An Open-label, Randomized, Single-dose, Parallel-group Study to Investigate the PK Profile of Single Dose Buprenorphine Transdermal Patch 20 mg Applied for 3 Days, 40 mg for 3 Days and 40 mg for 4 Days in Chinese Subjects With Chronic Pain
Phase: PHASE1
Conditions: Chronic Pain
Sponsor: Mundipharma (China) Pharmaceutical Co. Ltd

 
 
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Protocol Number: 
BUP14-CN-101 
 
 
Title: 
An open-label, randomized, single-dose, parallel-group study to investigate 
the pharmacokinetic profile of single dose Buprenorphine transdermal patch 
20 mg applied for 3 days, 40 mg for 3 days and 40 mg for 4 days in 
Chinese subjects with chronic pain. 
 
 
EudraCT/IND 
number: 
Not applicable 
 
 
Sponsor: 
Mundipharma (China) Pharmaceutical Co. LTD 
18F, Tower D Central International Trade Center, 6A Jianguomen Wai 
Avenue, Chaoyang District, Beijing, China 100022 
 
 
 
 
Test IMP: 
Buprenorphine transdermal patches 
 
 
Indication: 
Not applicable 
 
 
Phase: 
Phase 1 
 
 
Release Date and 
version number: 
10 Jan 2019, Version 2.0  
 
 
GCP Statement: 
This study is to be performed in full compliance with the protocol, 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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 VERSION HISTORY 
 
Version number and Date 
Reason for update 
1.0 
Initial version 
2.0 
Inclusion criteria #1 updated following EC 
review 
 
 
 

 
 
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 CLINICAL PROTOCOL SUMMARY 
Name of Company: Mundipharma (China) Pharmaceutical Co., Ltd. 
Name of Finished Product:  
Buprenorphine Transdermal Patch 20 mg and 40 mg 
Name of Active Ingredient: 
Buprenorphine 
Protocol No.: BUP14-CN-101 
<EudraCT><IND> No.:  N/A 
Registration: https://register.clinicaltrials.gov 
Short Title of the Study: A single dose PK study of Buprenorphine Transdermal Patch (20 mg, 40 mg 
application for 3 days and 40 mg application for 4 days) in Chinese subjects with chronic pain. 
Full Title of the Study: An open-label, randomized, single-dose, parallel-group study to investigate the 
pharmacokinetic profile of single dose Buprenorphine transdermal patch 20 mg applied for 3 days, 40 mg 
applied for 3 days and 40 mg applied for 4 days in Chinese subjects with chronic pain. 
Objectives: 
Primary  
To evaluate the pharmacokinetic (PK) profile of buprenorphine and its primary metabolite, 
norbuprenorphine of single dose buprenorphine transdermal patch (BUP TDS) 20 mg applied for 3 days, 
40 mg for 3 days and 40 mg for 4 days. 
Secondary 
To evaluate the safety and tolerability following a single application of BUP TDS. 
Sample size and Investigator(s)/Site(s):  
Total sample size of 45 subjects (15 subjects/arm) will be randomised to receive IMP with the aim to 
have at least 36 subjects (12 subjects/arm) completing the study and providing valid PK data. The study 
will be conducted in 1-3 sites in China. 
Summary of Study Design:  
This is an open-label, randomised, single-dose, 3 arms study design. Subjects will be randomised into 
one of 3 arms, in a 1:1:1 ratio, wearing BUP TDS 20 mg for 3 days or 40 mg for 3 days or 40 mg for 4 
days. 
 
 
 
 

 
 
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Study Diagram 
 
 
 
 
 
 
20mg/3d 
40mg/4d 
Arm 1 
(n=15) 
Arm 2 
(n=15) 
Arm 3 
(n=15) 
Randomization 
(N=45) 
≤ 21 days 
7 – 9 days after patch removal 
Screen 
visit      
Admission to site     
(Day 00) 
End of sampling  
Screening 
Treatment & Sampling 
Safety follow-up 
40mg/3d 
End of study 
20mg/3d = BUP TDS 20 mg application for 3 days 
40mg/3d = BUP TDS 40 mg application for 3 days 
40mg/4d = BUP TDS 40 mg application for 4 days 

 
 
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Page 
1 TITLE PAGE ......................................................................................................... 1 
 VERSION HISTORY ............................................................................................. 2 
 CLINICAL PROTOCOL SUMMARY ..................................................................... 3 
4 TABLE OF CONTENTS ....................................................................................... 5 
 LIST OF ABBREVIATIONS ................................................................................ 11 
 STUDY CONDUCT AND OVERSIGHT .............................................................. 13 
6.1 Sponsor .......................................................................................................... 13 
6.2 Declaration of Ethical Conduct ..................................................................... 13 
6.3 Investigators and Study Personnel .............................................................. 13 
6.4 Data Management .......................................................................................... 13 
6.5 Monitoring....................................................................................................... 13 
6.6 Medical Monitoring & Safety ......................................................................... 14 
6.7 Central Review/Central Laboratory/Bioanalytical Laboratory .................... 14 
 INTRODUCTION ................................................................................................. 14 
 Therapeutic Area/Background ........................................................................ 14 
 Investigational Medicinal Product (IMP) ......................................................... 14 
 Study Rationale and Aim ................................................................................. 16 
 Design Rationale .............................................................................................. 16 
 Benefit Risk Assessment ................................................................................ 17 
 STUDY OBJECTIVES ........................................................................................ 17 
 Primary Objectives ........................................................................................... 17 
 Secondary Objectives ...................................................................................... 17 

 
 
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 STUDY ENDPOINTS .......................................................................................... 17 
 Primary Endpoint ............................................................................................. 17 
 Safety Endpoints .............................................................................................. 17 
10 STUDY SUMMARY AND GRAPHIC ................................................................ 18 
 Overall Study Design and Plan ..................................................................... 18 
 Study Diagram ................................................................................................ 18 
 Data Monitoring Board ................................................................................... 18 
 SELECTION OF SUBJECTS ............................................................................ 18 
 Inclusion Criteria ............................................................................................ 18 
 Exclusion Criteria. .......................................................................................... 19 
 ASSESSMENTS AND PROCEDURES ............................................................ 21 
 Summary of procedures (specific data collection) ..................................... 21 
 Schedule Overview ........................................................................................ 25 
 Screening Period ............................................................................................ 30 
 Re-Screening Instructions ............................................................................. 30 
 Randomisation ............................................................................................... 31 
 Treatment and Sampling Period ................................................................... 31 
 Three-day application period ......................................................................... 31 
 Four-day application ...................................................................................... 34 
12.7 End of study ................................................................................................. 36 
12.8 Early Discontinuation/Withdrawal/Loss to Follow-up ............................... 36 
12.9 Safety follow-up (telephone contact) ......................................................... 36 
12.10 Withdrawal Criteria .................................................................................... 36 
12.11 Study Restrictions ..................................................................................... 37 
12.11.1 Food and Beverages ................................................................................. 37 
12.11.1 Alcohol, Caffeine, Smoking and other Restrictions ................................... 37 

 
 
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13 STUDY TREATMENTS AND CONCOMITANT THERAPIES ........................... 37 
13.1 Study Treatments (IMPs and NIMPs) ............................................................... 37 
13.1.1 Test Investigational Medicinal Product(s), Dose and Mode of 
Administration .......................................................................................................... 37 
13.1.2 Reference IMP, Dose and Mode of Administration ........................................ 38 
13.1.3 Non-Investigational Medicinal Product (NIMP / Auxillary product), Dose 
and Mode of Administration ...................................................................................... 38 
13.2 Study Treatments to be supplied ................................................................ 38 
13.3 Dosing Schedule .......................................................................................... 38 
13.4 Method of Administration ............................................................................ 39 
13.5 Treatment Assignment ................................................................................ 40 
13.6 Blinding ......................................................................................................... 40 
13.7 Treatment Compliance/IMP Accountability ................................................ 40 
13.8 Concomitant Therapies – Permitted ........................................................... 40 
13.9 Concomitant Therapies - Prohibited .......................................................... 41 
13.10 Shipping, Handling, Storage, and Destruction/Return............................ 41 
14 SAFETY ASSESSMENTS ................................................................................ 42 
14.1 Safety Definitions and Requirements ......................................................... 42 
14.1.1 Adverse Event (AE) ....................................................................................... 42 
14.1.2 Serious Adverse Event (SAE) ....................................................................... 42 
14.1.3 Special Situations ........................................................................................ 43 
14.1.4 Pregnancy ................................................................................................... 43 
14.2 Period of Observation .................................................................................. 44 
14.3 Reporting of Adverse Events ...................................................................... 44 
14.4 Follow Up of Adverse Events ...................................................................... 47 
14.5 Reporting By Investigator to Sponsor........................................................ 48 
15 STATISTICAL ANALYSES .............................................................................. 48 
15.1 General Considerations ............................................................................... 49 

 
 
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15.2 Analysis Populations ................................................................................... 49 
15.3 Protocol Deviations ..................................................................................... 49 
15.4 Sample Size and Power Considerations .................................................... 50 
15.5 Interim Analysis ........................................................................................... 50 
15.6 Efficacy Analysis .......................................................................................... 50 
15.7 Safety Analyses ............................................................................................ 50 
15.7.1 Treatment Exposure and Compliance ......................................................... 50 
15.7.2 Adverse Events ........................................................................................... 50 
15.7.3 Laboratory Values ....................................................................................... 51 
15.7.4 Vital Signs ................................................................................................... 51 
15.7.5 ECG ............................................................................................................ 52 
15.8 Pharmacokinetic Measurements and Analyses ........................................ 52 
15.8.1 Drug Concentration Measurements ............................................................ 52 
15.8.2 Pharmacokinetic Analyses .......................................................................... 52 
16 ETHICS & REGULATORY ............................................................................... 52 
16.1 Declaration of Ethical Conduct ................................................................... 53 
16.2 Ethical and Regulatory Review ................................................................... 53 
16.3 Subject Information and Consent ............................................................... 54 
16.4 Data Protection and Human Tissue Sampling ........................................... 54 
16.5 Quality Assurance & Inspection Requirements ........................................ 54 
17 STUDY MANAGEMENT RECORDS & PUBLICATION ................................... 55 
17.1 Protocol Amendments ................................................................................. 55 
17.2 Record Maintenance and Retention ........................................................... 56 
17.3 Adherence to the Protocol .......................................................................... 56 
17.4 Discontinuation of Study ............................................................................. 57 
17.5 Retention of Tissue Samples ...................................................................... 57 
17.6 Registration and Publication of Study Summary and Results ................. 57 

 
 
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18 REFERENCE LIST ........................................................................................... 58 
19 APPENDICES ................................................................................................... 60 
19.1 Adverse Event Reporting Process ............................................................. 60 
19.2 Classification of Treatments ....................................................................... 61 
19.3 Sample Processing and Shipment ............................................................. 63 
19.3.1 Pharmacokinetic Sample Handling and Shipping ........................................ 63 
19.3.2 Sample Procurement and Processing ......................................................... 63 
19.3.3 Sample Shipment ........................................................................................ 63 
19.4 Clinical Laboratory Tests ............................................................................ 64 
19.5 Pain Intensity Scale ..................................................................................... 65 
19.6 Dermal response scale ................................................................................ 66 
19.7 Karnofsky score ........................................................................................... 67 
 
 
 

 
 
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LIST OF TABLES 
Page No. 
Schedule of visits and procedures for the 3-day application and 4-day application 
respectively. All procedures will be collected in the source documents. ....................... 25 
Table 1.1: Investigation schedule for 3-day application ....................................................... 25 
Table 1.2: Investigation schedule for 4-day application ....................................................... 27 
Table 1.3 PK Blood Sampling Schedule for 3-day application ............................................. 29 
Table 1.4 PK Blood Sampling Schedule for 4-day application ............................................. 29 
Table 2: Test IMP Identity ................................................................................................... 37 
Table 3: NIMP Identity ......................................................................................................... 38 
Table 4: Adverse Event Severity ......................................................................................... 45 
Table 5: Clinical Laboratory Tests ....................................................................................... 64 
 
LIST OF FIGURES 
Page No. 
Figure 1: Study diagram ...................................................................................................... 18 
Figure 2: Flow diagram for AE reporting (to be considered alongside Section 14 of the 
protocol) ....................................................................................................................... 60 
Figure 3: Overview of classification of treatments ............................................................... 61 
 
 
 
 
 
 
 

 
 
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 LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine transaminase (also SGPT) 
AST 
Aspartate transaminase (also SGOT) 
AUC 
Area under the plasma concentration-time curve 
AUCt 
Area under the plasma concentration-time curve calculated from the time of 
dosing to the last measurable concentration 
BP 
Blood Pressure 
bpm 
Beats per minute 
BMI 
Body Mass Index 
BUP 
Buprenorphine 
CA 
Competent Authorities 
CS 
Clinical Significant  
cm 
centimeter 
Cmax 
Maximum observed concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CYP 
Cytochrome 
D 
Day 
DMP 
Data Management Plan 
DRM 
Data Review Meeting 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
g 
gram 
GGT 
Gamma-glutamyl-transferase 
GLP 
Good Laboratory Practice 
H 
Laboratory value above the reference range 
h 
Hour 
hrs 
hours 
HBsAg 
Hepatitis B surface antigen 
HCV Ab 
Hepatitis C virus Antibodies 
hCG 
Human chorionic gonadotropin 
HCO3- 
Bicarbonate 
HIVAb 
Human immunodeficiency virus antibodies 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
I/E 
Inclusion/Exclusion 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
kg 
Kilogram 
L 
Laboratory value below the reference range 
LC-MS/MS 
Liquid Chromatography - Tandem Mass Spectrometry 
LDH 
Lactate dehydrogenase 

 
 
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LLN 
Lower limit of the laboratory reference (normal) range 
LNH 
Classification according to whether the Laboratory test result was below 
(L), within (N), or above (H) the reference range 
µg  
Micrograms 
m 
Meter 
MAH 
Marketing Authorisation Holder 
MCPC 
Mundipharma (China) Pharmaceutical Co., Ltd 
MOA 
Monoamine oxidase 
mg 
Milligram 
mL 
Millilitre 
mmHg 
Millimetre mercury 
N 
Laboratory value within the reference range 
NCS 
Non Clinical Significant 
NIMP 
Non-Investigational Medicinal Product/Auxillary Product 
NMPA 
National Medical Products Administration 
NRS 
Numeric Rating Scale 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetic 
PR 
Pulse rate 
PT 
Preferred Term 
QA 
Quality Assurance 
RBC 
Red blood cell (count) 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analyses Software 
SMP 
Safety Management Plan 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOPs 
Standard Operating Procedures 
t1/2Z 
Apparent terminal phase half-life 
tmax 
Time from dosing to the maximum observed concentration 
TEAA 
Treatment Emergent adverse event 
TDS 
Transdermal Delivery System 
ULN 
Upper limit of the laboratory reference (normal) range 
USA 
United States of America 
WBC 
White blood cell (count) 
WHO 
World Health Organisation 
 
 

 
 
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 STUDY CONDUCT AND OVERSIGHT 
 
6.1 
Sponsor 
This study will be conducted by qualified Investigators under the Sponsorship of Mundipharma 
(China) Pharmaceutical Co., Ltd (MCPC). 
6.2 
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 16 of this protocol. 
6.3 
Investigators and Study Personnel 
The study will be conducted in 1-3 centres in China. The contact details of the Investigator and 
other contact persons at the Sponsor and CRO will be listed in the study site file. 
6.4 
Data Management 
All data management related tasks will be outsourced to a CRO. The Data Management Plan 
(DMP) will include a task and responsibility list for all data management tasks.  
Clinical data will be captured by using an Electronic Data Capture (EDC) system. Quality control 
and data validation procedures will be applied to ensure the validity and accuracy of the clinical 
data. The Monitoring Plan and supporting documents will detail the data entry, source data 
verification, data validation, and locking procedures to be followed by all relevant study staff. 
The DMP describes the data flow between the EDC system, external vendors (e.g. lab) and 
different functional parties involved in the handling of clinical data.  
At the end of the study each site will be provided with an archiving media including one PDF per 
subject with the clinical data and audit trail extracted from the EDC system. 
6.5 
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 GCP and 
Good Laboratory Practice (GLP) as applicable. The EDC system and subject’s corresponding 
original medical records (source documents) are to be fully available for review by the 
CRO/Sponsor’s representatives at regular intervals. These reviews verify adherence to study 
protocol and data accuracy in accordance with local regulations and GCP.  All records at the site 
are subject to inspection by the local competent and local health authorities. 

 
 
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6.6 
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 contact list stored in the study site file. 24-
hour medical support will be provided by the CRO; the contact details are supplied in the 
Investigator Site File. 
6.7 
Central Review/Central Laboratory/Bioanalytical Laboratory 
Local laboratories will be used for sample analysis for safety assessment.  A qualified 
bioanalytical laboratory will be employed to process all study samples to generate bioanalytical 
data.   
 
 INTRODUCTION 
 
 Therapeutic Area/Background 
Pain is one of the most common symptoms for cancer patients, seriously affecting their quality 
of life. The incidence of pain is about 25% in newly diagnosed cancer patients and around 60% 
to 80% in advanced cancer patients, where one third is assessed as severe pain (China Ministry 
of Health, Cancer pain clinical guidelines, 2011).  
Pain is classified on the basis of its duration (i.e. acute and chronic pain) and underlying 
pathophysiology (i.e. nociceptive, neuropathic, mixed and psychogenic pain). Cancer pain 
patients commonly experience more than one kind of pain. The highest prevalence of pain 
(>85%) is related to cancers of pancreas, bone, brain, lung and head and neck. 
Current treatment of cancer pain is based on the World Health Organisation’s (WHO) concept of 
an “analgesic ladder” which involves a stepwise approach to the use of analgesic drugs and is 
essentially a framework of principles rather than a rigid protocol (WHO, 1996). This three-step 
approach is broadly established and 80 – 90% effective for the treatment of malignant and non-
malignant pain.  
Opioids are the mainstay of pain management for patients with moderate-to-severe cancer pain 
and are increasingly used for the treatment of chronic pain that is non-malignant in origin. 
Buprenorphine containing formulations are considered step III agents in the WHO analgesic 
ladder for pain. 
 Investigational Medicinal Product (IMP) 
Buprenorphine is a synthetic opioid analgesic derived from the opium alkaloid thebaine. It is a μ-
opioid receptor agonist, while it shows an antagonistic effect on к-opioid receptors (Cowan et al, 
1977). The analgesic potency of buprenorphine was found to be 25-50 times higher (on a 
weight-by-weight basis) than that of morphine (Budd, 2002).  
With the indication for alleviation of moderate/severe pain, buprenorphine injection was first 
launched in the United Kingdom in 1978 and in the United States in 1982. It was mainly used for 
postoperative pain control, but also used for alleviation of moderate to severe pain in patients 
with cancer, trigeminal neuralgia, ureteral stones, myocardial infarction, and trauma. Moreover, a 

 
 
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sublingual tablet (Subutex®) was approved as a treatment for opioid dependency at doses of up to 16 
mg/day, which was well above the analgesic range. Through international clinical experience for 
almost 4 decades, the safety and efficacy of buprenorphine for treating various types of 
moderate and severe pain have been demonstrated (Heel et al, 1979; Hoskin & Hanks, 1991; 
Lewis, 1995; Wolff et al, 2012). Pharmacokinetics of buprenorphine was found to be dose-
proportional after both sublingual and intravenous administration (Walsh et al., 1994; Budd, 
2002). In China, buprenorphine injection and sublingual tablet were approved in 1995 and 1997 
respectively, and used for many kinds of pain treatment.  
However, the immediate-release formulations administered sublingually showed marked 
fluctuations of buprenorphine plasma concentration, i.e. high peak and low trough concentration 
during a dosing interval, which tend to induce inconsistent pain relief at trough or increased 
adverse events (AEs) at peaks. Oral formulations are not available for buprenorphine as the 
absolute bioavailability was found to be insufficient to achieve analgesic drug concentrations 
(Tegeder et al. 1999) due to the high first-pass effect.  
In order to achieve a sustainable analgesic effect, the 3-day buprenorphine transdermal patch 
(Transtec®) was developed in the 1990s, and firstly approved in Switzerland in June 2000, for 
the management of moderate to severe cancer pain and severe pain refractory to non-opioid 
analgesics. As of August 2017, it has been approved in 32 countries worldwide but not yet in 
China.  
The transdermal patch consists of a polymer matrix in which the active substance 
buprenorphine is dispersed. When applied to the skin, buprenorphine is continuously released 
from the matrix leading to constant transdermal invasion of the drug into the systemic 
circulation. The rate-controlled release of buprenorphine from the transdermal patch ensures 
relatively constant plasma levels which translate into long-term and consistent pain relief with 
the chance of minimizing the potential for of side effects.  
Three dose strengths of Transtec® have been developed containing 20, 30, or 40 mg 
buprenorphine. The in-vivo release rates were found to be 35 μg/h, 52.5 μg/h, and 70 μg/h over 
72 hours (3 days), respectively. Plasma concentrations increased in a linear fashion according 
to dose.  
After the initial application of Transtec®, the minimum clinically effective plasma concentration 
(100 pg/ml) was reached in about 11 hours for 70 μg/h patch and about 21 hours for 35 μg/h 
patch, and tmax across patch strengths was found to be 60 – 80 hours on average. After 
removing the patch, a steady decrease of plasma concentrations occurred about 1 hour later. 
The average terminal half-lives across patch strengths ranged from 20 to 27 hours. 
Buprenorphine is metabolized in the liver, primarily to norbuprenorphine glucuronide (Kacinko et 
al, 2009). Cytochrome P450 (CYP) 3A4 is the phase 1 enzyme involved in metabolism of 
buprenorphine to norbuprenorphine (Kacinko et al, 2009).  
Biliary excretion is the predominant route of elimination. After intravenous administration of 
buprenorphine, only 10% to 27% of the administered drug was excreted in urine. The faeces 
contain mainly unchanged buprenorphine, while urinary excretory products are conjugates of the 
parent compound and norbuprenorphine (Hand et al, 1986; Heel et al, 1979). 
Clearance of buprenorphine was shown to be relatively independent of the renal system and is 
not altered in patients with renal impairment (Hand et al, 1990). Administration of the 
buprenorphine transdermal patch was found to be safe in these patients (Filitz et al, 2006).  
Neither buprenorphine nor norbuprenorphine plasma levels were found to be elevated. No 

 
 
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difference in pain relief before and after haemodialysis was observed. No dose adjustment is 
needed in these patients. 
Additional data showed that each patch could provide sustained delivery of buprenorphine for up 
to 4 days (Likar, 2005), thus enabling the patient to change the patch twice a week, e.g. always 
on Monday and on Thursday. This is expected to improve the convenience of the usage of 
buprenorphine patch and positively contribute to the compliance of patients.  
In addition to the 3 - 4 day patch, a 7-day patch formulation has been developed by 
Mundipharma / Purdue (Butrans® or Norspan®) and was first approved in Denmark in 2003. 
Since then, with the main indication of non-cancer pain, it has been approved in 47 countries up 
to January 2018. In the USA, 3 doses of buprenorphine (5, 10 and 20 mg with a release rate of 
5, 10 and 20 μg/h, respectively) were approved by the FDA in July 2010 for management of 
moderate to severe chronic pain requiring 24-hour sustained opioid analgesia. The 7-day 
buprenorphine patch was launched in China in December 31st, 2012 under trade name of 
Norspan®. 
 Study Rationale and Aim 
The aim of this study is to evaluate the pharmacokinetic (PK) profile of buprenorphine and its 
primary metabolite, norbuprenorphine, after a single dose of buprenorphine transdermal patches 
being applied in Chinese subjects. The safety of buprenorphine transdermal patches will also be 
evaluated in the study.  
This study consists of three treatment arms.  Subjects will be randomised in a 1:1:1 ratio to BUP 
TDS 20 mg for 3 days, or BUP TDS 40 mg for 3 days or BUP TDS 40 mg for 4 days.  The doses 
chosen cover the lowest and highest doses to be used in clinic in the future. These doses have 
been found to be well tolerated to date. The known and potential risks are those described in the 
latest version of the Investigator Brochure (IB). 
Per Technical Guideline for Pharmacokinetic Studies of Chemical Drug Products (NMPA, 2005), 
if the drug will be used in clinics consecutively for multiple times, its PK characteristics at steady 
state with multiple administrations should be identified. This will be completed in a second PK 
study, BUP18-CN-101.  
According to the regulations on narcotic drugs and psychotropic substances (State Council 
Order No. 442), the clinical trials of narcotic drugs and the first class psychotropic substances 
are not allowed to be conducted in healthy populations, the participants will therefore be chronic 
mild pain patients.  
 Design Rationale 
The study design and data analysis follow the recommendations issued from the “Technical 
Guideline for Pharmacokinetic Studies of Chemical Drug Products prepared by China National 
Food and Drug Administration (NMPA, 2005) and from Pharmacopoeia of the P.R.C. (2015).  
As the main study criterion is PK parameters which are objective and not subject to bias, an 
open label study design is therefore acceptable.  
The plasma elimination half-life of buprenorphine is about 20-27 hours.  

 
 
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No formal sample size calculation was performed. The planned number of subjects will meet the 
requirement of the PK study guideline (NMPA, 2005), which recommends 8 to 12 subjects in 
each treatment arm.  
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), the 
ethical principles that have their origin in the declaration of Helsinki and the applicable regulatory 
requirements. 
 Benefit Risk Assessment 
The safety and tolerability of buprenorphine are well established and generally regarded as 
favourable. Its safety profile has been described and summarized in a number of publications 
(Budd, 2002; Budd & Collett, 2003; Walsh et al, 1994; Dahan et al, 2005). Buprenorphine has 
been approved for more than 4 decades for intravenous and sublingual use in many countries, 
including the United States and many European countries. 
The controlled-release method of buprenorphine administration via the transdermal matrix patch 
technology further enhances the safety margins of buprenorphine, without compromising the 
therapeutic value in the management of chronic pain in Chinese subjects. 
Overall the assessment of all currently available published clinical data indicates a positive 
benefit-risk ratio of 3- or 4-day BUP TDS. 
 STUDY OBJECTIVES 
 
 Primary Objectives 
- 
To evaluate the pharmacokinetic profile of buprenorphine and its primary metabolite, 
norbuprenorphine of single dose Buprenorphine transdermal patch (BUP TDS) 20 mg 
applied for 3 days, 40 mg for 3 days and 40 mg for 4 days.  
 Secondary Objectives 
- 
To evaluate the safety and tolerability following single application of BUP TDS. 
 
 STUDY ENDPOINTS 
 
 Primary Endpoint 
The primary endpoint will be the PK assessment. Pharmacokinetic parameters of the prototype 
buprenorphine, and the primary metabolite norbuprenorphine, calculated from plasma 
concentration-time data following a single application of BUP TDS 20 mg (3 days), 40 mg (3 
days) and 40 mg (4 days). 
 Safety Endpoints 
Subjects will be closely monitored throughout the study for evidence of any AE. Vital signs, 
including pulse rate, respiration rate, sitting blood pressure and body temperature, will be 
measured at regular intervals.  Furthermore, examinations including physical examination, 12-

 
 
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lead ECG as well as laboratory parameters, will be performed on the day of the last blood 
sample taken. 
 
 
 Overall Study Design and Plan 
This is a randomised open-label, single dose PK study.  Subjects will be randomised into one of 
3 treatment arms, wearing BUP TDS 20 mg for 3 days or 40 mg for 3 days or 40 mg for 4 days. 
 Study Diagram 
Figure 1: Study diagram 
 
 
 
 Data Monitoring Board 
Not applicable in this study.  
 SELECTION OF SUBJECTS 
Subjects to be included in the study must comply with the eligibility criteria as detailed in 
Sections 11.1 and 11.2. 
 Inclusion Criteria 
Only subjects meeting all of the following inclusion criteria will be considered for study inclusion:  
20mg/3d 
40mg/4d 
Arm 1 
(n=15) 
Arm 2 
(n=15) 
Arm 3 
(n=15) 
Randomization 
(N=45) 
≤ 21 days 
7 – 9 days after patch removal 
Screen 
visit      
Admission to site     
(Day 00) 
End of sampling  
Screening 
Treatment & Sampling 
Safety follow-up 
40mg/3d 
End of study 
20mg/3d = BUP TDS 20 mg application for 3 days 
40mg/3d = BUP TDS 40 mg application for 3 days 
40mg/4d = BUP TDS 40 mg application for 4 days 

 
 
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1. Chinese male or female subjects with chronic pain (regardless of the aetiology, cancer-
pain excluded), aged 18-55 years (both inclusive). 
2. The average pain over the last 24 hours should attain ≤ 3 assessed with Numeric Rating 
Scales (NRS) refer to section 19.5.  The pain condition has been lasting for at least 1 
month and stable for 7 days prior to entering into the screening and is expected to be 
stable during the study duration.  
3. Patients on stable permissible non-opioid analgesics, who in the opinion of the 
investigator are unlikely to require a change in treatment during the study.  
4. Karnofsky score of Performance Status ≥ 70. 
5. Body mass index (BMI) of 19 to 28 kg/m2 (both inclusive); and a total body weight 
≥50 kg.  
6. Normal dietary habits (e.g. not vegetarian nor vegan) and willing to only take the food 
supplied during the period of hospitalization. 
7. Subjects who are able to read, understand and sign written informed consent prior to 
study participation and are willing to follow the protocol requirements. 
8. Female subjects of child bearing potential (less than 1 year post-menopausal) must have 
a negative urine pregnancy test prior to first dose of study medication, be non-lactating, 
and willing to use adequate and highly effective methods of birth control throughout the 
study such as sterilisation, implants, injectables, combined oral contraceptives, some 
intra-uterine devices, sexual abstinence or vasectomised partner. 
Male subjects (surgical history of bilateral vasectomy excluded) with a partner of child 
bearing potential must be willing to use adequate and highly effective methods of birth 
control throughout the study. 
 Exclusion Criteria. 
Subjects having any of the following criteria, either at screening or at baseline will not be 
included in the study. 
1. Unstable condition of the primary disease of chronic pain, which, in the opinion of the 
investigator, would complicate the subject’s participation in the study (e.g. require 
initiation of new medication). 
2. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease 
(including drug allergies). 
3. History of seizures or at risk (i.e. head trauma, epilepsy in family, anamnesis, unclear 
loss of consciousness). 
4. Any history of frequent nausea or emesis regardless of aetiology. 
5. Malignancy or a history of malignancy. 
6. History of orthostatic hypotension. 
7. Subjects who have any medical or surgical conditions that might interfere with 
transdermal absorption, distribution, metabolism, or excretion of drugs. 
8. Positive results for Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibodies 
(HCV Ab), human immunodeficiency virus antibodies (HIVAb). 
9. Urine screening before study is positive for opioids, barbiturates, amphetamines, cocaine 
metabolites, methadone, benzodiazepines, phencyclidine, methamphetamine, or 
cannabinoids or alcohol breath test is positive. 
10. Subjects who have a current or past (within 5 years) history of substance or alcohol 
abuse, or subjects who, in the opinion of the investigator or the sub-investigator, have 
demonstrated addictive or substance abuse behaviors. Alcohol abuse is defined as 

 
 
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regular alcohol consumption exceeding 14 drinks/week (1 drink = 150 mL of wine or 360 
mL of beer or 45 mL of hard liquor). 
11. Consumption of alcoholic beverages within 48 hours before patch application, and / or 
refusal to abstain from alcohol throughout the study until at least 48 hours after patch 
removal.  
12. Use of tobacco- or nicotine-containing products in excess of the equivalent of 
5 cigarettes per day. 
13. Use of any medicinal product which inhibits CYP3A4 (e.g. troleandomycin, ketoconazole, 
gestodene, etc) or induces CYP3A4 (e.g. glucocorticoids, barbiturates, rifampicin,etc) 
within 4 weeks prior to first patch administration. 
14. Subjects who are currently taking tricyclic antidepressants or have used tricyclic 
antidepressants within 4 weeks prior to the first patch administration. 
15. Subjects taking monoamine oxidase (MAO) inhibiters within the past 14 days prior to the 
first patch administration 
16. Subjects taking any opioid drug within the past 14 days prior to the first patch 
administration. 
17. Use of prescription or nonprescription drugs, vitamins and dietary supplements within 
7 days prior to the first patch administration. As an exception, acetaminophen could have 
been used at doses of 1 g/day. 
18. Subjects who participated in a clinical research study involving a new chemical entity or 
an experimental drug within 30 days prior to the screening visit. Concurrent enrolment in 
another clinical trial is not permitted unless the sole purpose of the other trial is for 
collection of long-term follow-up/survival data. 
19. Donated 400 mL or more of blood or blood products within 3 months prior to the start of 
the study. 
20. Screening sitting blood pressure (BP) 140 mm Hg (systolic) or 90 mm Hg (diastolic), 
following at least 5 minutes of rest. If BP is 140 mm Hg (systolic) or 90 mm Hg 
(diastolic), the BP should be repeated two more times and the average of the three BP 
values should be used to determine the subject’s eligibility. 
21. 12-lead ECG demonstrating QTc>450 msec or a QRS interval >120 msec at Screening. 
If QTc exceeds 450 msec, or QRS interval exceeds 120 msec, the ECG should be 
repeated two more times and the average of the three QTc or QRS interval values 
should be used to determine the subject’s eligibility. 
22. Subjects who have history of hypersensitivity to opioid analgesic formulations. 
23. Subjects who have history of hypersensitivity to naltrexone. 
24. Subjects who have history of hypersensitivity to transdermal delivery system or patch 
adhesives. 
25. Subjects with any potential dermatological disorder at a patch application site, e.g. 
previous and/or current unhealed extensive dermal damage in the area where the patch 
will be applied (e.g. dermatitis, burns, tattoos, scarring of the skin) 
26. Subjects who could not discontinue therapy that involved direct heat sources (e.g. heat 
lamps, electric blankets, heating pads or heated water beds) for the duration of the study 
27. Subjects with hairy areas who could not, or would not, cut the hair at the patch site for 
proper placement of the patch 
28. Special diets such as caffeine or xanthine-containing foods and beverages (including 
pitaya fruit, mango, grapefruit, coffee, tea, cola, chocolate, grapefruit juice, etc.) should 
be taken within 48 hours before patch application or during the study. 
29. Subjects who have difficulty swallowing tablets. 
30. Subjects who cannot tolerate venipuncture, or subjects who have difficulty in collecting 
blood, or subjects who have a history of fainting at the sight of blood or needles. 

 
 
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31. Unwilling or suspected of not being able to comply with the study protocol. 
 
 ASSESSMENTS AND PROCEDURES 
 Summary of procedures (specific data collection) 
Data will be collected for each assessment/procedure as indicated in Tables 1.1, 1.2, 1.3 and 
1.4. 
Adverse Events (AEs) 
AE data is obtained by the Investigator through observation of the subject (including 
examinations and investigations), from any information volunteered by the subject and through 
active questioning. Throughout the study, after informed consent has been signed, subjects will 
be asked about AEs and will be reminded to immediately report AEs experienced to medical 
staff. 
Occurrence, frequency, nature and severity of AEs will be recorded. This includes observations 
or abnormalities in physical examination, vital signs, laboratory or other investigations reported 
as AEs. Any treatment for AEs will also be recorded. 
For further details regarding AEs including definitions and reporting procedures refer to section 
14.  
Physical examination  
Physical examination includes inspection of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, vascular system, extremities, 
musculo-skeletal system and nervous system. The skin check should include a dermatological 
assessment of the application site.  Abdominal ultrasound scan can be performed to understand 
the medical history per investigator’s judgement. 
Please note:  
A new appearance of an abnormal finding or worsening of a concomitant disease that is 
considered clinically significant and occurs after signature of informed consent have to be 
documented as AE. If the abnormal lab result is considered as clinical significance, the 
investigator should judge the start time of this situation, if it is considered as happening before 
the signature of informed consent, this case should be recorded as medical history, if it is 
considered as happening after the signature of informed consent, this case should be recorded 
as AE. 
Pharmacokinetic samples:  
Blood samples for determining the plasma concentration of buprenorphine and 
norbuprenorphine will be collected as the following schedule: 
 
3-day application (20 mg/3d & 40 mg/3d): Pre-dose (0), 12, 24, 48, 72 (pre-removal), 73, 
74, 76, 84, 96, 120, 144 and 168 hours post administration of patch, 13 blood samples in 
total.  
 
4-day application (40 mg/4d): Pre-dose (0), 12, 24, 48, 72, 96 (pre-removal), 97, 98, 100, 
108, 120, 132, 144, 168 and 192 hours post administration of patch, 15 blood samples in 
total. 

 
 
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For each sample, about 6 mL blood sample will be drawn from a Upper limb  vein into a tube 
containing K2EDTA anticoagulant, 0.5-1 mL of blood discarded before blood collection. Soft 
reversal of blood vessels 6-8 times to make blood samples and anticoagulants fully mixed The 
total volume of blood to be collected from each subject will be approximately 85 mL (3-day 
application) and 98 mL (4-day application). After procurement, samples should be kept in a cool 
environment, preferably in a container of ice water, until processing. Samples must be 
centrifuged within 60 minutes of collection. Following centrifugation (2000 g, 2-8°C , 10 minutes), 
the plasma will be equally transferred, via pipettes, into two labelled polypropylene tubes, and 
stored at ≤ -60°C  within two hours of collection. All details will be provided in lab manual.  
Plasma concentration of buprenorphine and norbuprenorphine will be quantified by Liquid 
Chromatography - Tandem Mass Spectrometry (LC-MS/MS) methodology using a previously 
validated assay. 
Vital signs:   
Vital signs and body weight are measured with the following methods/ units: 
 
Supine blood pressure is measured in mmHg according to the Riva Rocci method 
while the subject has been resting in sitting position for at least 5 minutes. The same arm 
should be used as possible for blood pressure measurements throughout the study. The 
size of the cuff has to be chosen appropriately in relation to the subject’s arm 
circumference. 
 
Respiration rate is measured in breaths per minute when subjects have been resting in 
supine position for at least 5 minutes. The measurement involves counting the number of 
breaths for one minute by counting how many times the chest rises is suggested.  
 
Pulse rate is measured in beats per minute either electronically or by palpation for 1 
minute, while the subject is supine and has been resting for at least 5 minutes. 
 
Body temperature is measured in °C  from forehead. If another region is used for body 
temperature measurement, this must be indicated in the eCRF. 
 
Weight should be measured with shoes and coat taken off and pockets emptied of 
heavy objects (e.g. keys, coins). 
 
Height is measured once at screening visit for the purpose of calculation of body mass 
index (BMI). Shoes have to be taken off during the measurement. 
ECG 
A standard 12-lead ECG will be performed at the time points specified in section 12.2. The ECG 
recordings are to be reviewed by the Investigator, under consultation with a specialist, if 
necessary. Results must be summarized in the source data and classified as ‘normal’ or 
‘abnormal’. Abnormal ECGs must be classified as ‘clinically significant’ or ‘not clinically 
significant’. For consistency, the same physician should read all ECGs from one subject. 
Original printouts are to be retained in the source notes. 
Abnormal, clinically significant findings occurring after signature of informed consent have to be 
reported as AE (unless already pre-existing at baseline). 
Laboratory samples and tests 

 
 
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The local laboratory will perform tests to qualify subjects for entry into the study. Laboratory 
certification will be included in the clinical study report for this protocol.  Appendix 19.4.2 
presents the clinical laboratory tests to be performed. 
Values out of the normal range do not automatically lead to a discontinuation of the subject from 
the study. The decision to discontinue a subject from the study due to values out of the lower 
and higher limit of normal should be based on the medical judgement of the Investigator. 
Blood and urine samples for laboratory safety assessment will be taken at the time points 
specified in Section 12.2. 
Subjects should be fasting, i.e. instructed accordingly by the site not to eat or drink anything but 
water for 12 hours before the blood and urine samples collected. Date and time of sampling will 
be documented. Sample handling at the site, shipment and assessment methods will be 
described in the Laboratory Manual. 
All laboratory results have to be evaluated in the eCRF and or laboratory report form provided to 
the Investigator according to the following pattern: 
a) Within reference range (normal range) 
b) Outside reference range but not clinically relevant (e.g. due to already known conditions, 
due to sampling conditions, marginal deviation only, due to underlying diseases in the 
study population) 
c) Outside reference range and clinically relevant  
 
The following items should be considered for the evaluation of the laboratory reports: 
 
Laboratory values occurring (by date of blood sampling) after signature of informed 
consent, which are outside the reference range and assessed as a clinically relevant 
change versus pre-treatment values (as determined by Investigator), have to be 
controlled and documented as an AE. 
 
Where an Investigator does not deem an abnormal (or markedly abnormal) laboratory 
value to be clinically significant, the reason must be clearly documented in the source 
notes (e.g. normal fluctuation of the disease). 
 
An abnormal laboratory value that is a sign of an AE (e.g. infection) that has already 
been reported, has to be documented but the respective abnormal laboratory value does 
not constitute a separate AE. 
 
Abnormalities in laboratory values which result in a change in Investigational Medicinal 
Product (IMP) schedule of administration (change in dose, delay in administration, IMP 
discontinuation or other medical or treatment intervention e.g. anaemia requiring 
transfusions or hyperglycaemia requiring potassium supplement) have to be reported as 
an AE. 
Wherever reasonable the Investigator should use the clinical term rather than the laboratory 
term (e.g. anemia vs. low hemoglobin value). 
Assessment of patch adhesion 
The status of IMP application will be confirmed. The result of these inspections should be 
recorded in the source documentation and eCRFs in accordance with the following criteria: 

 
 
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1. Not detached at all 
2. The edge is partially detached 
3. Patch detached reaches 1/4 but less than 1/3 
4. Patch detached reaches 1/3 but less than 1/2 
5. Patch detached reaches 1/2 or more 
6. 
Trial drug patch is completely detached (or missing) 
In cases where an IMP became loose or detached from the skin, the patch will be secured by 
the attachment of tape.  Any occurrence of a patch becoming loose and requiring taping will be 
documented in the eCRF with start dates and times recorded. 
Dermatological examination of IMP application site  
The dermatological response at patch site after removal should be assessed by investigators 
using the skin status scale (see Appendix 19.6). The assessment will be rated where possible 
by the same observer each time. Only a skin reaction assessment score ≥ 2 on the scale should 
be recorded as an AE. 
 
 

 
 
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 Schedule Overview 
Schedule of visits and procedures for the 3-day application and 4-day application respectively. All procedures will be collected in the source 
documents. 
Table 1.1: Investigation schedule for 3-day application 
Phase 
Screening 
3-day application  
Safety follow-up 
(telephone contact)11 
 
Day 
D-21 to D-1 
D00 
D01 
D02 
D03 
D04 
D05 
D06 
D07 
D08 
7-9 days after patch 
removal (D4) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Average pain over last 24 hours on 0-
10 score NRS 
X 
X 
 
 
 
 
 
 
 
 
 
Karnofsky score 
X 
 
 
 
 
 
 
 
 
 
 
Medical / surgical history1 
X 
 
 
 
 
 
 
 
 
 
 
Drug, Alcohol, Tobacco History 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Dermatological assessment of 
application site 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
X 
 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
HIV Ab, HBsAg, HCV Ab, Syphilis 
Antibody 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
Urine Drug Test 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
 
X 
 
Clinical Laboratory Test (Chemistry, 
Hematology, Urinalysis) 
X 
 
 
 
 
 
 
 
 
X 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
X 
X 
 
 
 
 
 
 
 
X 
 
Vital Signs3 (body temperature, 
respiration rate, PR and BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant treatment 
 
X (recorded continuously throughout the study) 
Adverse Event 
 
X (monitored continuously throughout the study) 
Non-Pharmacological Therapies 
 
X ( monitored continuously throughout the study) 

 
 
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Phase 
Screening 
3-day application  
Safety follow-up 
(telephone contact)11 
 
Day 
D-21 to D-1 
D00 
D01 
D02 
D03 
D04 
D05 
D06 
D07 
D08 
7-9 days after patch 
removal (D4) 
Admission to site  
 
X4 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Naltrexone Dosing5 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Study Patch Administration 
 
 
X 
 
 
 
 
 
 
 
 
Study Patch Removal6 
 
 
 
 
 
X 
 
 
 
 
 
Assessment of patch adhesion7 
 
 
X 
X 
X 
X 
 
 
 
 
 
Dermatological examination of IMP 
application site8 
 
 
 
 
 
X 
X 
X 
 
 
 
Blood sampling9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
End of blood collection visit 
 
 
 
 
 
 
 
 
 
X 
 
End of the study10 
 
 
 
 
 
 
 
 
 
 
X 
 
1. Abdominal ultrasound scan might be performed to understand the medical history per investigator’s judgement. 
2. Pregnancy test will be performed for females of childbearing potential and less than one year post-menopausal. Serum pregnancy test at screening. Urine pregnancy test at admission to 
site and discharge from site (or early termination). 
3. Timing for vital signs:  
- 
At screening  
- 
At Day 00: 13 hours prior to IMP application, within 30 min prior to naltrexone taken.  
- 
From Day 01 to Day 04: twice a day, within 30 min prior to each dosing of naltrexone.  
- 
From Day 05 to Day 08: once in the morning, within 30 min prior to PK blood sampling. 
4. Admission to site at latest in the afternoon (before dinner), at least 15 hours before the patch administration of D01. 
5. On Day 00, naltrexone 50 mg will be orally taken only in the evening, 13 hours (± 5 min) prior to the patch administration of D01; From D ay 01 to Day 04, naltrexone 50 mg will be orally 
taken every 12 hours, in the morning and in the evening, at the fixed time in each morning or evening, with a time window of ± 5 min based on scheduled time. The intake in the morning of 
Day 01 should be 1 hour (± 5 min)  prior to IMP administration. Naltrexone to be taken after meal.  
6. Patches will be removed 72 hours (±2min)  after administration.  Blood sampling should occur in the last 2 minutes of dosing i.e. within 2 minutes prior to the patch being removed  
7. Assessment of patch adhesion will be performed twice a day in the morning and in the evening (every 12±1 hours). The first evaluation on Day 01 will be conducted immediately after the 
first patch applied on Day 01. On Day 04, the evaluation will be done once just before the patch removed.  
8. Dermatological examination of IMP application site will be conducted within 0.5 hour after IMP removal and in the morning of D05 and D06. In case that the result of the examination 
conducted at D05 is judged "No evidence of irritation", the examination scheduled for D06 will not be conducted. In case AE was reported for the skin reaction and not recovered at D06, 
more examinations may be needed for the AE follow-up. 
9. Blood sampling timing: Pre-dose (0), 12, 24, 48, 72 (pre-removal), 73, 74, 76, 84, 96, 120, 144 and 168 hours post administration of patch. Time window: within 30 minutes prior to the 
patch administration for pre-dose (0); ± 2 minutes  for 12-48 hours and 73-76 hours; within 2 minutes prior to the patch being remuved for 72 hours; ±1 hour for 84 -168 hours. In case of IMP 
being removed ahead of schedule, blood sampling for drug concentration measurement will not be conducted following removal. 
10. Safety follow-up completion or early termination. 
11 Safety follow-up visit can be performed as a telephone visit.  

 
 
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Table 1.2: Investigation schedule for 4-day application 
Phase 
Screening 
4-day application 
Safety follow-up 
(telephone contact)11 
 
Day 
D-21 to D-1 
D00 
D01 
D02 
D03 
D04 
D05 
D06 
D07 
D08 
D09 
7-9 days after patch 
removal (D5) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Average pain over last 24 hours on 
0-10 score NRS  
X 
X 
 
 
 
 
 
 
 
 
 
 
Karnofsky score 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical / surgical history1 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug, Alcohol, Tobacco History 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Dermatological assessment of 
application site 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV Ab, HBsAg, HCV Ab, Syphilis 
Antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Clinical Laboratory Test (Chemistry, 
Hematology, Urinalysis) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Vital Signs3 (Body Temperature, 
respiration rate, PR and BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant treatment 
 
X (recorded continuously throughout the study) 
Adverse Event 
 
X (monitored continuously throughout the study) 
Non-Pharmacological Therapies 
 
X ( monitored continuously throughout the study) 
Admission to site 
 
X4 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Naltrexone Dosing5 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study Patch Administration 
 
 
X 
 
 
 
    
 
 
 
 
 
Study Patch Removal6 
 
 
 
 
 
 
X 
 
 
 
 
 
Assessment of patch adhesion7 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 

 
 
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Phase 
Screening 
4-day application 
Safety follow-up 
(telephone contact)11 
 
Day 
D-21 to D-1 
D00 
D01 
D02 
D03 
D04 
D05 
D06 
D07 
D08 
D09 
7-9 days after patch 
removal (D5) 
Dermatological examination of IMP 
application site8 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Blood sampling9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
End of blood collection visit 
 
 
 
 
 
 
 
 
 
 
X 
 
End of the study10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1. Abdominal ultrasound scan might be performed to understand the medical history per investigator’s judgement. 
2. Pregnancy test will be performed for females of childbearing potential and less than one year post-menopausal. Serum pregnancy test at screening. Urine pregnancy test at admission to site 
and discharge from site (or early termination). 
3. Timing for vital signs:  
- 
At screening  
- 
At Day 00: 13 hours prior to IMP application, within 30 min prior to naltrexone taken.  
- 
From Day 01 to Day 05: twice a day, within 30 min prior to each dosing of naltrexone.  
- 
From Day 06 to Day 09: once in the morning, 30 minutes prior to  PK blood sampling.  
4. Admission to site at latest in the afternoon (before dinner), at least 15 hours before the patch administration of D01. 
5. On Day 00, naltrexone 50 mg will be orally taken only in the evening, 13 hours (± 5 min) prior to the patch administration of D01; From Day 01 to Day 05, naltrexone 50 mg will be orally taken 
every 12 hours, in the morning and in the evening, at the fixed time for every morning or evening, with a time window of ± 5 min based on scheduled time. The intake in the morning of Day 01 
should be 1 hour (± 5 min) prior to IMP administration. Naltrexone to be taken after meal. 6. Patches will be removed 96 hours (± 2 min) after administration.  Blood sampling should occur in the 
last 2 minutes of dosing i.e. within 2 minutes prior to the patch being removed.  
7. Assessment of patch adhesion will be performed twice a day in the morning and in the evening (every 12±1 hours). The first evaluation on Day 01 will be conducted immediately after the patch 
applied on Day 01. On Day 05, the evaluation will be done once just before the patch removed.  
8. Dermatological examination of IMP application site will be conducted within 0.5 hour after IMP removal and in the morning of D06 and D07. In case that the result of the examination conducted 
at D06 is judged "No evidence of irritation", the examination scheduled for D07 will not be conducted. In case AE was reported for the skin reaction and not recovered at D07, more examinations 
may be needed for the AE follow-up.  
9. Blood sampling timing: Pre-dose (0), 12, 24, 48, 72, 96 (pre-removal), 97, 98, 100, 108, 120, 132, 144, 168 and 192 hours post administration of patch, Time window: within 30 minutes prior to 
the patch administration for pre-dose (0); ± 2 minutes  for 12-72 hours and 97-100 hours; within 2 minutes prior to the patch being remuved for 96 hours; ±1 hour for 108 -192 hours., blood 
sampling for drug concentration measurement will not be conducted following removal. 
10. Safety follow-up completion or early termination. 
11 Safety follow-up visit can be performed as a telephone visit. 
 
 

 
 
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Tables 1.3 and 1.4 present the schedule of PK blood sampling for 3-day application arm and 4-day application respectively. 
Table 1.3 PK Blood Sampling Schedule for 3-day application  
 
3-day application 
Day 
Day 01 
Day 02 
Day 03 
Day 04 
Day 05 
Day 06 
Day 07 
Day 08 
Time after administration (h)1 
Pre-dose2 
12 
24 
48 
72 (pre-removal)  
73 
74 
144 
84 
96 
120 
144 
168 
6 mL Blood Sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 .Blood samples collected after IMP administration should be performed strictly according to scheduled nominal time. Time window: ± 2 minutes  for 12-48 hours and 73-76 hours; within 2 minutes prior to the 
patch being removed for 72 hours; ±1 hour for 84 -168 hours.. 
2. Pre-dose: within 30 minutes before the IMP administration (patch administration is defined as 0 hour). 
 
 
Table 1.4 PK Blood Sampling Schedule for 4-day application  
 
4-day application 
Day 
Day 01 
Day 
02 
Day 
03 
Day 
04 
Day 05 
Day 06 
Day 07 
Day 08 
Day 09 
Time after administration 
(h)1 
Pre-dose2 
12 
24 
48 
72 
96 (pre-removal) 
97 
98 
100 
108 
120 
132 
144 
168 
192 
6mL Blood Sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. Blood samples collected after IMP administration should be performed strictly according to scheduled nominal time. Time window: ± 2 minutes  for 12-72 hours and 97-100 hours; within 2 minutes prior to the 
patch being removed for 96 hours; ±1 hour for 108 -192 hours. 
2. Pre-dose: within 30 minutes before the IMP administration (patch administration is defined as 0 hour). 

 
 
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 Screening Period 
No study procedure will be completed until the subject has given written informed consent. 
The Screening Period (up to 21-days before the first study check in at Day 00) aims to evaluate 
if subjects are eligible for the study according to inclusion/exclusion (I/E) criteria. The reasons 
for screening failures will be documented. subjects will perform the following procedures in the 
Screening Period: 
 The ICF (subjects will sign an ICF prior to executing all other activities) 
 Demography 
 Dermatological assessment to check for potential dermatological disorder at the patch 
application site 
 Medical / surgical history collection 
 Abdominal ultrasound if deemed necessary by the investigator 
 Details of Alcohol/Tobacco/Sensitivity/blood donation history 
 Physical examination 
 Karnofsky score 
 Vital signs: pulse rate, respiration rate, sitting blood pressure and body temperature will be 
examined. It will be repeated if any vital sign falls outside the normal range and is considered 
potentially clinically significant.  
 Weight, height and BMI 
 Average pain over last 24-hours on 0-10 score NRS - see section 19.5. 
 12-Lead ECG 
 Haematology, blood chemistry (fasted), and urinalysis 
 Serology testing (HBsAg, anti-HIV, anti-HCV, and syphilis antibody) 
 Urine drug screen (opioids, barbiturates, amphetamines, cocaine metabolites, methadone, 
benzodiazepines, phencyclidine, methamphetamine, or cannabinoids) and alcohol breath test 
 Blood β-HCG test for female subjects up to less than one-year post-menopause  
 AEs collection after the ICF acquisition 
 Collection of prior and concomitant medication and non-pharmacological therapies 
 Inclusion/Exclusion criteria list will be checked when all the results of examinations are 
available. 
Subjects who do not meet the inclusion/exclusion criteria are not permitted to attend the study. 
Throughout the study, subjects will be reminded to immediately report AEs experienced to the 
medical staff. These will be recorded in the AE section of eCRF and reported according to 
Section 13.3. 
 Re-Screening Instructions  
Subjects who do not meet the criteria for study entry can be re-screened if there is an indication 
that the reason for exclusion has changed. Any screening measurements that fall outside of the 
21-day window must be repeated and subjects must meet the study entry criteria during these 

 
 
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assessments. A new subject screening number will be assigned each time a subject is re-
screened and the subject must be re-consented.  Any subject re-screening judged by 
investigator should be informed and agreed by sponsor.    
 Randomisation 
Randomisation will be completed once all inclusion and exclusion criteria are verified.  Refer to 
Section 13.5 for further details on the treatment assignment. 
 Treatment and Sampling Period 
Refer to section 12.8 for the food restrictions during the study. 
 Check-in Visit (Day 00) 
The check-in visit (Day 00) aims to further confirm eligibility to continue in the study. At Day 00 if 
the subjects meet all I/E criteria, they will be randomized into one of the 3 treatment arms. 
Subjects will complete all the following examinations: 
 
Subjects will report to the study unit on the day at least 15 hours before the scheduled study 
drug dosing. 
 
Physical examination  
 
Average pain over last 24-hours on 0-10 score NRS - see section 19.5. 
 
Alcohol breath test and urine drug screen; the results must be negative before IMP 
application in each period 
 
Urine β-HCG test for female subjects before menopause and less than one year after 
menopause and the results must be negative prior to IMP application. 
 
Subjects will be asked whether they have taken any prescribed or over the-counter 
medications, or any vitamins or mineral supplements or herbal products since their last visit, 
and whether they have abstained from alcohol and strenuous exercise within 48 hours 
before the scheduled study drug dosing. I/E criteria will be verified again to notice any 
changes 
 
12-Lead ECG 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
executed within 30 minutes before taking naltrexone 
 
At 13 hours (± 5 minutes) before the study drug dosing, 50 mg of naltrexone tablet will be 
administered with 150 mL water in a standing position 
 
AE collection 
 
Concomitant medications and non-pharmacological therapies 
 
Inclusion/Exclusion criteria list will be checked when all the results of examinations are 
available. 
 
 Three-day application period 
12.6.2.1 Day 01 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained every 12 hours, within 30 min prior to the dosing of naltrexone.  

 
 
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 
50 mg of naltrexone tablet will be administered twice a day (every 12 hours) with 150 mL 
water in a standing position, the first dosing at 1 hour (± 5 minutes) before the IMP 
application and the second at 11 hours (± 5 minutes) after IMP application. 
 
Pre-dose PK sampling: a blood sample (6 mL) drawn within 30 minutes before the IMP 
application. 
 
Based on the randomization schedule, either 20 mg or 40 mg BUP TDS will be applied 
respectively (see section 13 for details of IMP application).   
 
Observe patch adhesion status immediately after patch applied and 12 hours (± 1 hour)  
later and assess whether additional taping is required. 
 
Post-dose PK sampling: a blood sample (6 mL) will be drawn at 12 hours after patch 
application. Blood sample collection will be performed ± 2 minutes of scheduled time post 
dose.  Every effort should be made to ensure accurate sampling time and deviations should 
be kept to a minimum. 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
 
12.6.2.2 Day 02 and Day 03 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained within 30 min prior to the dosing of naltrexone.  
 
50 mg of naltrexone tablet will be administered twice a day (every 12 hours) with 150 mL 
water in a standing position, with a time window of ± 5 min based on scheduled time.  
 
A blood sample (6 mL) will be drawn at: 
- 
Day 02: 24-hours after patch application 
- 
Day 03: 48-hours after patch application 
 
Blood sample collection will be performed ± 2 minutes of scheduled time post dose.  Every 
effort should be made to ensure accurate sampling time and protocol deviations should be 
kept to a minimum.  
 
Observe patch adhesion status twice a day (every 12 hours ± 1 hours) and assess whether 
additional taping is required. 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
12.6.2.3 Day 04 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained within 30 min prior to each dosing of naltrexone.  
 
50 mg of naltrexone tablet will be administered twice a day (every 12 hours) with 150 mL 
water in a standing position, with a time window of ± 5 min based on scheduled time.  
 
Observe patch adhesion status once, just before patch removal. 
 
BUP TDS will be removed. 
 
BUP patch will be removed 72 hours (±2 minutes)  after being applied. 
 
Prior to IMP removal PK sampling: PK blood sampling to occur in the last 2 minutes of 
dosing i.e. within 2 minutes before the patch is removed, a blood sample (6 mL) will be 
drawn. 

 
 
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 
A blood sample (6 mL) will be drawn at 73, 74, 76 and 84 hours after administration of patch 
with a time window of ± 2 minutes for 73-76 hours and ± 1 hour for 84 hours . Every effort 
should be made to ensure accurate sampling time and deviations should be kept to a 
minimum. 
 
Dermatological examination of patch application site will be conducted within 0.5 hour after 
patch removal using a 0 – 7 skin status scale – refer to section 19.6.  
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
12.6.2.4 Day 05 and Day 07 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained in the morning within 30 minutes prior to PK blood sampling. 
 
A blood sample (6 mL) will be drawn at: 
- 
Day 05: 96 hours after patch application  
- 
Day 06: 120 hours after patch application. 
- 
Day 07: 144 hours after patch application. 
Blood sample collection will be performed ± 1 hour of scheduled time post dose.  Every 
effort should be made to ensure accurate sampling time and deviations should be kept to a 
minimum. 
 
Dermatological examination of patch application site will be conducted in the morning of D05 
and D06 using a 0 – 7 dermal response score (section 19.6).  In case that the result of the 
examination conducted at D05 is judged "No evidence of irritation", the examination 
scheduled for D06 will not be conducted. In case AE was reported for the skin reaction and 
not recovered at D06, more examinations may be needed for the AE follow-up. 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
 
12.6.2.5 Day 08 
 
A blood sample (6 mL) will be drawn at 168 hours after patch application. Blood sample 
collection will be performed ± 1 hour of scheduled time post dose.  Every effort should be 
made to ensure accurate sampling time and deviations should be kept to a minimum. 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
 
The following procedures will only be conducted for 3-day application on Day 08 of the third 
period, or early termination: 
- 
Physical examination and weight 
- 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature), 
within 30 minutes prior to the PK sampling. 
- 
12-Lead ECG 
- 
Urine β-HCG test for female subjects before menopause and less than one year after 
menopause 
- 
Haematology, blood chemistry (fasted), and urinalysis 

 
 
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Following completion of the above procedures, the subject will complete the blood collection 
visit.  
 Four-day application 
12.6.3.1 Day 01 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained within 30 min prior to each dosing of naltrexone.  
 
50 mg of naltrexone tablet will be administered twice a day (every 12 hours) with 150 mL 
water in a standing position, the first dosing at 1 hour (± 5 minutes) before the IMP 
application and the second at 11 hours (± 5 minutes) after IMP application. 
 
Pre-dose PK sampling: a blood sample (6 mL) drawn within 30 minutes before the IMP 
application. 
 
Based on the randomization schedule, 40 mg BUP TDS will be applied (see section 13 for 
details of IMP application).   
 
Observe patch adhesion status immediately after patch applied and 12 hours (±1 hour) 
later, and assess whether additional taping is required. 
 
Post-dose PK sampling: a blood sample (6 mL) will be drawn at 12 hours after patch 
application. Blood sample collection will be performed ± 2 minutes of scheduled time post 
dose.  Every effort should be made to ensure accurate sampling time and deviations should 
be kept to a minimum. 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
 
12.6.3.2 Day 02, Day 03 and Day 04 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained within 30 min prior to each dosing of naltrexone.  
 
50 mg of naltrexone tablet will be administered twice a day (every 12 hours) with 150 mL 
water in a standing position, with a time window of ± 5 min based on scheduled time.  
 
A blood sample (6 mL) will be drawn at: 
- 
Day 02: 24 hours after patch application 
- 
Day 03: 48 hours after patch application 
- 
Day 04: 72 hours after patch application 
Blood sample collection will be performed strictly according to scheduled nominal time and 
within ± 2 minutes of scheduled time post dose; every effort should be made to ensure 
accurate sampling time and deviations should be kept to a minimum. 
 
Observe patch adhesion status twice a day (every 12 hours ± 1 hour ) and assess whether 
additional taping is required. 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
 

 
 
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12.6.3.3 Day 05 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained within 30 min prior to each dosing of naltrexone.  
 
50 mg of naltrexone tablet will be administered twice a day (every 12 hours) with 150 mL 
water in a standing position, with a time window of ± 5 min based on scheduled time.  
 
Observe patch adhesion status once, just before patch removal. 
 
BUP patch will be removed 96 hours (± 2 minutes)  after being applied. 
 
Prior to IMP removal PK sampling: PK blood sampling to occur in the last 2 minutes of 
dosing i.e. within 2 minutes before the patch is removed, a blood sample (6 mL) will be 
drawn.  
 
A blood sample (6 mL) will be drawn at 97, 98, 100 and 108 hours after administration of 
patch, with a time window of ± 2 minutes for 97-100 hours and ± 1 hour for 108 hours.   
Every effort should be made to ensure accurate sampling time and deviations should be 
kept to a minimum. 
 
Dermatological examination of patch application site will be conducted within 0.5 hour after 
patch removal using a 0 – 7 skin status scale – refer to section 19.6.  
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
12.6.3.4 Day 06 and Day 08 
 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature) will be 
obtained in the morning within 30 minutes prior to PK blood sampling.   
 
A blood sample (6 mL) will be drawn at: 
- 
Day 06: 120 and 132 hours after patch application  
- 
Day 07: 144 hours after patch application. 
- 
Day 08: 168 hours after patch application. 
 
Blood sample collection will be performed ± 1 hour of scheduled time post dose.  Every 
effort should be made to ensure accurate sampling time and deviations should be kept to a 
minimum. 
 
Dermatological examination of patch application site will be conducted in the morning of 
D06 and D07 using a 0 – 7 dermal response score (refer to section 19.6). In case that the 
result of the examination conducted at D06 is judged "No evidence of irritation", the 
examination scheduled for D07 will not be conducted. In case AE was reprted for the skin 
reaction and not recovered at D07, more examinations may be needed for the AE follow-up. 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
 
12.6.3.5 Day 09 
 
A blood sample (6 mL) will be drawn at 192 hours after patch application. Blood sample 
collection will be performed ± 1 hour of scheduled time post dose.  Every effort should be 
made to ensure accurate sampling time and deviations should be kept to a minimum. 
 
AE collection. 

 
 
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 
Collection of concomitant medication and non-pharmacological therapies. 
 
The following procedures will only be conducted for 4-day application on Day 08 of the third 
period, or early termination: 
- 
Physical examination and weight 
- 
Vital signs (pulse rate, respiration rate, sitting blood pressure and body temperature), 
within 30 minutes prior to the PK sampling.  
- 
12-Lead ECG 
- 
Urine β-HCG test for female subjects before menopause and less than one year after 
menopause 
- 
Haematology, blood chemistry (fasted), and urinalysis.  
Following completion of the above procedures, the subject will complete the blood collection 
visit. 
12.7 
End of study 
The end of study for each subject is defined as the day of the safety follow-up visit.  The end of 
the study is defined as last subject last follow-up visit.  
12.7.1 Early Discontinuation/Withdrawal/Loss to Follow-up 
The Investigator or subjects themselves may stop study treatment at any time for safety or 
personal reasons. Whenever possible, the subjects will be instructed to complete the end-of-
study procedures (listed in Table 1.1 and Table 1.2) and the Investigators or a designee will give 
phone contacts to the discontinued subjects to complete the safety follow-up as described in 
Section 12.8.  A subject removed from the study for any reason may not be replaced. i.e. the 
same randomisation number will not be reused. 
12.7.2 Safety follow-up (telephone contact) 
Subjects who complete treatment or discontinue from treatment will be followed up 7 – 9 days 
after the last BUP TDS removal will be telephoned by site staff. 
The following evaluations will be performed over the telephone: 
 
AE collection. 
 
Collection of concomitant medication and non-pharmacological therapies. 
12.7.3 Withdrawal Criteria 
The participation of an individual subject may be terminated prematurely for reasons such as: 
1. Withdrawal of written informed consent 
2. Adverse Events during administration of the IMP 
3. Evidence of exclusion criteria 
Any other condition which in the opinion of the Investigator no longer permits a safe participation 
in the study. 

 
 
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12.8 Study Restrictions 
12.8.1 Food and Beverages 
Menus will be standardised while subjects are resident in the study unit. However, the menus for 
each day will not be identical. Subjects must consume only the food given to them while in the 
unit.  
A standardised breakfast, lunch, dinner and an evening snack will be provided to subjects at the 
same time in each treatment period during hospitalisation.  
On the days of admitting to hospital, a standard dinner and a snack will be served, and on the 
day of discharging from hospital, an optional breakfast will be provided.  
There will be free access to drinking water throughout the day, except for 1 hour after each 
dosing of Naltrexone and 30 minutes before vital sign measurements.  Naltrexone to be taken 
after meal. 
 
12.8.2 Alcohol, Caffeine, Smoking and other Restrictions 
Subjects must comply with alcohol restrictions per exclusion criteria 11 and smoking restrictions 
per exclusion criteria 12 (section 11.2) during the study. Grapefruit (and its juices), caffeine- and 
xanthine-containing food or beverages will not be permitted while subjects are in the study unit. 
Intense physical activity will also be prohibited during the study.  
13 
STUDY TREATMENTS AND CONCOMITANT THERAPIES 
13.1 Study Treatments (IMPs and NIMPs) 
The definitions of IMPs and NIMPs (auxiliary products) are described in Appendix Section 19.22.  
13.1.1 Test Investigational Medicinal Product(s), Dose and Mode of Administration 
The buprenorphine transdermal patches (Transtec®) are manufactured by LTS Lohmann 
Therapie-Systeme AG, Germany, and the marketing authorization holder (MAH) is Grünenthal 
GmbH, Germany.  
The buprenorphine transdermal patches are rectangular or square, beige-coloured system 
consisting of a protective liner and functional layers. 
Store at 15-25 ℃. 
Table 2: Test IMP Identity 
Test IMP 
Effective 
area 
Buprenorphine 
load 
Buprenorphine 
release rate 
Mode of 
Administration 
Buprenorphine 
transdermal patch 20 mg 
25 cm2 
20 mg 
35 µg/h 
Transdermal 
Buprenorphine 
transdermal patch 40 mg 
50 cm2 
40 mg 
70 µg/h 
Transdermal 

 
 
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13.1.2 Reference IMP, Dose and Mode of Administration 
Not applicable.  
13.1.3 Non-Investigational Medicinal Product (NIMP / Auxillary product), Dose and 
Mode of Administration 
The NIMP is defined in Section 19.22. NIMPs will be supplied by the Sponsor. 
Table 3: NIMP Identity 
NIMP 
Dosage 
Form 
Unit Strength 
Active 
Ingredients 
Dosing 
frequency 
Mode of 
Administration 
Naltrexone 
hydrochloride 
Tablet 
50 mg 
Naltrexone 
Twice daily 
Oral 
Naltrexone hydrochloride is manufactured by Aesica Queenborough Limited and the MAH is 
Bristol-Myers Squibb Pharmaceuticals Limited. 
13.2 Study Treatments to be supplied 
The Sponsor will package the study treatments. IMPs will be supplied in labelled containers by 
the Sponsor. The Product Release Certificate(s) for the IMP 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, including generic 
name, strengths, storage requirements etc.  
13.3 Dosing Schedule 
Table 1.1 and Table 1.2 present the schedule of visits and procedures for the 3-day application 
and 4-day application respectively.  All procedures will be collected in the source documents. 
Procedures should be completed in the order presented.  
The BUP TDS will be administrated in the morning for each subject.   
One patch (20 mg or 40 mg) will be applied in the morning of Day 01:  
 
For the 3-day application (20 mg or 40 mg): the patch will be removed in the morning of 
Day 04, 72 hours after administration. 
 
For the 4-day application (40 mg): the patch will be removed in the morning of Day 05, 
96 hours after administration. 
 
Naltrexone cover: 
The study patch will be applied under the cover of naltrexone to reduce opioid related side-
effects. 
Naltrexone 50 mg will be taken orally every 12 hours, from the evening of Day 00 (13 hours prior 
to IMP application), until the evening of the patch removal. Naltrexone should be taken at the 

 
 
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fixed time in each morning or evening, with a time window of ± 5 min based on scheduled time. 
 
For 3-day application: the last dose will be taken in the evening of Day 04, for a total of 9 
dosing’s.  
 
For 4-day application: the last dose will be taken in the evening of Day 05, for a total of 
11 dosing’s. 
13.4 Method of Administration 
Do not use the patch on any skin with larger scars, but on skin with less or no hair. If this is not 
possible, you should use scissors to cut off the hair, but don't use a razor to shave off the hair. In 
the morning of the test day, the skin should be cleaned with water first. Soap, alcohol, oil, lotion 
or scrubbing equipment should not be used. The skin must be dry before using the patch.The 
patch should be applied immediately after removal from the sachet to non-irritated, clean and 
intact skin.   
• 
Cut open foil pouch (use scissors carefully avoiding damaging the BTDS), tear pouch open, 
remove the BTDS from foil pouch. The pouch containing the patch should only be opened 
immediately prior to application.  Do not discard the opened pouch. 
• 
Remove larger half of the BTDS liner and grasp smaller half (taking care not to touch the 
central part of the adhesive which may contain buprenorphine). 
• 
Apply BTDS to skin, remove smaller half of the backing.  Do not discard the liner.  If the 
person applying the BTDS inadvertently touches the adhesive part behind the protective 
liner, they should wash the affected area with water (some soaps, lotions, alcohol or other 
solvents may facilitate buprenorphine transfer through the skin). 
• 
Press down on BTDS with the palm of your hand for 30 seconds, making sure contact is 
complete, especially round the edges (do not rub).  
• 
It is important that the BTDS patch application sites on the back do not overlap. 
• 
Place the opened pouch and liner into a separate, clean plastic bag, sealed and labelled for 
storage of the used BTDS. 
• 
After removal of each BTDS patch, it will be placed on the original release liner with care 
taken to ensure it is returned to the correct side of the liner (side with a dull, matte like 
appearance). 
• 
If at any time the edges of the patch begin to peel off, the edges should be taped down with 
suitable skin tape e.g. Tegaderm. Any occurrence of a patch becoming loose or detached 
will be documented in the eCRF with start dates and times recorded. If a patch has detached 
completely it should be re-applied to the same site using suitable skin tape. 
 
During the period with IMP application, attention should be paid to ensure that no rubbing or 
warming (e.g. sauna, infrared-radiation) occurs at the site of application. Regarding washing, 
showering will be only permitted. Soap or any other cleansing agents should not be used to the 
application site. Cosmetics, lotions or creams should not be applied to the application site. 
For this study the IMP should be applied to right upper chest. 

 
 
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BUP patch removal will be conducted by pinching the edge of the patch and gradually peeling 
away from the skin. 
13.5 Treatment Assignment 
Randomisation will be performed by the Sponsor using a validated system that automates the 
random assignment of treatment to randomisation numbers. The randomisation 
scheme will be reviewed by the Sponsor’s Data Management and Statistics Department and 
locked after approval. The randomisation scheme and identification for each subject will be 
included in the Clinical Study report. 
 
Subjects will be randomised to which IMP they receive at Visit 2. 
 
 
Treatment A: BUP TDS 20 mg applied for 3 days 
 
Treatment B: BUP TDS 40 mg applied for 3 days 
 
Treatment C: BUP TDS 40 mg applied for 4 days 
13.6 Blinding 
Not applicable, this is an open-label study. 
13.7 Treatment Compliance/IMP Accountability 
The Investigator and study staff will be responsible for the IMP accountability and will record 
maintenance of all clinical supplies, and rescue medication (dispensing, inventory, and returns) 
following Sponsor instructions and will adhere to GCP guidelines as well as applicable country 
specific regulations.  
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.  
13.8 Concomitant Therapies – Permitted 
All medications are not allowed during the study, but the medication considered necessary for 
the subject’s welfare may be administered under the supervision of the Investigator. 
For subjects who receive IMP, 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 in the respective section of the EDC 
and must be approved by the Sponsor. The forms for Concomitant Therapy and non-
pharmacological therapies and procedures will be maintained and updated throughout the 
subject’s participation in the study for any new therapies of changes to existing therapies. The 
use of such concomitant medications should be approved in advance by the Sponsor, when 
possible. The Investigator will record the AE for which the concomitant medication was 
administered on the eCRF. 
Acetaminophen up to 2.0 g/day will be used as rescue medicine for subjects who need the 
analgesic for pain relief.  
Nausea and vomiting may be treated with Ondansetron as deemed appropriate.  

 
 
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The study site must hold a supply of naloxone for injection as emergency rescue medication. 
This will be supplied by the investigator site. 
The use of other concomitant medications during this trial is discouraged, unless necessary to 
treat adverse events. The use of other concomitant medications should be approved by the 
Sponsor in advance, when possible. 
13.9 Concomitant Therapies - Prohibited 
Monoamine oxidase inhibitors cannot be used during this trial and must be withheld for at least 
two weeks prior to IMP administration. 
Tricyclic antidepressants cannot be administered during the trial or have been used within 4 
weeks prior to the first IMP administration.  
Use of any medicinal product which inhibits CYP3A4 (e.g. troleandomycin, ketoconazole, 
gestodene, etc) or induces CYP3A4 (e.g. glucocorticoids, barbiturates, rifampicin,etc) are 
prohibited from the start of the study (admission to site) to end of the study.  If the patient needs 
to receive these drug therapies for any adverse events, the patient should withdraw from the 
study 
13.10 Shipping, Handling, Storage, and Destruction/Return 
IMP and NIMP will be supplied to the Principal Investigator or the delegated staff by the 
Sponsor, either directly or via a local warehouse contracted by the Sponsor. Specific Good 
Distribution Practice requirements for the shipment will be assessed by the Sponsor and 
requirements for handling and monitoring of temperature sensitive products will be 
communicated to the Investigator within the Investigator instructions. Once the shipment has 
been opened, the products must be stored according to the conditions specified on the labels 
and must be kept in an appropriate secure area (e.g. locked cabinet/pharmacy). 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. 
Investigational site personnel must maintain an accurate and timely record of the receipt of all 
clinical supplies, dispensing of IMP/NIMP to the subject, collection of unused supplies returned 
by the subject and subsequent return of unused or expired IMP/NIMP to the Sponsor. This 
includes, but may not be limited to: (a) documentation of receipt of clinical supplies, (b) 
IMP/NIMP dispensing/return reconciliation log, (c) IMP/NIMP accountability log, and (d) all 
shipping service receipts. All forms will be provided by the Sponsor. 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 study. 
The supplies and inventory records must be made available, upon request, for inspection by the 
designated representative of the Sponsor, or Competent Authority (CA). 
All used and unused IMP/NIMPs, including empty containers, are to be returned to the Sponsor 
or Sponsor designated warehouse at 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 IMP/NIMP labels or any partly used or 
unused IMP/NIMP supply until directed by the Sponsor or designee following accountability 

 
 
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checks. Upon completion of IMP/NIMP accountability and reconciliation procedures by 
investigational site personnel and monitoring procedures by Sponsor personnel, IMP/NIMP that 
is to be returned to the Sponsor or Sponsor designated warehouse must be sealed with tamper-
evident seals and shipped back to the Sponsor or Sponsor designated warehouse following 
China regulatory and shipment laws, including but not limited to Good Clinical Practice 
Guideline, Regulation on the Control of Narcotic Drugs and Psychotropic Drugs and 
Management Measures of Mailing Narcotic Drugs and Psychotropic Drugs. 
14 SAFETY ASSESSMENTS 
Safety assessments will be recorded from the point at which the Informed Consent is signed. 
Please refer to Sections 9 and 12 for actual safety variables and endpoints. 
The obligations and responsibilities with regards to collection, distribution and onward reporting 
of AEs and reactions to the appropriate regulatory bodies, committees and other Investigators 
will be carried out in accordance with local regulations and are documented in a separate Safety 
Management Plan (SMP). 
14.1 Safety Definitions and Requirements 
14.1.1 Adverse Event (AE) 
An 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 (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. 
14.1.2 Serious Adverse Event (SAE) 
A SAE is any AE that: 
 
results in death 
 
is life-threatening (i.e. the subject was at immediate risk of death from the AE as it 
occurred) 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation  
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
IMP) 

 
 
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 
is a medically important event or reaction. 
14.1.3 Special Situations 
Special situations may occur that may or may not be associated with AEs. Such situations, 
whether or not associated with an AE, are documented on dedicated forms. Any AE that 
occurred in association with such a special situation has to be entered on the eCRF form. For 
these situations special reporting provisions apply. Special situations have to be reported within 
24 hrs by the Investigator to the Sponsor. 
For this study special situations comprises: 
 
Pregnancy 
 
Drug exposure via parent 
 
Medication errors (including overdose) 
 
Abuse/misuse of the IMP 
 
Drug Diversion - Defined as IMP 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. 
 
14.1.4 Pregnancy 
Pregnant women are excluded from the study, and female study subjects of child-bearing 
potential undergo pregnancy testing at screening and regularly during the study (see section 
12.2 (Flowchart of study)). If pregnancy is suspected in a study subject during treatment with the 
IMP, the IMP must be immediately withheld until the result of a confirmatory test is available. If 
confirmed, the subject must be withdrawn from the study. 
Although not an AE per se, pregnancy in a female study subject or the partner of a male study 
subject must be reported via the paper pregnancy form if it occurs during the period of 
observation of the study. 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. 
The Investigator must contact the Sponsor immediately in such a situation.  
The following forms have to be used: 
Pregnancy in female study 
subject  
Patient Pregnancy Notification Form 
Pregnancy in partner of male 
study subject  
Partner Pregnancy Notification Form  
If an SAE or AE occurs in relation to the pregnancy, it has to be recorded in the eCRF according 
to Section 14.2 and 14.3.  For follow up information, see Section 14.4. 
The Investigator must make all reasonable efforts to follow up the pregnancy until its end and 
will report all outcomes associated with the pregnancy to the Sponsor. In the situation of 

 
 
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pregnancy of the female partner of a male study subject, consent for the release of medical data 
should be obtained from the female partner to allow collection of information on the outcome of 
the pregnancy. 
14.2 Period of Observation 
The period of observation for each subject for collection of AEs extends from the time the 
subject signs the informed consent form until the subjects last study visit (telephone call), which 
is scheduled at least 7 to 9 days after removal of IMP. 
Abnormal, clinically relevant findings or observations made prior to signature of informed 
consent are to be recorded as medical history/ concomitant disease but not as AEs. 
 
If an adverse drug reaction (ADR) occurs in a subject after the period of observation, i.e. after 
the last study visit, usual spontaneous reporting should occur to the relevant marketing 
authorization holder (MAH).  
All laboratory results and other clinical observations such as ECGs, vital signs, etc. from 
scheduled and unscheduled tests, taken from Consent through to the subject’s last scheduled 
visit (i.e. follow up visit) are included in the eCRF.  
If a lab test or clinical observation isn’t scheduled until after the follow up visit then the 
Investigator will determine CS (and therefore AE) or not clinically significant (NCS) for the initial 
laboratory result or clinical observation. The repeat lab test or observation result is then only 
captured in the source documents. 
Additional follow up laboratory tests or clinical observations if required after the follow up date 
would be through routine clinical practice and local laboratory services if applicable and not 
through the central laboratory services. 
The same follow up period is applied for each subject (i.e. to their follow up visit/telephone call 
and not until database lock). 
14.3 Reporting of Adverse Events 
See also Figure 2, Appendix Section 19.1. 
All AEs that occur during the period of observation defined for the study (see section 14.2) 
have to be fully recorded in the eCRF according to the provisions in this section of the study 
protocol and eCRF completion guidelines, as well as in the subject’s source data. This applies 
also to AEs in subjects who signed the informed consent but never received IMP/NIMP. 
For the recording/reporting of adverse events the following shall be considered: 
 
Diagnosis vs. Signs/ Symptoms 
o The diagnosis rather than individual signs and symptoms, should be provided 
wherever possible and appropriate. 
 
if there is not enough information to provide a diagnosis, individual signs 
and symptoms are to be recorded. 
 
If a diagnosis is accompanied by unusual symptoms, the diagnosis itself 
and the unusual symptoms have to be reported separately. 

 
 
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o For SAEs the Investigator should provide any other supporting information that is 
required for the assessment of the events, specifically in the free text narrative 
description of the case. 
 
Onset date, end date 
o If an AE started during the study but did not end before the final follow-up visit, 
the Investigator must make a reasonable effort to establish the outcome and the 
end date. If this is not possible, e.g. because the AE is still ongoing, or the subject 
is lost to follow-up, there will be no end date for the AE. 
o For all AEs that resolve, resolve with sequelae, or have a fatal outcome, an end 
date must be provided.  
o If an AE stops and restarts later. If the investigators consider that this event 
belongs to the same event as the previous AE, that is, the recurrence of the 
previous event, and the previous AE did not achieve a true recovery, they can be 
recorded as an AE. If nor, all occurrences have to be recorded separately. 
 
Intensity/Severity 
Refers to the extent to which an AE affects the subject’s daily activities.  This is not the 
same as seriousness, which is based on set criteria and/or subject/event outcome. 
Severity will be categorized according to the following criteria: 
Table 4: Adverse Event Severity 
Mild 
The AE does not interfere with the subject’s routine activities. 
Moderate 
The AE interferes with the subject’s daily routine, but usual 
routine activities can still be carried out. 
Severe 
The AE results in inability to perform routine activities. 
 
 
Seriousness 
For definition of seriousness criteria refer to Section 14.1.2. All seriousness criteria that 
apply have to be recorded. 
 
Action Taken with the IMP 
The action taken with the IMP as a result of the AE has to be documented. 
 
Treatment for the AE 
Any treatment for an AE, whether pharmacological or other (e.g. surgical) treatment, has 
to be recorded in the eCRF. 
 
Outcome 
The outcome recorded should be reflective of the outcome at the time of reporting the 
AE. The following categories should be used: 
o Not recovered/Not Resolved 
o Indicates that the event is ongoing and there has been no recovery. 
o Recovering/Resolving 
o Indicates that the event is in the process of recovery but has not yet fully 
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o Recovered/Resolved 
o Indicates that the event has fully resolved. 
o Recovered/Resolved with sequelae 
o Indicates that there is a residual, possibly permanent consequence of the event 
(e.g. residual hemiparesis subsequent to stroke). 
o Fatal 
o Indicates that the subject died due to the event. The outcome “fatal” applies only 
to the event(s) that were the cause(s) of death. For other adverse events that 
were ongoing at the time of death, the outcome must be recorded as “not 
recovered” and not “fatal”. 
o Unknown 
o Indicates that the outcome of the AE cannot be determined despite the best 
efforts of the Investigator.  This may be due to the subject being ‘Lost to Follow-
up’ and therefore the Safety Follow-Up visit could not be performed. 
 
 
Causal Relationship of AE 
The causal relationship refers to the presence or absence of a reasonable possibility of a 
causal relationship between the IMP and the adverse event. The following assessments 
should be used: 
o Reasonable Possibility: there are facts (evidence) or arguments to suggest a 
causal relationship between the IMP and the AE. 
This could be based on but not limited the information below: 
 
Temporal relationship to IMP exposure  
 
Event is known to be associated with the IMP drug class. 
 
Event improved on discontinuation or dose reduction of IMP  
 
Event reoccurred on Re-challenge of IMP  
 
Biological plausibility  
 
Other: a free text field to include any other text 
 
o No Reasonable Possibility: there are no facts (evidence) or arguments to suggest a 
causal relationship between the IMP and the AE. 
This could be based on but not limited to the information below: 
 
Event attributed to concomitant medication (if this is ticked further details of the 
concomitant medication are to be provided in the free text field) 
 
Event attributed to the existing disease/ condition (if this is ticked further details of the 
disease/condition are to be provided in the free text field) 
 
Event attributed to NIMP 
 
No reasonably temporal relationship associated with IMP administration 
 
Event is expected in target disease and/or population  
 
Due to the negative De-challenge and/or Re-challenge criteria  
 
Other: a free text field. 
 

 
 
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The Investigator must provide a causal relationship with the IMP for each recorded AE, 
using medical judgement and taking into account the above, in addition to the subject’s 
medical history and nature of the AE. 
SAE causality to NIMP 
If in the study a non-investigational medicinal product (NIMP) is used, e.g. as 
background or rescue medication, the Investigator will be asked for causality assessment 
with the NIMP as well. Please use the relevant fields in the eCRF and on the SAE form 
for this purpose.  
NOTE: If upon receipt of further information, the Investigator considers the causality 
assessment to be different to their initial assessment, this should be reported 
immediately. 
Assessment of Expectedness 
The expectedness of an AE is determined by the Sponsor based on the reference safety 
information (RSI). 
IMP: 
The reference safety document used for assessing expectedness of AEs in this study is: 
the current IB for BUP TDS. The MAH is Grünenthal GmbH, Germany. The reference 
safety information is included in section 6 of IB. This document will be found in the 
Investigator Site File. 
NIMP (Naltrexone): 
The reference safety document used for assessing expectedness of AEs against the 
NIMP in the SmPC. The MAH is Bristol-Myers Squibb Pharmaceuticals Limited.  The 
reference safety information is included on the Summary of Product Characteristics 
(SmPC) and will be found in the Investigator Site File. 
14.4 Follow Up of Adverse Events 
Adverse events should be followed up to determine the outcome.  The cut off for information 
collection in the eCRF for AEs and SAEs including any follow up lab information is according to 
Section 14.2.  Any AE that is still ongoing at this visit will have an outcome of 
‘Recovering/Resolving’ or ‘Not Recovered/Not Resolved’ in the eCRF. After that all information 
still needs to be collected in the source and for SAEs the information needs to be forwarded to 
the Sponsor. 
 
All efforts to collect follow-up information must be documented in the subject’s source 
data as soon as it is received. 
 
All AEs must be followed up by the Investigator until: 
o the AE is resolved or resolved with sequelae and all other queries related to the 
AE have been clarified, or 
o the end of the period of observation (= last study visit), or 
o the Investigator considers it medically justifiable to stop further follow-up 
 
If the subject had an AE with fatal outcome, an autopsy report should be provided if 
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 
If SAEs are ongoing at the time of the subject’s last study visit, an additional safety 
follow-up visit should be scheduled for those subjects.  This visit will be documented in 
the source notes and not in the eCRF. 
o The Investigator should set the interval to the additional safety follow-up visit 
according to his/ her medical judgement. If the EDC system is closed, information 
from this visit should be forwarded to the Sponsor using the paper SAE form. 
 
The Investigator should respond to any queries raised by the Sponsor in relation to 
adverse events, including provision of supporting documentation within the requested 
timeline. 
o In case of fatal or life-threatening SAEs the Sponsor may request urgent 
clarification within one business day. 
Subjects who were treated with IMP but did not complete the study as per protocol, should 
receive all the examinations and investigations scheduled for the last study visit. The 
Investigator should make all efforts to contact subjects lost to follow-up and document the 
attempts in the subject’s source data. 
14.5 Reporting By Investigator to Sponsor 
When SAE is found, doctors should be contacted in time for rescue. Investigators should fill in 
the paper SAE report form and record it in eCRF within 24 hours of being informed of SAE, and 
inform the principal investigator, sponsor and EC, provincial and National medical products 
administration.  
Whenever follow-up information becomes available to a previously reported SAE, this has to be 
reported by the Investigator immediately but no later than 24 hours after becoming aware of the 
follow-up information by use of an SAE form via fax or e-mail. 
In addition to the AE page, the following eCRF pages have to be updated or completed at the 
same time as necessary: 
o subject demographics 
o medical history 
o concomitant medication 
o study completion/termination (in case of an AE leading to withdrawal) 
For questions regarding SAEs or to notify the Sponsor of an SAE in the event of technical failure 
of the e-mail or fax system, the Investigator should contact the Sponsor or CRO by phone. 
All AEs that result in a subject’s withdrawal from the study have to be recorded in the eCRF as 
soon as possible after the investigational site becoming aware of the event. 
All Special situations have to be reported as soon as possible (ideally within 24 hours) to the 
Sponsor using the relevant forms provided to the Investigator site. 
15 
STATISTICAL ANALYSES 
Statistical analyses will be performed by the Sponsor or a designated CRO. All statistical 
analyses will be performed using Statistical Analyses Software (SAS) and/or other statistical 
software as required, details will be provided in the SAP. 

 
 
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15.1 General Considerations 
In general, continuous data will be summarised by dose group using the following descriptive 
statistics: number of non-missing observations (n), mean, standard deviation, median, minimum 
and maximum. Categorical data will be summarised by dose group as the number and 
percentage of subjects in each category. 
In general, baseline is defined as last value prior to first dose of IMP of each period. 
All details of statistical methods and analyses will be documented in the Statistical Analysis Plan 
(SAP). 
15.2 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. 
Safety Population 
The safety population is defined as all randomised subjects who receive at least one dose of 
IMP. 
Pharmacokinetic Population 
The pharmacokinetic population is defined as all subjects who received IMP and have at least 
one pharmacokinetic concentration measurement. This will be the primary PK analysis 
population. 
15.3 Protocol Deviations 
The investigators should comply with all the requirements in the proposal approved by the 
sponsor, the regulatory authority (if necessary) and the EC, and must strictly implement them. 
Any intentional or unintentional deviation or violation of the protocol or GCP can be classified as 
protocol deviation. 
This study does not allow deviations from the protocol unless the immediate danger elinination 
of participants is needed. 
If a protocol deviation occurs, the investigator must notify the sponsor or the designated 
personnel of the sponsor. Any deviation must be recorded in the deviation report form. The time 
of discovery, the time and process of the event, the cause and the corresponding treatment 
measures should be recorded in detail. The investigator shall sign the deviation and notify the 
EC and sponsor. At the end of the study, it is submitted to the statistical analysis party. When 
serious deviation of the protocol occurs, the evaluation should be made and the sponsor may 
terminate the study in advance if necessary. 
The following major protocol deviations may exclude a subject from the PK analysis: 
1) Failure to comply with the inclusion/exclusion criteria 
2) Received incorrect study treatment 

 
 
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3) Received study prohibited concomitant drugs 
4) Failure to collect data for the primary endpoint as detailed in the protocol. 
Further details will be documented in the SAP. Additional factors leading to exclusion of subjects 
or data points from the PK analysis may be included in the SAP for the study. 
Major protocol deviations will be agreed at the Data Review Meeting (DRM) prior to database 
lock. 
15.4 Sample Size and Power Considerations 
The study is descriptive and no formal sample size calculation has been performed for this 
study. 
The China National Drug Administration (NMPA) recommended to investigate at least 8-12 
Chinese subjects per treatment arm.  Therefore, 15 subjects per arm will be randomised to 
receive IMP with the aim to have at least 12 subjects/arm completing the study and providing 
valid PK data. 
15.5 Interim Analysis  
Not applicable.  
15.6 Efficacy Analysis  
Not applicable. 
15.7 Safety Analyses 
Safety data that will be summarised includes exposure, AEs, clinical laboratory assessments, 
vital signs and ECGs. All safety analyses will be based on the safety population and will be 
summarised by dose group unless otherwise stated. 
15.7.1 Treatment Exposure and Compliance 
IMP will be summarised as treatment exposure. 
Treatment exposure will be defined and calculated as the dose of IMP taken by subjects. 
Treatment exposure will be summarised by dose group as continuous data. 
Treatment exposure will be summarised by dose group and overall for subjects in the safety 
population. 
15.7.2 Adverse Events 
Adverse events (AEs) will be coded using the most recent version of Medical Dictionary for 
Regulatory Activities (MedDRA) coding system to give a System Organ Class (SOC) and 
Preferred Term (PT) for each AE. 
A treatment emergent AE (TEAE) is 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 – 9 days after the 
removal of last IMP. In addition, this will include AEs with an onset date more than 7 – 9 days 
after the removal of last IMP considered as related to IMP by the Investigator. 
Only treatment-emergent AEs will be summarised. 

 
 
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The number and percentage of subjects reporting at least one AE will be summarised by PT 
nested within SOC for each of the following AE types: 
• Any AE 
• Any related AE 
• Any severe AE 
• Any related severe AE 
• Any SAE 
• Any related SAE 
• Any SAE leading to death 
• Any AE leading to discontinuation 
• Any AE requiring additional therapy 
Moreover, the number and percentage of subjects with any AE will be summarised by 
• Worst severity (i.e. mild, moderate, and severe) by PT nested within SOC 
• Relationship to IMP (i.e. related and not related) by PT nested within SOC. 
 
15.7.3 Laboratory Values 
Clinical laboratory data to be summarised includes haematology, blood chemistry, and 
urinalysis. The clinical laboratory parameters to be assessed are listed in Table 5 and the 
scheduled time-points for assessment are tabulated in Section 12.  
Clinical laboratory parameters at each time-point and change from baseline to each post-
baseline time-point will be summarised using descriptive summary statistics for each parameter 
by dose group and graphical illustrations.  
Clinical laboratory values for each parameter will be assigned an LNH classification according to 
whether the value is lower (L), within (N) or higher (H) than the reference range for that 
parameter. The values will be summarised using shift tables from baseline to end of study with 
respect to reference range values (low, normal, high) for each parameter by dose group. 
15.7.4 Vital Signs 
Vital sign parameters to be summarised include pulse rate, respiration rate, systolic blood 
pressure, diastolic blood pressure and body temperature. The scheduled time-points for 
assessment are presented in Section 12. 
Vital sign parameters at each time-point, and change from baseline to each post-baseline time-
point will be summarised using descriptive summary statistics for each parameter by dose group 
and graphical illustrations.  
Vital sign values for each parameter will be assigned an LNH classification according to whether 
the value is lower (L), within (N) or higher (H) than the reference range for that parameter. The 
values will be summarised using shift tables from baseline to end of study with respect to 
reference range values (low, normal, high) for each parameter by dose group. 

 
 
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15.7.5 ECG 
The scheduled time-points for ECG assessment are presented in Section 12. 
ECGs will be judged by the Investigator as clinically significant (yes/no). The number and 
percentage of subjects with clinically significant ECG findings will be summarised by dose group 
for each time-point. 
15.8 Pharmacokinetic Measurements and Analyses 
 
15.8.1 Drug Concentration Measurements 
Blood samples for PK assessments will be drawn at the time points described in section 12.2 
and analysed for plasma concentrations of the analytes (buprenorphine and norbuprenorphine). 
Plasma concentration data will be listed by analyte, dose group (i.e. 3 dose groups: 20 mg 3-
day, 40 mg 3-day and 40 mg 4-day). 
Plasma concentration data for each analyte will be summarised descriptively by dose group, 
dose administration (i.e. single dose) and nominal time-point. Individual and mean plasma 
concentrations for each analyte will also be plotted over time by dose group and administration 
(if applicable). All plasma concentration summaries will be provided for the PK population. 
Handling of values below the level of quantification for these summaries will be described in the 
SAP. 
15.8.2 Pharmacokinetic Analyses  
The main analysis population for all PK analyses will be the PK population. Further, only valid 
PK parameters will be used for analysis. To have a valid PK parameter, the subject must not 
receive incorrect study treatment, or have an incomplete plasma profile that cannot detail the PK 
concentration parameters or have a pre-dose concentration >5% Cmax. 
All summaries and statistical analyses will be done for the PK population. 
All statistical analyses are exploratory and not for formal hypothesis testing. 
The following PK parameters will be summarized descriptively for analytes buprenorphine and 
norbuprenorphine:  
- 
Cmax: Maximum observed plasma concentration 
- 
Tmax: Time corresponding to Cmax 
- 
AUC0-t: Area under the concentration-time curve from zero (time of drug administration) to 
time of last quantifiable observed concentration 
- 
AUC0-inf: Area Under the concentration-time Curve from zero (time of drug administration) to 
infinity 
- 
λz (where possible): First order rate constant of the terminal phase calculated 
- 
t1/2z (where possible): Terminal elimination half-life 
 
16 
ETHICS & REGULATORY 
 

 
 
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16.1 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 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. The relevant version of the Declaration of 
Helsinki will be available in the Investigator Site File. 
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. 
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. 
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. 
16.2 Ethical and Regulatory Review 
The protocol, any protocol amendments, the subject 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 
Ethics Committee (EC) of all study centres 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/CRO. 

 
 
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16.3 Subject Information and Consent 
Informed consent should be obtained by means of a PIS and 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 
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 subject 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 CRO monitors and kept in the 
study centre investigational site files. This applies for any additional ICFs signed (e.g. for re-
consent). 
16.4 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 and applicable regulation in China. 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 subject’s notes 
held with the Investigator.  
Samples collected for the purpose of laboratory tests will not be retained after analysis. 
16.5 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 
GCP and the applicable regulatory requirements’. Sponsor QA activity will be undertaken as 
outlined in the Sponsor’s respective 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 independent consultants. The Investigator is required to support 
audit or inspection activities, to be available to the auditors/inspectors upon request and to 
permit the auditor/inspector direct access to source data/documents. The informed consent form 
will also obtain the subject’s consent for direct access to source data for audit or inspection 
purposes.  

 
 
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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. 
The clinical trial wards are equipped with necessary medical equipment, rescue drugs and 
emergency measures to regularly verify and calibrate the instruments and equipment. All 
participants in the trial were trained by GCP and follow the protocol, GCP and related SOP to 
ensure the quality of clinical trials. For this reason, clinical trial institution has carried out the 
following quality control of the trial process: 
Before the start of the clinical trial, confirm that the clinical trial project starts after obtaining the 
approval of the EC, confirm the complete documentation of the preparation stage such as 
archiving materials and research materials, confirm that the rescue drugs and equipment in the 
rescue room are complete and within the validity period, confirm that all investigators accept the 
training of the protocol. Investigators and relevant personnel review and complete protocol, ICF, 
study data records and CRF forms. 
In the course of the trial, the investigators should strictly follow the requirements of the protocol 
and the relevant SOPs of the institutions, and record in a true, timely, complete and 
standardized manner. Quality control personnel should control the trial process and the 
corresponding original records. 
After the trial, the institution arranges the corresponding project documents, and after checking 
by the quality control personnel, the documents are filed and saved. If problems are found, 
investigators should be promptly notified to correct them and follow up the corrections. Confirm 
that all the original data are complete and filed in time. Finally, the investigators and relevant 
personnel review and complete the summary report. 
17 STUDY MANAGEMENT RECORDS & PUBLICATION 
 
17.1 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 NMPA and 
the applicable ECs.  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 within 1 business day 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. 

 
 
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17.2 Record Maintenance and Retention 
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 are to be collected in the source documents throughout the 
study. 
 
EDC/eCRF 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/SmPC, 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. 
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. 
It is requested that at the completion of the required retention period, or should the Investigator 
retire or relocate, the Investigator contact the Sponsor, allowing the Sponsor the option of 
permanently retaining the study records. Records retained will be stored independently of the 
Sponsor, and the Sponsor will not be permitted direct access to this data. 
17.3 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 within one business day. 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 enter in to the study. 
The Investigator and research team must comply with ICH GCP and all applicable local 
regulatory laws and regulations. 

 
 
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17.4 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. 
17.5 Retention of Tissue Samples 
Blood samples will be retained per local China regulations. 
17.6 Registration and Publication of Study Summary and Results 
The Sponsor will determine the identity of the Co-ordinating Investigator for the study who will 
review and sign off the Clinical Study Report. This decision will be based on involvement in the 
study including, but not limited to, study design, subject recruitment and interpretation of study 
data. 
Clinical trials will be registered in public databases and summary results released / disseminated 
via publically available clinical trials databases according to the Sponsor’s standard operating 
procedures (SOPs) and local requirements. If such studies and trials do require public 
registration and/or reporting, this will be undertaken according to local requirements.  
The Sponsor registers clinical trials and posts the summary results as follows: 
- 
https://register.clinicaltrials.gov  
Following the end of the clinical trial, the summary results should be made publically available 
according to accepted timelines and requirements, usually within 12 months of study 
completion.    

 
 
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Budd K. Buprenorphine: a review. Evidence Based Medicine in Practice 2002, 1-24. 
Budd K, Collett BJ. Editorial III. Old dog-new (ma)trix. Br J Anaesth 2003; 90 (6): 722-4. 
China Ministry of Health, Cancer pain clinical guidelines (2011 version) [J/CD]. Chin J Crit Care Med 
(Electronic Edition), 2012, 5(1): 31-38. 
Cancer pain relief: With a guide to opioid availability, World Health Organization, (1996), 1-75 
Cowan A, Doxey JC, Harry EJ. The animal pharmacology of buprenorphine, an oripavine analgesic agent. 
Br J Pharmacol., 1977; 60(4): 547-554. 
Dahan A, Yassen A, Bijl H, Romberg R, Sarton E, Teppema L, et al. Comparison of the respiratory effects 
of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 2005; 94 (6): 825-34. 
Filitz J, Griessinger N, Sittl R, Likar R, Schüttler J, Koppert W. Effects of intermittent  hemodialysis on 
buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with 
transdermal buprenorphine. Eur J Pain 2006; 10 (8): 743-8. 
Hand CW, Baldwin D, Moore RA, Allen MC, McQuay HJ. Radioimmunoassay of buprenorphine with iodine 
label: analysis of buprenorphine and metabolites in human plasma. Ann Clin Biochem 1986; 23: 47-53. 
Hand CW, Sear JW, Uppington J, Ball MJ, McQuay HJ, Moore RA. Buprenorphine disposition in patients 
with renal impairment: single and continuous dosing, with special reference to metabolites. Br J Anaesth 
1990; 64 (3): 276-82. 
Heel RC, Brogden RN, Speight TM, Avery GS. Buprenorphine: a review of its pharmacological properties 
and therapeutic efficacy. Drugs 1979; 17 (2): 81-110. 
Hoskin PJ, Hanks GW. Opioid agonist-antagonist drugs in acute and chronic pain states. Drugs, 1991; 41(3): 
326-44. 
Kacinko SL, Jones HE, Johnson RE et al. Urinary excretion of buprenorphine, norbuprenorphine, 
buprenorphine-glucuronide, and norbuprenorphine-glucuronide in pregnant women receiving 
buprenorphine maintenance treatment. Clinical Chemistry 2009; 55:6 1177-1187. 
Lewis JW. Clinical pharmacology of buprenorphine in relation to its use as an analgesic. In: Cowan, A., and 
Lewis, JW, eds. Buprenorphine: combating drug abuse with a unique opioid. New York, Wiley-Liss. 
1995:151-63. 
Likar R. Efficacy and safety of a buprenorphine-transdermal patch with 4 days’ wearing time compared with 
the current application period of 3 days – a randomized cross-over study. Book of Abstracts, 4th 
International Conference on Pain Control and Regional Anaesthesia; 18–22 November; Cape Town, South 
Africa. 2005. 
Technical Guideline for Clinical Pharmacokinetic Studies on Chemical Drug Products – State China Food 
and Drug Administration (March 2005). 
Tegeder I, Geisslinger G, Lötsch J. Therapy with opioids in liver or renal failure [Einsatz vo n Opioiden bei 
Leber- oder Niereninsuffizienz]. Schmerz 1999a; 13 (3): 183-95. 

 
 
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Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling 
effects at high doses. Clin Pharmacol Ther 1994; 55 (5): 569-80. 
Wolff RF, Aune D, Truyers C, V Hernandez A, Misso K, Riemsma R, Kleijnen J. Systematic review of 
efficacy and safety of buprenorphine versus fentanyl or morphine in subjects with chronic moderate to 
severe pain. Curr Med Res Opin. 2012; 28(5): 833-45. 

 
 
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19 APPENDICES 
 
19.1 Adverse Event Reporting Process 
Figure 2: Flow diagram for AE reporting (to be considered alongside Section 14 of the 
protocol) 
 
 
 
 
Adverse event 
Complete 
eCRF AE pages 
considering the following: 
Provide diagnosis instead of 
signs/symptoms 
Assess causal relationship 
of AE (YES/NO?) 
Does the AE meet any 
of the following 
criteria? 
SERIOUSNESS CRITERIA 
fullfilled? 
AE results in subjects’ withdrawal 
from the study? 
Adverse event of special interest? 
Record  
carefully  
all details of AE 
and 
follow-up AE 
YES 
NO 
Report using related form(s) and 
capture associated AE on AE form 
in eCRF if applicable. 
NO: 
Provide detailed information what you consider was 
the alternative cause for the AE (e.g. concomitant 
medications, NIMP) 
Special Situation 
- Drug exposure via parent (DEVP) 
- Medication error, abuse/misuse? 
Yes: 
Provide detailed information why you consider there 
is a possible causal relationship to IMP? 
Assign 
intensity/severity grade 
YES 
Report immediately 
(within 24 hours) to 
sponsor/CRO with 
completed forms 
and follow-up AE 
Enter into eCRF as soon 
as possible, ideally within 
24 hrs and follow up AE 
Withdrawal) 

 
 
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19.2 Classification of Treatments 
Figure 3: Overview of classification of treatments 
 
 
The Investigational Medicinal Product (IMP) is defined as a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical trial, including products 
already with a marketing authorisation but used or assembled (formulated or packaged) in a way 
different from the authorised form, or when used for an unauthorised indication, or when used to 
gain further information about the authorised form. 
 
The term test IMP is used to indicate only the experimental product under study or 
development. Note: This term is more specific than “investigational medicinal product” which 
includes comparators and placebos.  
 
Investigational Medicinal 
Product (IMP) 
Non-Investigational 
Medicinal Product 
(NIMP/Auxillary product) 
Reference 
IMP(s): 
Not 
applicable 
Naltrexone cover 
Test IMP: 
BUP TDS 
Concomitant Therapies 
Study Treatments 
Study Treatments and Concomitant Therapies 

 
 
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The non-IMP (NIMP) is defined as any medicinal products intended for research and 
development trials, which does not fall within the definition of an IMP. 
NIMPs include: 
 
Rescue medication (for ineffective treatment, anticipated adverse reactions, or 
anticipated emergency situations): e.g. analgesic rescue medication or laxative in opioid 
studies, naltrexone. 
 
Challenge agents, e.g. skin prick tests 
 
Medicinal products used to assess end-points in the clinical trial, e.g. any diagnostic 
agents used to assess the disease under study 
 
Concomitant medicinal products systematically prescribed to the study subjects, e.g. 
cancer treatment in an opioid trial with cancer patients who all get the same cancer 
treatment according to the protocol 
 
Background treatment, standard care that all patients receive in addition to the IMP and 
for the same indication, e.g. standard chemotherapy in addition to a new oncological 
product to be tested.  
 
 

 
 
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19.3 Sample Processing and Shipment 
 
19.3.1 Pharmacokinetic Sample Handling and Shipping 
Samples and Sample Log Forms will be shipped by the Investigator to the bioanalytical 
laboratory. Analysis will be performed by means of LC-MS/MS methodology. Details on the 
analytical methodology, the method of validation, and the analytical within-study quality control 
procedures will be included in the clinical study report for this protocol. 
19.3.2 Sample Procurement and Processing 
Blood samples, about 6 mL each, will be drawn into tubes containing K2EDTA anticoagulant. 
After procurement, samples should be kept in a container of ice water, until processing. 
Samples must be centrifuged within 60 minutes of collection. Following centrifugation (2000 g, 
2-8 °C, 1 0 minutes) the plasma will be transferred via pipette into two labelled polypropylene 
tubes and stored at least ≤ -60°C  within two hours of collection. 
19.3.3 Sample Shipment 
Samples will be shipped in accordance with the standard procedures provided by the 
Bioanalysis Laboratory. 
 
 
 
 

 
 
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19.4 Clinical Laboratory Tests 
Table 5 presents the clinical laboratory tests to be performed. 
Table 5: Clinical Laboratory Tests 
Category 
Parameters 
Haematology 
RBC, haemoglobin, haematocrit, platelets, and WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Chemistry 
 
Electrolytes 
sodium, potassium, chloride, bicarbonate (HCO3-) 
Liver function tests 
alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl-transferase (GGT), total 
bilirubin, direct bilirubin 
Renal function parameters 
blood urea, creatinine 
Other 
glucose, calcium, albumin, cholesterol, triglycerides, phosphorus 
(inorganic phosphate), lactate dehydrogenase (LDH), total protein, 
globulin, uric acid 
 
 
Urinalysis 
pH, protein, glucose, ketone, occult blood, RBC, WBC, epithelial 
cells, bacteria, casts, crystals, specific gravity 
 
 
 

 
 
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19.5 Pain Intensity Scale 
 
 Numeric Rating Scale (NRS) 
Rate your average pain: circle ONE number that best describes your AVERAGE pain over the 
last 24 hours. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
     No Pain 
 
 
 
 
 
 
 
 
 
Pain as bad 
as you can 
imagine 
 
 
 

 
 
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19.6 Dermal response scale 
 
 
 
 
 
 
 
Score 
Dermal Response at patch site 
0 
No evidence of irritation 
1 
Minimal erythema, barely perceptible  
2 
Definite erythema, readily visible; minimal oedema or 
minimal papular response 
3 
Erythema and papules 
4 
Definite oedema 
5 
Erythema, oedema, and papules 
6 
Vesicular eruption  
7 
Strong reaction spreading beyond the application site 

 
 
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19.7 Karnofsky score