Characterisation and Epidemiology of Breakthrough Cancer Pain in Spain
Conditions: Breakthrough Cancer Pain
Sponsor: Takeda



•
Title: Characterisation and Epidemiology of Breakthrough Cancer Pain in Spain
NCT Number: NCT02899884
Protocol Approve Date: 19 Feb 2016 
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

CARPE-DIO 
Observational/Non-Interventional 
Study Protocol 
Page 1 of 56 
Non-Interventional Study Protocol 
Short title: 
Characterisation and Epidemiology of Breakthrough Cancer Pain in Spain 
Title: 
Characterisation and Epidemiology of Breakthrough Cancer Pain in Spain 
Study ID: 
CARPE-DIO 
Sponsor: 
Takeda Farmacéutica España S.A. 
Address: C/ Alsasua 20, 28023 - Madrid (Spain) 
Phone: +34 91 7149900 
Fax: +34 91 6574904 
Study phase:  Medical Affairs, Non-registration Company Sponsored (Observational) 
Date of final version of protocol:  19 Feb 2016 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Takeda except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. Furthermore, the information is only meant for review and compliance by 
the recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable 
conduct of the study. 

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CARPE-DIO 
Observational/Non-Interventional 
Study Protocol 
 
 
 
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Summary 
 
Short Title of Study 
Characterisation and Epidemiology of Breakthrough Cancer Pain in Spain 
 
Study sites 
66 planned sites from Spain 
 
Objectives 
To determine the prevalence of breakthrough cancer pain in an unselected, representative 
cohort of oncology outpatients with pain that is controlled with opioids. 
 
Methodology 
Non Interventional, non post-authorization, cross-sectional, epidemiological study 
 
Number of subjects 
We estimate that more than 10 patients per day attend consultations for cancer in Medical 
Oncology, Radiotherapeutic Oncology, Hematology and Palliative Care Departments and 
around 5 patients in Pain Units. Breakthrough cancer Pain (BCP) is a common and 
incapacitating subtype of pain that affects a percentage of patients with cancer that varies 
between 40% and 90% according to different publications. Conservatively, we hope to detect 
the prevalence in 50% of patients, and we estimate that at each site a total of approximately 
200 patients, or around 13,200 across the 66 planned sites, will be interviewed on the 
prevalence of breakthrough cancer pain. This sample will enable us to detect the prevalence 
of breakthrough pain with a 95% confidence interval and precision of ±1%. 
For the assessment of the secondary objective, i.e., characterising the breakthrough pain 
based on aetiology, underlying pathology and other clinical characteristics, if we consider the 
detection of common characteristics in at least 10% of patients in our population to be 
representative, it will be necessary to recruit 529 patients in order to detect said 
characteristics with a 95% confidence interval and precision of ± 2.5%. 
 
Diagnosis/Disease/Condition and main selection criteria 
Inclusion criteria 
 
Patient ≥ 18 years old 
 
Patients with baseline cancer pain that is adequately controlled with opioids 

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Observational/Non-Interventional 
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 
Presence of episodes of breakthrough pain associated with the cancer pain 
 
Meeting the diagnostic criteria for breakthrough cancer pain (patient history and 
Portenoy’s criteria) and the Davies algorithm 
 
Patients who are not receiving treatment for breakthrough pain. It is not permitted the 
inclusion of patients receiving treatment for breakthrough cancer pain in order to 
avoid bias that may involve the treatment for the characterisation of breakthrough 
pain  
 
Signing of the informed consent 
 
Exclusion criteria 
 
 
No severe mental illness 
 
Any medical condition or situation complicating the collection of study data as 
determined by the investigator is not permitted  
 
Time (if cross-sectional) or Duration of data collection per subject 
Investigator will collect the study data in a single visit.  
 
Criteria for evaluation 
Population descriptors 
The primary assessment variable is the prevalence of breakthrough pain in patients with 
cancer pain controlled with opioids. 
Demographic data and information relating to the characteristics of the cancer will be 
collected from all patients.  
The characterisation of breakthrough pain will be carried out using the information collected 
in the tools used for the clinical assessment of the breakthrough pain:  
- Alberta Breakthrough Pain Tool 
- BPI questionnaire and  
- Numerical Rating Scale for the assessment of pain intensity 
To assess the quality of life of patients, we will use: SF-12 Questionnaire and Karnofsky 
performance status. 
 
Main outcome variables 
The primary assessment variable is the prevalence of breakthrough pain in patients with 
cancer pain controlled with opioids. All patients who attend pain consultations with cancer 
pain during 1 month will be used to determine the prevalence of breakthrough pain. 

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Observational/Non-Interventional 
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Health economics 
None. 
 
Statistical methods 
The incidence/prevalence of breakthrough cancer pain and corresponding 95% confidence 
interval will be calculated as the percentage of subjects presenting breakthrough pain among 
patients with cancer pain controlled with opioids, collected by each investigator over one 
month. 
The incidence/prevalence of breakthrough cancer pain and corresponding 95% confidence 
interval will also be calculated relative to the number or cancer patients collected. 
The statistical methodology used will be based primarily on an exploratory analysis of the 
data through the calculation of descriptive parameters. 
A descriptive analysis of the study variables will be carried out and the values of the 
continuous variables will be summarised in a table showing the mean, median, standard 
deviation and maximum-minimum range for each. The categorical variables will be 
presented as absolute frequencies and percentages.  
The assessment of breakthrough pain intensity will be performed using the scores obtained 
on the numerical rating scale. A description of the scores will be given using the mean, 
median, standard deviation, maximum and minimum.  
Each of the items on the BPI questionnaire and Alberta scale will be described, using the 
mean, median, standard deviation and range to describe the continuous variables and 
frequency distributions and percentages to describe the categorical variables. 
The SF-12 quality of life scale scores will be given using the mean, median, standard 
deviation and range.  
Breakthrough pain in patients with cancer pain will be characterised based on aetiology and 
pathogenesis, as well as other clinical characteristics. Continuous variables will be 
summarised showing the mean, median, standard deviation and maximum-minimum range 
for each and categorical variables will be presented as absolute frequencies and 
percentages. 
The quality of life of patients with breakthrough cancer pain will be analysed based on its 
possible relationship with demographic characteristics and other clinically significant 
variables related to the cancer or to the breakthrough pain such as aetiology, frequency of 
episodes, pain intensity, time until peak of pain, crisis duration, cause, etc.  
 

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Table of Contents 
1 
Administrative information................................................................................................ 2 
1.1 
Contacts ................................................................................................................. 2 
1.2 
Approval ................................................................................................................. 3 
2 
Introduction .................................................................................................................... 10 
3 
Study Objective(s) ......................................................................................................... 14 
4 
Study Administrative Structure ....................................................................................... 15 
4.1 
Study Sites ........................................................................................................... 16 
4.2 
Sponsor Personnel ............................................................................................... 16 
4.3 
Contract Research Organisation (CRO) ............................................................... 16 
4.4 
Essential Documents ............................................................................................ 17 
5 
Ethics ............................................................................................................................ 17 
5.1 
Ethical conduct of the Study ................................................................................. 17 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities ......... 19 
5.3 
Subject Information and Written Informed Consent ............................................... 20 
5.4 
Risk–benefit analysis for research subjects. ......................................................... 22 
6 
Study Design and Plan .................................................................................................. 22 
6.1 
Study Schedule .................................................................................................... 23 
6.2 
Discussion of Study Design .................................................................................. 23 
6.3 
Selection of Study Population ............................................................................... 24 
6.4 
Treatments ........................................................................................................... 25 
7 
Conduct ......................................................................................................................... 25 
8 
Safety Reporting ............................................................................................................ 31 
8.1 
Definitions............................................................................................................. 31 
8.2 
Classifications ...................................................................................................... 31 
8.3 
Reporting of Adverse Drug Reactions and Adverse Events .................................. 33 
9 
Data Quality Control and Assurance .............................................................................. 34 
9.1 
Quality Control ...................................................................................................... 34 
9.2 
Audit from Quality Assurance Unit ........................................................................ 35 
9.3 
Inspection by IRB/IEC or Competent Authority ..................................................... 35 
9.4 
Data Management ................................................................................................ 35 
9.4.1 
Data Collection Tools and Flow ............................................................... 35 
9.5 
Methods for obtaining data. .................................................................................. 36 
9.6 
Data handling. ...................................................................................................... 36 

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10 Statistical Methods and Determination of Sample Size .................................................. 37 
10.1 Statistical Analysis Plan ........................................................................................ 37 
10.2 Interim Analyses ................................................................................................... 39 
10.3 Determination of Sample Size .............................................................................. 39 
11 Reports .......................................................................................................................... 40 
12 Publications ................................................................................................................... 40 
13 Archiving of Study Documentation ................................................................................. 41 
14 References .................................................................................................................... 42 
Appendix 1: Brief Pain Inventory (BPI). ................................................................. 45 
Appendix 2: SF-12 Questionnaire. ........................................................................ 47 
Appendix 3: Karnofsky performance status. .......................................................... 49 
Appendix 4: Alberta Breakthrough Pain Assessment Tool. ................................... 50 
Appendix 5: Adverse reaction report form ............................................................. 56 
 
APPENDICES 
 
Appendix 1: Brief Pain Inventory (BPI). ......................................................................... 45 
Appendix 2: SF-12 Questionnaire. ................................................................................ 47 
Appendix 3: Karnofsky performance status. .................................................................. 49 
Appendix 4: Alberta Breakthrough Pain Assessment Tool. ............................................ 50 
Appendix 5:: Adverse reaction report form. ................................................................... 56 
 
 
 
 

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List of Abbreviations and Definition of Terms 
 
AE: 
 
Adverse Event 
ADR:  
Adverse Drug Reaction 
AEMPS 
Spanish Agency of Medicines and Medical Devices 
CA: 
 
Competent Authority 
BCP   
Breakthrough cancer pain 
BPI 
 
Brief Pain Inventory (BPI) 
CCSI:  
Core Company Safety Information 
CRF:  
Case Report Form 
CRO:  
Contract Research Organisation 
CV: 
 
Curriculum Vitae 
GCP:  
Good Clinical Practice 
GPP:  
Good Pharmacoepidemiology Practices 
ICH: 
 
International Conference on Harmonisation 
IDS: 
 
International Drug Safety 
IEC: 
 
Independent Ethics Committee 
IRB: 
 
Institutional Review Board 
NRS    
Numerical Rating Scale 
PAS 
 
Post-authorisation study 
PSUR:  
Periodic Safety Update Report 
PSUR:  
Periodic Safety Update Report 
QA  
 
Quality Assurance 
SAE:  
Serious Adverse Event 
SAP:  
Statistical Analysis Plan 
SADR:  
Serious Adverse Drug Reaction 
SPC:  
Summary of Product Characteristics 
 
 
 

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2 
Introduction 
Oncology consultations are generally short in duration (20-30 minutes). The primary 
consideration for most oncologists during this time is treatment of the tumour: the choice of 
treatment to be administered to the patient (chemotherapy, radiotherapy, etc.), the 
administration of recommended treatment, and the monitoring and control of the efficacy and 
safety of these treatments, principally in relation to tumour response and survival [4]. 
 
Symptoms, such as pain, are often given less attention during diagnosis and treatment. Pain 
is one of the most common symptoms of cancer [5-7]. However, published estimates of the 
prevalence of pain in outpatients are inconsistent and vary between 18% and 62%, probably 
due to differences between the various selection criteria, the use of dissimilar assessment 
tools and/or different tumour stages [5-7]. 
 
Breakthrough pain is understood as the temporary exacerbation of pain occurring either 
spontaneously or in relation to a specific, predictable or unpredictable trigger in spite of 
relatively stable and adequately controlled baseline pain. 
 
Breakthrough cancer pain is a common and distressing subtype of pain that affects a 
percentage of patients with cancer that varies between 40% and 90% according to different 
publications [1, 2]. The type of breakthrough pain seen in cancer is described as “a 
temporary increase in pain with an intensity above that considered moderate, overlying 
baseline pain of moderate or low intensity” in cancer patients treated with opioids [8].  
 
Breakthrough cancer pain is a high intensity, short duration pain that manifests in several 
daily episodes and does not respond to normal treatment. The clinical approach to 
breakthrough cancer pain is changeable. The data show that daily exacerbations of pain 
need to be monitored closely, differentiating where possible between fluctuations in baseline 
pain and the end-of-dose effect [9]. 
 
The causes of cancer breakthrough pain are the same as those of cancer pain, and they can 
be related to the neoplasm, with diagnostic tests, treatment or other concomitant problems 
concurrent with cancer [10]. In terms of physiology, breakthrough pain may be nociceptive, 
neuropathic or mixed [10]. 

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Even today, clinical focus in breakthrough pain varies considerably between clinics, from 
complete denial of its existence to overestimation [9]. 
 
Recently it carried out a study with the participation of specialists from Medical Oncology 
services, Radiation Oncology services, pain units and palliative care units. The survey 
showed a high level of agreement among the experts consulted, but there were some areas 
where no agreement was reached, indicating that there are some areas for improvement 
related to clinical practice in the management of breakthrough pain that are worth 
investigating [11]. In patient evaluation a correct diagnosis and proper classification of 
breakthrough pain are the essential steps to achieve optimal pain treatment [12]. 
 
The management of breakthrough pain requires an interdisciplinary approach that includes 
all stakeholders involved in the treatment of patients with cancer. Since the breakthrough 
pain affects the patient during the course of the disease, all the specialists who treat cancer 
should be familiar with its detection and management. Moreover, treatment of breakthrough 
pain should be multimodal. An integrated strategy that includes the availability of specific 
cancer treatment, the use of appropriate analgesics, basal proper pain control, and adequate 
pain management procedures is required [13].Patients with breakthrough cancer pain report 
a reduction in quality of life, a high level of anxiety and depression, more dissatisfaction with 
treatment, and are more prone to using healthcare resources [14]. Data on breakthrough 
cancer pain in patients attending outpatient oncology consultations are insufficient; however, 
recent studies report a prevalence of breakthrough cancer pain of 33-37% in these patients 
[15, 16]. The studies are usually conducted by a specialty and lack of the approach of the 
other specialties. This justifies the disparate prevalence between studies, the lack of real 
characterization of breakthrough pain and also the need for multidisciplinary and rigorous 
studies to assess the breakthrough cancer pain in a transversal manner. 
 
With the aim of identifying those patients with clinically significant pain, questions can be 
formulated regarding the intensity of the pain. Once patients have been identified, the next 
essential step is the diagnosis/appropriate classification of the pain. In addition to pain 
intensity, it is important to identify the characteristics of this pain. 
 
Before the routine assessment of symptoms such as pain can be incorporated into normal 
clinical practice, it is important to accurately estimate the prevalence of these symptoms. A 

CARPE-DIO 
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Page 12 of 56 
 
 
suitable methodology that will allow the symptoms to be correctly classified will then need to 
be developed. 
 
Breakthrough pain is classified based on its relationship with specific events: 1) spontaneous 
pain (also known as idiopathic pain), that occurs unexpectedly and 2) incident pain (also 
known as precipitated pain or, where appropriate, movement-related pain) that is triggered 
by specific events and may be sub-classified in three categories: volitional, non-volitional 
and procedural [17]. 
 
The objective of this study will be to characterise breakthrough pain in a diverse population 
of cancer patients in Spain, using the recommended diagnostic algorithm (Davies algorithm) 
and medical history to assess patients with regard to the presence of breakthrough pain [3], 
as well as the Alberta questionnaire, designed specifically for the assessment of 
breakthrough pain in cancer patients [18]. 
 
Although investigators have used various surveys or questionnaires to collect information on 
breakthrough pain in the context of clinical research, we preferred to use a standardised 
assessment tool for breakthrough pain, of demonstrated reliability and validity, that is used in 
patients with breakthrough cancer pain. The tool that will be used in this study was 
developed to support a research programme to assess novel interventions for breakthrough 
pain. The Alberta Breakthrough Pain Assessment Tool’s design is well-researched and it is 
easy to understand for both patients and physicians [18]. 
 
We will also use the Spanish version of the BPI (Brief Pain Inventory), which has been 
validated in cancer patients, as a secondary assessment criterion [19]. The BPI 
questionnaire has two sections: pain intensity (4 items) and interference with activities of 
daily living (7 items). Each item is given a score on a numerical scale from 0 (no 
pain/interference with activities of daily living) to 10 (worst pain imaginable/maximum impact 
on activities of daily living). The results for these 11 items are then used to obtain two overall 
scores, one for each section: pain intensity and interference with activities of daily living. 
It should be noted that the studies published previously on the characterisation of 
breakthrough cancer pain included a low number of patients and were often carried out at a 
single research site, with the exception of the study by Davies et al. (2013) [17]. However, in 
this study they included all specialties that see cancer pain. 

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Quality of life assessment is essential in these patients due to the impact that breakthrough 
cancer pain may have on patients’ wellbeing and in particular because the patient may feel 
that it is a real threat to his/her life [20] having no previous studies with so many patients 
that assess the quality of life. 
 
On the other hand, pain is a problem that is frequently accentuated in older patients in 
particular, whether caused by cancer or otherwise [21]. 
 
The incidence of cancer increases with age and approximately half of all cancer cases occur 
in patients over 65 years of age [22]. 
 
The treatment of cancer pain in elderly patients is challenging due to the increased risk of 
therapeutic complications resulting from the loss of performance status, associated 
comorbidities, geriatric syndromes and decreased cognitive function [22]. Moreover, despite 
the existence of effective treatments for pain, older patients are often undertreated [23]. 
 
Consequences include depression, anxiety, falls, malnutrition, decreased cognitive function, 
poor quality sleep, altered performance status, decreased social and leisure activities, 
increased healthcare costs and, overall, reduced quality of life [24]. 
 
The SF-12 health questionnaire is an abbreviated form of the SF-36 questionnaire, designed 
for use in situations in which the latter would be too long. The SF-12 questionnaire only 
takes around two minutes to complete. This questionnaire is a self-administered tool that 
measures health from the patient’s perspective, through standardised responses to 
standardised questions [25]. 
 
Assessment of performance status in medicine (oncology and other fields) seeks to quantify 
the general wellbeing and activities of daily living of cancer patients. This measurement is 
used to determine whether patients can have chemotherapy, whether it is necessary to 
adjust the dose and as a means for establishing palliative care. It is also used as a 
measurement of quality of life in controlled and randomised oncological clinical cancer trials. 
There are various scoring systems, one of the most widely used being the Karnofsky 
performance status scale [26]. The Karnofsky performance status score includes 11 

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Page 14 of 56 
 
 
categories scored from 100 to 0, where 100 is “patient asymptomatic with no evidence of 
illness” and 0 is “death”, and a version is available in Spanish [27]. 
 
3 
Study Objective(s) 
Primary objective 
 
To estimate the prevalence of breakthrough cancer pain in an unselected 
representative cohort of cancer outpatients with or without pain who attend 
consultations at Medical Oncology, Hematology , Radiotherapeutic Oncology 
Departments, Pain Units and Palliative Care Units at participating sites. 
The estimated annual prevalence will be calculated relative to the population of 
cancer patients with or without pain seen in participating practices over one month.  
Secondary objectives 
 
To estimate the annual incidence of patients with breakthrough cancer pain relative 
to the population of cancer patients with or without pain seen in participating 
practices over one month. 
 
To characterise breakthrough pain in patients with cancer pain based on medical 
history, aetiology and pathogenesis, tumour type, location, stage, comorbidities, etc., 
as well as other clinical characteristics (type of breakthrough pain, number of 
episodes per day, duration and intensity, and baseline pain management). This 
information will be collected with the tools used for the clinical assessment of 
breakthrough pain. 
 
To assess the prevalence of each of the different causes of pain. 
 
To determine the percentage of patients who present each of the different 
profiles/types of breakthrough cancer pain (characterisation/classification) and 
classify them based on the results obtained in the Alberta and BPI questionnaires.  
 
To determine the percentage of patients who present each of the profiles/types of 
breakthrough cancer pain and assess possible relationships with demographic 
characteristics and other clinically significant variables related to the cancer such as 
diagnosis, pain intensity, comorbidities, etc. 
 
To assess the quality of life of patients with breakthrough cancer pain and its 
possible relationship with demographic characteristics and other clinically significant 
variables related to the cancer or to the breakthrough pain such as aetiology, 
frequency of episodes, pain intensity, time until peak of pain, crisis duration, cause, 
etc. 
 
To assess the performance status of patients using the Karnofsky scale in order to 
know the degree of general wellbeing and ability to cope with activities of daily living 
presented by the patients studied. 
 
 

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CCI

CARPE-DIO 
Observational/Non-Interventional 
Study Protocol 
 
 
 
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The investigators are responsible for the accuracy of the data collected. The data obtained 
are completely confidential and only the sponsor, the coordinator and the investigators will 
have access to them. 
 
With regard to the thoroughness of the study and the sponsor’s obligations, when the 
personal data of the investigators and/or patients are held or handled, appropriate measures 
must be taken to protect these and avoid access to the same by unauthorised third parties. 
In the interest of confidentiality, only the investigator, his/her staff and the technical staff 
participating in the collection of the study data will have access to patients’ data. 
 
The confidentiality of the information will be maintained to the extent permitted under the 
applicable legislation. If the results of this study are published, the identities of the 
participating subjects will remain confidential. The provisions of Spanish Organic Law 
15/1999 of 13 December on Personal Data Protection will be complied with under all 
circumstances. 
 
Takeda/the appointed CRO will ensure that the protocol, any amendments and the Subject 
Information Sheet/Informed Consent Form are submitted to the relevant Independent Ethics 
Committees (IECs)/Institutional Review Boards (IRBs) according to local requirements. 
Takeda as the sponsor is responsible for meeting the ICH requirement for yearly updates to 
the IECs/IRBs, if applicable. 
 
This study will be financed by the Sponsor, Takeda Farmacéutica España S.A. 
 
The sponsor shall finance the study in accordance with the directions given in this protocol. 
This funding includes the cost of submitting the study for approval to an accredited IEC, 
submitting the study for classification to the AEMPS, the design, maintenance and 
management of the database, as well as the statistical analysis and corresponding statistical 
report. 
 
This study is observational, therefore it will not under any circumstances interfere in the 
physician’s normal clinical practice, as it is limited to the collection of patient data and does 
not entail any diagnostic or therapeutic procedure outside of normal clinical practice. 
 

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For this reason, each physician will have to select those individuals eligible to participate in 
the study from among the population he/she treats. Whether the investigator decides to use 
a treatment or not will be independent of the study, and treatments may be altered based on 
normal clinical practice regardless of the patient’s participation. 
 
Before accepting and signing the investigator’s commitment, the participating professionals 
must ensure that their participation in the study does not interfere with their prescribing 
habits or their healthcare duties. 
 
No intervention outside of normal clinical practice will be performed; patients will receive the 
treatment considered most suitable by the investigator and this will not be provided by the 
sponsor.  
 
The study does not entail any extraordinary expenses for the investigator or the site beyond 
the time spent by the investigator filling out the case report form with the required 
information. 
 
All changes made to the protocol must be the subject of a written amendment that shall be 
signed by the investigator and the sponsor and filed together with the protocol. In some 
cases, the amendment may require that changes be made to the informed consent 
document. Any changes made to this protocol shall be reported to the IEC that performed its 
review. In the case of substantial amendments, those that affect the objectives, methods or 
ethical considerations shall be subject to a new evaluation by the IEC that gave a favourable 
opinion on the same, and administrative authorisation shall be sought for the amendment. 
For amendments that do not affect these aspects, the IEC will be notified, giving the reasons 
why the amendment is not considered substantial. 
 
5.2 Independent Ethics Committee / Institutional Review Board and 
Authorities 
IEC/ IRB 
According to applicable regulations, the appointed CRO or the Site Study Responsible will: 
 
notify or obtain approval from the relevant IEC/IRB of the protocol, any amendments and 
the Subject Information Sheet / Informed Consent Form  

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The appointed CRO or the Site Study Responsible will submit required documents to the 
IEC / IRB, such as: 
 
periodic updates on the progress of the study 
 
notification of the end-of-study 
 
a summary of the study results 
 
Global Research will keep an updated list of all submission and approval dates of all 
documents submitted to the IEC / IRB and will provide the Site Responsible with a copy of 
this list. Copies of the documents will be distributed upon request. 
 
Authorities 
Global Research or the appointed Contract Research Organisation (CRO) will send required 
documents to the competent authority (CA) and/or other national or regional authorities. 
Global Research will keep an updated list of submission and approval dates and a copy of 
all documents submitted.   
Once the study has obtained classification from the AEMPS [Spanish Agency of Medicines 
and Medical Devices], approval by an IEC and the other administrative procedures have 
been completed, the study will commence at the participating sites. 
 
5.3 Subject Information and Written Informed Consent 
This study will follow standards of good clinical practice (GCP) as they apply to 
epidemiological studies, thereby ensuring that its design and conduct and the 
communication of the data are reliable and protect the rights and integrity of the participating 
subjects and the confidentiality of their data. 
Before starting the study, the protocol, patient information sheet and informed consent form 
for the study will be submitted for approval to the Independent Ethics Committee (IEC) of 
one hospital and to any of the IECs of any participating sites that request it. The sponsor will 
keep the IEC’s favourable opinion, together with the versions of the documents approved 
and the list of members of the committee having issued the opinion.  
Patients who meet the inclusion criteria and give their informed consent will be recruited to 
the pain characterisation study until the indicated sample size is reached. Each subject 
invited to participate in the pain characterisation study will be given a written document 
called a “Patient Information Sheet” that will contain the relevant and necessary information 
to enable him/her to decide whether to participate in the study. 

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The investigator must inform the patient as fully as possible, using language and terms that 
the latter can understand, about the voluntary nature of participation and that this will not 
entail any change to his/her treatment or medical care with regard to what he/she would 
receive if not participating. The investigator will respond to the patient’s doubts and 
questions and, in accordance with current legislation, obtain the subject’s written informed 
consent which must be signed by the subject (in his/her own hand with name and date) or, if 
not possible, that of an impartial witness, in which case he/she shall sign the verbal 
informed consent form before witnesses, or of the patient’s legal representative. The patient 
will receive a signed and dated hard copy of the informed consent form, signed also by the 
investigator. 
Subjects participating in the study may at any time withdraw their consent to the use of their 
data in the analysis, without giving a reason and without incurring any liability or loss.  
The Site Study Responsible must give the subject (and if applicable, parent or legal 
guardian) oral and written information about the study in a form that the subject (, parent or 
legal guardian) can understand, and obtain the subject’s (and if applicable, the subject’s 
assent and the parent’s or legal guardian’s) written consent before collection of identifiable 
subject information (hereinafter referred to as personal data). Before consenting, the subject 
(and if applicable, parent or legal guardian) must be left with ample time to consider and to 
pose questions. Since the study is observational the consent only concerns the data 
collection per see and is not consent to any interventional procedure or treatment.  
 
The subject must agree that sponsor personnel, their representatives or IEC/IRB or CA 
personnel (national or other) may require direct access to the subject’s data / personal 
records which were collected, processed and stored in an anonymous form.   
 
The subject must agree that his / her data will be processed and stored in an anonymous 
form for evaluation of this study and any later overviews. Data may also be transferred in 
anonymous form to third parties, e.g. other companies or authorities, that may be located in 
other countries with potentially different regulations for data.  
 
The subject and parent or legal guardian, if applicable, has the right to withdraw his/her 
consent at any time without prejudice. In the Informed Consent Form it is stated that if 
consent is withdrawn, any data collected before withdrawal of consent will be kept. The 
original, signed Informed Consent Forms must be kept on the Site. 

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For details, see the Subject Information Sheet and Informed Consent Form. 
 
5.4 Risk–benefit analysis for research subjects. 
Due to its observational nature, there is no possibility of the study generating any risk 
whatsoever for the subjects studied as it does not entail any change in patient care with 
respect to normal clinical follow-up. The patient will not receive any benefit as a result of 
his/her participation in the study and will be treated in accordance with the participating 
physician’s normal clinical practice. Nevertheless, this study may help to improve knowledge 
of the incidence and prevalence of patients with breakthrough cancer pain, as well as the 
characterisation of this type of pain, that can be incapacitating for the patient, which may 
enable improvements to be made in the care of such patients in normal clinical practice. 
 
6 
Study Design and Plan 
This study is a ‘non-interventional study’ as defined in: G-STND-PV-006, Pending SOP, 
Directive 2001/20/EC (4) and will follow the guidelines for GPP (2).  
 
This means that: 
 
The assignment of a subject to a particular therapeutic strategy is not decided in 
advance by the study protocol but falls within current practice 
 
No additional diagnostic or monitoring procedures shall be applied to the subjects 
 
Epidemiological methods shall be used for the analysis of collected data. 
 
This is a cross-sectional, non-PAS, non-interventional, epidemiological study. Given the 
observational and cross-sectional nature of the study, the protocol does not include any 
interventions with regard to patient follow-up by the investigator. 
 
The proposed design is considered sufficient to enable the collection of the data required to 
meet the study’s objectives. 
 
 
 
 

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6.1 Study Schedule 
Start of recruitment:   
September 2016 
End of recruitment:   
June 2017 
Data collection:  
 
3 months 
Data analysis:  
 
December 2017 
Total duration of study:  
15 months 
 
The Start of Study is defined as date of first Site Initiation.  
 
Global Research will ensure that End-of-Study notification is submitted to the concerned 
authorities and IEC/IRB for each site, for each country and for the complete study, as locally 
required. 
 
Global Research will ensure that results are posted on “clinicaltrials.gov” and as required by 
local authorities.  
 
Based on upcoming knowledge, Takeda might choose to terminate the study prematurely. In 
such case the Committee(s), study sites, IECs/IRBs and authorities will be informed 
promptly. 
 
6.2 Discussion of Study Design   
The study’s limitations derive from its design as a cross-sectional, non-PAS, non-
interventional study in which the proportion of patients with breakthrough cancer pain 
attending consultations in Medical Oncology, Hematology, Radiotherapeutic Oncology 
Departments, Pain Units and Palliative Care Units may not be representative of the general 
population of cancer sufferers. However, it will allow us to obtain a valid estimate in the 
population attending said consultations. 
A further limitation relates to the extrapolation of the results to the national population, as 
although 66 sites distributed throughout the country will participate in the study, it is possible 
that these may not be representative of Spain as a whole, due to the characteristics of the 
sites selected. 
 

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6.3  Selection of Study Population 
Patients with cancer pain assessed in in Medical Oncology, Hematology, Radiotherapeutic 
Oncology Departments, Pain Units and Palliative Care Units at the hospitals participating in 
the study. 
Inclusion criteria: 
 
Patient ≥ 18 years old 
 
Patients with baseline cancer pain that is adequately controlled with opioids 
 
Presence of episodes of breakthrough pain associated with the cancer pain 
 
Meeting the diagnostic criteria for breakthrough cancer pain (patient history and 
Portenoy’s criteria) and the Davies algorithm 
 
Patients who are not receiving treatment for breakthrough cancer pain. It is not 
permitted the inclusion of patients receiving treatment for breakthrough cancer 
pain in order to avoid bias that may affect  the characterisation or taxonomy of 
breakthrough cancer pain 
 
Signing of the informed consent 
Exclusion criteria: 
 
Severe mental illness 
 
Any medical condition or situation complicating the collection of study data as 
determined by the investigator 
The source of information will in all cases be the medical history, the patient and the 
questionnaires completed during the visit. In accordance with the study design, the 
investigator will collect the study variables and data in a single visit.  
 
For a period of one month, each investigator must identify cancer patients who attend 
consultations 
in 
Medical 
Oncology, 
Hematology 
and 
Radiotherapeutic 
Oncology 
Departments or Pain and Palliative Care Units, using the Davies diagnostic algorithm [3] to 
confirm the presence of breakthrough pain. From those patients who report breakthrough 
pain, the first two patients each day who meet the inclusion criteria and give their informed 
consent for the characterisation of breakthrough pain will be recruited, until reaching 10 
patients in Medical Oncology, Hematology, Radiotherapeutic Oncology and Palliative Care 
Departments and 5 patients in Pain Units. If an investigator has been unable to include the 

CARPE-DIO 
Observational/Non-Interventional 
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Page 25 of 56 
 
 
expected number of patients planned for the characterization of breakthrough pain during 
the month that has collected prevalence data, the investigator will have two additional 
months to include them, and the investigator must confirm the presence of breakthrough 
pain by Davies algorithm before inclusion as detailed above. 
 
 
Subjects should be included in the study only once.  
 
Data erroneously collected from subjects for which written consent is not available, will not 
be included in the final analysis and will be deleted from the database. All relevant actions 
will be taken according to GCP standarts and local legislation. 
 
6.4 Treatments 
The patients participating in this cross-sectional, non-PAS, non-interventional study will not 
receive treatment in relation to the study aside from the treatment already prescribed by their 
usual physician. 
 
7 
Conduct 
Once the study has obtained classification from the AEMPS [Spanish Agency of Medicines 
and Medical Devices], approval by an IEC and the other administrative procedures have 
been completed, the study will commence at the participating sites.  
Data will be collected from patients with cancer pain being treated with third-step opioids 
who attend consultation at the in Medical Oncology, Hematology, Radiotherapeutic 
Oncology Departments, Pain Units and Palliative Care Units of participating sites during a 
period of 1 month. Each of the participating investigators must identify the patients with 
cancer pain and confirm the presence of breakthrough pain using the Davies diagnostic 
algorithm [3]. The investigator will propose participation in the study on the characterisation 
of breakthrough pain to the first two patients each day who meet the selection criteria. If the 
patient agree to participate in the study they will be asked to sign the informed consent.If any 
of the patients refuses to participate the enrolment will continue the next day. It is expected 
that each investigator in the Medical Oncology, Hematology, Radiotherapeutic Oncology and 
Palliative Care Departments will recruit 10 patients to the study and investigators in the Pain 
Units will recruit 5 patients due to the lower number of cancer patients in Pain Units. In 

CARPE-DIO 
Observational/Non-Interventional 
Study Protocol 
 
 
 
Page 26 of 56 
 
 
accordance with the study design, the investigator will collect the necessary variables and 
data in a single visit. 
The fieldwork will take 1 month to collect prevalence data and maximum 3 months for the 
collection of data for the characterization of breakthrough pain, if the investigator could not 
recruit all foreseen patients for this purpose in the first month. First month corresponds to the 
recruitment period required for the incidence/prevalence calculation, as due to the study’s 
characteristics no follow-up period is planned. Data entry in the database, analysis and the 
drafting of the final report will be carried out once the recruitment period is concluded.  
As this is an observational, cross-sectional, non-PAS and non-interventional study, it will not 
under any circumstances involve changes to normal clinical practice or the performance of 
tests not considered normal clinical practice. Throughout the study, each investigator must 
treat the patients diagnosed with breakthrough cancer pain and recruited to the study, 
whether treatment-naïve or currently untreated, after characterising their pain, in accordance 
with the criteria habitually used in clinical practice for patients of this type. 
The study period is initially estimated at 12 months for data collection. This corresponds to 
the recruitment and data entry periods, as due to the study’s characteristics no follow-up 
period is planned. Data entry in the database, analysis and the drafting of the final report will 
be carried out once the recruitment period is concluded. If, following the recruitment period 
planned in the protocol (maximum 3 months), the expected number of patients for the 
characterisation of breakthrough pain has not been reached, recruitment will be continued 
competitively within each specialty (120 patients included in each specialty except 60 
patients in hematology), until 529 patients have been recruited.  
The investigator will be responsible for ensuring the correct completion of all sections of the 
Case Report Form.  
 
Description of the visit 
 
A single visit per patient will be carried out for the purposes of this study, coinciding with the 
study recruitment visit. 
For a period of one month, each investigator must identify patients with cancer pain being 
treated with opioids who attend consultations in in Medical Oncology, Hematology, 
Radiotherapeutic Oncology Departments, Pain Units and Palliative Care Units, using the 
patient's medical history and the Davies diagnostic algorithm [3] to confirm the presence of 
breakthrough pain.  

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Information relating to the prevalence of breakthrough pain will be collected in the 
corresponding section of the CRF, detailing for each patient whether he/she has pain, 
whether he/she has breakthrough pain, age, sex, Karnofsky PS, tumour type and stage. 
From those patients who report breakthrough pain, the first two patients each day who meet 
the inclusion criteria and give their informed consent will be recruited, until reaching the 
indicated sample size of 10 patients in Medical Oncology, Hematology, Radiotherapeutic 
Oncology and Palliative Care Departments and 5 patients in Pain Units, until a total of 529 is 
reached. 
If, following the recruitment period planned in the protocol (maximum 3 months), the 
expected number of patients for the characterisation of breakthrough pain has not been 
reached, recruitment will be continued competitively within each specialty (120 patients 
included in each specialty except 60 patients in hematology), until 529 patients have been 
recruited.  
The information will be recorded on the Case Report Forms (CRFs) designed for this 
purpose. All the information will be filled in by the investigating physician using the data 
obtained during the study visit or by checking the patient’s medical records when 
necessary. 
The following information will be collected during the visit: 
o Visit date 
o Demographic data (age, sex, weight, height) 
o Characteristics of the cancer (type, stage, treatments the patient has 
received for the underlying tumour: chemotherapy, radiotherapy, surgery, 
etc.) as well as whether he/she is currently receiving treatment for the 
tumour. 
o Comorbidities 
o Adverse events associated with the cancer treatment or sequelae of the 
tumour: (mucositis, xerostomia, nausea, vomiting, dysphagia, dyspnoea, 
peripheral neuropathy, tiredness/weakness, constipation, diarrhoea, sleep 
disorders, other) 
o Clinical assessment of the breakthrough pain:  
 
Alberta Breakthrough Pain Assessment Tool for the assessment of 
breakthrough pain in cancer patients 
 
Brief Pain Inventory (BPI) 

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Observational/Non-Interventional 
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Page 28 of 56 
 
 
intensity 
time 
 
Numerical Rating Scale (NRS) for the assessment of pain intensity 
o Quality of life assessment:  
 
SF-12 Questionnaire 
 
Karnofsky performance status  
 
Using an anatomical drawing or doll, the exact location in which the patient presents the 
breakthrough cancer pain crisis will be identified, determining whether one or several 
breakthrough pains are involved.  
A series of graphs illustrating various profiles for the behaviour of breakthrough pain will 
then be used, in order to determine which type(s) of breakthrough pain each patient 
recruited to the study presents.  
The following graphs will be used:  
 
BCP type I graph:  
This graph represents BCP of short duration 
 and high intensity, that begins and ends  
suddenly.  
 
 
 
 
 
BCP type II graph: 
This graph represents BCP of long duration and 
moderate-high intensity, that begins and ends 
gradually. 
 
 
 
 
 
 
BCP type III graph:  
This graph represents BCP with successive pain 
peaks of gradually decreasing intensity. 
 
intensity 
time 
intensity 
time 

CARPE-DIO 
Observational/Non-Interventional 
Study Protocol 
 
 
 
Page 29 of 56 
 
 
 
 
 
 
 
 
BCP type IV graph:  
This graph represents BCP that starts gradually, 
reaches a maximum peak and is maintained for a 
period, before gradually decreasing.  
 
 
The fundamental exposure factor in this study is patients with cancer who attend 
consultation at in Medical Oncology, Hematology, Radiotherapeutic Oncology 
Departments, Pain Units and Palliative Care Units with cancer pain controlled with 
opioids. Using patients’ medical history and the Davies diagnostic algorithm [3], the 
investigator will confirm the presence of breakthrough pain. Those patients who agree to 
participate in the study to characterise breakthrough pain by signing the informed 
consent will be questioned on the other study variables and asked to complete the 
corresponding questionnaires. 
All study data will be collected during the visit in which the patient signs the informed 
consent.  
The data detailed below will be collected in relation to the study objectives: 
- 
The primary assessment variable is the prevalence of breakthrough pain in 
patients with cancer pain controlled with opioids who attend consultations in 
Medical Oncology, Hematology and Radiotherapeutic Oncology Departments 
or Pain and Palliative Care Units for any reason. 
Breakthrough pain is understood as the temporary exacerbation of pain 
occurring either spontaneously or in relation to a specific, predictable or 
unpredictable trigger in spite of relatively stable and adequately controlled 
baseline pain. 
intensity 
time 

CARPE-DIO 
Observational/Non-Interventional 
Study Protocol 
 
 
 
Page 30 of 56 
 
 
For a period of one month, each investigator will identify patients with cancer 
pain being treated with opioids who attend consultations, using the patient’s 
medical history and the Davies diagnostic algorithm [3] to confirm the 
presence of breakthrough pain. 
The investigator will continue collecting information from patients to estimate 
the prevalence for a month, regardless of whether the investigator recruited 
the 10 assigned patients (5 in pain units) for the characterization of 
breakthrough pain before. 
- 
The prevalence of breakthrough pain in patients with cancer who attend 
consultations in Medical Oncology, Hematology, Radiotherapeutic Oncology 
Departments, Pain Units and Palliative Care Units for any reason over one 
month will also be determined. 
- 
In order to determine the incidence of breakthrough pain in patients with 
cancer pain controlled with opioids, the investigator will indicate on the 
prevalence data sheet whether the breakthrough pain has been diagnosed 
during the current visit or was diagnosed at an earlier date. Cases of 
breakthrough pain diagnosed during 1 month will be used to calculate its 
incidence. 
- 
The incidence of breakthrough pain in patients with cancer who attend 
consultations in in Medical Oncology, Hematology, Radiotherapeutic 
Oncology Departments, Pain Units and Palliative Care Units for any reason 
over one month will also be determined. 
- 
During the same visit, demographic data and information relating to the 
characteristics of the cancer will be collected from all patients with 
breakthrough cancer pain who agree to participate in the study.  
- 
The characterisation of breakthrough pain in patients with cancer pain will be 
carried out using the information collected in the tools used for the clinical 
assessment of the breakthrough pain:  
o Alberta Breakthrough Pain Tool 
o BPI questionnaire and  
o Numerical Rating Scale for the assessment of pain intensity 
- 
To assess the quality of life of patients with cancer pain, we will use:  
o SF-12 Questionnaire 

CARPE-DIO 
Observational/Non-Interventional 
Study Protocol 
 
 
 
Page 31 of 56 
 
 
o Karnofsky performance status 
 
8 
Safety Reporting 
 
8.1 Definitions 
 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with 
this treatment. An adverse event can therefore be any unfavourable and unintended sign 
(e.g. an abnormal laboratory finding), symptom, a new disease or worsening in severity or 
frequency of a concomitant disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
Adverse Drug Reaction  
An ADR is any response to a medicinal product which is noxious and unintended and which 
occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of diseases 
or for the restoration, correction or modification of physiological function.  
Response in this context means that a causal relationship between a medicinal product and 
an adverse event is at least a reasonable possibility. 
Adverse reaction also includes adverse clinical consequences associated with use of the 
product outside the terms of the Summary of Product Characteristics or other conditions laid 
down for the marketing and use of the product (including prescribed doses higher than those 
recommended, overdoses or abuse).  
 
8.2 Classifications 
Seriousness 
A serious ADR or AE (SADR/SAE) is any ADR or AE which results in death, is life 
threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, 
results in persistent or significant disability or incapacity, or is a congenital anomaly or birth 
defect. 

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Life-threatening in this context refers to a reaction/event in which the subject was at risk of 
death at the time of the reaction/event. It does not refer to a reaction/event that 
hypothetically might have caused death if more severe 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalisation but might jeopardise the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, 
or development of dependency or abuse.  
Any suspected transmission of an infectious agent via a medicinal product is considered a 
serious adverse reaction. 
 
Severity  
Severity is a clinical observation and describes the intensity of the event. 
 
Mild: 
 
Transient symptoms, no interference with the subject’s daily activities 
 
Moderate: 
Marked symptoms, moderate interference with the subject’s daily activities 
 
Severe: 
Considerable interference with the subject’s daily activities. 
 
Causality  
 
Related: 
A reasonable temporal relationsship between the medicinal product 
administration and the event where there is no other obvious explanation 
for the occurrence of the event 
 
Not related: There is evidence for (an) alternative explanation(s) for the event (e.g. the 
event is explained by one or more of the following: a) the subject’s medical 
condition (medical history, disease progress, indication), b) a concomitant 
medication for which the event is labelled, or c) AE occurrence prior to the 
introduction of the medicinal product. 
 
Outcome  
 
Fatal:  
The subject died due to the event. If the subject died due to other 
circumstances than the event the outcome should be stated as ‘Not 
recovered’ or ‘Recovering’ 

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The Study Site Responsible must sign off the complete data set for each subject, confirming 
the collected data. ADR data reported according to section 7 and data on serious AE/ADR 
reactions collected according to section 6 should be signed off separately by a physician 
who may or may not be involved in the study.  
 
9.5 Methods for obtaining data. 
This study entails the cross-sectional collection of data over one month at each participating 
site. Given the observational nature of the study, the data will be obtained in a single visit 
from patients’ medical history and/or from the patient using the tools detailed above and in 
accordance with the physician’s normal clinical practice. 
 
The presence of breakthrough pain and its characterisation will be assessed using the 
questionnaires detailed in section H4 of the protocol in those patients who agree to 
participate in the study by signing the informed consent. 
 
9.6 Data handling. 
In order to guarantee the confidentiality of the study data, only the following persons and 
entities will have access thereto: the investigator and his/her staff, the sponsor or a person 
designated by the sponsor, the IEC, the relevant healthcare authorities and the persons 
responsible for analysing the data. 
 
The content of the CRFs, as well as the documents generated during the study, will be 
protected against non-permitted use by persons not involved in the investigation and will 
therefore be considered strictly confidential and will not be revealed to third parties. 
The investigator must make sure to maintain patients’ anonymity and protect their identity 
from unauthorised parties. Patients will not be identified by name on the CRFs, but by an 
identification code. The investigator must keep a record of patient recruitment, including the 
codes assigned for participation in the study. 
 
The investigator will organise the safeguarding of the study documentation until the end of 
the study. He/she must also comply with the local standards/recommendations regarding the 
safeguarding of patients’ records. 
 

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The processing of data of a personal nature required for this study is subject to Organic Law 
15/1999 of 13 December on Personal Data Protection. 
 
10 Statistical Methods and Determination of Sample Size 
This section describes the statistical analyses as foreseen at the time of planning the study. 
Any known deviations from the planned analyses, the reason for such deviations and all 
alternative / additional statistical analyses that may be performed as well as the final 
statistical analysis must be described in a revised Statistical Analysis Plan (SAP) before 
completion of data collection.  
 
 
10.1 Statistical Analysis Plan 
This study is observational and epidemiological methods will be employed for data analyses. 
 
Descriptive analysis will be performed of all collected data except data collected only for the 
purpose of data cleaning. 
 
For a period of one month, each investigator must identify patients with cancer pain being 
treated with opioids who attend consultations in in Medical Oncology, Hematology, 
Radiotherapeutic Oncology Departments, Pain Units and Palliative Care Units, using the 
Davies diagnostic algorithm [3] to confirm the presence of breakthrough pain. All patients 
who attend pain consultations with cancer pain during this period will be used to determine 
the incidence/prevalence of breakthrough pain.  
 
All patients who meet the selection criteria and have given their informed consent will be 
included in the breakthrough pain characterisation and quality of life study. 
 
Before beginning the statistical analysis of the data, a Statistical Analysis Plan will be 
prepared, detailing all the analyses to be performed. 
 
The incidence/prevalence of breakthrough pain and corresponding 95% confidence interval 
will be calculated as the percentage of subjects presenting breakthrough pain among 
patients with cancer pain controlled with opioids, collected by each investigator on the 
corresponding page of the CRF over one month. This incidence/prevalence will also be 

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Page 38 of 56 
 
 
calculated by age group and sex. It will also be made an analysis by specialty to see the 
difference between the various participating specialties. 
 
The incidence/prevalence of breakthrough pain and corresponding 95% confidence interval 
will also be calculated relative to the number or cancer patients, collected by each 
investigator on the corresponding page of the CRF over one month.  
 
Given the descriptive nature of the study, the statistical methodology used will be based 
primarily on an exploratory analysis of the data through the calculation of descriptive 
parameters. 
 
Initially, a descriptive analysis of the study variables will be carried out and the values of the 
continuous variables will be summarised in a table showing the mean, median, standard 
deviation and maximum-minimum range for each. The categorical variables will be 
presented as absolute frequencies and percentages.  
 
The assessment of breakthrough pain intensity will be performed using the scores obtained 
on the numerical rating scale. A description of the scores will be given using the mean, 
median, standard deviation, maximum and minimum.  
 
Each of the items on the BPI questionnaire and Alberta scale will be described, using the 
mean, median, standard deviation and range to describe the continuous variables and 
frequency distributions and percentages to describe the categorical variables. 
 
The SF-12 quality of life scale consists of 12 items, from which total scores for the physical 
and psychological components are obtained. The correction methods indicated in the scale’s 
validation manual will be used for the total score for each sub-scale, and the mean, median, 
standard deviation and range will be presented.  
 
Breakthrough pain in patients with cancer pain will be characterised based on aetiology and 
pathogenesis, as well as other clinical characteristics (type of breakthrough pain, number of 
episodes per day, duration and intensity, and pain management). This information will be 
collected with the tools used for the clinical assessment of breakthrough pain.  
 

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Given the special characteristics of the elderly population and patients with multiple 
myeloma, a sub-analysis of pain characterisation will be performed in patients over 70 years 
of age and in those with multiple myeloma. 
 
The percentage of patients who present the various profiles/types of breakthrough cancer 
pain (characterisation/classification) and the causes for the same will be determined.  
 
The percentage of patients with the various profiles/types of breakthrough cancer pain will 
be given based on demographic characteristics and other clinically significant variables 
relating to the cancer diagnosis (tumour type, stage, etc.), pain intensity, comorbidities, etc. 
The quality of life of patients with cancer breakthrough pain will be analysed based on its 
possible relationship with demographic characteristics and other clinically significant 
variables related to the cancer or to the breakthrough pain such as aetiology, frequency of 
episodes, pain intensity, time until peak of pain, crisis duration, cause, etc.  
 
10.2 Interim Analyses 
No interim analyses are planned for this study.  
 
10.3 Determination of Sample Size 
We estimate that more than 10 patients per day attend consultations for cancer in Medical 
Oncology, Radiotherapeutic Oncology, Hematology and Palliative Care Departments and 
around 5 patients in Pain Units, and each site shall have a recruitment period of 1 month. 
Cancer breakthrough pain is a common and incapacitating subtype of pain that affects a 
percentage of patients with cancer that varies between 40% and 90% according to different 
publications [1, 2]. Conservatively, we hope to detect the prevalence in 50% of patients, and 
we estimate that at each site a total of approximately 200 patients, or around 13,200 across 
the 66 planned sites, will be interviewed on the prevalence of breakthrough pain. This 
sample will enable us to detect the prevalence of breakthrough pain with a 95% confidence 
interval and precision of ±1%. 
 
For the assessment of the secondary objective, i.e., characterising the breakthrough pain 
based on aetiology, underlying pathology and other clinical characteristics (type of 
breakthrough pain, number of episodes per day, duration and intensity, comorbidities and 
baseline pain management), if we consider the detection of common characteristics in at 

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Page 40 of 56 
 
 
least 10% of patients in our population to be representative, it will be necessary to recruit 
529 patients in order to detect said characteristics with a 95% confidence interval and 
precision of ± 2.5%.  
 
All patients recruited for characterisation of breakthrough cancer pain will be newly 
diagnosed and previously untreated for breakthrough cancer pain, although patients may be 
recruited who have been treated for breakthrough cancer pain in the past but are not 
currently being treated (at least 1 month wash-out) to avoid possible distortions in the 
classification of pain that may result from treatment.  
 
Patients eligible to participate in the study must meet all the selection criteria, have a 
confirmed diagnosis of breakthrough cancer pain based on the Davies algorithm and must 
have given their informed consent in writing. 
 
11 Reports 
A Non-Interventional Study Report based on the results obtained will be prepared and 
submitted to Global Research for distribution. The Final Study Report should be available 
within one year from collection of the last data point, and the participating sites should be 
informed about the results when the report is finalised. 
 
The definitive closure of this study will occur once all the data of the last patient included in 
the study has been completed. After closing the database, the statistical analysis shall be 
carried out and a report submitted, that will be reviewed and approved by the study sponsor 
and coordinating investigator.  
 
In accordance with current legislation, a copy of the final report shall be submitted to the 
IECs that have authorised the study, the competent bodies in the autonomous communities 
where the study is conducted and the AEMPS.  
 
 
12 Publications 
Takeda aims to have the results of this study published. 
 

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Takeda has the right to use the data and results for regulatory purposes and for internal 
presentation within the company and to partners. 
 
All information relating to the study is considered confidential and the property of the sponsor 
until its publication. It may not be revealed to others without the prior written consent of the 
sponsor and may not be used for any reason other than for the execution of this study.  
 
Only the sponsor or its representatives may extend the information obtained in this study to 
physicians and regulatory bodies, unless this is demanded by means of an order. 
 
The results of this study will be published in scientific journals and/or presented at 
conferences. 
 
The final decision to publish any article/abstract/presentation shall be made by the sponsor. 
 
13 Archiving of Study Documentation 
During the course of the study the Site Responsible must as a minimum file the essential 
documents (Section 3.5), the protocol, any amendments, the list of participating subjects, the 
written informed consents, the CRFs and the progress reports in the Study Site File. After 
final database lock the Site Responsible must as a minimum store the list of participating 
subjects and the signed Informed Consent Forms on site for 5 years. The Site Responsible 
should store additional study documentation for a longer period of time as required by any 
local regulations and/or hospital requirement. 
 
 
 

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14 References 
 
1. Mercadante S, Radbruch L, Caraceni A, Cherny N, Kaasa S, Nauck F, Ripamonti C, De 
Conno F. Episodic (breakthrough) pain: Consensus Conference of an Expert Working 
Group of the European Association for Palliative Care. Cancer. 2002;94:832–839 
2. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough 
pain in cancer patients admitted to a hospice. J Pain Symptom Manage. 2000;20:87–92 
3. Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-
related breakthrough pain: recommendations of a task group of the Science Committee 
of the Association for Palliative Medicine of Great Britain and Ireland. E J Pain 
2009;13:331e338 
4. Sunil XR, Thronaes M, Brunelli C, Hjermstad MJ, Klepstad P, Kaasa S. A cross-sectional 
study on prevalence of pain and breakthrough pain among an unselected group of 
outpatients in a tertiary cancer clinic. Support Care Cancer. 2014;22:1965-1971 
5. Barbera L, Seow H, Howell D, Sutradhar R, Earle C, Liu Y, Stitt A, Husain A, Sussman J, 
Dudgeon D. Symptom burden and performance status in a population-based cohort of 
ambulatory cancer patients. Cancer. 2010;116:5767–5776 
6. Cleeland CS. Measurement of pain by subjective report. In: Chapman CR, Loeser JD 
(eds) Advances in pain research and therapy. Raven, New York, 1989;391–403 
7. O’Connor M, Weir J, Butcher I, Kleiboer A, Murray G, Sharma N, Thekkumpurath P, 
Walker J, Fallon M, Storey DJ, Sharpe M. Pain in patients attending a specialist cancer 
service: prevalence and association with emotional distress. J Pain Symptom Manage. 
2011;43(1): 29–38 
8. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. 
Pain. 1990;41:273–281 
9. Zucco F, Bonezzi C, Fornasari D. Breakthrough cáncer pain (Breakthrough Cancer 
Pain): a synthesis of taxonomy, pathogenesis, therapy, and good clinical practice in adult 
patients in italy. Adv Ther. 2014;31:657-682 
10. Virizuela JA, Escobar Y, Cassinello J, Borrega P; SEOM (Spanish Society of Clinical 
Oncology) (2012) Treatment of cancer pain: Spanish Society of Medical Oncology 
(SEOM) recommendations for clinical practice. Clin Transl Oncol 14: 499-504. 

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11. Porta-Sales J, Pérez C, Escobar Y, Martínez V. Diagnosis and management of 
breakthrough cancer pain: Have all the questions been resolved? A Delphi-based 
consensus assessment (DOIRON). Clin Transl Oncol. 2015 Dec 22 
12. Escobar Y, Mañas A, Juliá J, Gálvez R, Zaragozá F, Margarit C, López R, Casas A, 
Antón A, Cruz JJ.  Clin Transl Oncol. 2013 Jul;15(7):526-34. D 
13. Margarit C, Juliá J, López R, Anton A, Escobar Y, Casas A, Cruz JJ, Galvez R, Mañas A, 
Zaragozá F.  Breakthrough cancer pain - still a challenge. J Pain Res. 2012;5:559-66.  
14. Payne R. Recognition and diagnosis of breakthrough pain. Pain Med. 2007;8(Suppl 
1):S3–S7 
15. Portenoy RK, Bruns D, Shoemaker B, Shoemaker SA. Breakthrough pain in community-
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