 12
4.1 DEFINITION OF POPULATIONS FOR ANALYSIS ................................................................................................. 12 
4.2 SUBJECT DISPOSITION ....................................................................................................................................... 12 
4.3 PROTOCOL DEVIATIONS/VIOLATIONS ............................................................................................................. 15 
5. STATISTICAL ANALYSIS ...................................................................................................................... 16
5.1 WORKING PLATFORM ........................................................................................................................................ 16 
5.2 TIME-POINTS FOR ANALYSIS ............................................................................................................................ 16 
5.3 METHODS FOR HANDLING MISSING DATA ...................................................................................................... 16 
5.4 STATISTICAL ANALYSIS ...................................................................................................................................... 16 
5.4.1 Categorical Data .......................................................................................................................................... 16 
5.4.2 Continuous Data .......................................................................................................................................... 16 
5.4.3 Statistical Comparison .............................................................................................................................. 16 
6. EVALUATION OF DEMOGRAPHICS/BASELINE CHARACTERISTICS ...................................... 17
6.1 DEMOGRAPHICS ................................................................................................................................................. 17 
6.2 CURRENT MEDICAL CONDITION (BASELINE) ................................................................................................. 17 
7. EFFICACY ANALYSIS ............................................................................................................................ 19
7.1 PRIMARY EFFICACY ASSESSMENTS ANALYSIS ................................................................................................. 19 
7.2 SECONDARY EFFICACY ASSESSMENTS ANALYSIS ............................................................................................ 20 
8. SAFETY ANALYSIS ................................................................................................................................ 24
8.1 ADVERSE EVENT ................................................................................................................................................ 24 
8.2 LABORATORY ASSESSMENT ............................................................................................................................... 26 
8.3 VITAL SIGNS ........................................................................................................................................................ 27 


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8.4 ELECTROCARDIOGRAM ...................................................................................................................................... 28 
9. OTHER ANALYSIS ................................................................................................................................. 29 
9.1 IMP ANALYSIS .................................................................................................................................................... 29 
9.2 CONCOMITANT MEDICATION ANALYSIS ........................................................................................................... 29 
9.3 PHYSICAL EXAMINATION ................................................................................................................................... 30 
9.4 PREGNANCY TEST .............................................................................................................................................. 30 
10. LIST OF TABLES .................................................................................................................................. 31 
11. LIST OF LISTINGS .............................................................................................................................. 33 
12. LIST OF FIGURES ............................................................................................................................... 34 
13. APPENDIX ............................................................................................................................................ 35 
13.1 FLOW CHART .................................................................................................................................................... 35 
 
 


Statistical Analysis Plan for OXN10-CN-303 
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TABLES 
TABLE 1: SUMMARY OF SUBJECT DISPOSITION 
TABLE 2: SUMMARY OF DEMOGRAPHIC DATA 
TABLE 3: SUMMARY OF CURRENT MEDICAL CONDITIONS 
TABLE 4: SUMMARY OF ANCOVA ANALYSIS FOR BFI LOCF DATA AT FINAL VISIT 
TABLE 5: SUMMARY OF SENSITIVITY ANALYSIS FOR BFI DATA AT FINAL VISIT 
TABLE 6: SUMMARY OF ANCOVA ANALYSIS FOR BPI-SF LOCF DATA AT FINAL VISIT 
TABLE 7: SUMMARY OF USE OF LAXATIVE MEDICATION (BISACODYL) 
TABLE 8: SUMMARY OF RESCUE MEDICATION (MORPHINE SULPHATE) 
TABLE 9: SUMMARY OF BPI-SF FOR INDIVIDUAL ITEMS 
TABLE 10: SUMMARY OF BPI-SF FOR PAIN INTERFERENCE 
TABLE 11: SUMMARY OF SOWS 
TABLE 12: SUMMARY OF EQ-5D 
TABLE 13: SUMMARY OF BOWEL MOVEMENT 
TABLE 14: SUMMARY OF OVERALL ADVERSE EVENTS INFORMATION 
TABLE 15: SUMMARY OF INCIDENCE OF DEATHS, OTHER SAE AND OTHER SIGNIFICANT EVENTS 
TABLE 16: SUMMARY OF SERIOUS ADVERSE EVENTS 
TABLE 17: SUMMARY OF ADVERSE EVENTS  5% IN DOUBLE-BLIND PHASE 
TABLE 18: SHIFT TABLE OF LABORATORY ASSESSMENTS FOR OXN PR /OXY PR TREATMENT-BLOOD 
CHEMISTRY/HEMATOLOGY/URINALYSIS 
TABLE 19: SUMMARY OF LABORATORY ASSESSMENT ABNORMALITY-BLOOD 
CHEMISTRY/HEMATOLOGY/URINALYSIS 
TABLE 20: SHIFT TABLE OF VITAL SIGNS FOR OXN PR /OXY PR TREATMENT 
TABLE 21: SUMMARY OF CLINICALLY NOTABLE ABNORMALITY OF VITAL SIGNS 
TABLE 22: SUMMARY OF ELECTROCARDIOGRAM ASSESSMENTS 
TABLE 23: SUMMARY OF IMP EXPOSURE 
TABLE 24: SUMMARY OF CONCOMITANT MEDICATION BY ATC 
TABLE 25: SUMMARY OF PHYSICAL EXAMINATION 
TABLE 26: SUMMARY OF PREGNANCY TEST 
 
FIGURES 
FIGURE 1: SUBJECT DISPOSITION ................................................................................................................................ 13 


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ABBREVIATIONS 
 
Term 
 
 
 
Definition of Term 
 
 
 
 
 
 
 
 
 
 
 
AE  
 
 
 
Adverse Event 
ANCOVA  
 
 
Analysis of Covariance 
ATC  
 
 
 
Anatomical-Therapeutic-Chemical 
BFI  
 
 
 
Bowel Function Index 
BMI  
 
 
 
Body Mass Index 
BPI-SF 
 
 
 
Brief Pain Inventory Short-Form 
CFDA 
 
 
 
China Food and Drug Administration 
CI 
 
 
 
 
Confidence Interval 
CRF  
 
 
 
Case Report Form 
CRO  
 
 
 
Contracted Research Organization 
DBP  
 
 
 
Diastolic Blood Pressure 
DOSEA  
 
 
Determination of Subject Evaluability 
ECG  
 
 
 
Electrocardiogram 
FAP  
 
 
 
Full Analysis Population 
IMP  
 
 
 
Investigational Medicinal Product 
IRT  
 
 
 
Interactive Response Technology 
LOCF 
 
 
 
Last Observation Carried Forward 
LS means 
 
 
Least Square Means 
MedDRA  
 
 
Medical Dictionary for Regulatory Activities 
MMRM  
 
 
Mixed Model Repeated Measures 
N 
 
 
 
 
Number of Subjects 
NA  
 
 
 
Not Applicable 
NAS  
 
 
 
Numerical Analogue Scale 
NIMP 
 
 
 
Non-Investigational Medicinal Product 
OXN PR  
 
 
Oxycodone / Naloxone Prolonged Release Tablet 
OXY PR  
 
 
Oxycodone Prolonged Release Tablet 
PPP  
 
 
 
Per-Protocol Population 
PT  
 
 
 
Preferred Terms 
SAE  
 
 
 
Serious Adverse Event 
SAP  
 
 
 
Statistical Analysis Plan 
SBP  
 
 
 
Systolic Blood Pressure 
SD  
 
 
 
Standard Deviation 
SOC  
 
 
 
System Organ Class 
SOP  
 
 
 
Standard Operating Procedure 
SOWS 
 
 
 
Subjective Opiate Withdrawal Scale 


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1. SYNOPSIS 
This study is designed as a Phase III, Randomized, Double-blind, Double-dummy, Parallel 
Group Study to Determine the Safety and Efficacy of Oxycodone / Naloxone Prolonged Release 
Tablets 5/2.5mg, 10/5mg, 20/10mg or 40/20mg compared to Oxycodone PR 5mg, 10mg, 
20mg or 40mg in Subjects with Moderate to Severe, Chronic Cancer Pain. 
 
The protocol and CRF version approved by CFDA are as follows: 
-
Protocol Version/date:   
V1.0/13 March 2013 
-
CRF Version/date:  
 
V2.0/08 May 2013 
 
This study is composed of three phases: a screening phase (<7 days) and a 4-week 
double-blind phase and follow up phase (1 week after last dose). Approximately 230 subjects 
who qualify for entry into the Double-blind Phase of the study will be randomized to 
Oxycodone/naloxone PR (OXN PR) or Oxycodone PR (OXY PR) treatment in 1:1 ratio.  
 
Summary statistics will be produced and sorted by treatment group and visit number where 
appropriate. Statistics to be reported for continuous variables are: number of subjects (N), 
mean, median, standard deviation (SD) and range (minimum and maximum). For categorical 
variables, number and percentage of subjects will be reported 
 
For the superiority test (bowel function) the Full Analysis Population (FAP) will be used for 
the primary analysis and the Per Protocol Population (PPP) will be used for sensitivity 
analysis. For the non-inferiority test (pain), the PPP will be used for the primary analysis and 
the FAP will be used for sensitivity analysis. All secondary endpoints will be analyzed with the 
FAP only and all safety analysis will be based on Safety Population. 
 
For the primary endpoints analyses including Bowel Function Index (BFI) and Brief Pain 
Inventory Short-Form (BPI-SF), ANCOVA will be used for comparing the treatments at final 
visit; method of Last Observation Carried Forward (LOCF) will be applied for missing values, 
adjust for baseline observation. 
 
Additional sensitivity analyses will be performed. A MMRM model will be used that has fixed 
effects for visit, treatment within visit, baseline; random intercept over subjects; an 
unstructured covariance matrix over the visits. The comparison between treatments at final 
visit will be reported. A similar model will be estimated that assumes a constant treatment 
effect over visits. .


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2. OBJECTIVES 
This randomized, double-blind, double-dummy, parallel study is to assess the effectiveness in 
relieving cancer pain and the improvement of adverse reaction of opioid of Oxycodone / 
Naloxone prolonged release tablets 5/2.5mg, 10/5mg, 20/10mg or 40/20mg compared to 
Oxycodone prolonged release 5mg, 10mg, 20mg or 40mg in subjects with moderate to severe 
chronic cancer pain. 
 
The main objectives are to  
-
Determine the improvement in symptoms of constipation in subjects with moderate to 
severe cancer pain receiving treatment with oxycodone/naloxone prolonged release 
tablets (OXN PR) compared to oxycodone prolonged release tablets (OXY PR) based on 
the Bowel Function Index (BFI). 
-
Demonstrate the non-inferiority (comparability) of oxycodone / naloxone prolonged 
release tablets (OXN PR) compared to oxycodone prolonged release tablets (OXY PR) for 
the management of chronic cancer pain as assessed by the average pain of the Brief Pain 
Inventory (BPI) recorded by subjects. 
 
The other objectives are to  
-
Compare the improvement in symptoms of constipation in subjects receiving treatment 
with oxycodone/naloxone prolonged release tablets (OXN PR) to oxycodone prolonged 
release tablets (OXY PR) based on laxative use. 
-
Compare the management of chronic cancer pain of oxycodone / naloxone prolonged 
release tablets (OXN PR) compared to oxycodone prolonged release tablets (OXY PR) as 
assessed by rescue medication use recorded by subjects. 
-
Compare the management of chronic cancer pain of oxycodone / naloxone prolonged 
release tablets (OXN PR) compared to oxycodone prolonged release tablets (OXY PR) as 
assessed by Brief Pain Inventory Short-Form (BPI-SF) (Cleeland, 1991) recorded at each 
visit assesses subject’s’ pain (worst, least, right now), pain relief from medication and 
pain interference over the last 24 Hours. BPI will be assessed on V1, V2, V5, V6, V7 and 
V8. 
-
Assess safety of treatment with OXN PR compared with OXY PR based on the Modified 
Subjective Opiate Withdrawal Scale (SOWS), Adverse Events (AEs), Electrocardiograms 
(ECG) and laboratory tests. 
-
Assess quality of life based on EQ-5D 
 


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3. STUDY DESIGN 
3.1 General Design and Plan 
This is a multi-center, randomized, double-blind, double-dummy, active-controlled, parallel 
study using OXN PR 5/2.5mg, 10/5mg, 20/10mg or 40/20mg and OXY PR 5mg, 10mg, 20mg 
and 40mg to treat moderate to severe, chronic cancer pain.  
 
This study is composed of three phases: a screening phase (<7 days) and a 4-week 
double-blind phase and follow up phase (1 week after last dose). 
 
Approximately 280 subjects may be screened to obtain 230 eligible subjects who will be 
randomized in a 1:1 ratio to OXN PR / OXY PR via an IRT system. Each group will have 115 
subjects. 
 
At the start of the double-blind phase (Randomization), subjects will discontinue their current 
(pre study) opioid and change to an effective dose of study medication (OXY PR/OXN PR). 
Subjects will also stop taking any pre study laxatives at the time of randomization and revert 
to the study laxative regime. 
 
3.2 Treatment 
There are Investigational Medicinal Products (IMPs) and Non-Investigational Medicinal 
Products (NIMPs) used in this study.
 
Investigational Medicinal Products (IMPs) 
In double-blind phase, subjects randomized to test treatment group will take OXN PR and 
matching placebo of OXY PR. The dosage would be fixed and symmetrical (20/10, 30/15, 
40/20, 60/30, 80/40,100/50 or 120/60 mg/day of oxycodone/naloxone) 
 
Test Treatment Group (OXN PR) 
Treatment 
Dosage 
Form 
Strength 
Dosing 
Frequency 
Mode of 
Administration 
Oxycodone 
/naloxone 
prolonged release (OXN PR) 
Tablet 
5/2.5, 
10/5, 
20/10 
and 
40/20mg OXN PR 
Q12h 
Oral 
Matched placebo for 
OXY PR 
Tablet 
Matching placebos for 5, 10,  
20 and 40 mg OXY PR 
tablets 
Q12h 
Oral 
 
In double-blind phase, subjects randomized to reference treatment group will take OXY PR 
and matching placebo of OXN PR. The dosage would be fixed and symmetrical (20, 30, 40, 60, 


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80,100 or 120mg/day) 
 
Reference Treatment Group (OXY PR) 
Treatment 
Dosage 
Form 
Strength 
Dosing 
Frequency 
Mode of 
Administration 
Oxycodone 
Prolonged release (OXY PR) 
Tablet 
5, 10, 20 and 40 mg Oxy PR 
Q12h 
Oral 
Matched placebo 
for OXN PR 
Tablet 
5/2.5, 
10/5, 
20/10 
and 
40/20 mg OXN PR placebo 
Q12h 
Oral 
 
Non-Investigational Medicinal Products (NIMPs) 
The rescue medications are not IMPs. Rescue medications include Analgesics and Laxative 
treatment.  
 
During the double-blind treatment phase, all subjects can receive Morphine Sulphate Tablets 
as rescue medication up to 6 times a day at a dose 
Rescue Medication (Pain) 
Treatment 
Dosage 
Form 
Strength 
Dosing 
Frequency 
Mode of 
Administration 
Morphine Sulphate Tablets 
Tablet 
10 mg 
P.R.N, q4-6h 
Oral 

Throughout the double-blind treatment phase subjects will be given bisacodyl tablets to take 
as a laxative medication. 
Laxative Medication 
Treatment 
Dosage 
Form 
Strength 
Dosing 
Frequency 
Mode of 
Administration 
Bisacodyl 
Tablet 
5 mg 
q3d 
PRN 
(10mg/day) 
Oral 
 
3.3 Sample Size 
Approximately 280 patients may be screened to obtain 230 patients who will be randomized 
in a 1:1 ratio to OXN PR group and OXY PR group. Each group will have 115 subjects 
randomized to ensure 105 patients in the FAP per group. 
 
With 105 subjects in the FAP per treatment group, the study has a power of 90% to detect a 
treatment difference of 12, assuming a common standard deviation of 26, on the BFI on a 
two-sided level of significance level of 0.05. 
 


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3.4 Randomization 
Subjects who have signed informed consent and meet all study criteria after screening period 
will be randomized to receive either OXN PR or OXY PR treatment. Randomization will be 
completed using a validated system by the Sponsor in a 1:1 ratio. An interactive response 
technology (IRT) system will be employed to manage study treatment supply.  
 
3.5 Blinding 
The study medication (OXN PR or OXY PR) will be packaged in a double-blind, double-dummy 
manner, rendering the active tablets indistinguishable from the matched placebo tablets. 
During the double-blind phase, the subject and all personnel involved with the conduct and 
the interpretation of the study, including the Investigators, investigational site personnel, and 
the Sponsor’s and CRO’s staff, will be blinded to the medication codes. 
 
Randomization data will be kept strictly confidential, filed securely by the Sponsor, and 
accessible only to authorized persons per Sponsor’s Standard Operating Procedures (SOPs) 
until the time of unblinding. 
 
Emergency unblinding will be done via the IRT system. Unblinding is not to be done unless an 
actual emergency occurs and knowledge of the subject’s randomization code may affect 
his/her medical treatment. If possible, before breaking the blind, the Investigator should 
consult with the Sponsor’s Medical Monitor to ascertain the necessity of breaking the code. A 
record will be made of the date, time and reason for breaking the blind. 
 
3.6 Laboratory Assessments 
All scheduled clinical laboratory tests include hematology, blood chemistry and urinalysis will 
be performed by local laboratories. 
 
 
 


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4. STUDY POPULATIONS 
4.1 Definition of Populations for Analysis 
¾
Enrolled Population  
The enrolled population is defined as all subjects who signed informed consent. 
 
¾
Randomized Population 
The randomized population is defined as all randomized subjects. 
 
¾
Full Analysis Population (FAP) 
The full analysis population is defined as all randomized subjects who receive at least one 
dose of study medication (IMP) and have at least one post-baseline primary efficacy endpoint. 
 
¾
Per Protocol Population (PPP) 
The Per Protocol Population is defined as all FAP subjects without major protocol violations. 
 
Major protocol violations will be agreed at the Determination of Subject Evaluability meeting 
prior to database lock. 
 
¾
Safety Population 
The safety population is defined as all randomized subjects who receive at least one dose of 
IMP and with at least one post-baseline safety assessment. 
 
4.2 Subject Disposition 
A clear picture of subjects regarding screened, screen failure, primary reason of screen failure, 
randomized and completion status and the reason why subjects were withdrawn from study 
will be summarized in Figure 1.  
 
The number and percentage of subjects in each population will be summarized by treatment 
group and overall for subjects in the enrolled set. Reasons for exclusion from the PPP will also 
be summarized. 
 
The number and percentage of subjects enrolled and the primary reason for screen failure 
will be summarized for subjects in the enrolled population. 
 
The number and percentage of subjects that complete the study and the primary reason for 


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CONFIDENTIAL                             Page 13 of 36 
discontinuation will be summarized for subjects in the randomized population. 
 
The number and percentage of subjects enrolled from each site will be summarized for 
subjects in the randomized population. 
 
Details of analysis population will be tabulated as Table 1: Summary of Subject Disposition as 
appropriate. 
 
Table 1: Summary of Subject Disposition 
Variable 
Status 
OXN PR 
OXY PR 
Enrolled Population 
Number of total screened 
N 
 
Number of screen failure 
N (%) 
 
 
 
Major reason of screen failure Failed screening procedure 
N (%) 
 
Not meet all inclusion/exclusion criteria 
N (%) 
 
Subject's Choice 
N (%) 
 
Lost to Follow-up 
N (%) 
 
AE 
N (%) 
 
SAE 
N (%) 
 
Other 
N (%) 
 
 
 
Randomized Population 
Number of randomization 
N (%) 
N (%) 
 
Site1 
N (%) 
N (%) 
 
Site2 
N (%) 
N (%) 
 
 
 
 
Safety Population 
Number of Safety Population 
N (%) 
N (%) 
 
 
 
 
FAP 
Number of FAP 
N (%) 
N (%) 
 
 
 
 
PPP 
Number of PPP 
N (%) 
N (%) 
 
 
 
 
Reason for PPP exclusion 
Failure to comply with the inclusion/exclusion criteria N (%) 
N (%) 
 
Being non-compliant with study treatments 
N (%) 
N (%) 
 
Taking any prohibited concomitant therapies 
N (%) 
N (%) 
 
 
 
 
Complete study  
N 
N 
N 
 
Yes 
N (%) 
N (%) 
 
No 
N (%) 
N (%) 
 
 
 
 
Reason for not complete study Number of subject 
N 
N 
Adverse Event 
N (%) 
N (%) 
Subject’s choice 
N (%) 
N (%) 
Lost to follow-up 
N (%) 
N (%) 
Administrative 
N (%) 
N (%) 
Lack of Therapeutic Effect 
N (%) 
N (%) 
FAP: Full Analysis Population 
PPP: Per Protocol Population 
 


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Figure 1: Subject Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomized 
N=
Screened 
N= 
Screening Failures 
N= 
OXN 
N= 
Adverse Event 
N= 
Subject’s choice 
N= 
Lost to follow-up 
N= 
Administrative 
N= 
Lack of Therapeutic Effect N= 
 
 
 
 
Not Completed 
N= 
 
 
 
 
Completed 
N= 
Safety Population 
N= 
FAP 
N= 
Failure to comply with 
the inclusion/exclusion 
criteria 
N= 
Being non-compliant 
with study treatments 
N= 
Taking any prohibited 
concomitant therapies  
N= 
Not PPP 
N=
PPP 
N=
OXY PR 
N= 
Adverse Event 
N= 
Subject’s choice 
N= 
Lost to follow-up 
N= 
Administrative 
N= 
Lack of Therapeutic Effect N= 
 
 
 
 
Not Completed 
N= 
 
 
 
 
Completed 
N= 
Safety Population 
N= 
FAP 
N= 
Failure to comply with 
the inclusion/exclusion 
criteria 
N= 
Being non-compliant 
with study treatments 
N= 
Taking any prohibited 
concomitant therapies  
N= 
Not PPP 
N=
PPP 
N=
Failed screening procedure 
N= 
Not meet all 
inclusion/exclusion criteria 
N= 
Subject's Choice 
N= 
Lost to Follow-up 
N= 
AE 
N= 
SAE 
N= 
Other 
N= 


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4.3 Protocol Deviations/Violations 
The following protocol violations may exclude a subject from the PPP. Major protocol 
violations will be agreed at the Determination of Subject Evaluability (DOSEA) meeting prior 
to database lock. 
 
1) Failure to comply with the inclusion/exclusion criteria. 
2) Being non-compliant with study treatments. 
3) Taking any prohibited concomitant therapies. 
 
Information regarding subject identification, reason for protocol deviations/protocol 
violation will be listed in the DOSEA Report which will be attached as appendix in statistical 
analysis report. 
 
 
 
 


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5. STATISTICAL ANALYSIS 
5.1 Working platform 
Statistical analysis programs will be generated with SAS 9.3 on Windows platform. 
 
5.2 Time-Points for Analysis 
Statistical analysis will be performed after database lock. 
 
5.3 Methods for Handling Missing Data 
For the primary analyses use ANCOVA comparing the treatments at final visit, method of Last 
Observation Carried Forward (LOCF) will be applied for missing values.  
 
No imputation will be implemented for missing data in regard of secondary and other efficacy 
variables and safety analysis. 
 
5.4 Statistical Analysis 
5.4.1 Categorical Data 
Categorical data will be summarized by treatment group with number and percentage of 
subject. 
 
5.4.2 Continuous Data 
Continuous data will be summarized by treatment group with number of subject (N), mean, 
median, SD and range (minimum and maximum). 
 
For the primary efficacy endpoint LS means of the treatment difference with corresponding 
95% confidence intervals will be provided as well. 
 
5.4.3 Statistical Comparison 
Significance tests (2-sided significance level of alpha=0.05) will be performed for the primary 
efficacy endpoint as appropriate and p-value will be rounded to three decimal places. 
 
 
 


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6. EVALUATION OF DEMOGRAPHICS/BASELINE CHARACTERISTICS  
6.1 Demographics  
FAP will be applied for the analysis of demographics. Age, weight, height, and body mass index 
(BMI) will be summarized as continuous data while gender and race will be summarized as 
categorical data and presented as Table 2: Summary of Demographic Data. 
 
Table 2: Summary of Demographic Data 
Parameter 
Statistics 
Total 
OXN PR 
OXY PR 
Age (year) 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
 
 
 
 
 
Weight (kg) 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
 
 
 
 
 
Height (cm) 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
 
 
 
 
 
BMI (kg/m2) 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
 
 
 
 
 
Gender 
N 
N 
N 
N 
 
Male 
N (%) 
N (%) 
N (%) 
 
Female 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
Race 
N 
N 
N 
N 
 
Caucasian 
N (%) 
N (%) 
N (%) 
 
Black 
N (%) 
N (%) 
N (%) 
 
Asian 
N (%) 
N (%) 
N (%) 
 
Other 
N (%) 
N (%) 
N (%) 
 
6.2 Current Medical Condition (Baseline) 
FAP will be applied for the summary of current medical condition. The current medical 
conditions will be coded with MedDRA version 15.0 and summarized by System Organ Class 
(SOC) and Preferred Term (PT). The results will be summarized by treatment group as 
categorical data as Table 3: Summary of Current Medical Conditions. 
 


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Table 3: Summary of Current Medical Conditions  
SOC 
PT 
Total 
OXN PR 
OXY PR 
Total 
 
N, N (%) 
N, N (%) 
N, N (%) 
SOC1 
Total 
N, N 
N, N 
N, N 
 
PT1 
N, N (%) 
N, N (%) 
N, N (%) 
 
PT2 
N, N (%) 
N, N (%) 
N, N (%) 
 
… 
N, N (%) 
N, N (%) 
N, N (%) 
 
 
 
 
 
SOC2 
Total 
N, N 
N, N 
N, N 
 
PT1 
N, N (%) 
N, N (%) 
N, N (%) 
 
PT2 
N, N (%) 
N, N (%) 
N, N (%) 
 
… 
N, N (%) 
N, N (%) 
N, N (%) 
N, N (%): Number of Event, Number of Subject (Percentage of Subject) 
 
 


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7. EFFICACY ANALYSIS 
The efficacy analysis will be analyzed based on subjects in FAP and PPP as defined in the 
protocol.  
 
Descriptive statistics of efficacy variables will be produced. These will be sorted by treatment 
group and visit where appropriate. Visit 2 measurements will be used as baseline data and 
Visit 1 measurements will be used when Visit 2 data is not available. 
 
7.1 Primary Efficacy Assessments Analysis 
There are 2 primary efficacy variables: one is Bowel Function Index (BFI) and the other is 
Brief Pain Inventory Short-Form (BPI-SF).  
 
x
Bowel Function Index (BFI) 
Bowel Function Index (BFI) is the mean of Numerical Analogue Scale (NAS) for the 
following items: 
− Ease of defecation  
− Feeling of incomplete bowel evacuation. 
− Personal judgment of constipation. 
 
The analysis of the primary endpoint uses an ANCOVA comparing the treatments at final visit 
using LOCF for missing values, adjusted for baseline observation. The FAP is the primary 
population for this BFI analysis and the PPP will be analyzed as well. The result will be 
presented as Table 4: Summary of ANCOVA analysis for BFI LOCF data at final visit. 
 
Table 4: Summary of ANCOVA analysis for BFI LOCF data at final visit 
Variable 
Statistics 
OXN PR 
OXY PR 
P-value* 
Bowel Function Index (BFI) 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
 
 
 
 
 
Difference in BFI between OXN PR and OXY PR 
LS Mean 
 
 
 
95% CI 
 
 
* ANCOVA analysis 
 
Additional sensitivity analyses will be performed in which LOCF will not be applied for 
missing values. A MMRM model will be used that has fixed effects for visit, treatment within 
visit, baseline; random intercept over subjects; an unstructured covariance matrix over the 
visits. The comparison between treatments at final visit will be reported. A similar model will 
be estimated that assumes a constant treatment effect over visits. 


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The comparison between treatments at final visit will be reported and the result will be 
presented as Table 5: Summary of Sensitivity analysis for BFI data at final visit. 
 
Table 5: Summary of Sensitivity analysis for BFI data at final visit 
Variable 
Statistics 
OXN PR 
OXY PR 
P-value* 
Bowel Function Index (BFI) 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
 
 
 
 
 
Difference in BFI between OXN PR and OXY PR 
LS Mean 
 
 
 
95% CI 
 
 
* MMRM model applied 
 
To observe trend, BFI will also be summarized by visit. 
 
x
Brief Pain Inventory Short-Form (BPI-SF) 
 
Brief Pain Inventory Short-Form (BPI-SF) (Cleeland, 1991) recorded at each visit assesses 
subjects’ average pain over the last 24 Hours. For average pain uses an ANCOVA comparing the 
treatments at final visit using LOCF for missing values, adjusted for baseline observation. The 
PPP is the primary population for this pain analysis. FAP will be analyzed as well. The result 
will be presented as Table 6: Summary of ANCOVA analysis for BPI-SF LOCF data at final visit. 
 
Table 6: Summary of ANCOVA analysis for BPI-SF LOCF data at final visit 
Variable 
Statistics 
OXN PR 
OXY PR 
P-value* 
Brief Pain Inventory Short-Form (BPI-SF) 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
 
 
 
 

Difference in BFI between OXN PR and OXY PR 
LS Mean 
 

 
95% CI 
 

* ANCOVA analysis 
 
7.2 Secondary Efficacy Assessments Analysis 
Only FAP will be used for secondary efficacy analysis. 
 
x
To compare the improvement in symptoms of constipation based on laxative use. 
 
Amount of laxative medication use recorded at each assessment visit. Total number of 
bisacodyl tablets used per week, and the number of Bisacodyl tablets used per day will be 
calculated using the data recorded on CRF in section “Study Laxative (Bisacodyl) Use” section. 
The results will be summarized as continuous data as Table 7: Summary of use of Laxative 


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Medication (Bisacodyl). 
Table 7: Summary of use of Laxative Medication (Bisacodyl) 
Parameter 
Visit 
Statistics 
OXN PR 
OXY PR 
Number of laxative tablets took 
during the last 7 days (per week) 
 
N 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
(Min, Max) 
 
 
Daily number of laxative tablets took 
during the last 7 days (per day) 
 
N 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
(Min, Max) 
 
 
* Daily tablets = Total tablets took / Number of days with medication 
 
x
To compare the management of chronic cancer pain as assessed by rescue 
medication use recorded by subjects. 
 
Amount (mg) of rescue medication used per day (24 hours) recorded on the OXY IR wallet. 
Average rescue medication (Morphine Sulphate) used per day will be summarized as 
continuous data as Table 8: Summary of Rescue Medication (Morphine Sulphate). 
 
Table 8: Summary of Rescue Medication (Morphine Sulphate) 
Parameter 
Visit 
Statistics 
OXN PR 
OXY PR 
Average rescue medication used per 
day (mg) 
 
N 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
(Min, Max) 
 
 
 
x
Brief Pain Inventory Short-Form (BPI-SF) (Cleeland, 1991) recorded at each visit 
assesses subjects’ pain (worst, least, right now), pain relief from medication in 
percentage and pain interference over the last 24 Hours. 
 
The 11 individual items regarding subjects’ pain (worst, least, right now), pain relief from 
medication and pain interference will be summarized as continuous data as Table 9: Summary 
of BPI-SF.  
 
Table 9: Summary of BPI-SF for Individual Items 
Parameter 
Visit 
Statistics 
OXN PR 
OXY PR 
Pain at its worst in the last 24 
hours 
… 
 
N 
 
 
Mean (SD) 
 
 
Median 
 
 
(Min, Max) 
 
 
 
In addition, BPI pain interference will be scored as the mean of the seven interference items 


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and summarized as continuous data as Table 10: Summary of BPI-SF for Pain Interference. 
Table 10: Summary of BPI-SF for Pain Interference 
Parameter 
Visit 
Statistics 
OXN PR 
OXY PR 
Mean of seven interference items 
 
N 
 
 
Mean (SD) 
 
 
Median 
 
 
(Min, Max) 
 
 
 
x
Modified Subjective Opiate Withdrawal Scale (SOWS). 
 
SOWS will be scored as the total of the 15 symptoms and, change from baseline to visit 3 and 
visit 9 will be summarized as continuous data as Table 11: Summary of SOWS. 
 
Table 11: Summary of SOWS 
Parameter 
Visit 
Statistics 
OXN PR 
OXY PR 
Total of the 15 items 
 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
Scatter plots will be produced for SOWS comparing baseline and Visit 3 values as well. 
 
x
To assess quality of life based on EQ-5D. 
 
The scale of health state will be summarized as continuous data as Table 12: Summary of 
EQ-5D. 
 
Table 12: Summary of EQ-5D 
Parameter 
Visit 
Statistics 
OXN PR 
OXY PR 
EQ-5D 
 
N 
 
 
 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 
 
x
Number of bowel movements the subject has had in the last 7 days before the study 
visit and number of days the subject had a bowel movement in the last 7 days 
before the study visit. 
 
Number of bowel movements and number of days the subject had a bowel movement in the 
last 7 days before the study visit will be summarized as continuous data as Table 13: 
Summary of Bowel Movement. 
 


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Table 13: Summary of Bowel Movement  
Parameter 
Visit 
Statistics 
OXN PR 
OXY PR 
Number of bowel movement 
 
N 
 
 
… 
 
Mean (SD) 
 
 
 
 
Median 
 
 
 
 
(Min, Max) 
 
 


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8. SAFETY ANALYSIS 
The safety analysis will be summarized by treatment group and overall based on subjects in 
Safety population and the assessments include adverse events, vital signs, laboratory test, 
electrocardiogram (ECG) and physical examination. 
 
8.1 Adverse Event 
AEs will be coded with MedDRA version 15 and summarized by SOC and PT for each event. 
Only treatment emergent AEs will be summarized. A treatment emergent AE will be defined as 
any AE with an onset date on or after the first dose of IMP if the AE was absent before the first 
dose of IMP, or worsened after the first dose of IMP. This will also include AEs with an onset 
date up to and including 7 days after the last dose of IMP. 
 
The overall AE information including incidence, severe AE, AE related to IMP and SAE will be 
summarized as Table 14: Summary of Overall Adverse Events information. 
 
Table 14: Summary of Overall Adverse Events information 
Category 
Total 
OXN PR
OXY PR
Number of AEs 
N 
N 
N 
Number of subjects with AEs 
N (%) 
N (%) 
N (%) 
Number of related AEs 
N 
N 
N 
Number of subjects with related AEs 
N (%) 
N (%) 
N (%) 
Number of Severe AEs 
N 
N 
N 
Number of subjects with Severe AEs 
N (%) 
N (%) 
N (%) 
Number of SAEs 
N 
N 
N 
Number of subjects with SAEs 
N (%) 
N (%) 
N (%) 
Number of related SAEs 
N 
N 
N 
Number of subjects with related SAEs 
N (%) 
N (%) 
N (%) 
 
AEs leading to death, AEs leading to discontinuation from study, AEs requiring additional 
therapy, AEs leading to dose reduction, and AEs leading to dose interruption and SAE not 
related to IMP will be summarized as Table 15: Summary of Incidence of Deaths, Other SAE 
and Other Significant EventsTable 14: Summary of Overall Adverse Events information. 
 
Table 15: Summary of Incidence of Deaths, Other SAE and Other Significant Events 
Category 
Total 
OXN PR
OXY PR
AEs leading to Deaths 
N (%) 
N (%) 
N (%) 
AEs leading to withdraw from study 
N (%) 
N (%) 
N (%) 
AEs requiring treatment given 
N (%) 
N (%) 
N (%) 
AEs leading to dose decrease 
N (%) 
N (%) 
N (%) 
AEs leading to withheld transiently 
N (%) 
N (%) 
N (%) 
SAE not related to IMP 
N (%) 
N (%) 
N (%) 
 
 


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The number and percentage of subjects reporting any AE and the number of reported AEs will 
be summarized by PT nested within SOC  
 
AEs will also be summarized by PT nested within SOC for worst severity, relationship to IMP, 
IMP action taken, other action taken and outcome. 
 
Serious AE will be summarized by PT nested within SOC as Table 16: Summary of Serious 
Adverse Events. 
 
Table 16: Summary of Serious Adverse Events  
SOC 
PT 
Total 
OXN PR 
OXY PR 
Total 
 
N, N (%) 
N, N (%) 
N, N (%) 
SOC1 
Total 
N, N 
N, N 
N, N 
 
PT1 
N, N (%) 
N, N (%) 
N, N (%) 
 
PT2 
N, N (%) 
N, N (%) 
N, N (%) 
 
… 
N, N (%) 
N, N (%) 
N, N (%) 
 
 
 
 
 
SOC2 
Total 
N, N 
N, N 
N, N 
 
PT1 
N, N (%) 
N, N (%) 
N, N (%) 
 
PT2 
N, N (%) 
N, N (%) 
N, N (%) 
 
… 
N, N (%) 
N, N (%) 
N, N (%) 
N, N (%): Number of Event, Number of Subject (Percentage of Subject) 
 
The most frequent AEs (PT  5% in any treatment group) will be summarized for the 
double-blind phase as Table 17: Summary of Adverse Events  5% in Double-Blind phase.  
 
Table 17: Summary of Adverse Events ≥ 5% in Double-Blind phase  
SOC 
PT 
Total 
OXN PR 
OXY PR 
Total 
N 
N, N (%) 
N, N (%) 
N, N (%) 
SOC1 
N 
N, N 
N, N 
N, N 
 
PT 1 
N, N (%) 
N, N (%) 
N, N (%) 
 
PT 2 
N, N (%) 
N, N (%) 
N, N (%) 
… 
 
 
 
 
N, N (%): Number of Event, Number of Subject (Percentage of Subject) 
 
These will also be presented graphically using a dot plot and a caterpillar plot within which 
the percentage of subjects reporting each of the most common AEs will be presented 
alongside the odds ratio (and associated 95% CI) for comparing the incidence of AEs. 
 


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8.2 Laboratory Assessment 
Safety population will be used for the analysis of laboratory assessments including blood 
chemistry, hematology and urinalysis. Laboratory results recorded at each visit and change 
from baseline to each visit will be summarized as continuous or categorical data as 
appropriate for each parameter by treatment group and overall. P-values will not be provided. 
 
Each parameter will be assigned an LNH classification according to whether the value is lower 
than (L), within (N) or higher than (H) the reference range for that parameter. Results will be 
summarized using shift tables to evaluate categorical changes from baseline to end of study 
with respect to reference range values (lower than, within, higher than) as Table 18: Shift 
table 
of 
Laboratory 
Assessments 
for 
OXN 
PR 
/OXY 
PR 
treatment-Blood 
Chemistry/Hematology/Urinalysis. For those tests with qualitative results which cannot be 
categorized to LNH level, will only be summarized according to abnormality. 
 
Table 18: Shift table of Laboratory Assessments for OXN PR /OXY PR treatment-Blood 
Chemistry/Hematology/Urinalysis 
Parameter 
Baseline 
Final Visit 
L 
N 
H 
Hemaglobin 
L 
 
 
 
… 
N 
 
 
 
 
H 
 
 
 
L: Lower than 
N: Within 
H: Higher than 
 
Laboratory values after first dose of IMP will be evaluated for markedly abnormal value. The 
number and percentage of subjects reporting markedly abnormal value with or without 
clinical significance will be summarized for each parameter by treatment group and overall as 
Table 
19: 
Summary 
of 
Laboratory 
Assessment 
Abnormality-Blood 
Chemistry/Hematology/Urinalysis. 
 
Table 19: Summary of Laboratory Assessment Abnormality-Blood 
Chemistry/Hematology/Urinalysis 
Parameter 
Visit 
Status 
Total 
OXN PR 
OXY PR 
Hemaglobin 
 
N 
N 
N 
N 
… 
 
Normal 
N (%) 
N (%) 
N (%) 
 
 
Abnormal, NCS 
N (%) 
N (%) 
N (%) 
 
 
Abnormal, CS 
N (%) 
N (%) 
N (%) 


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Scatter plots will be produced for each laboratory parameter comparing baseline (Visit 2) and 
end of study values. 
  
8.3 Vital Signs 
Safety population will be used for the analysis of vital sign parameters to be summarized 
include systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiration 
rate, and temperature. Vital sign results recorded at each visit and change from baseline to 
each visit will be summarized as continuous data for each parameter by treatment group and 
overall. P-values will not be provided 
 
Each parameter will be assigned an LNH classification according to whether the value is lower 
than (L), within (N) or higher than (H) the reference range for that parameter. Results will be 
summarized using shift tables to evaluate categorical changes from baseline to end of study 
with respect to reference range values (lower than, within, higher than) as Table 20: Shift 
table of Vital Signs for OXN PR /OXY PR Treatment .  
 
Table 20: Shift table of Vital Signs for OXN PR /OXY PR Treatment  
Parameter 
Baseline 
Final Visit 
L 
N 
H 
SBP 
L 
 
 
 
… 
N 
 
 
 
 
H 
 
 
 
L: Lower than 
N: Within 
H: Higher than 
 
Vital sign values after first dose of IMP will be evaluated for clinically notable abnormalities 
according to Appendix 7 of protocol and each subject can be counted once in the parameter 
high and low categories as applicable. The number and percentage of subjects reporting 
clinically notable abnormalities will be summarized for each parameter by treatment group as 
Table 21: Summary of Clinically Notable Abnormality of Vital Signs.  
 
Table 21: Summary of Clinically Notable Abnormality of Vital Signs 
Parameter 
Visit 
Clinically Notable Abnormal 
Total 
OXN PR 
OXY PR 
SBP 
 
N 
N 
N 
N 
… 
 
High 
N (%) 
N (%) 
N (%) 
 
 
Normal 
N (%) 
N (%) 
N (%) 
 
 
Low 
N (%) 
N (%) 
N (%) 


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Scatter plots will be produced for each vital sign parameter comparing baseline (Visit 2) and 
end of study values. 
 
8.4 Electrocardiogram 
Safety population will be applied for the analysis of Electrocardiogram assessment. 
Electrocardiogram assessment will be summarized by treatment and visit as Table 22: 
Summary of Electrocardiogram Assessments. 
 
Table 22: Summary of Electrocardiogram Assessments 
Characteristics 
Visit 
Statistics 
Total 
OXN PR 
OXY PR 
Electrocardiogram 
 
N 
N 
N 
N 
 
Normal 
N (%) 
N (%) 
N (%) 
 
Abnormal, NCS 
N (%) 
N (%) 
N (%) 
 
Abnormal, CS 
N (%) 
N (%) 
N (%) 
 
 


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9. OTHER ANALYSIS  
9.1 IMP Analysis  
Safety population will be applied for the analysis of IMP. Treatment exposure will be defined 
as the number of days on IMP which will be calculated as the number of days between the first 
and last dose of IMP. Treatment exposure will be summarized by treatment group as 
continuous data and summarized as Table 23: Summary of IMP Exposure. 
 
Table 23: Summary of IMP Exposure 
Parameter 
Statistics 
OXN PR 
OXY PR 
IMP exposure (Day) 
N 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
(Min, Max) 
 
 
 
9.2 Concomitant Medication Analysis  
FAP will be applied for concomitant medication analysis. Concomitant medications will be 
coded with World Health Organization Drug Dictionary of version Q4/2012. 
 
The number and percentage of subjects taking concomitant medications will be summarized 
by ATC class level 1 and level 4 for treatment group as Table 24: Summary of Concomitant 
Medication by ATC  
 
Table 24: Summary of Concomitant Medication by ATC 
ATC class 
OXN PR 
OXY PR 
Alimentary… 
N, N (%) 
N, N (%) 
Level 4 
N, N (%) 
N, N (%) 
… 
N, N (%) 
N, N (%) 
 
N, N (%) 
N, N (%) 
 
 
 
Blood … 
N, N (%) 
N, N (%) 
Level 4 
N, N (%) 
N, N (%) 
… 
N, N (%) 
N, N (%) 
 
N, N (%) 
N, N (%) 
 
 
 


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9.3 Physical Examination 
Safety population will be applied for the analysis of physical examination. Summary of 
physical examination will be summarized as categorical data in Table 25: Summary of Physical 
Examination. 
 
Table 25: Summary of Physical Examination 
Parameter 
Visit 
Status 
OXN PR 
OXY PR 
Any clinical significant finding 
 
N 
N 
N 
 
 
No 
N (%) 
N (%) 
 
 
Yes 
N (%) 
N (%) 
 
9.4 Pregnancy Test 
Safety population will be applied for the analysis of pregnancy test. Pregnancy test result will 
be summarized as categorical data in Table 26: Summary of Pregnancy Test.   
 
Table 26: Summary of Pregnancy Test 
Parameter 
Visit 
Result 
OXN PR 
OXY PR 
Pregnancy Test 
 
N 
N 
N 
 
 
No 
N (%) 
N (%) 
 
 
Yes 
N (%) 
N (%) 
 
 
ND 
N (%) 
N (%) 
 
 
 


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10. LIST OF TABLES  
Tables will be presented for Enrolled, Randomized, FAP, PPP and Safety population as 
appropriate. 
 
Table 14.1.1: Summary of Subject Disposition (All subjects) 
Table 14.1.2: Summary of Demographic Data (FAP) 
Table 14.1.3: Summary of Current Medication Conditions (FAP) 
 
Table 14.2.1: Summary of ANCOVA analysis for BFI LOCF data at final visit (FAP) 
Table 14.2.2: Summary of ANCOVA analysis for BFI LOCF data at final visit (PPP) 
Table 14.2.3: Summary of Sensitivity analysis for BFI data at final visit – MMRM model (FAP) 
Table 14.2.4: Summary of Sensitivity analysis for BFI data at final visit - MMRM model constant 
treatment effect over visits (FAP) 
Table 14.2.5: Summary of BFI (FAP) 
Table 14.2.6: Summary of ANCOVA analysis for BPI-SF LOCF data at final visit (PPP)  
Table 14.2.7: Summary of ANCOVA analysis for BPI-SF LOCF data at final visit (FAP)  
Table 14.2.8: Summary of use of Laxative Medication (Bisacodyl) (FAP) 
Table 14.2.9: Summary of Rescue Medication (Morphine Sulphate) (FAP) 
Table 14.2.10: Summary of BPI-SF (FAP) 
Table 14.2.11: Summary of BPI-SF for Pain Interference (FAP) 
Table 14.2.12: Summary of SOWS (FAP) 
Table 14.2.13: Summary of EQ-5D (FAP) 
Table 14.2.14: Summary of Bowel Movement (FAP) 
 
Table 14.3.1: Summary of Overall Adverse Events information (Safety) 
Table 14.3.2: Summary of Incidence of Deaths, Other SAE and Other Significant Events (Safety) 
Table 14.3.3: Summary of Adverse Events (Safety) 
Table 14.3.4: Summary of Serious Adverse Eventsġ(Safety) 
Table 14.3.5: Summary of Adverse Events by Outcomeġ(Safety) 
Table 14.3.6: Summary of Adverse Events by Severityġ(Safety) 
Table 14.3.7: Summary of Adverse Events by Relationshipġ(Safety) 
Table 14.3.8: Summary of Adverse Events by Action Takenġ(Safety) 
Table 14.3.9: Summary of Adverse Events by Other Action Takenġ(Safety) 
Table 14.3.10: Summary of Adverse Events ı 5% in Double-Blind phaseġ(Safety) 
Table 14.3.11: Summary of Laboratory Assessments-Blood Chemistryġ(Safety) 
Table 14.3.12: Summary of Laboratory Assessments-Hematologyġ(Safety) 
Table 14.3.13: Summary of Laboratory Assessments-Urinalysisġ(Safety) 


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Table 14.3.14: Shift table of Laboratory Assessments for OXN PR treatment-Blood Chemistryġ(Safety) 
Table 14.3.15: Shift table of Laboratory Assessments for OXY PR treatment-Blood Chemistryġ(Safety) 
Table 14.3.16: Shift table of Laboratory Assessments for OXN PR treatment-Hematologyġ(Safety) 
Table 14.3.17: Shift table of Laboratory Assessments for OXY PR treatment-Hematologyġ(Safety) 
Table 14.3.18: Shift table of Laboratory Assessments for OXN PR treatment- Urinalysisġ(Safety) 
Table 14.3.19: Shift table of Laboratory Assessments for OXY PR treatment-Urinalysisġ(Safety) 
Table 14.3.20: Summary of Laboratory Assessment Abnormality-Blood Chemistryġ(Safety) 
Table 14.3.21: Summary of Laboratory Assessment Abnormality-Hematologyġ(Safety) 
Table 14.3.22: Summary of Laboratory Assessment Abnormality-Urinalysisġ(Safety) 
Table 14.3.23: Summary of Vital Signsġ(Safety) 
Table 14.3.24: Shift table of Vital Signs for OXN PR Treatmentġ(Safety) 
Table 14.3.25: Shift table of Vital Signs for OXY PR Treatmentġ(Safety) 
Table 14.3.26: Summary of clinically notable abnormality of Vital Signsġ(Safety) 
Table 14.3.27: Summary of Electrocardiogram Assessmentsġ(Safety) 
Table 14.3.28: Summary of IMP Exposure (FAP) 
Table 14.3.29: Summary of Concomitant Medication by ATC level 1 (FAP) 
Table 14.3.30: Summary of Concomitant Medication by ATC level 4 nested within Level 1 (FAP) 
Table 14.3.31: Summary of Physical Examinationġ(Safety) 
Table 14.3.32: Summary of Pregnancy Testġ(Safety) 


Statistical Analysis Plan for OXN10-CN-303 
 Version/Date: V2, 15-Oct-2014 
 
                    CONFIDENTIAL                             Page 33 of 36            
                       
11. LIST OF LISTINGS 
All subject data will be presented in subject data listings.  
 
Listing 16.1.1.: Listing of Subjects' Population  
Listing 16.1.2: Listing of Eligibility Evaluation  
Listing 16.1.3: Listing of Screening Result at V1 & V2 
Listing 16.1.4: Listing of Study completion / Early Study Termination  
Listing 16.1.5: Listing of Protocol Deviations/Violations  
Listing 16.1.6: Listing of Subjects Excluded from the FAP  
Listing 16.1.7: Listing of Subjects Excluded from the PPP  
Listing 16.1.8: Listing of Informed Consent and Visit Dates  
 
Listing 16.2.1: Listing of Demographics  
Listing 16.2.2: Listing of Medical History and Current Medical Conditions 
Listing 16.2.3: Listing of Prior and Current Medication/Therapies 
 
Listing 16.3.1: Listing of Rescue Medication dosing (Morphine Sulphate) 
Listing 16.3.2: Listing of Laxatives Rescue Medication dosing (Bisacodyl) 
Listing 16.3.3: Listing of Investigational Medicinal Product dosing 
Listing 16.3.4: Listing of Questions on Bowel Movements and Study Laxative (Bisacodyl) Use 
Listing 16.3.5: Listing of Bowel Function Index (BFI) 
Listing 16.3.6: Listing of Brief Pain Inventory Short Form (BPI-SF) 
Listing 16.3.7: Listing of EuroQol EQ-5D 
Listing 16.3.8: Listing of Modified Subjective Opiate Withdrawal Scale (SOWS) 
 
Listing 16.4.1: Listing of Adverse Event  
Listing 16.4.2: Listing of Serious Adverse Event 
Listing 16.4.3: Listing of Laboratory Tests Results - Hematology 
Listing 16.4.4: Listing of Laboratory Tests Results - Blood Chemistry 
Listing 16.4.5: Listing of Laboratory Tests Results - Urinalysis 
Listing 16.4.6: Listing of Pregnancy Test 
Listing 16.4.7: Listing of Physical Examination  
Listing 16.4.8: Listing of Vital Signs  
Listing 16.4.9: Listing of Electrocardiogram Assessments 
Listing 16.4.10: Listing of Investigator Comments  
 
 


Statistical Analysis Plan for OXN10-CN-303 
 Version/Date: V2, 15-Oct-2014 
 
                    CONFIDENTIAL                             Page 34 of 36            
                       
12. LIST OF FIGURES 
Figure 14.1.1: Scatter plot of SOWS at Baseline and Visit 3 (FAP) 
Figure 14.1.2: Dot plot of most frequent AEs (preferred term ı 5% in any treatment group) (Safety) 
Figure 14.1.3: Caterpillar plot of most frequent AEs (preferred term ı 5% in any treatment group) 
(Safety) 
Figure 14.1.4: Scatter plot of Blood Chemistry at baseline and Visit 8 (Safety) 
Figure 14.1.5: Scatter plot of Hematology at baseline and Visit 8 (Safety) 
Figure 14.1.6: Scatter plot of Urinalysis at baseline and Visit 8 (Safety) 
Figure 14.1.7: Scatter plot of Vital Signs at baseline and Visit 8 (Safety) 
 
 


Statistical Analysis Plan for OXN10-CN-303 
Version/Date: V2, 15-Oct-2014 
 
                    CONFIDENTIAL                             Page 35 of 36            
                       
13. Appendix 
13.1 Flow chart 
 
 
 


Statistical Analysis Plan for OXN10-CN-303 
Version/Date: V2, 15-Oct-2014 
 
                    CONFIDENTIAL                             Page 36 of 36