PROSPECTIVE, MULTICENTRE, OBSERVATIONAL STUDY ON FATIGUE- AND HAND-FOOT SYNDROME-RELATED QUALITY OF LIFE IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA RECEIVING A TYROSINE KINASE INHIBITOR AS FIRST-LINE TREATMENT (TROYA STUDY).
Conditions: Metastatic Renal Cell Carcinoma
Sponsor: Pfizer

 
TROYA study A6181218 NON-INTERVENTIONAL STUDY PROTOCOL 
Version 28 October 2015  
 
 
 
Pfizer Confidential 
 
Page 1 of 56 
 
 
 
 
 
 
Prospective, multicentre, observational study on fatigue- and hand-foot 
syndrome-related quality of life in patients with metastatic renal cell 
carcinoma receiving a tyrosine kinase inhibitor as first-line treatment 
(TROYA Study) 
 
 
NON-INTERVENTIONAL (NI) STUDY PROTOCOL  
 

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CONTENTS 
CONTENTS .....................................................................................................................................3 
1. LIST OF ABBREVIATIONS ......................................................................................................5 
2. PERSONS RESPONSIBLE FOR THE STUDY .........................................................................7 
3. ABSTRACT .................................................................................................................................7 
3.1.1. Inclusion Criteria ..............................................................................................10 
3.1.2. Exclusion Criteria .............................................................................................10 
4. MILESTONES ...........................................................................................................................12 
5. STUDY RATIONALE ..............................................................................................................13 
6. OBJECTIVES ............................................................................................................................16 
7. METHODS OF INVESTIGATION ..........................................................................................16 
7.1. Study design ..................................................................................................................16 
7.2. Scope .............................................................................................................................17 
7.2.1. Inclusion Criteria ..............................................................................................18 
7.2.2. Exclusion Criteria .............................................................................................18 
7.3. Variables ........................................................................................................................19 
7.4. Source documents .........................................................................................................20 
7.5. Sample size (statistics) ..................................................................................................20 
7.6. Data processing (statistics) ............................................................................................21 
7.7. Data analysis (statistics) ................................................................................................21 
7.8. Quality control ...............................................................................................................22 
7.9. Limitations of the research methods .............................................................................22 
7.10. Further aspects .............................................................................................................23 
8. PROTECTION OF STUDY SUBJECTS ..................................................................................23 
8.1. Patient information and consent ....................................................................................23 
8.2. Withdrawal of patients ..................................................................................................23 
8.3. IEC ................................................................................................................................24 
8.4. Ethical considerations of the study ................................................................................24 
8.5. Interference with the physician's prescribing habits .....................................................24 
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/REACTIONS ....................25 
9.1. Single reference safety document..................................................................................33 

 
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10. PUBLICATION OF RESULTS ..............................................................................................34 
11. REFERENCES ........................................................................................................................35 
12. LIST OF TABLES ...................................................................................................................36 
13. LIST OF CHARTS ..................................................................................................................36 
ANNEX 1. LIST OF INDEPENDENT DOCUMENTS ...............................................................37 
ANNEX 2. CASE REPORT FORM ..............................................................................................38 
ANNEX 3: COORDINATING INVESTIGATOR’S STATEMENT ...........................................39 
ANNEX 4. IEC APPROVAL ........................................................................................................39 
ANNEX 5. PATIENT INFORMATION SHEET AND INFORMED CONSENT FORM ..........40 
ANNEX 6: SCHEDULE OF STUDY PAYMENTS ....................................................................49 
ANNEX 7: LIST OF SITES, LIST OF INVESTIGATORS AND CONTACT 
INFORMATION ..................................................................................................................50 
ANNEX 8: FACIT-FATIGUE QUALITY OF LIFE QUESTIONNAIRE ...................................51 
ANNEX 9. QUALITY OF LIFE - HAND-FOOT SYNDROME .................................................52 
ANNEX 10. SERIOUS ADVERSE EVENT REPORT FORM ....................................................53 
ANNEX 11. SUMMARY OF PRODUCT CHARACTERISTICS FOR SUTENT, 
VOTRIENT, NEXAVAR ....................................................................................................56 
 
 

 
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1. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AEM 
Adverse event monitoring 
AEMPS 
Agencia Española de Medicamentos y Productos Sanitarios (Spanish Agency 
of Medicines and Medical Devices) 
AR 
Autonomous Regions 
AUC 
Area Under the Curve 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
version 4 
Common Terminology Criteria (Common Terminology Criteria for Adverse 
Events, version 4) of the U.S. Department of Health and Human Services 
CVA 
Cerebrovascular Accident 
DMP 
Data management plan 
DOR 
Duration of response 
DP 
Disease Progression 
ECOG 
Eastern Cooperative Oncology Group. Scale to measure the quality of life of 
oncology patients with scores running from 0 to 5 
eCRF 
Electronic Case Report Form 
EDP 
Exposure during pregnancy 
FDA 
Food & Drug Administration 
GCP 
Good Clinical Practice 
HFS 
Hand-Foot Syndrome 
IC 
Informed Consent 

 
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ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
mRCC 
Metastatic Renal Cell Carcinoma 
NIS 
Non-interventional study 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PR 
Partial Response 
RCC 
Renal cell carcinoma 
SAE 
Serious Adverse Event 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SRSD 
Single reference safety document 
TKI 
Tyrosine kinase inhibitor 
TT 
Treatment Time 
TTF 
Time to Treatment Failure 
 
 
 

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STUDY OBJECTIVES 
 
PRIMARY OBJECTIVE 
Fatigue-related quality of life of patients receiving a tyrosine kinase inhibitor evaluated using the 
validated 13-item FACIT-Fatigue scale for patients with metastatic renal cancer in Spanish.1,2 
 
SECONDARY OBJECTIVES 
 
1) Quality of life in patients with palmar-plantar erythrodysaesthesia (hand-foot syndrome).  
 
2) To assess the following adverse effects according to version 4 of the CTCAE (Common 
Terminology Criteria for Adverse Events): any grade of fatigue and hand-foot syndrome 
(HFS).  
 
3) To study what role aerobic exercise (walking quickly, running, swimming, playing 
tennis, dancing and/or riding a bike) plays in the onset of fatigue before starting and 
during treatment. 
 
4) To evaluate what impact the time of drug administration, napping, off-treatment periods, 
temporary treatment breaks and dose reductions have on controlling fatigue and hand-
foot syndrome.  
 
5) Time to Treatment Failure (TTF), defined as the time from the start of treatment with a 
tyrosine kinase inhibitor to tumour progression, treatment discontinuation for any reason 
or death from any cause. 
 
6) Progression-Free Survival (PFS) (median): time from the start of treatment with a 
tyrosine kinase inhibitor to tumour progression or death from any cause. 
 
7) Objective Response Rate according to RECIST version 1.1. 
 
DESIGN 
 
Prospective, multicentre, observational, post-authorisation study in patients aged ≥ 18 years 
diagnosed with metastatic renal cell carcinoma who are to be given a tyrosine kinase inhibitor as 
first-line treatment. 
This is a non-interventional study and therefore the decision to prescribe any treatment will be 
made prior to and independently of the patient's participation in the study; i.e. patients will 
receive the same medication whether they participate in the study or not according to the clinical 
judgement and normal clinical practice of the doctor responsible for the patient. Moreover, no 
additional tests are to be performed as part of the study. 
 
 
 

 
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STUDY CONDITION 
Metastatic renal cell carcinoma. 
 
STUDY POPULATION AND TOTAL NUMBER OF SUBJECTS 
 
A population of 100 patients aged 18 years or over and diagnosed with metastatic renal cell 
carcinoma who are to start first-line treatment with a tyrosine kinase inhibitor according to 
routine clinical practice is to be studied at 35 Spanish sites. 
 
INCLUSION AND EXCLUSION CRITERIA 
 
3.1.1. Inclusion Criteria 
The patients must meet all the inclusion criteria to participate in the study: 
 
1) Patients ≥ 18 years old and diagnosed with metastatic RCC who, in the investigator's 
opinion, are candidates for starting first-line treatment with a tyrosine kinase inhibitor according 
to routine clinical practice.  
2) Patients who have no contraindications to the treatment. 
3) Baseline ECOG ≤ 2.  
4) Patients who are able to give informed consent on their own without the need for a 
legal representative. 
5) Committed patients who are able to complete the quality of life questionnaires and 
patient diary on their own without the need for a legal representative. 
 
3.1.2. Exclusion Criteria 
Patients must not meet any of the exclusion criteria described below. 
 
1) Patients who are not candidates for first-line treatment with a tyrosine kinase inhibitor. 
2) Patients who are receiving the treatment as second-line or subsequent therapy. 
3) Untreated hypothyroidism. 
4) Untreated severe anaemia. 
5) Pregnancy or breast-feeding. 
6) Myocardial infarction or cerebrovascular accidents (CVA) within the last 6 months. 
7) Severe hepatic impairment. 
8) Concomitant use of potent inhibitors or inducers that interact with hepatic cytochrome 
CYP3A4. 
 
QUALITY OF LIFE: 
 
1) Fatigue-related quality of life of patients evaluated using the validated 13-item FACIT- 
Fatigue scale for patients with kidney cancer in Spanish. Company FACIT.ORG (USA) 
(ANNEX 8). 

 
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2) Quality of life in patients with palmar-plantar erythrodysaesthesia (hand-foot syndrome). 
To be evaluated according to CTCAE Version 4.0 Published: May 28, 2009 (v4.03: June 
14, 2010) with scores running from 1 to 3 (see ANNEX 9).  
 
SCHEDULE 
 
Date of submission to AEMPS for classification: October 2015 
Proposed date of submission to the IEC: November 2015 
Proposed date of inclusion of the first patient in the study: February 2016 
Proposed end-of-recruitment date: August 2017 or after recruiting 100 patients, whichever 
occurs first. 
Recruitment period: 18 months. 
Proposed date of the end of data collection: May 2018 or whenever the last patient passes to the 
2nd line of treatment, whichever occurs first.  
 
Expected date of Interim study report: After completing the 9 months of fatigue-related quality 
of life follow-up in all patients, estimated July 2018.  
Expected date of Final study report: October 2018 
 
 
SOURCE OF FUNDING 
 
Pfizer SLU, as sponsor of the study, will provide financial compensation to the participating 
sites/investigators. Such compensation will be explicit and transparent, without prejudice to the 
internal rules of their employing agencies and in accordance with specific regulations in the ARs 
and at the sites where the study is conducted. 
Fees are to fund the collection and transcription of clinical and epidemiological data from 
patients and the quality of life questionnaires to the case report forms.  
 
 AMENDMENTS AND UPDATES 
 
None 
Amendment 
No. 
Date 
Substantial or 
administrative 
amendment 
Amended 
protocol 
section(s) 
Summary of 
change(s) 
Reason 
 
 
 
 
 
 
 

 
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4. MILESTONES 
 
Milestone 
Proposed date 
Start of data collection  
Proposed date of the first patient's first visit, FSFV 
February 2016 
End of data collection  
Proposed date of the last patient's last visit, LSLV 
May 2018 
Interim study report  
Proposed date of drafting (or remittance) of Interim report  
July 2018  
Final study report 
Proposed date of drafting (or remittance) of Final report  
October 2018 
 

 
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5. STUDY RATIONALE 
BACKGROUND 
Over recent years, a better understanding of the molecular biology of renal cell cancer (RCC) has 
led to an unprecedented development of therapies for this disease. As a result, various targeted 
agents have been approved and used for the management of RCC that have led to an 
improvement in both the progression-free survival (PFS) and overall survival (OS) of patients 
diagnosed with this disease.3 
 
Among these new agents, sunitinib, pazopanib and sorafenib are drugs that are recommended in 
all guidelines for the first-line treatment of RCC. Sunitinib is the targeted agent most widely used 
in routine clinical practice today. Sunitinib and sorafenib are oral tyrosine kinase inhibitors that 
inhibit vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2 and VEGFR-3), 
platelet-derived growth factor receptors (PDGFR), c-Kit, RET and FLT3. Pazopanib is an oral 
tyrosine kinase receptor inhibitor that inhibits vascular endothelial growth factor receptors, 
platelet-derived growth factor receptors (PDGFR) and c-Kit. 
 
Sunitinib has been approved for the management of patients diagnosed with metastatic RCC 
(mRCC) based on the results of the randomised, controlled, double-blind, phase III study4 
comparing sunitinib with interferon alpha as first-line treatment for 750 patients with mRCC. 
The study showed significant improvement in the efficacy of sunitinib compared with interferon 
with a median PFS (primary endpoint of the study) of 11 months vs. 5 months (p < 0.001) for the 
sunitinib and interferon arms, respectively. 
 
Pazopanib has been approved for patients diagnosed with mRCC based on data from a 
randomised, multicentre, double-blind, placebo-controlled study that included 435 patients with 
advanced and/or metastatic RCC who had not received previous treatment, or who had received 
first-line treatment with IL-2 or interferon alpha. PFS was 9.2 months for the pazopanib group 
versus 4.2 months for the placebo group (< 0.0000001).10 
 
Sorafenib was initially approved for the treatment of mRCC in patients with advanced renal cell 
carcinoma in whom previous therapy with interferon alpha or interleukin-2 had failed or who 
were considered unsuitable for such therapy based on the results of a randomised, multicentre, 
double-blind, placebo-controlled, phase III trial involving 903 patients. The median PFS was 167 
days in patients randomised to sorafenib compared to 84 days in patients receiving placebo (p < 
0.000001). Currently, as a result of the approval of new drugs for the treatment of mRCC, its use 
in the first-line setting (approval for patients who are not candidates for cytokine therapy) is not 
very common and it is more habitually used as second-line or subsequent therapy.11 
 
With most drugs used for the treatment of mRCC, data indicate the importance of maintaining 
dose intensity, since it is correlated with response and survival. This is shown, for example, in a 
meta-analysis of 6 studies including a total of 443 patients with pharmacokinetic data diagnosed 
with mRCC and treated with sunitinib. This meta-analysis demonstrated that increased exposure 

 
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to sunitinib, reflected by a greater area under the curve (AUC), was associated with improved 
PFS, improved OS and a higher response rate.5 A relationship has also been found between 
exposure to pazopanib and efficacy.6 
 
In the pivotal phase III clinical trial involving sunitinib, 19% of patients discontinued treatment 
due to side effects and 38% of patients had to temporarily interrupt treatment, while 50% of 
patients had to reduce the standard dose in order to control adverse effects.7,8 In fact, temporary 
dose interruptions are one strategy contemplated in the summary of product characteristics for 
this medicinal product.  
The most common grade 3-4 toxicity was hypertension (12%), followed by fatigue (11%), 
diarrhoea (9%) and HFS (9%).4,7 
 
In the sunitinib expanded access programme, 8% of patients discontinued treatment due to 
serious adverse effects while 30% required dose reductions due to toxicity.9 
 
Pazopanib: 19% of cytokine-pretreated patients discontinued treatment versus 12% of treatment-
naive patients.10 
 
10% of patients being treated with sorafenib stopped treatment due to side effects in the pivotal 
trial.11 
 
Although the therapeutic goal in the treatment of metastatic renal cell carcinoma is to prolong the 
survival of patients, it is equally important to keep treatment-related toxicities as low as possible 
in order to achieve patient adherence to treatment, thereby maximising dose intensity, which is 
the determining factor for obtaining better results in the long term. The high incidence of dose 
reduction and treatment interruptions due to adverse effects could lead to decreased plasma drug 
exposure and reduced clinical benefit.5,6 The drug's tolerability may be a barrier when it comes to 
maximising the potential efficacy of therapy. 
 
Therefore, maintaining the dose is a challenge, with side effects such as fatigue, diarrhoea, hand-
foot syndrome or hypertension. In fact, fatigue and diarrhoea are the most worrying symptoms 
when questioning patients,12 to such an extent that 50-75% of patients receiving treatment 
complains about some degree of asthenia, although only 7-11% of cases interfere with the 
activities of daily living. 
 
In studies, TKI-related fatigue is highly variable in both degree and duration, although it is 
generally mild to moderate.13 In the case of sunitinib, this is especially significant since this is a 
drug that is administered intermittently. Fatigue typically occurs 2-3 weeks after the start of 
treatment, increases in intensity during weeks 3 and 4, and tends to improve during the 2-week 
off-treatment period, during which patients are comparatively better than during on-treatment 
weeks. This has resulted in the use of alternate sunitinib scheduling in clinical practice in order 
to improve tolerability and maintain effective dose intensity, with the schedule of 14 days on and 
7 days off being the most commonly used (2/1 schedule). Results based on the use of these 
schedules by different groups have recently been published (retrospective analyses).14,15 The 
European Association of Urology Guidelines16 on Renal Cell Carcinoma 2015 describe the 

 
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schedule of 2 weeks on and 1 week off treatment for the management of toxicity in patients 
being treated with sunitinib. 
 
It is not clear what percentage of fatigue is cancer-related and what percentage is attributable to 
the tyrosine kinase inhibitor as both types of fatigue are very similar and often coexist. The 
mechanisms of fatigue are not well described. Changes at muscle level can cause peripheral 
fatigue, whereas central nervous system failure to activate the motor neurons adequately would 
cause central fatigue. 
 
Fatigue is more common in men, particularly in young men, resulting in repeated treatment 
interruptions.   However, fatigue tends to decrease with increasing treatment cycles. Whether this 
phenomenon represents an adaptation and/or learning by the patient or a true lower incidence is 
unknown. 
 
It is important to rule out other causes that may cause or exacerbate fatigue, such as dehydration, 
hypothyroidism, hypercalcaemia, anaemia or depression. These adverse effects must be 
monitored every 2-3 cycles.13 
 
In the phase I study published by Faivre,17 asthenia was associated with an increase in daytime 
napping and night-time somnolence. Age and baseline status (ECOG) at the start of the study did 
not predict asthenia. 
 
Patient education is crucial. It is necessary to explain that this adverse effect will quite probably 
appear and we have strategies to manage it if it occurs.  
It is interesting to see fatigue in the context of the disease and to readjust the patient's 
expectations, explaining that it will be necessary to adapt his/her everyday activities to save 
energy.13 
 
 
Some authors recommend training with aerobic exercises for 30 minutes 3 times a week. 
Randomised clinical trials have demonstrated better responses in oncology patients using 
resistance training. It is important to take into account the patients' previous level of activity and 
cardiac output before recommending exercise. 
 
RATIONALE FOR THIS STUDY  
 
In view of the above, we believe it is appropriate to initiate a study to prospectively assess 
fatigue-related quality of life in patients with mRCC who are starting treatment with a tyrosine 
kinase inhibitor.  
The patients' quality of life will be evaluated using the FACIT-Fatigue questionnaire and a 
Patient Diary (both to be completed by the patient) every 6 weeks.  
 
To our knowledge, no fatigue-related quality of life studies in European patients with this 
condition have been published to date.  
 

 
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6. OBJECTIVES 
PRIMARY OBJECTIVE 
 
Fatigue-related quality of life of patients receiving a tyrosine kinase inhibitor evaluated using the 
validated 13-item FACIT-Fatigue scale for patients with metastatic renal cancer in Spanish.1,2 
 
SECONDARY OBJECTIVES 
 
1) Quality of life in patients with palmar-plantar erythrodysaesthesia (hand-foot syndrome).  
 
2) To assess the following adverse effects according to version 4 of the CTCAE (Common 
Terminology Criteria for Adverse Events): any grade of fatigue and HFS.  
 
3) To study what role aerobic exercise (walking quickly, running, swimming, playing 
tennis, dancing and/or riding a bike) plays in the onset of fatigue before starting and 
during treatment. 
 
4) To evaluate what impact the time of drug administration, napping, off-treatment periods, 
temporary treatment breaks and dose reductions have on controlling fatigue and hand-
foot syndrome.  
 
5) Time to Treatment Failure (TTF), defined as the time from the start of treatment with a 
tyrosine kinase inhibitor to tumour progression, treatment discontinuation for any reason 
or death from any cause. 
 
6) Progression-Free Survival (PFS) (median): time from the start of treatment with a 
tyrosine kinase inhibitor to tumour progression or death from any cause. 
 
7) Objective Response Rate according to RECIST version 1.1. 
 
7. METHODS OF INVESTIGATION 
7.1. Study design  
Prospective, multicentre, observational, post-authorisation study in patients aged ≥ 18 years 
diagnosed with metastatic renal cell carcinoma who are to be given a tyrosine kinase inhibitor as 
first-line treatment. 
 
The study will evaluate measures to improve patients' quality of life, such as time of drug 
administration, napping, temporary treatment breaks and dose reductions.  
 
Fatigue-related quality of life will be evaluated using the Spanish version of the FACIT–Fatigue 
Questionnaire, which will be completed by the patient individually after having been explained 
by the clinician or a person appointed by the investigator (nursing staff, clinical trial coordinator) 

 
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in the treatment room or another room during the scheduled visits, once the patient understands 
how to complete the form. 
 
The FACIT–Fatigue questionnaire will be handed out together with the patient diary at the 
following treatment times, which coincide with the visits, according to the department's protocol: 
 
1) Baseline (before starting the treatment) 
2) Month 3 
3) Month 6  
4) Month 9 or upon treatment discontinuation 
5) Additional visits according to the oncology department's clinical practice: additional 
visits may be recorded on the case report form (e.g. at 15 days)  
 
The patient will also complete this FACIT-Fatigue questionnaire at home at the start of each 
cycle (for sorafenib and pazopanib a cycle will be 6 weeks of treatment), even if this does not 
coincide with scheduled visits to the hospital. 
 
The hand-foot syndrome-related quality of life evaluation that patients may be asked to take 
part in will be performed on the basis of the CTCAE V4.03 2010 with scores running from 1 to 3 
(see ANNEX 9).  
 
7.2. Scope 
The study will start at each site after the contract has been signed by all parties and all 
documentation and information on the procedures and objectives of the study have been received 
by the person appointed by the sponsor. 
 
Recruitment will be competitive between all the participating sites (estimating between 1 and 4 
patients per site) and will finish once 100 patients have been recruited.  
 
The investigator will be guided by routine clinical practice at all times when making decisions 
regarding the best available treatment option for the patient.  
 
At the Baseline Visit, patients will sign the informed consent form and their participation in the 
TROYA study will be recorded in their medical records. 
 
There should be evidence of a signed and personally dated informed consent document 
indicating that the patient (or his/her legal representative) has been informed of all aspects of the 
study and the patient information sheet, with a record being made in the patient's medical 
records that the patient received a copy.  
All patients who are about to start first-line treatment with a tyrosine kinase inhibitor and who 
meet all the inclusion criteria and no exclusion criterion are candidates for this study. 
 
The information requested at all of the study visits will be recorded on the electronic CRF (Case 
Report Form) attached in Annex 2. 

 
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Different aspects for improving the quality of life of patients, such as drug administration time, 
weekly mild-moderate aerobic exercise and napping, will be evaluated. For this purpose the 
patient will complete this information in a diary (Patient Diary).  
 
Other aspects, such as temporary treatment interruptions and dose reductions, will be recorded 
on the CRF at each visit.  
 
Quality of life will be evaluated at the Baseline visit, the 3 month visit (coinciding with the first 
control CT according to routine clinical practice), the 6 month visit (second CT) and the 9 month 
visit (third CT) using the validated Spanish version of the FACIT–Fatigue questionnaire. Other 
evaluations may also be conducted using this questionnaire at any additional visits scheduled for 
the patient according to the site's clinical practice. 
 
Each patient will complete the questionnaire after it has been explained by the clinician or a 
person appointed by the investigator (nursing staff, clinical trial coordinator). 
 
Any adverse events experienced by the patient will be recorded according to clinical practice, in 
compliance with the toxicity manuals of the National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.0. 
 
7.2.1. Inclusion Criteria 
The patients must meet all the inclusion criteria to participate in the study: 
 
1) Patients ≥ 18 years old and diagnosed with metastatic RCC who, in the investigator's 
opinion, are candidates for starting first-line treatment with a tyrosine kinase inhibitor according 
to routine clinical practice.  
2) Patients who have no contraindications to the treatment. 
3) Baseline ECOG ≤ 2.  
4) Patients who are able to give informed consent on their own without the need for a 
legal representative. 
5) Committed patients who are able to complete the quality of life questionnaires and 
patient diary on their own without the need for a legal representative. 
 
7.2.2. Exclusion Criteria 
Patients must not meet any of the exclusion criteria described below. 
 
1) Patients who are not candidates for first-line treatment with a tyrosine kinase inhibitor. 
2) Patients who are receiving the treatment as second-line or subsequent therapy. 
3) Untreated hypothyroidism. 
4) Untreated severe anaemia. 
5) Pregnancy or breast-feeding. 
6) Myocardial infarction or cerebrovascular accidents (CVA) within the last 6 months. 
7) Severe hepatic impairment. 

 
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8) Concomitant use of potent inhibitors or inducers of hepatic cytochrome CYP3A4. 
 
7.3. Variables 
The variables to be analysed for this study will be obtained from the patients' medical records, 
quality of life questionnaires and Patient Diaries in accordance with the protocol.  Data will be 
recorded on the electronic CRF design for this study (ANNEX 2). The following data will be 
included:  
 
DEMOGRAPHICS AND DISEASE INFORMATION 
1) Age at the baseline visit 
2) Gender 
3) ECOG at the time of diagnosis (0,1 2) 
4) Heng prognostic criteria 
5) Site of metastasis and number thereof  
6) Date on which the disease was diagnosed 
7) Date of diagnosis of advanced stage disease 
8) Type of histology  
 
LIFESTYLE 
 
1) Napping 
2) Aerobic exercise 
3) Smoking 
4) FACIT – Fatigue questionnaire score at the scheduled visits 
 
TREATMENT 
 
1) Time when the oral treatment is taken  
2) Tyrosine kinase inhibitor dose and treatment regimen  
3) Number of changes to dose and which cycle they occur in 
4) Temporary treatment interruptions, number of interruptions and which cycle they occur 
in  
5) Best response achieved with first-line treatment 
6) Mean duration of treatment 
7) Time to treatment failure 
8) How long each patient stays on first-line treatment / No. of cycles received 
9) Reason for discontinuing the first-line drug  
10) Date of disease progression and/or death  
 
Through the analysis of the collected variables the following aspects will be assessed:  
 
- Progression-Free Survival (PFS): defined as the interval from the start of treatment to the 
date of the first documentation of objective tumour progression or death from any cause.  
 

 
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- Objective Response Rate (ORR): defined as the proportion of subjects achieving either 
complete response (CR) or partial response (PR). In addition, subjects with stable disease 
(SD) will also be evaluated to obtain clinical benefit along with subjects with tumour 
progression. Subjects will be evaluated according to RECIST 1.1. 
 
- Duration of Response (DOR): in patients with PR or CR, it will be defined as the interval 
from the date response is documented to the first date that disease progression is observed. 
 
- Safety: the safety of the tyrosine kinase inhibitor will be evaluated by describing the 
incidence of serious adverse effects, side effects in the potential drug risk management plan 
(described in the table) and all grades if fatigue and/or hand-foot syndrome are present.  
 
- Fatigue-related quality of life of patients: this will be measured based on the results 
obtained after completion of the FACIT-Fatigue questionnaire by the patient.  
 
- HFS-related quality of life of patients in those cases where HFS is present with a score 
from 1 to 3 according to version 4 of the CTCAE (Common Terminology Criteria for 
Adverse Events). 
 
- Date of disease progression and/or death. 
 
7.4. Source documents  
The investigator will, at all times, be fully responsible for the accuracy and authenticity of all 
clinical and epidemiological data reported by the patient and included on the CRFs. 
The source documents will be the medical records of each patient and any tests performed in 
relation to the disease, plus all quality of life questionnaires and the Patient Diary. The 
investigator undertakes to safeguard these records together with the study documentation for 
review by the clinical monitor appointed.  
 
The information on the CRFs should be consistent with the data in the medical records. 
The sponsor will establish the monitoring plan. 
 
7.5. Sample size (statistics) 
Plans are to include 100 patients in the study to receive first-line treatment over the course of 18 
months at 35 sites.  
This is a descriptive study; therefore, a specific number of patients is not required to calculate the 
sample size. 
In order to study the fatigue-related quality of life of patients who are receiving a tyrosine kinase 
inhibitor, evaluated using the validated 13-item FACIT-Fatigue scale for patients with metastatic 
renal cancer on Spanish, the inclusion of 100 patients with metastatic renal carcinoma who are 
about to receive first-line treatment with a tyrosine kinase inhibitor and who meet the screening 
criteria of the study is proposed. 

 
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This sample size will allow us to estimate percentages of patients with fatigue (severe/non-
severe) during follow-up, with a 95% level of significance and an estimated replacement rate of 
10%, assuming a replacement rate of 5%. 
7.6. Data processing (statistics) 
The investigator will collect data from the recruited patients using an electronic Case Report 
Form specially designed for this study.  
The patient number we provide is a serial number devoid of any identifying value. 
The information is stored in an Access database, which is in turn associated with a file, 
"WorkGroup", detailing the user code and the investigator's permissions within the database. 
People not within this working group cannot access the database. 
A Data Management Plan (DMP) will be developed, and once approved by the person 
responsible for the study, "Queries" will be programmed in the electronic case report form so 
that when the investigator saves the data, he/she will be informed of any queries regarding the 
data. 
All changes made by the investigators during the collection of data will be stored in a table 
specially designed for this purpose, indicating the user, date, modified field, the old value and the 
new value. 
 
7.7. Data analysis (statistics) 
The fatigue-related quality of life of the patients and the quality of life of patients with palmar-
plantar erythrodysaesthesia (hand-foot syndrome) will be studied using the mean, standard 
deviation and confidence intervals if they follow normal distribution, or the median, minimum, 
maximum and interquartile range if they do not follow Gaussian distribution.  The Wilcoxon test 
will be used to analyse the inter-visit correlation for patients’ quality of life.  
The objective response rate according to RECIST version 1.1 will be studied using absolute and 
relative frequencies.  
 
In order to study the impact of drug administration time, napping, temporary treatment 
interruptions and dose reductions on fatigue and hand-foot syndrome control, independent 
samples will be compared using Pearson's chi-square test (or Fisher's exact test for 2x2 tables or 
likelihood ratio test for MxN tables, if necessary) in the case of qualitative variables and 
Student's t-test, one-way ANOVA test or non-parametric equivalents, such as the Mann-Whitney 
U test or Kruskal-Wallis H test in the case of quantitative variables.  
 
The Kaplan-Meier survival estimate will be used to study both the PFS and TTF of patients. The 
log-rank test will be used to compare survival estimates.  

 
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The assumptions of normality and homoscedasticity of the variables will be studied for the use of 
parametric tests. Estimates will be calculated with a 95% confidence level and the SPSS 
statistical analysis software package, V19.0 or later, will be used. 
 
7.8. Quality control 
As this is a post-authorisation study, the same procedures will be followed by the investigator as 
in routine clinical practice. 
However, the investigators are responsible for ensuring that the protocol and principles of Good 
Clinical Practice (GCP) are complied with. 
Study sites may be subject to face-to-face or remote monitoring by the person appointed by the 
sponsor (at least 20% of patients monitored face-to-face) and review by the Independent Ethics 
Committee (IEC) and/or quality assurance audits conducted by the relevant regulatory authorities 
and the study sponsor. 
Case Report Form/Electronic data collection 
The CRF is required and must be completed for each patient included. 
The investigator will be responsible for reviewing and approving the CRFs, for ensuring that 
they are completed and for ensuring that the patients complete the quality of life questionnaires 
and the Patient Diary.  
The investigator will, at all times, be fully responsible for the accuracy and authenticity of all 
clinical data included on the CRFs.  
Storing the records 
In order to allow monitoring of the study by the sponsor or assessments or audits by the 
regulatory authorities, the investigator agrees to keep records, including the identity of all 
participating patients (enough information to link the records, e.g. CRFs and hospital records), 
all original signed informed consent forms, copies of all serious adverse events forms and source 
documents. The records must be kept by the investigator in accordance with ICH guidelines or 
local regulations, or as specified in the contract, whichever is longer. 
7.9. Limitations of the research methods  
The Patient Diary will contain epidemiological data that cannot be confirmed by the Investigator, 
although guidelines will be provided during the initial visit to each site to standardise the 
collection of such data. 
PFS will be evaluated by each investigator in line with routine clinical practice with no 
centralised evaluation.   
 

 
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7.10. Further aspects 
Not applicable.  
8. PROTECTION OF STUDY SUBJECTS 
The study will be conducted according to routine clinical practice as described in the protocol, 
the International Conference on Harmonisation's Guideline for Good Clinical Practice and 
applicable local requirements and laws (Order SAS/3470/2009 of 16 December).   
 
8.1. Patient information and consent 
All parties will ensure that personal data are protected and will not include patients' names on 
any of the sponsor's forms, reports, publications or any other text for disclosure, unless so 
required by law. For data transfer, Pfizer will maintain a high level of confidentiality and 
protection of patients’ personal data. 
The informed consent form must comply with local legal and regulatory requirements. The 
informed consent form used in this study and any changes made during the course of the study 
must be prospectively approved by the IEC and by Pfizer prior to implementation. 
The investigator must ensure that each study patient or his/her legal representative is informed of 
the nature and objectives of the study and possible risks associated with his/her participation 
therein. The investigator, or a person appointed by the same, will obtain written informed 
consent from each patient or his/her legal representative before performing any study-specific 
procedure. The investigator will retain the original of each patient's signed informed consent 
form. 
The Patient Information Sheet and Informed Consent document must comply with ICH GCP, 
local administrative regulations and legal requirements. 
The informed consent form used in the study and all amendments must be approved by the 
independent ethics committee prior to use. The investigator will keep the original consent 
documents signed by subjects. 
8.2. Withdrawal of patients 
Patients may leave the trial at any time voluntarily or they may be withdrawn at the discretion of 
the investigator or the sponsor for safety, behaviour or administrative reasons. In any event, 
every effort should be made to document the results of any such patient. The investigator should 
inquire about the reason for the withdrawal and conduct follow-up on the patient in relation to 
any unresolved adverse event.   
If the patient leaves the study and also withdraws his/her consent for future disclosure of 
information, no further data evaluation or collection should be performed. The sponsor may 
retain and continue to use any data collected before the withdrawal of consent. 

 
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8.3. IEC 
Pfizer, as the study sponsor, is responsible for obtaining the prospective approval of the study 
protocol, amendments and informed consent forms, and other relevant documents, if necessary, 
from the IEC.  All correspondence with the IEC should be kept in the Investigator's File. 
The requirements of local regulations will be followed for the submission and management of 
initial approvals or amendments to the protocol. 
All correspondence with the central IEC and AEMPS should be kept in the Investigator's File. 
Any notification or opinion of the IECs or competent bodies of each AR should be sent to the 
study sponsor. 
 
 
8.4. Ethical considerations of the study 
The study will be conducted in accordance with legal and regulatory requirements and scientific 
rigour, respect and responsibility, and will follow the generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) published by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice (GEP) 
guidelines published by the International Epidemiological Association (IEA), Good Practices 
for Outcomes Research published by the International Society for Pharmacoeconomics and 
Outcomes Research (ISPOR), International Ethical Guidelines for Epidemiological Research 
published by the Council for International Organizations of Medical Sciences (CIOMS), 
European Medicines Agency (EMA) European Network of Centres for Pharmacoepidemiology 
and 
Pharmacovigilance 
(ENCePP) 
Guide 
on 
Methodological 
Standards 
in 
Pharmacoepidemiology, and FDA Guidance for Industry: Good Pharmacovigilance and 
Pharmacoepidemiologic Assessment, FDA Guidance for Industry and FDA Staff: Best Practices 
for Conducting and Reporting of Pharmacoepidemiologic Safety Studies Using Electronic 
Healthcare Data Sets, Guidance for Industry: Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labelling Claims and/or equivalent. 
8.5. Interference with the physician's prescribing habits  
There will be no interference with the investigator's decision on the most appropriate treatment 
for the patient. 
 
This is a non-interventional study and therefore the decision to prescribe any treatment will be 
made prior to and independently of the patient's participation in the study; i.e. patients will 
receive the same medication whether they participate in the study or not according to the clinical 
judgement and normal clinical practice of the doctor responsible for the patient. Moreover, no 
additional tests are to be performed as part of the study. 

 
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9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/REACTIONS  
The following table summarises requirements for the recording of safety events on the case 
report form (CRF) and for reporting safety events to the Department of Drug Safety at Pfizer, 
using the “Non-Interventional Study (NIS) Adverse Event Monitoring (AEM) Report Form” 
(ANNEX 10).   
 
These requirements are set out for three types of events: (1) Serious Adverse Events (SAEs); (2) 
Non-serious Adverse Events (AEs) (as appropriate); and (3) scenarios involving drug exposure, 
including exposure during pregnancy, exposure during breast-feeding, medication errors, 
overdose, incorrect use of the drug, extravasation and occupational exposure.   
 
These events are defined in the "Definitions of safety events" section. 
 
Safety Event 
Recorded on the Case 
Report Form  
Reported on the NIS AEM 
Report Form to the 
Department of Drug 
Safety at Pfizer within 24 
hours of becoming aware 
of the same 
SAE 
(Serious Adverse Event) 
All 
All 
AE 
(Non-serious Adverse Event) 
All 
Carcinogenicity 
Reproductive and 
developmental toxicity  
Retinal detachment 
Other potential cardiac 
events 
     Ischaemic events 
     Tachycardia events 
     Conduction events 
Scenarios involving exposure 
to a drug during the study, 
including exposure during 
pregnancy, exposure during 
breast-feeding, medication 
error, overdose, incorrect use 
of the drug, extravasation, lack 
of efficacy and occupational 
exposure 
 
In paediatric patients and 
patients with impaired liver 
and heart function 
All (regardless of whether 
they are associated with an 
AE), except occupational 
exposure  
 
 
 
 
 
 
All AEs (including non-
serious AEs)  
All (regardless of whether 
they are associated with an 
AE) 
 

 
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For each AE, the investigator must obtain adequate information to determine the outcome of the 
adverse event and to assess whether it meets the criteria for classification as an SAE (see the 
"Serious Adverse Events" section below).  
The safety events listed in the table above must be reported to Pfizer within 24 hours of the 
investigator becoming aware of the event, regardless of whether the investigator determines 
that it is related to the study drug. In particular, if the SAE has resulted in death or is life-
threatening, it must be reported to Pfizer immediately, regardless of the amount of information 
available on the event. This period should also apply to any additional new information (follow-
up) on previously reported safety events. In the unlikely event that the investigator does not 
immediately detect a safety event, he/she must report it within 24 hours of becoming aware of 
the same and document the date and time he/she became aware for the first time. 
 
For safety events that are considered serious or that are identified in the right-hand column of the 
above table, which should be reported to Pfizer within 24 hours of becoming aware of them, the 
investigator is required to obtain and provide Pfizer with any additional information within 24 
hours. Pfizer may also require that an investigator obtain specific follow-up information in an 
expeditious manner.  This information is more detailed than that recorded on the CRF. In 
general, it should include a description of the adverse event in sufficient detail to allow a full 
medical evaluation of the case and an independent determination of the possible causality. Any 
relevant information related to the event should be provided, such as medication and 
comorbidities. In the case of the death of a patient, a summary of available post-mortem findings 
must be sent as soon as possible to Pfizer or its appointed representative.  
 
Reporting period   
 
For each patient, the safety event reporting period begins when the patient receives the first dose 
of sunitinib, sorafenib or pazopanib or signs the informed consent if he/she has already been 
exposed to sunitinib, sorafenib or pazopanib and it lasts until the end of the study observation 
period, which should cover at least 28 calendar days after the last administration of the study 
drug; a report must be sent to the Department of Drug Safety at Pfizer (or its appointed 
representative) in the event that any of the types of safety events listed in the above table occur 
during this period. In this study, for patients included retrospectively without signing the ICF, the 
reporting period will run from administration of the first dose until 28 calendar days after 
administration of the last dose. If a patient receives a study drug on the last day of the 
observation period, the reporting period should be extended 28 calendar days after the end of the 
observation period. The date of informed consent frequently coincides with the date of 
recruitment. In some situations, there may be a delay between the date of informed consent and 
the date of recruitment. In these situations, if a patient gives his/her informed consent but is 
never included in the study (e.g. the patient changes his/her mind about participating, screening 
failure, etc.), the reporting period ends on the date on which it is decided not to recruit the 
patient.   
If the investigator is aware of an SAE occurring at any time after completion of the study and 
believes that the SAE is related to sunitinib, sorafenib or pazopanib, the SAE should also be 
reported to the Department of Drug Safety at Pfizer.  
 

 
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Causality assessment 
The investigator is obliged to assess and record the causal link. For all AEs, the investigator 
should obtain sufficient information to determine the causality of each adverse event. For 
sunitinib, sorafenib or pazopanib-related AEs, the investigator is required to follow the AE until 
the event and/or its consequences are resolved or stabilised to an acceptable level from their 
point of view, and Pfizer agrees with that assessment.   
The causality assessment by the investigator is to determine whether there is a reasonable 
possibility that sunitinib, sorafenib or pazopanib caused or contributed to an adverse event. If the 
final determination of causality by the investigator is "unknown" and he/she is unable to 
determine whether sunitinib, sorafenib or pazopanib caused the event, it must be reported within 
24 hours.   
If the investigator cannot determine the aetiology of the event but has determined that sunitinib, 
sorafenib or pazopanib was not the cause, this should be recorded on the CRF and the NIS AEM 
Report Form.  
DEFINITIONS OF SAFETY EVENTS 
Adverse Events 
An AE is any unwanted medical event that happens to a patient who has received a drug. The 
event does not necessarily have a causal link with the treatment.   
Below are some examples of adverse events:   
 Abnormal test results (see below for the circumstances under which an abnormal test 
result is an adverse event); 
 Clinically significant signs and symptoms; 
 Changes in physical examination findings; 
 Hypersensitivity; 
 Lack of efficacy;  
 Drug abuse; 
 Drug dependence. 
In addition, for medications, such events may include signs and symptoms arising from: 

 
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 Drug overdose; 
 Drug discontinuation; 
 Incorrect use of the drug; 
 Off-label use; 
 Drug interactions; 
 Extravasation; 
 Exposure during pregnancy; 
 Exposure during breast-feeding; 
 Medication error; 
 Occupational exposure. 
Abnormal test results 
The criteria for determining whether an abnormal result of an objective test should be reported as 
an adverse event are:  
 The test result is associated with accompanying symptoms; and/or 
 The test result requires additional diagnostic tests or medical or surgical intervention; and/or 
 The test result leads to modification of the study dosage or withdrawal from the study, 
requires a major additional concomitant drug treatment or another kind of treatment; and/or 
 The investigator or the sponsor considers the test result to be an adverse event. 
Simply repeating a test with an abnormal result in the absence of the above conditions is not an 
adverse event. It is not necessary to report as adverse events any abnormal test results that are 
found to be not correct. 
Serious adverse events 
A serious adverse event is any undesirable medical episode in a patient who has received a drug 
or nutritional product (including paediatric formulations) of any dose that: 
 Causes death; 
 Is life-threatening; 

 
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 Requires hospitalisation of the patient or prolongation of existing hospitalisation (see 
below for the circumstances that do not constitute an adverse event); 
 Causes persistent or significant disability/incapacity (significant disruption of the 
ability to perform the functions necessary to lead a normal life); 
 Causes a congenital anomaly or birth defect. 
The progression of the cancer being studied (including signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is death during the study or 
during the reporting period. Hospitalisation due to signs and symptoms of disease progression 
should not be reported as a serious adverse event. If the malignant tumour is fatal during the 
study or in the reporting period, the death-causing episode should be recorded as a serious 
adverse event with grade 5 severity. 
Medical and scientific judgement should be applied to determine whether a particular episode is 
a medically important adverse event. It is possible that a medically important adverse event is not 
immediately life-threatening or does not cause death or hospitalisation. However, if it is 
determined that the adverse event may endanger the patient and/or may require intervention to 
prevent one of the other outcomes included in the above definitions, the adverse event should be 
reported as serious. 
These events comprise, for example, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or seizures that do not require hospitalisation or 
development of drug dependency or abuse. 
Suspected transmission of an infectious, pathogenic or non-pathogenic agent through a Pfizer 
product is considered serious. The event may be suspected due to clinical symptoms or 
laboratory results indicating an infection in a patient exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and are managed as serious and expeditious by the pharmacovigilance 
staff. These cases are also considered for reporting as product defects, if deemed appropriate. 
Hospitalisation 
Hospitalisation is defined as any initial admission (even if less than 24 hours) to a medical 
facility or any extension if already admitted. Also considered as admission is transfer within the 
hospital to an acute care or intensive care unit (e.g. from a psychiatric ward to a medical ward, 
from a medical ward to the coronary care unit, from a neurology ward to a tuberculosis unit). 
Attending A&E does not necessarily constitute hospitalisation; however, an event that causes the 
patient to go to A&E should be evaluated to determine its medical relevance.  
Hospitalisations in the absence of a medical adverse event are not considered an adverse event as 
such and need not be reported. For example, the following reports of hospitalisation without 
adverse events need not be reported: 
 Social hospitalisation (e.g. if the patient has nowhere to spend the night) 

 
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 Administrative hospitalisation (e.g. for an annual check-up) 
 Optional hospitalisation not precipitated by an adverse event (e.g. for elective cosmetic 
surgery) 
 Hospitalisation for observation without an adverse medical event 
 Hospitalisation for the treatment of a pre-existing condition not associated with the 
development of a new adverse event or aggravation of a pre-existing condition (e.g. 
investigation of pre-existing laboratory abnormalities) 
 Hospitalisation described in the protocol during the study (e.g. for a procedure required 
by the study protocol)  
Situations that need reporting to the Department of Drug Safety at Pfizer within 24 hours  
Situations involving exposure during pregnancy, exposure during breast-feeding, medication 
error, overdose, incorrect use of the drug, extravasation, lack of efficacy and occupational 
exposure are described below. 
Exposure during pregnancy  
Exposure during pregnancy (EDP) takes place if: 
1. A woman becomes pregnant or discovers that she is pregnant while receiving sunitinib, 
sorafenib or pazopanib or having been directly exposed (whether in treatment or through 
environmental exposure) to sunitinib, sorafenib or pazopanib; or if the woman becomes 
pregnant or discovers she is pregnant after stopping or having been directly exposed to 
sunitinib, sorafenib or pazopanib (maternal exposure); 
An example of environmental exposure would be a case involving direct contact of a 
pregnant woman with a Pfizer product (e.g. a nurse reports that she is pregnant and has 
been exposed to chemotherapy agents). 
2. A man has been exposed, whether in treatment or through environmental exposure, to 
sunitinib, sorafenib or pazopanib before or around the time of conception and/or exposed 
during the pregnancy of the partner (paternal exposure). 
As a general rule, exposure during pregnancy, prospective and retrospective of any kind, is 
reportable regardless of whether it involves an AE and the procedures for reporting SAEs should 
be followed. 
If a study participant or a participant's partner becomes pregnant or discovers that she is pregnant 
while receiving treatment with sunitinib, sorafenib or pazopanib, this information must be 
reported to Pfizer using the NIS AEM Report Form and the EDP Supplemental Form, regardless 
of whether it involves an adverse event.  

 
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Also, information relating to environmental exposure to sunitinib, sorafenib or pazopanib in a 
pregnant woman (e.g. she reports that she is pregnant and has been exposed to a cytotoxic 
product by inhalation or spillage) must be reported using the NIS AEM Report Form and the EDP 
Supplemental Form. This should be done regardless of whether there has been an AE.   
The information reported shall include expected delivery date (see information related to 
abortion below). 
Follow-up should be performed to obtain general information on the pregnancy; also, for all EDP 
reports where the outcome of the pregnancy is unknown, the case should be followed up to 
obtain information on the outcome.  The pregnancy will be followed up to the end or until 
termination (e.g. abortion) and Pfizer will be notified of the outcome.  This information will 
provided as follow-up to the initial EDP report.  In the case that the birth takes place, the 
structural integrity of the newborn can be assessed at the time of birth.  In the case of abortion, 
the reasons for the termination should be established and, if clinically possible, the structural 
integrity of the foetus should be evaluated by visual inspection (unless there are previous 
conclusive laboratory findings that denote congenital anomalies and these findings are reported). 
If the pregnancy outcome meets SAE criteria (e.g. ectopic pregnancy, spontaneous abortion, 
intrauterine foetal death, neonatal death or congenital anomaly [in a child born alive, post-
abortion foetus, intrauterine foetal death or neonatal death]), the procedures for reporting SAEs 
must be followed. 
Additional information on the outcome of the pregnancy that should be reported as SAEs:  
 Spontaneous abortion includes natural miscarriage and retained products of 
conception 
 Neonatal deaths that occur within a month of birth should be reported as SAEs, 
regardless of causality.  Also, deaths that occur after the first month must be reported 
as SAEs when the investigator qualifies them as related or possibly related to 
exposure to the investigational medicinal product 
Additional information regarding exposure during pregnancy may be requested.  The need for 
increased follow-up of the birth outcome will be determined on an individual basis (e.g. 
monitoring of premature infants to identify developmental delays).   
In the case of paternal exposure, the participant in the study will be provided with a "Pregnant 
Partner Release of Information Form" to give to his partner.  It must be documented that this 
document was provided to the participant to give to his partner. 
Exposure during breast-feeding 
Cases of exposure during breast-feeding should be reported, regardless of the presence of an 
associated AE. A report of exposure during breast-feeding will not be generated when a Pfizer 
drug specifically approved for use in breastfeeding women (e.g. vitamins) is administered 
according to the authorised use.  However, if the child experiences an AE associated with 

 
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administration of the drug, the AE should be reported along with the exposure during breast-
feeding. 
 
Medication error 
A medication error is an unintended mistake in the prescription, dispensing or administration of a 
drug that may cause or lead to inappropriate use of the medication or patient harm when the 
medication is under the control of the healthcare professional, the patient or the consumer. These 
events may be related to professional practice, products, healthcare procedures and systems, 
including: prescription, order form, package leaflet, packaging and nomenclature; composition, 
dispensing, distribution; administration; education, monitoring; and use. 
 
Medication errors include: 
 
 Potential medication errors, whether or not linked directly to a patient (e.g.  
unintentional/incorrect administration, which may be an accidental off-label use or 
prescription of the product by the healthcare professional or the patient/consumer) 
 Confusion related to trademarks (e.g. trade name, brands) 
The investigator must notify Pfizer of the following medication errors, regardless of the 
occurrence of an associated AE/SAE: 
 
 Medication errors in which the patient has been exposed to the drug, whether or not the 
error is accompanied by an AE 
 Medication errors that do not involve a patient directly (e.g. potential medication errors). 
When a medication error does not involve a patient being exposed to the drug, the 
following minimum reporting criteria are required: 
 An identifiable reporter; 
 A suspect drug; 
 Medication error. 
Overdose, Incorrect use of the drug, Extravasation 
Reports of overdose, incorrect use of the drug and extravasation associated with using a Pfizer 
product should be reported to Pfizer by the investigator, regardless of the presence of an 
associated AE/SAE.  
Lack of efficacy 
Reports of lack of efficacy of a Pfizer product should be reported to Pfizer by the investigator, 
regardless of the presence of an associated AE/SAE or the indication of the Pfizer product. 

 
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Occupational exposure 
Reports of occupational exposure to a Pfizer product should be reported to Pfizer by the 
investigator, regardless of the presence of an associated AE/SAE. 
9.1. Single reference safety document 
The Summary of Product Characteristics of the medicinal product will be used as the single 
reference safety document (SRSD) during the study, which will be used by the Department of 
Drug Safety at Pfizer to evaluate any safety event reported to Pfizer by the Investigator during 
the course of the study.  
 
The SRSD should be used by the investigator as a guideline for prescribing and evaluating any 
event relating to patient safety in relation to the drug received. 
 
Evaluation of severity 
The investigator will use the following definitions of severity according to version 4.0 of the 
CTCAE to describe the maximum severity of the adverse event. If the adverse event is serious, 
the CTCAE grade reported in the adverse events section of the CRF should match the description 
of the CTCAE grade included in the narrative section of the serious adverse event report. 
GRADE 
Clinical description of severity 
0  
No change from the normal or reference range (this grade is not in version 4.0, but 
may be used in certain circumstances) 
1 
MILD Adverse Event 
2 
MODERATE Adverse Event 
3 
SEVERE Adverse Event 
4 
LIFE-THREATENING OR DISABLING Adverse Event 
5 
DEATH RELATED TO an adverse event 
 
Note the distinction between the severity and seriousness of an adverse event. A severe event is 
not necessarily a serious event. For example, a headache may be severe (significantly interferes 
with the subject’s normal functioning), but would not be classified as serious unless it met one of 
the serious adverse event criteria listed above. 
The incidence of AEs leading to discontinuation of the investigational medicinal product and/or  
Reporting requirements 
An adverse event report form (Non-Interventional Study (NIS) Adverse Event Monitoring (AEM) 
Report Form) is included as annex 10 to the protocol, which, once COMPLETED, will be 

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The investigator will also inform Pfizer immediately of any urgent safety measures taken to 
protect the study patients from any danger and any violation of the protocol of which he/she is 
aware. 
11. REFERENCES 
1. FACIT- Fatigue de 13 ítems validada en castellano. Yellen SB1, Cella DF, Webster K, Blendowski C, 
Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of 
Cancer Therapy (FACT) measurement system.  J Pain Symptom Manage. 1997 Feb;13(2):63-74. 
2. Dapueto JJ, Abreu Mdel C, Francolino C, Levin R. Psychometric assessment of the MSAS-SF and the 
FACIT-Fatigue Scale in Spanish-speaking patients with cancer in Uruguay. J Pain Symptom Manage. 2014 
May;47(5):936-45 
3. Figlin R, Sternberg C, Wood CG. Novel agents and approaches for advanced renal cell carcinoma. J 
Urol.2012;188:707-15 
4. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alpha in metastatic renal-cell 
carcinoma. N Engl J Med 2007; 356:115-24 
5. Houk BE, Bello CL, Poland B et al. Relationship between exposure to sunitinib and efficacy and 
tolerability end points in patients with cáncer:results of a pharmacokinetic/pharmacodynamic meta-
analysis. Cancer Chemother Pharmacol 2010;66:357-71 
6. Suttle AB, Ball HA, Molimard M et al. Relationships between pazopanib exposure and clinical safety and 
efficacy in patients with advanced renal cell carcinoma. Br J  Cancer 2014 11;111(10): 1909-16 
7. Motzer RJ, Hutson TE, Tomczac P, et al Overall survival and updated results for sunitinib compared with 
interferón alfa in patients with metastatic renal cell carcinoma. J CLin Oncol 2009;27:3584-90 
8. Gore ME, Sczylik C, Porta C et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an 
expanded-access trial. Lancet Oncol 2009;10:757-63 
9. Gore ME, Sczylik C, Porta C et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an 
expanded-access trial. Lancet Oncol 2009;10:757-63 
10. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, 
Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally 
advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 
20;28(6):1061-8. doi: 10.1200/JCO.2009.23.9764. Epub 2010 Jan 25. 
11. Escudier B1, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, 
Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, 
Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J 
Med. 2007 Jan 11;356(2):125-34. 
12. Wong MK, Mohamed AF, Hauber AB, Yang JC, Liu Z, Rogerio J, Garay CA. Patients rank toxicity 
against progression free survival in second-line treatment of advanced renal cell carcinoma. J Med Econ. 
2012;15(6):1139-48. doi: 10.3111/13696998.2012.708689. Epub 2012 Jul 18. 
13. Négrier S, Ravaud A. Optimisation of sunitinib therapy in metastatic renal cell carcinoma: adverse event 
management. EJC Supplements 2007; 5, 7 12-19. 
14. Bjarnason GA, Khalil B, Hudson JM, et al. Outcomes in patients with metastatic renal cell cáncer treated 
with individualized sunitinib therapy: correlation with dynamic micrpbubble ultrasound data and rewiew of 
the literatura. Urol Oncol 2014;32:480-7 
15. Lee JL, Kim MK, Park I, Ahn JH, Lee DH, Ryoo HM, Song C, Hong B, Hong JH, Ahn H. Randomized 
phase II trial of Sunitinib four weekson and two weeksoffversusTwo weekson and One week offin 
metastaticclear-cell type REnal cell carcinoma: RESTOREtrial. Annals of Ocnology Sept 2015 

 
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16. Ljungberg B, Bensalah K, Bex A, Canfield S, Dabestani S, Giles RH, Hofmann F, Hora M, Kuczyk MA, 
Lam T, Marconi L, Merseburguer AS, Powles T, Staehler M, Volpe A. Guidelines on Renal Cell 
Carcinoma. European Association of Urology 2015. 
17. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, 
Armand JP, Scigalla P, Raymond E. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel 
oral multitarget tyrosine kinase inhibitor, in patients with cáncer. J Clin Oncol. 2006;24:25-35 
 
12. LIST OF TABLES  
Not applicable 
13. LIST OF CHARTS 
Not applicable 

 
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ANNEX 1. LIST OF INDEPENDENT DOCUMENTS 
 
Number 
Date 
Title 
Annex 1 
N/A 
List of Annexes to the Protocol 
Annex 2 
 
Case Report Form 
Annex 3 
N/A 
Coordinating Investigators' Statement 
Annex 4 
N/A 
Reference IEC Approval 
Annex 5 
Version 1.0 
Patient Information Sheet/Informed 
Consent Form 
Annex 6 
Version 1.0 
Schedule of Payments/Financial 
Report 
Annex 7 
Version 1.0 
List of Sites and Investigators 
Annex 8 
Version 
Quality of Life Questionnaire 
Annex 9 
Version 
Quality of Life - Hand-Foot 
Syndrome 
Annex 10 
Version 4.0_July 2014 
Serious Adverse Event Report Form 
Annex 11 
N/A 
Summary of Product Characteristics 
for Sutent, Votrient and Nexavar 
 
 
 

 
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ANNEX 2. CASE REPORT FORM 
Attached as a separate document 
 
 
 
 
 
 

 
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ANNEX 3: COORDINATING INVESTIGATOR’S STATEMENT 
Attached as a separate document  

 
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ANNEX 4. IEC APPROVAL 
Attached as a separate document  

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The following sections describe the research study. Before deciding whether to 
participate, take all the time you need to ask the site staff any questions you may have 
and to talk to your family and friends, your GP or another healthcare professional. The 
site staff will answer all of your questions in detail before you make a decision. 
 
1. WHAT IS THE AIM OF THE STUDY?  
You are being asked to take part in this research study because you are going to 
receive treatment for your disease (kidney cancer) in the form of an oral drug from the 
group of drugs called tyrosine kinase inhibitors and we are investigating the effect that 
these drugs have on your quality of life.  
The treatment may cause adverse effects, such as fatigue (tiredness) or hand-foot 
syndrome (skin changes on the hands and/or feet), among other side effects that your 
doctor will explain to you before starting the treatment. Knowing more about these 
effects in clinical practice may help prevent or improve them. 
This study is going to assess the impact of fatigue on your everyday life and the effect 
that this treatment may have on the skin on the palms of your hands and the soles of 
your feet.  
The study also aims to evaluate the influence of lifestyle (habits such as exercise, 
smoking or napping) on the development of fatigue (tiredness) or skin changes and how 
these adverse effects can be managed by taking breaks during the treatment, reducing 
the dose received or temporarily interrupting drug administration.  
The appearance of these side effects has been associated with a greater response to 
treatment. It has also been observed that maintaining the medication dose leads to a 
greater possibility of tumour reduction and therefore greater effectiveness of the drug. It 
is therefore important to find out how to maintain the dose of medication without having 
to suffer from severe side effects. 
As a result, Pfizer is carrying out a prospective, non-interventional study, without a 
comparison medicine, in accordance with clinical practice to gather more information 
about the good and bad effects of tyrosine kinase inhibitors, like the one prescribed by 
your doctor. 
 
2. HOW MANY PEOPLE WILL PARTICIPATE IN THE STUDY AND HOW LONG WILL 
PARTICIPATION IN THE STUDY LAST? 
There will be approximately 100 people enrolled in this study. This study is being carried 
out at approximately 35 different hospitals in Spain.  Approximately 3 people will take 
part at this hospital. 
3. HOW LONG WILL PARTICIPATION IN THE STUDY LAST? 
You will participate in this study for approximately 9 months and will have to visit the 
hospital the same number of times as if you were not part of the study since your 

 
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doctor's usual clinical practice will be followed. Therefore, you will have to visit the 
hospital at least 4 times during the study. 
 
4. WHAT WILL HAPPEN DURING THE STUDY? 
If you are included in the study, you will receive the same treatment as you would if you 
were not part of the study and you will not have any medical tests other than those 
ordered by your doctor to diagnose and monitor your disease. Your participation in the 
study will therefore not require any additional visits to the hospital other than visits 
scheduled according to clinical practice, which will be approximately every 3 months. 
You will also not require any procedures other than those deemed necessary by your 
doctor to diagnose and assess your disease.  
 
You will be asked to complete some questionnaires about different aspects of your 
habits and quality of life. This will take you approximately 15 minutes. 
 
One of the questionnaires, the fatigue scale, will include 13 questions about how you 
feel during the day and how the treatment is affecting your usual activities. This 
questionnaire should be completed every 6 weeks; therefore, you will sometimes 
complete it during your hospital visit and on other occasions the questionnaire will be 
given to you and explained so that you can complete it at home. You will have to take it 
with you to the hospital the next time you have a visit scheduled by your doctor and give 
it to the doctor. 
 
You will be asked about whether you do any aerobic exercise, such as walking quickly, 
swimming, dancing, riding a bike, playing tennis or running, and whether you take naps 
or smoke before starting the treatment. During treatment, you will be asked to complete 
a patient diary every week (one day a week, for example every Sunday) about whether 
you take a nap and whether you do any type of physical exercise. 
Your oncologist will ask you whether you have any discomfort affecting the palms of 
your hands and the soles of your feet at each visit. 
 
5. WHAT ARE THE RISKS AND POTENTIAL INCONVENIENCES OF 
PARTICIPATING IN THIS STUDY? 
Tyrosine kinase inhibitor drugs can cause some side effects, as described in the 
package leaflet or patient information sheet attached to your prescription. Any negative 
effects you may experience must be reported to your doctor. If you experience a serious 
adverse event, such as a disease or condition requiring hospitalisation, even if you are 
treated at another hospital and for another reason not related to the study treatment you 
are receiving, tell your study doctor immediately.   
As this is a non-interventional study and you are going to be treated with a tyrosine 
kinase inhibitor drug as part of your normal healthcare, an adverse reaction to the 
tyrosine kinase inhibitor may not be considered a research-associated complication. 

 
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If you or your partner becomes pregnant during the study, tell the study doctor 
immediately. Also tell the doctor responsible for your care during your pregnancy that 
you were taking [tyrosine kinase inhibitor]. The study doctor will ask you if you/your 
partner or the doctor responsible for providing care during the pregnancy are willing to 
provide information on the pregnancy and its outcome. If you/your partner consent, this 
information will be given to the study sponsor so that the sponsor can carry out follow-
up activities to monitor safety. 
 
6. WHAT OTHER OPTIONS ARE AVAILABLE BESIDES PARTICIPATING IN THIS 
STUDY? 
 
This study is to be conducted for the sole purpose of research. You can decide not to 
participate in his study and to continue with your usual healthcare/treatment. 
 
7. WHAT ARE THE POSSIBLE BENEFITS OF MY PARTICIPATION IN THIS 
STUDY? 
This study is to be conducted for the sole purpose of research. You will not obtain any 
direct benefit from your participation in the study since you will receive your usual 
healthcare and treatment. However, the information gathered during the study may help 
others in the future. 
 
8.  IS PARTICIPATION IN THE STUDY VOLUNTARY? 
Yes.  You decide whether or not to take part in this study. You can choose not to 
participate or you can change your mind and withdraw from (leave) the study at a later 
date. There will be no penalty and you will not lose any of the benefits you are currently 
receiving or are entitled to receive.  
Your decision will not affect your access to healthcare in the future.   
9. WHAT WILL I HAVE TO PAY FOR IF I PARTICIPATE IN THIS STUDY? 
You will not have to pay anything to participate in this study. 
As this study is only being carried out to obtain information and the healthcare you usually 
receive will not be modified in any way, the sponsor will not pay for any treatment or procedure 
you may receive during your participation in this study or for the tyrosine kinase inhibitor 
prescribed by your doctor. 
 
10. WILL I RECEIVE ANY PAYMENT FOR MY PARTICIPATION IN THIS STUDY? 
You will not receive any payment for participating in this study. 
 
11. IF I PARTICIPATE IN THIS RESEARCH STUDY, HOW WILL MY PRIVACY BE 
PROTECTED? 
 

 
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Access to your medical records  
For the purpose of this study, the study team may need to access your medical records, 
even if just to take only the necessary information from your clinical history and the 
results of earlier tests. On signing this consent form, you are authorising the study team 
to contact the other healthcare professionals who provide you with care and to access 
the healthcare information in their power. 
According to the current data protection act, you expressly agree to information from 
your medical records and other data obtained through your participation in the study 
being included in a personal information file kept by the Site.  
Confidentiality of your medical information 
Your medical information may include data regarding physical examinations and also 
results from medical, analytical or testing procedures. All medical information will be 
confidential. Your medical information will not be disclosed outside the research site, 
unless required by law and in the cases explained below.   
Access to your personal information will be limited to the study doctor and his/her 
collaborators, health authorities, Independent Ethics Committee and representatives of 
the sponsor, companies from the sponsor's group and representatives from the 
authorised services that will control and audit the study. When checking the study data 
and procedures, everyone has a professional duty to guarantee that confidentiality is 
maintained according to current guidelines. 
These persons will be able to see materials that can identify you to ensure that the 
study is being conducted properly and that you and the other individuals participating in 
the study are protected.  
Use and disclosure of coded medical information 
All the individuals involved in the study, including the study sponsor and the study team, 
recognise the importance of data protection and their legal obligations to protect your 
privacy and your well-being. The study team will therefore take measures to protect 
your privacy and you will only be identified with a code in all study documents. This will 
allow your medical information to be used, processed and disclosed without identifying 
you.  Only the study team will have access to the code key (the key allows the study 
team to identify participants). Reports or publications generated during this study will not 
identify you in any way.   
Some of the entities that have access to your coded medical information may be based 
in other countries, such as the United States and other countries where data protection 
and privacy laws may be less strict than in your country of residence. Nevertheless, the 
study sponsor and the institution will take all the necessary measures to protect your 
information. The sponsor is involved in the U.S.-EU Safe Harbor program and meets 
requirements thereof for handling your information.  For more information on the Safe 
Harbor program, go to the website of the U.S. Department of Commerce:  
http://www.export.gov/safeharbor. 
 
Future research 

 
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Your medical information may be used for related research in the future.  On signing 
this consent form, you are authorising use of your medical information for future 
research in the area of oncology.   
 
Withdrawal from the study 
If you decide to withdraw from the study, tell the study doctor. If you withdraw your 
consent for this study, you will no longer be able to participate in the study.  If you 
withdraw from the study without telling your study doctor, your information may be used 
to contact you again to confirm whether you want to continue with the study.  
If you withdraw from the study, the study team will not continue to gather information 
about you, although you give authorisation for information already obtained to continue 
to be used, processed and shared as described above. Additionally, during and after 
your participation in the study, your study doctor must give the sponsor information 
relating to all serious adverse effects you may have suffered during your participation in 
the study. If you have any questions or concerns about this, we recommend asking your 
study doctor. 
 
Storage of research data 
All data obtained during the research will be kept for a period of 15 years.  
 
Your right to access the research data 
You have the general right to access your medical information and to ask for any 
incorrect information to be corrected. Requests to access or modify the information 
must be addressed to your study doctor.   
Your right to access your information may have to be postponed until after the study has 
been completed in order to protect the scientific integrity of the study. If your right to 
access your medical information needs to be postponed, you will be guaranteed access 
to such information as soon as it is reasonably possible.   
 
Compliance with current regulations on the confidentiality of your medical 
information 
Pfizer undertakes to guarantee compliance with the principles established in Spanish 
Law 14/2007 on Biomedical Research, Spanish Organic Law 15/1999 on Personal Data 
Protection and Spanish Royal Decree 1720/2007 approving Regulations to implement 
Organic Law 15/1999.  
Finally, Pfizer undertakes to ensure that you can exercise your rights of access, 
rectification, cancellation and opposition under the terms stipulated in Spanish Organic 
Law 15/1999 on Personal Data Protection. For this purpose, you must contact the site 
where the study is being conducted. 
 
Consent 
On signing this informed consent form, you are explicitly giving authorisation for your 
medical information to be collected, recorded, stored, transferred or disclosed as 
described above.  You understand that you will not be allowed to participate in the study 
if you do not consent to the obtaining and use of your medical information. 

 
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12. WHO CAN I CONTACT ABOUT MY RIGHTS OR IF I HAVE A QUESTION?   
Before signing this document, you must ask about anything you do not understand. The 
site staff will answer any questions you may have before, during and after the study.  If 
you feel that your question has not been fully answered or you do not understand the 
answer, please continue to ask questions until you are happy. 
If you have any concerns or complaints about this study or about how it is being 
conducted, express your concerns to the site staff.  
 
13. CONSENT   
I have read and understand the information contained in this informed consent document. I have 
been able to ask questions and they were all answered satisfactorily. I have had enough time 
and opportunities to ask about details of the study and to decide whether to participate or not. I 
voluntarily agree to take part in this study.  On signing this consent document, I do not waive 
any of my legal rights.   
□ Yes, I agree   
 
□ No, I do not agree 
I have been told that I will receive a signed and dated copy of this document.  
 
_________________________________________ 
Name of the study participant in block capitals 
 
________________________________     ______________         _____________ 
Signature of the study participant              
Date signed§          
Time (if necessary)* 
 
§The patient / legal representative / impartial witness should personally date his/her 
signature. 
 
* The time is only necessary if the information was provided on the same day as 
consent was given, or if consent is given on the same day as study-specific activities 
are to be carried out. 
 
†The investigator, or a person with adequate training and experience appointed by the 
investigator to carry out the informed consent process, must sign and date the consent 
document at the same time as the patient. 
 
‡ Impartial witness:  a person who is independent of the study, who cannot be unfairly 
influenced by people involved with the study, who attends the informed consent process 

 
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if the patient or the patient's legal representative cannot read and who reads the 
informed consent form and any other written information supplied to the patient.  
Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance. 
 
PERSON OBTAINING CONSENT 
 
 
____________________________________ 
 
 
 
Name of the person obtaining  
consent in block capitals  
 
 
 
_________________________________     ______________     _____________ 
Signature of the person obtaining                 Date signed        
Time (if necessary)* 
consent †  
 
 
 
 
 
 
 
 
 
 

 
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ANNEX 6: SCHEDULE OF STUDY PAYMENTS  
Financial Report attached as a separate document 

 
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ANNEX 7: LIST OF SITES, LIST OF INVESTIGATORS AND CONTACT 
INFORMATION 
Principal Investigator(s) 
Attached as a separate document 

 
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ANNEX 8: FACIT-FATIGUE QUALITY OF LIFE QUESTIONNAIRE 
 

 
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ANNEX 9. QUALITY OF LIFE HAND-FOOT SYNDROME 
 

 
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ANNEX 10. SERIOUS ADVERSE EVENT REPORT FORM 
 

 
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ANNEX 11. SUMMARY OF PRODUCT CHARACTERISTICS FOR SUTENT, 
VOTRIENT, NEXAVAR 
Attached as a separate document