REGISTRY OF COMPLETE RESPONSES TO SUNITINIB IN SPANISH PATIENTS WITH METASTATIC RENAL CELL CARCINOMA (ATILA STUDY)
Conditions: Carcinoma, Renal Cell
Sponsor: Pfizer

 
Sunitinib Malate 
A6181227 NON-INTERVENTIONAL STUDY PROTOCOL 
ATILA study 18th October 2018  
 
 
 
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Study Information 
Title 
REGISTRY OF COMPLETE RESPONSES TO 
SUNITINIB IN SPANISH PATIENTS WITH 
METASTATIC RENAL CELL CARCINOMA  
(ATILA STUDY) 
Protocol Code 
A6181227 
Protocol Version 
Version 1.0 of 18th October 2018 
Date of the latest Protocol version 
18th October 2018 
Active substance 
Sunitinib Malate  
Drug 
SUTENT® 
Objectives of the registry: 
To identify patients with metastatic renal 
cell carcinoma (mRCC) who obtained 
complete response (CR) to treatment with 
sunitinib alone or with sunitinib and a local 
treatment to eliminate residual disease and 
achieve CR in the clinician’s opinion. 
The clinical baseline characteristics of these 
patients and the tumour will be described in 
order to find predictive factors of response. 
The aim is to describe the therapeutic 
strategy adopted in patients who obtained 
greater clinical benefit in the cases described 
once the macroscopic lesions have been 
eradicated in order to draft recommendations 
to follow once the statistical analysis of the 
registry is available. 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 3 
1. LIST OF ABBREVIATIONS............................................................................................... 5 
2. PERSONS RESPONSIBLE FOR THE STUDY ................................................................... 9 
3. ABSTRACT ...................................................................................................................... 10 
4. AMENDMENTS AND UPDATES .................................................................................... 16 
5. MILESTONES .................................................................................................................. 16 
6. STUDY RATIONALE ...................................................................................................... 17 
7. HYPOTHESIS AND OBJECTIVES .................................................................................. 26 
7.1. Primary objectives: .............................................................................................. 26 
7.2. Secondary objectives:........................................................................................... 27 
7.3. Exploratory analysis: ........................................................................................... 28 
8. METHODS OF INVESTIGATION.................................................................................... 28 
8.1. Study design .......................................................................................................... 28 
8.2. Scope .................................................................................................................... 29 
8.2.1. Inclusion Criteria ....................................................................................... 30 
8.2.2. Exclusion Criteria ...................................................................................... 30 
8.3. Variables ............................................................................................................... 31 
8.4. Source documents .................................................................................................. 33 
8.5. Sample size............................................................................................................ 33 
8.6. Treatment of data ................................................................................................... 34 
8.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic 
Data Record ........................................................................................... 34 
8.6.2. Records preservation .................................................................................. 34 
8.7. Data analysis ......................................................................................................... 35 
8.8. Quality control ....................................................................................................... 35 
8.9. Research methods limitations ................................................................................. 36 
8.10. Other aspects ....................................................................................................... 36 

 
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9. PROTECTION OF STUDY SUBJECTS ............................................................................ 37 
9.1. Patient information and consent .............................................................................. 37 
9.2. Patient consent ....................................................................................................... 38 
9.3. Withdrawal of patients ........................................................................................... 38 
9.4. Independent Ethics Committee (IEC)...................................................................... 38 
9.5. Ethical aspects of the study..................................................................................... 38 
9.6. Interference with doctor's prescription habits .......................................................... 38 
10. HANDLING AND COMMUNICATION OF ADVERSE EVENTS/ADVERSE 
REACTIONS ............................................................................................................... 38 
10.1. Single reference safety document.......................................................................... 39 
11. DISSEMINATION OF RESULTS ................................................................................... 40 
12. REFERENCES ................................................................................................................ 40 
13. TABLES LISTING .......................................................................................................... 40 
14. GRAPHICS LISTING ..................................................................................................... 40 
15. ANNEX 1. LISTING OF INDEPENDENT DOCUMENTS .............................................. 40 
 

 
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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 
Classification of the 
prognostic group 
according to Heng. 
Heng risk criteria for anti-VEGF targeted therapies; Prognostic 
Factors for poor Overall Survival: 
KPS <80 
Time from diagnosis to start of treatment <1 year 
Anaemia 
Hypercalcaemia 
Neutrophilia 
Thrombocytosis 
 
0 Factors: favourable prognosis group 
1-2 Factors: intermediate prognostic group 
≥3 Factors: poor prognostic group. 
 
Continuous CR 
Continuous CR with no changes in the last recorded imaging test 

 
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(CT). 
CR 
Complete Response 
CR + Local treatment 
Complete pharmacological response and with local treatment 
CR investigator 
Complete response: disappearance of all measurable lesions according 
to investigator’s criteria in at least 2 consecutive CT scans 
CRF 
Case Report Form 
CT scan 
Computerised axial tomography 
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 
Cardiovascular Accident (Stroke) 
DMP 
Data management plan 
DOR 
Duration of Response 
DOR Duration of 
Complete Response 
(CR) 
Duration of complete response (CR) to sunitinibSunitinib; date from 
the first Computerised axial tomography (CT) scan in which CR was 
detected to the CT scan in which there was disease progression. If CR 
continues, continuous CR must be indicated. 
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 

 
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HFS 
Hand-Foot Syndrome 
IC 
Informed Consent 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
KPS 
Karnofsky Performance Scale. Scale to quantify the general well-
being of patients with cancer and activities of daily living 
LDH 
Lactate Dehydrogenase 
mRCC 
Metastatic Renal Cell Carcinoma 
mTOR  
Mammalian Target of Rapamycin 
N/L Ratio 
Neutrophil/lymphocyte ratio 
NIS 
Non-interventional study 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PR 
Partial Response 
Prognostic group 
according to Motzer 
(MSKCC) 
 
Prognostic factors for a poor Overall Survival: 
KPS <80 
Time from diagnosis to start of treatment <1 year 
Anaemia 
Hypercalcaemia 
Elevated lactate dehydrogenase (LDH) 
 

 
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0 Factors: favourable prognosis group 
1-2 Factors: intermediate prognostic group 
≥3 Factors: poor prognostic group. 
RCC 
Renal cell carcinoma 
RECIST 1.1 CR 
Complete response: disappearance of all measurable lesions according 
to RECIST 1.1 criteria if it is available in the radiological report 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Stable disease 
SRSD 
Single reference safety document 
Suni CR 
Complete response obtained exclusively with systemic treatment with 
sunitinib 
T. to CR 
Time to obtaining CR 
TKI 
Tyrosine kinase inhibitor 
TNM 
System used to describe the amount of cancer and its spread in a 
patient's body 
TT 
Treatment Time 
TTF 
Time to Treatment Failure 
. 
 
 
 

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3. ABSTRACT 
Observational, retrospective, multicentre study in spanish patients with metastatic 
Renal Cell Carcinoma (mRCC) treated with sunitinib as a first-line treatment 
(treatment with previous cytokine therapy is accepted) according to clinical 
practice who obtained a complete response (CR) to treatment in one of these 2 
situations: 
 
a) Complete response (CR) obtained exclusively with first-line sunitinib 
treatment (sunitinib CR). 
b) Response obtained after a period of time on treatment with sunitinib in 
which local treatment was also performed (surgery of the residual 
metastasis/metastases, radiofrequency ablation or radiotherapy) to achieve 
the total macroscopic disappearance of the disease, according to the opinion 
of the physician responsible for the patient (CR + local treatment). 
 
This is a retrospective registry of spanish patient cases, from the drug marketing in 
2007 to 30th October 2018. 
Since the Summary of Product Characteristics for sunitinib does not provide 
indications to be followed in patients with complete remission of the disease, there 
is an open debate on whether they should continue with the treatment for life, with 
the toxicity that this entails, or by contrast, whether sunitinib should be considered 
permanently discontinued after a certain time period (also under discussion).   
Cases have been reported in which, after a treatment period with the patient in 
complete remission, it was decided to discontinue the treatment and patients 
continue being disease free for years. Could we talk about a cure in these cases? 
What would the definition of CR be? 
 
 Primary study objectives: 

 
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To describe complete responses in daily clinical practice in Spain between 
2007 and 30 October 2018, such as the documented disappearance of all lesions of 
advanced renal cell carcinoma according to the investigator’s criteria in at least 2 
consecutive CT (Computerised axial tomography) scans. 
To look for associations between CR from a clinical point of view and the 
baseline characteristics of both the patient and the tumour, such as: 
o Demographic data (age at the start of treatment) 
o Previous nephrectomy 
o Classification of the risk group according to Motzer and/or Heng 
criteria and the association between each prognostic variable, such as: 
baseline patient status, time from nephrectomy to systemic treatment 
start, presence of anaemia, corrected calcium, LDH (lactate 
dehydrogenase) levels, neutrophil levels and platelet levels. 
o Tumour data: histology, Fuhrman grade, presence of tumour necrosis 
and number and location of metastases (organs involved). 
 
 Secondary objectives: 
o To establish recommendations to be followed in patients who 
obtain CR to sunitinib treatment based on the case recording and 
the adopted therapeutic strategy that obtained the greatest clinical 
benefit. 
o To define the median time on treatment with sunitinib until lesion 
complete remission is reached in the patient responsible physician 
opinion. 
o To define the median duration of CR. 

 
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o The time elapsed from the confirmation of CR to disease 
stabilisation/progression or treatment change due to unacceptable 
toxicity or death from any cause will be collected. 
o The dose and treatment regimens used will be recorded. In the 
case of treatment dose changes (increase or reduction), the reason 
(toxicity, efficacy, decision taken after lesion elimination or upon 
request of the patient) will be specified.  
o Description of local treatment techniques if they were used and at 
what time they were applied. In the case of a pathology report on the 
resected part, the percentage of necrosis and histology will be 
recorded, as well as the surgical complications in the case that they 
arose. 
o Sunitinib treatment safety profile: the adverse effects presented by 
the higher grade patients and whether the treatment had to be 
discontinued at any time due to toxicity will be recorded. Pfizer will 
be notified of the toxicities required in the section on reporting 
adverse effects. 
o In cases of systemic treatment discontinuation after a treatment period 
with CR maintenance, the reason for the decision and patient 
participation in this decision (if the patient was consulted, if it was at 
his/her request or the investigator’s decision). 
o Pharmacological group by mechanism of action used in patients 
on second-line treatment after disease progression: another TKI, 
treatment with a drug that acts on the immune system, an mTOR 
(mammalian target of rapamycin) 
 
 Exploratory analysis: baseline neutrophil-lymphocyte ratio and 
its progression during treatment in laboratory tests available at the 
follow-up visits that will be attributed to imaging tests (CT scans). 
 

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Since this is an observational and exploratory study, no hypotheses have been established and 
the number of included subjects will not be pre-determined, although a sample of close to 90 
cases is estimated in around 50 Spanish sites.  
The beginning of sunitinib treatment will have been performed before the patient’s enrolment in 
this registry. Therefore, the therapeutic decision will only depend on the responsible doctor’s 
clinical judgement.  
 
 
SCHEDULE 
 
It is planned to start the administrative procedures of the study with the central IEC and the 
AEMPS in October 2018, with the first sites expected to be opened in November-December 
2018. 
Patient recruitment will be for a maximum of 12 months from the opening of the first 
participating site.  
Patients will not be monitored after inclusion in the study.  
The end of the registry is expected to be when all data of the included patients have been 
collected and analysed, it is estimated for the year 2019. 
 
 
FUNDING SOURCE  
Pfizer España, as sponsor, shall fund the study. This funding includes all research materials, the 
cost of the recording and surveillance processes of the Committee and healthcare authorities, the 
design and management of the database, the cost of the statistical analysis of the information and 
the generated reports and the fees of the professionals involved in the data collection and 
analysis. 
In addition, Pfizer SLU, as sponsor of the study, will provide financial compensation to the 
sites/investigators participating in the study. 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 sites where the study is conducted. 
 

 
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4. AMENDMENTS AND UPDATES 
Amendment 
No. 
Date 
Substantial 
or 
administrative 
amendment 
Amended 
protocol 
section(s) 
Summary of change(s) 
Reason 
N/A 
 
 
 
 
 
 
5. MILESTONES 
In order to obtain sufficient information to carry out the data analysis, the work plan is as 
follows: once the study is approved by the competent authorities and the contracts signed at each 
site, each hospital will be opened and the investigator can start recording the required data in the 
case report form (CRF). 
The person appointed by the sponsor to monitor the study may request a face-to-face or remote 
visit from the site for the review of the data reported in the CRF at any time. 
The site undertakes to fill in the data in the CRFs, and to resolve any discrepancies that may arise 
(“queries”), without interfering with the study-planned schedule. 
The study sponsor will regularly inform the investigators involved in the study on its status by 
sending electronic monitoring reports. 
The administrative procedures for the study with the central IEC and the AEMPS are expected to 
start in October 2018, so the following schedule is being considered:  
Milestone 
Expected date 
Expected date of approval by the central IEC  
November 2018 
Start of data collection  
Expected date of opening of the first site and start of study recruitment 
December 2018 
End of data collection  
July 2019 
Final Results Report 
September 2019 

 
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6. STUDY RATIONALE 
Complete response (CR) to a tyrosine kinase inhibitor (TKI) is reached infrequently in clinical 
trials for the treatment of metastatic renal cell carcinoma, where the classic description of CR 
contemplates only pharmacological treatment and this response is evaluated either by the study 
investigator or by a centralised radiological committee (most common situation). 
 
Since the eradication of all measurable lesions will be reached in a small percentage of patients, 
the Summary of Product Characteristics for sunitinib does not provide guidelines regarding the 
therapeutic strategy to be followed in these cases, i.e. continuing the treatment and at which dose 
or to discontinue it definitively.  
 
The objective of this registry is to shed light on this matter, reviewing what was done in these 
patients in order to draft useful recommendations for the clinician who faces this dilemma. 
 
 
 Data from phase III clinical trials 
 
In the sunitinib pivotal clinical trial (Motzer et al., 2007), in the intermediate analysis and 
according to RECIST criteria, no patient reached CR to treatment by central radiological 
committee while there was one patient with CR in the opinion of the investigators, which 
accounted for less than 1% of the subjects who participated in the clinical trial. However, in the 
final analysis published 2 years later (Motzer et al., 2009), 11 patients (3%) in the sunitinib arm 
achieved CR to treatment in the opinion of the investigator. 
 
In the sorafenib clinical trial, TARGET study (Escudier et al., 2007) , there was no patient 
with CR by the independent committee in the intermediate analysis, while one CR case (<1%) 
was described by investigator.  
 
In the phase III trial of pazopanib versus placebo (Sternberg et al., 2010), there was one 
patient in the intermediate analysis who achieved CR to treatment with pazopanib (<1%) by the 
independent radiological committee 
 
In the COMPARZ study (Motzer et al., 2013), according to an independent radiological 
committee, 3 patients achieved CR to treatment with sunitinib versus 1 patient in the pazopanib 
treatment arm. 
 
 Data from expanded-access programmes: 
 

 
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In the sunitinib expanded-access programme (Gore et al., 2015)  where the tumour response 
rate was evaluated by the investigators, 1% of patients achieved CR to treatment as best 
response. 
 
In the sorafenib expanded-access programme in the USA and Canada (Stadler et al., 2010) 
less than 1% of patients achieved CR to treatment with sorafenib in the investigator’s opinion.  
 
 Retrospective data on real-world studies: 
 
However, in real life this figure may be higher than in a clinical trial setting because the 
definition of CR is laxer, follow-up of patients is greater and, therefore, the opportunity to reach 
CR is more feasible, as there are late responders to treatment. 
 
In daily clinical practice, the CT scan is used to assess tumour response, while in clinical trials 
other additional examinations may be performed, such as a bone scan or brain scans that may 
reveal metastases that otherwise may not be accounted for.  
 
In the pool analysis of 3 prospective studies published by Castellano (Castellano et al., 2017), 
6.1% of patients achieved complete response in the investigators’ opinion. 
 
In the retrospective Spanish SULONG study, in which 97 patients who had had a PFS to 
sunitinib greater than 22 months were selected, the percentage of patients who achieved CR 
reached 21% with a median CR of 33 months (Puente et al., 2017). 
 
In a retrospective series from the hospital Gustave Roussy, Dr Albiges analysed 64 patients 
who obtained CR to TKIs with the drug only (36 cases) or with the combination of local 
treatment (28 cases); surgery, radiotherapy or radiofrequency ablation (Albiges et al., 2012). 
 
The definition of CR according to RECIST 1.1 criteria was the disappearance of all known target 
lesions, the disappearance of all non-target lesions and the absence of new lesions. 
CR had to be confirmed with two consecutive CT scans performed with at least 4 weeks between 
them. Confirmation from the oncologist and radiologist was required at each site. 
 
The treatment received was sunitinib in 59 patients and sorafenib in the remaining 5. The dose 
and regimen used for sunitinib was 50 mg in a 4/2 regimen and sorafenib at 800 mg/24 hours. 
 
Most of the patients had a favourable (22 cases) or intermediate (39 cases) prognosis. However, 
3 patients were classified as having a poor prognosis. 
 
Almost all the patients displayed clear cell histology (60 out of 64 patients) and all had been 
nephrectomised.  

 
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There were 26 patients who had a single metastatic location versus 23 who had 2 affected organs 
and 15 patients who had 3 or more locations. 
 
The median time to eliminate all lesions from the beginning of TKI treatment exclusively was 
12.6 months, with a range of 2 to 28 months.  
The median time from CR to relapse was 7.9 months.  
 
In the case of subjects in whom remission of lesions was achieved with TKI plus local treatment, 
18.5 months were needed (range of 5-45 months).  
 
The median time from CR to relapse was 8.2 months.  
 
The decision taken regarding whether or not to discontinue the treatment was as follows: 
 
 
The conclusion of the author was that CR can be obtained in all the prognostic groups and with 
metastasis in any location.  
 
In the registry-based retrospective analysis of the kidney cancer Czech cooperative group 
(Buchler et al., 2016) (RENIS registry), which covers 95% of patients treated outside clinical 

 
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trials, out of 2,803 patients, 100 cases of CR were identified as the best response (3.6% of the 
total) obtained exclusively with TKI as a first-line treatment: 
 
- 
84 patients treated with sunitinib 
- 
4 patients treated with pazopanib 
- 
9 patients treated with sorafenib 
- 
3 patients treated with bevacizumab + Interferon alpha 
 
96% of patients had been nephrectomised and the same percentage of tumours displayed clear 
cell histology. 
Regarding the MSKCC classification of the prognostic group, 47% of patients had a good 
prognosis, while 51% had been classified as having an intermediate prognosis and 2% had a poor 
prognosis. 
 
The response assessment was performed by RECIST 1.1 criteria and an image was only 
necessary to confirm CR. 
 
The median for achieving CR was 10.1 months and the number of patients with CR increased 
linearly up to approximately 20 months after beginning treatment with the anti-angiogenic drug. 
 
The patients had a median PFS of 3.8 years (45.6 months) and OS had not been reached in this 
cohort. The five-year survival rate was 80%.                                                   
 
The decision on whether or not to continue the treatment after the lesions disappeared was shared 
by the clinician and the patient.  
The patients who achieved CR very soon (before 10 months) were more likely to continue with 
the treatment, while for those in whom the lesions were eliminated later, it was decided to 
discontinue the treatment in a higher proportion. 
 
Of the total cohort, 65 patients discontinued therapy in the absence of documented relapse. The 
reasons included medical or patient decision in 57 cases and 8 due to toxicity. Another 18 
patients stopped treatment due to disease progression at the cut-off time, while 17 patients were 
still on first-line treatment, despite all the lesions having disappeared. 
 
A second PFS was also defined as the time elapsed from obtaining CR to relapse of the disease 
or death from any cause; PFS from CR was reached at 2.3 years (27.6 months). 
 
Of the 30 patients who discontinued treatment after achieving CR, 14 had progressed at the data 
cut-off point, of which 12 received a second-line treatment, including 4 subjects who were re-
treated with the same drug. The median PFS of this second line was 14.5 months. 

 
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The authors’ conclusions were that patients who achieved CR to a TKI had an excellent long-
term prognosis, with very prolonged PFS and OS. 
No association was found between overall survival and progression-free survival after obtaining 
CR and the baseline prognostic group according to MSKCC. 
There were no significant differences in survival between patients who decided to continue 
treatment after removal of the lesions and those who discontinued it. 
 
In the editorial of the journal European Urology, Dr Alimohamed and Dr Sridhar (Alimohamed 
and Sridhar, 2016) emphasised the importance of maintaining a balance between efficacy and 
toxicity in cases where it was decided to continue treatment with TKIs after total eradication of 
lesions. The patient’s point of view is important. Discontinuing the treatment can generate 
anxiety in some people.  
On the other hand, continuing treatment once CR has been achieved can promote resistance to it. 
 
Confirmation of the disappearance of lesions from a radiological point of view does not exclude 
the presence of viable tumour cells. 
 
 Baseline characteristics associated with CR:  
 
Factors such as age do not seem to influence the impact of the TKI on the tumour.  
In a study by the Czech cooperative group of metastatic renal cell carcinoma published by 
Poprach in 2016, where 1,315 patients treated with sunitinib divided into two groups were 
retrospectively evaluated: 1,016 patients under 70 year-old versus 299 patients over 70 year-old, 
the percentage of patients <70 year-old who achieved CR was 5.1% versus 4.1% in those >70 
year-old, with the elderly nephrectomised patients in a smaller proportion and with a longer 
interval between the diagnosis of metastatic disease and the beginning of systemic treatment, as 
well as starting at a lower dose (Buchler et al., 2015).  
 
In the SULONG study, favourable baseline blood values and a longer time from nephrectomy to 
the onset of distant metastases were correlated with longer PFS (Puente et al., 2017). 
 
 
 Data from phase III clinical trials with drugs that act on the immune system 
alone or in combination with an anti-angiogenic agent. 
 
Before the introduction of targeted drugs, in the era of cytokines with interferon alpha or 
Interleukin 2, although the benefit of treatment for most patients was less than that obtained 
today, a group of patients achieved CR to treatment that was also long-lasting. This occurred in 
5-8% of the patients treated (Fisher, Rosenberg and Fyfe, 2000; McDermott et al., 2005). 
 

 
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More recently, in the second generation of drugs that act on the immune system alone or in 
combination with a tyrosine kinase inhibitor (TKI), a significant percentage of complete 
responses have been obtained.  
 
In the CheckMate 214 study (Motzer, Tannir, et al., 2018), a phase III clinical trial of 1,096 
patients with naive renal cell carcinoma of intermediate or poor prognosis and clear cell 
histology, in which there was a prospective examination of overall survival and response rate of 
the combination of ipilimumab (T4 cytotoxic anti-lymphatic antibody, CTLA4, at 1 mg/kg), + 
nivolumab (PD-1 inhibitor antibody at 3 mg/kg) I.V. over 4 doses every 3 weeks (induction 
phase) followed by nivolumab as monotherapy every two weeks (maintenance phase) versus 
sunitinib as monotherapy at 50 mg in a 4/2 regimen, 9% of patients in the experimental arm (40 
cases) versus 1% (5 cases) in the sunitinib arm obtained CR by a centralised radiological 
committee. 
By investigator, in the combination arm, 11% of the patients achieved CR while 1% obtained CR 
in the control arm. 
The assessment of the CT scans/MRIs took place every 6 weeks after the 2 weeks of rest from 
the sunitinib cycle. 
 
However, when the anti-tumour activity is evaluated according to programmed death-ligand 1 
(PD-L1) expression level in the tumour sample examined at a central laboratory and with the 
evaluation of the images by an independent radiological committee in the intermediate and poor 
prognosis patients, the percentage of complete responses in the ipilimumab + nivolumab group 
decreases to 7% in patients who do not express at least 1% of this biomarker, remaining at 1% 
for patients treated with sunitinib.  
 
In the positive PD-1 group, CR was achieved in 16% of patients and was maintained in 1% of 
patients in the sunitinib arm (Motzer, Tannir, et al., 2018). 
 
In the CheckMate 214 study, 26% of the mean or poor prognosis patients expressed PD-1 in 
tumours in ≥1%, while 74% of the patients expressed it in less than 1% (see table below) 
 
 
 

 
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In the IMmotion 151 study (Motzer, Powles, et al., 2018), a phase III study of atezolizumab 
plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell 
carcinoma, 915 patients were included, of whom 362 (39%) in the intention-to-treat (ITT) 
population expressed PD-L1 receptors in ≥1% of the immune cells that infiltrated the tumour.  
 
In this subgroup of patients, when the tumour response was evaluated by the investigator in the 
experimental arm of patients treated with atezolizumab + bevacizumab, up to 9% of the total of 
178 patients achieved CR, while in the sunitinib arm (184 patients), CR was achieved in 4% of 
patients expressing PD-L1 ≥1%. 
However, in the ITT population, i.e. subjects with or without PD-L1+, the percentage of 
complete responses was 5% for the atezolizumab + bevacizumab combination and 2% for the 
sunitinib arm. 
 

 
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When the analysis was performed by an independent radiological committee, CR rates for the 
PD-L1+ subgroup were 15% for atezolizumab + bevacizumab and 8% for patients treated with 
sunitinib.  
However, for the PD-L1 patients, the percentage of CR in the experimental arm was 8%, while 
the comparator arm was 6%. 
 
The investigators were blinded to PD-L1 status. 
 
 
In an analysis published by Lolli (Lolli et al., 2016), a retrospective analysis was conducted in 
335 patients treated with sunitinib as first-line treatment, this analysis assessed the prognostic 
and predictive value of the systemic immune-inflammation index (SII), based on the levels of 
lymphocytes, platelets and neutrophils at the start of treatment and the changes after 6 weeks of 
treatment.  
The patients were stratified into two levels according to these values (p<0.0001): 
High SII level and low SII level with a cut-off value of 730. 
SII values were associated with objective tumour response, PFS and OS. 
 
 SII >730 (inflamed tumours): 
. PFS 3.6 months 
. OS: 13.5 months 
SII <730 (Non-inflamed tumours): 
. PFS 18.7 months 
. OS: 43.6 months 
 

 
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Complete Response Rates 
TKI Pivotal Clinical Trials 
Sunitinib 
Motzer 2007 
Independent committee 
0% 
 
 
By investigator 
<1% 
 
 
 
Motzer 2009 
By investigator 
3% 
 
Sorafenib 
TARGET Study 
Escudier 2007 
Independent committee 
0% 
 
 
By investigator 
<1% 
 
 
Pazopanib 
Sternberg 2010 
Independent committee 
<1% 
 
 
Phase III clinical trial  
Comparz 
Motzer 2013 
Independent committee 
3 
patients 
sunitinib 
1 patient 
pazopanib 
Expanded-access programmes 
Sunitinib 
Gore 2015 
By investigator 
1% 
 
Sorafenib 
Stadler 2010 
By investigator 
<1% 
 
 
Retrospective real-world studies with sunitinib 
Pool analysis  
Castellano 2017 
By investigator 
6.1% 
 
SULONG 
Long-term responders to 
sunitinib >22 months 
Puente 2017 
By investigator 
21% 
 
Gustave Roussy 
Albiges 2012 
By investigator 
64 patients 
 
RENIS Registry 
Buchler 2016 
By investigator 
3.6% 
 
Clinical trials with immunotherapy alone or combined with a TKI 
versus sunitinib 

 
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CheckMate 214 
Intermediate and poor 
prognosis 
Motzer 2018 
Independent committee 
9% Ipi 
Nivo 
1% Suni 
IMmotion 151 
Powles 2018 
By investigator 
PD-L1 ≥1% 
(39% of the population) 
9% Atezo 
Beva 
4% Suni 
In ITT by investigator 
5% Atezo 
Beva 
2% Suni 
ITT population in total by 
independent committee 
11% Atezo 
Beva 
7% Suni 
ITT by independent 
committee 
 
PD-L1 + 
 
15% Atezo 
Beva 
8% Suni 
ITT by independent 
committee 
 
PD-L1 - 
 
8% Atezo 
Beva 
6% Suni 
 
7. HYPOTHESIS AND OBJECTIVES 
This study is a retrospective registry of cases of CR to treatment with sunitinib in patients with 
metastatic renal cell carcinoma and has a purely descriptive purpose. Therefore, no previous 
hypothesis has been established. 
 
 
7.1. Primary objectives: 
To describe complete responses in daily clinical practice in Spain between 2007 and 
30 October 2018, such as the documented disappearance of all lesions in the 
investigator’s opinion on at least 2 consecutive CT scans. 
 
To look for associations between CR from a macroscopic point of view and the 
baseline characteristics of both the patient and the tumour, such as: 
 
o Demographic characteristics (age at the start of treatment) 
o Comorbidities: cardiac, renal, endocrine, autoimmune and liver. 
o Previous nephrectomy 

 
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o Classification of the risk group according to Motzer and/or Heng criteria and the 
association between each prognostic variable, such as: baseline patient status, 
time from nephrectomy to systemic treatment start, presence of anaemia, 
corrected calcium, LDH levels, neutrophil levels and platelet levels. 
 
o Tumour data: histology, Fuhrman grade, presence of tumour necrosis and number 
and location of metastases (organs involved). 
 
7.2. Secondary objectives: 
o To establish recommendations to be followed in patients who obtain CR to 
sunitinib treatment based on the case recording and the adopted therapeutic 
strategy that obtained the greatest clinical benefit. 
 
o To define the median time on treatment with sunitinib until lesion complete 
remission is reached in the patient responsible physician opinion. 
 
o To define the median duration of CR. 
 
o The 
time 
elapsed 
from 
the 
confirmation 
of 
CR 
to 
disease 
stabilisation/progression or change of treatment due to unacceptable toxicity 
or death from any cause will be collected. 
 
o The dose and treatment regimens used will be recorded. In the case of changes 
in the treatment dose (increase or reduction), the reason (toxicity, efficacy, 
decision taken after lesion elimination or upon request of the patient) will be 
specified. 
 
o Description of local treatment techniques if they were used and at what time 
they were applied. In the case of a pathology report on the resected part, the 
percentage of necrosis and histology will be recorded, as well as the surgical 
complications in the case that they arose. 
 
o Sunitinib treatment safety profile: the adverse effects presented by the higher 
grade patients and whether the treatment had to be discontinued at any time due to 
toxicity will be recorded. 
 
o In cases of systemic treatment discontinuation after a treatment period with CR 
maintenance, the reason for the decision and patient participation in this decision 

 
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(if the patient was consulted, if it was at his/her request or the investigator’s 
decision). 
 
o Pharmacological group by mechanism of action used in patients on second-
line treatment after disease progression: another TKI, treatment with a drug 
that acts on the immune system. 
 
 
7.3. Exploratory analysis:  
Baseline neutrophil/leukocyte ratio and changes in neutrophil/lymphocyte ratio throughout 
treatment; after 4-6 weeks, at 3 months, at 6 months, at 9 months, 12 months, and then every 6 
months in the laboratory tests available at approximately these dates. 
 
 
8. METHODS OF INVESTIGATION 
The purpose of this study is to describe in the routine practice setting, outside the clinical trial 
setting, the clinical characteristics of Spanish patients with metastatic renal cell cancer who have 
been receiving treatment with Sunitinib since it was marketed in 2007 until 30 October 2018, 
obtaining CR to treatment on their tumour documented with at least 2 imaging tests.  
 
No hypothesis has been pre-specified, and all the study data will be analysed using descriptive 
statistical techniques. 
 
8.1. Study design 
Observational, retrospective, multicentre study in spanish patients with metastatic Renal Cell 
Carcinoma (mRCC) treated with sunitinib as a first-line treatment (treatment with previous 
cytokine therapy is accepted) according to clinical practice who obtained a complete response 
(CR) to treatment in one of these 2 situations: 
a) Complete response (CR) obtained exclusively with first-line sunitinib treatment (sunitinib 
CR). 
b) Response obtained after a period of time on treatment with sunitinib in which local 
treatment was also performed (surgery of the residual metastasis/metastases, 
radiofrequency ablation or radiotherapy) to achieve the total macroscopic disappearance 
of the disease, according to the opinion of the physician responsible for the patient (CR + 
local treatment). 

 
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. 
8.2. Scope 
The patient population eligible for this study includes any patient with advanced or metastatic 
renal cell cancer who has been treated with Sunitinib and has achieved CR of the tumour and its 
metastases at any time during treatment and according to the usual assessment criteria in daily 
clinical practice, whether it was obtained with sunitinib alone or if a local treatment was needed 
to eradicate all the lesions: (surgery of the residual metastases, radiofrequency ablation or 
radiotherapy) 
 
The requirements for inclusion are: 
 
1. 
These patients must have received Sunitinib as first-line treatment, according to their 
Summary of Product Characteristics. 
 
2. 
Data collection: clinical, safety, response in patients with advanced renal cancer. 
 
The study is expected to be conducted in 50 sites throughout Spain to reach the maximum 
number of patients in the registry. 
 
The collection of cases will start at each hospital after the agreement with the site is signed and 
all study documentation has been completed and the person appointed by the sponsor delivers 
training on the procedures and objectives of the protocol.  
 
As many patients at the site who meet the inclusion criteria and none of the exclusion criteria 
may be included.  
 
This is an observational study designed to reflect routine clinical practice, there will be no 
interference with the routine daily medical care of patients with renal cancer.  
 
The data collected will correspond to the data normally included in the medical records; 
demographic variables of the patients (never personal data that could lead to patient 
identification), age at the time of starting treatment, routine laboratory values required in the 
diagnosis and control of this condition, patient performance status and clinical status. It is also 
intended to collect treatment compliance, tolerability and adverse events and effectiveness of 
treatment. 
 
As this is a retrospective observational study, no additional material or additional examinations 
not contemplated in regular practice will be required. 
 

 
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A patient who meets the inclusion criteria, who does not meet any exclusion criteria, and who 
has received treatment with sunitinib prior to participation in the registry will be considered 
assessable.  
 
No patient follow-up period is established and there are no patient interviews, as there is only 
one time when the patient’s data are reviewed; this will be when the investigator completes 
his/her CRF. 
 
8.2.1. Inclusion Criteria 
Patients must meet all the inclusion criteria described below to be eligible for the study: 
1. Patients who are 18 year-old or over who have been treated for metastatic renal cell 
carcinoma with sunitinib as first-line treatment (treatment with prior cytokine therapy is 
accepted) between 2007 and 30 October 2018 and who have obtained as a best treatment 
response the total remission of the disease in the opinion of the doctor in charge from a 
clinical, radiological and/or macroscopic point of view. This response must have been 
reached through two possible strategies: 
A) Systemic treatment with sunitinib alone. 
B) Treatment with sunitinib and subsequent local treatment for one or more residual 
lesions that have not responded to the drug (traditional surgery, radiotherapy, SBRT 
(Stereotactic Body Radiation Therapy)).  
2. The duration of CR must have been confirmed with at least 2 consecutive imaging tests, 
without having a limit in the duration of this response. Although the patient had progressed 
subsequently, he/she may be included in this registry. 
3. Patients from any risk group 
4. Tumours of any histology 
 
The doctor responsible for the patient, in the event that he/she continues to attend routine reviews 
at the hospital, undertakes to send the patient a privacy alert according to the new EU legislation 
on personal data: regulation 2016/679 of the European parliament. 
8.2.2. Exclusion Criteria 
Patients who meet any of the following criteria will not be included in the study: 

 
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1. Patients treated with another drug other than Sunitinib. 
2. Patients with no radiology reports proving CR. 
3. Patients with no record of the dose and regimen received with Sunitinib. 
4. Patients who achieved complete remission after 30 October 2018.Variables 
ECOG 
Eastern Cooperative Oncology Group  
Risk groups 
Age of the patient at the time of 
diagnosis 
Epidemiological data 
Years 
TNM stage (T describes the size 
of the tumor and the spread of the 
cancer to nearby tissue; N 
describes the spread of the cancer 
to the nearby lymph nodes and 
the 
letter 
M 
describes 
the 
metastases) 
Epidemiological data 
Tumor stage 
Histology of the tumor 
Epidemiological data 
Pathological anatomy 
Tumor Fuhrman grade 
Epidemiological data 
Pathological anatomy 
KPS 
Karrnofsky Performance Status 
Risk groups 
Previous nephrectomy 
Epidemiological data 
Surgery 
Cardiac, 
renal, 
endocrine, 
autoimmune 
and 
hepatic 
comorbidities. 
Epidemiological data 
Disease data 
Risk group classification 
Epidemiological data 
Risk groups 
Baseline status of the patient 
Epidemiological data 
Risk groups 
Time from nephrectomy to the 
start of systemic treatment 
Epidemiological data 
Risk groups 
Hemoglobin 
Epidemiological data 
Risk groups 
Calcium correction 
Epidemiological data 
Risk groups 
LDH levels 
Epidemiological data 
Risk groups 
Lymphocytes 
Epidemiological data 
Risk groups 
Platelets  
Epidemiological data 
Risk groups 

 
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Neutrophil/lymphocyte index at 
baseline and after 6 weeks of 
treatment, at 3 months, at 6 
months, at 9 months, at 12 
months and then every 6 months 
Epidemiological data 
Risk groups 
Number of metastases 
Disease data 
Disease data 
Number of organs with 
metastasis 
Disease data 
Disease data 
Median time with treatment 
before reaching the CR 
Treatment data 
Disease data 
Median duration of the CR 
Treatment/disease data 
Disease data 
Reason why CR ends: 
progression, tumor stabilization 
or intolerable toxicity 
Disease data 
Disease data 
Doses and schemes of Sunitinib 
Treatment data 
Treatment data 
Temporary treatment 
interruptions 
Treatment data 
Treatment data 
Definitive treatment interruption 
after reaching CR 
Treatment data 
Treatment data 
Active participation of the patient 
in the decision to definitively 
interrupt the treatment once the 
CR has been reached 
Patient empowerment 
 
Time in Sunitinib treatment once 
the CR has been reached 
Treatment data 
Treatment data 
Local treatment techniques of 
residual lesions 
Treatment data 
Treatment data 
PA (pathological anatomy) of 
metastasectomy: histology and 
degree of necrosis 
Disease data 
Disease data 
Adverse 
effects 
related 
to 
Sunitinib treatment of the highes t 
degree achieved 
Treatment data 
Treatment data 
Serious 
side effects (SAEs) 
during Sunitinib treatment  
Treatment data 
Treatment data 
Pharmacological group of 2nd 
line 
treatment 
after 
disease 
Treatment data 
Treatment data 

 
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progression after a period of time 
in 
CR 
(TKI, 
mTOR, 
Immunotherapy) 
Cause of death 
Disease data 
Disease data 
For this observational study, demographic variables that do not imply personal data with which 
the patient can be identified will be recorded, medical history including date and stage of the 
disease at diagnosis and progression, surgical treatment, histology, risk criteria for the disease 
before of its onset, comorbidities, blood and biochemical hematimetry, history of Sunitinib 
treatment, associated adverse events, clinical efficacy, dose, date of onset and subsequent 
treatments, as well as the patient's condition (alive, deceased), and date of last contact. 
 
A full description of the variables, including the definitions, will be detailed in the Statistical 
Analysis Plan of the study.Source documents 
The investigator will have full responsibility for the accuracy and authenticity of the clinical and 
laboratory data included in the CRFs at all times. 
The source document of this study will be the patient's medical records in their clinical history, 
including their surgical records that will be kept at the centre where the study is conducted. All 
data will be captured in a CRF. 
If special problems and/or questions arise or governmental requirements to carry out an 
inspection, it will be necessary to access, in addition, to the complete file of the study, as long as 
the right to anonymity of the patients is protected. 
The information collected in the CRFs must match the data from the medical records. 
8.5. Sample size 
Since this is a case registry with descriptive intent, it is not necessary to make a sample size 
calculation. 
It is planned to include around 90 patients according to an initial estimation, but there is no limit 
of patients to be included as long as they are circumscribed to the period of case collection. 
There is no predetermined hypothesis with a defined sample. 
The period of case collection will be from the approval of the reference Independent Ethics 
Committee and opening of the centres until July 31, 2019 or the inclusion in the CRF of all 
localized cases, whichever occurs first. 

 
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8.6. Treatment of data 
The detailed methodology of the data management software that will be applied in this study will 
be documented in the Data Management Plan (DMP), which will be designed, archived and 
maintained by Pfizer. This document will include details about which data (eg adverse events, 
etc.) will be coded using the drug reference list (The World Health Organization [WHO] Drug 
Reference List [DRL]), which will use the ATC classification system (The Anatomical 
Therapeutic Chemical (ATC) classification System), or the dictionary of medical terms 
MedDRA (Medical dictionary for regulatory activities [MedDRA]). The specific versions of the 
coding dictionaries used will be documented within the DMP.Case Report Forms (CRFs) 
As used in this protocol, the term CRF should be understood as referring to a paper form or an 
electronic data record, or both, according to the method of data collection used in this study. 
In this study a paper CRF will be used that must be completed for each patient included. The full 
original CRFs are the exclusive property of Pfizer and should not be available in any form to 
third parties, except Pfizer authorized representatives or the corresponding regulatory authorities, 
without Pfizer's written permission. The investigator will ensure that the CRFs are stored 
securely in the study centre in paper format and will be secured in a locked room to prevent 
unauthorized third party access. 
The investigator has the final responsibility to collect and report all clinical, safety and 
laboratory data entered in the CRF and any other data collection form (source documents) and 
ensure that they are accurate, original, attributable, complete, consistent, legible, current, durable 
and available when necessary. The CRFs must be signed by the investigator or by an authorized 
staff member to certify that the data contained in the CRFs are true. Corrections to the entries 
made in the CRF or the documents of origin must be dated, signed and explained (if necessary) 
and should not hide the original data. 
In most cases, the source documents will be found in the hospital or doctor's history. In these 
cases, the data collected in the CRFs must match those clinical histories. 
In some cases, the CRF can also serve as the source document. In these cases, a document must 
be available in the investigator’s centre and in Pfizer that clearly identifies the data that will be 
registered in the CRF and for which the CRF will remain as a source document.Records 
preservation 
To facilitate evaluations and/or inspections/audits by the regulatory authorities or Pfizer, the 
investigator undertakes to maintain records, including the identity of all participating patients 
(sufficient information to link the records, for example, CRF with the hospital records), copies of 
all CRFs, safety notification forms, source documents, detailed records of treatment disposition 
and appropriate documentation of relevant correspondence (eg, patient privacy notice, letters, 

 
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meeting minutes or reports of telephone calls). Records must be kept by the investigator in 
accordance with local regulation or as specified in the clinical trial agreement, during the longer 
period of both. The investigator must ensure that the records are kept safely throughout the 
conservation period. 
If for any reason, the investigator can no longer keep the study records during the stipulated 
period (eg, retirement or transfer), he/she must notify Pfizer in advance. The study records must 
be transferred to a delegated person acceptable to Pfizer, as another investigator or other 
institution, or to an independent third party provided by Pfizer. 
The investigator’s records must be kept for a minimum of 15 years after the conclusion or 
interruption of the study, or for longer if required by applicable local regulations. 
The investigator must obtain written authorization from Pfizer before disposing of any record, 
even if the preservation requirements have been met. 
8.7. Data analysis 
The details of the methodology for the summary and statistical analysis of the data collected in 
this study will be documented in the Statistical Analysis Plan (SAP), will be archived, and 
maintained by the sponsor. The SAP can modify the plans originally described in the protocol; 
any major changes to the definitions of the primary objective of the study or its analysis will be 
reflected as an amendment to the protocol. 
The data will be analysed using descriptive statistics. A statistical summary will be provided 
including sample size, mean, standard deviation, median and range for continuous variables 
when applicable; frequency and percentages for categorical variables. Depending on the results 
of interest, a stratified analysis of the data can be carried out. 
Additional exploratory analyses will be developed, such as the neutrophil/lymphocyte index of 
the patients and additional analyses if required. 
8.8. Quality control 
This is a post-authorization study, and the procedures will be the same as those followed in the 
usual clinical practice by the investigator for the review of the patient’s medical records. No 
interview or additional testing will be carried out on patients at the time of their inclusion in the 
study. 
However, investigators are responsible to ensure the compliance with the protocol and Good 
Clinical Practices (GCP). 

 
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The study centres may be subject to face-to-face or distance monitoring by the person designated 
by the sponsor and to a review by the IEC and/or quality audits carried out by the appropriate 
regulatory authorities and the sponsor of the study. 
During the conduct of the present study, Pfizer (or its delegate) will monitor the activities of data 
collection by the centres and may also conduct monitoring visits to ensure the proper conduct of 
the study. 
During the visits in the centres, monitors will be able to review the source documents to confirm 
that the data registered in the CRF is correct. All information recorded in the CRF for this study 
must be consistent with the patient's source documentation (the medical record). 
Data included in the database and some integrated data from third parties (if applicable), will be 
verified/validated as documented in the components of the DMP, which will be prepared, stored, 
and maintained by the sponsor. After carrying out these activities, the investigator will be 
required to sign the CRF. 
 
8.9. Research methods limitations 
Due to the low incidence of patients with advanced kidney cancer treated with Sunitinib with the 
required response characteristics, it is difficult to estimate the number of patients that can be 
collected in the entire study. 
As this is a retrospective study it is possible that some data of the patients are not available. This 
will be reflected in the CRF. 
8.10. Other aspects 
For the inclusion of patients in the study, the investigator should review the inclusion/exclusion 
criteria 
The request for informed consent is not required in the case of not conducting an interview with 
the patient and to ensure the process of data dissociation in such a way that in the information 
that is handled from the clinical history there is no personal data, such and as stated in order 
SAS/3470/2009 of December 16 on observational post-authorization studies. 
These are patients who in some cases have already died and in others contact has been lost. Some 
patients may continue with routine visits for follow-up. In these cases, the investigator agrees to 
send the patient a privacy notice. 

 
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With the data available in the clinical history, the requested information will be recorded in the 
CRF in order to analyze the study variables. 
 
9. PROTECTION OF STUDY SUBJECTS 
The study will be carried out according to daily clinical practice, as described in the protocol, the 
standards of good clinical practice, the international conference on harmonization and the 
requirements and applicable local laws (order SAS/3470/2009 of December 16). The sponsor 
undertakes to follow the legislation in force regarding the post-authorization study and the 
commitments that result from it. 
9.1. Patient information and consent 
All parties will comply with all applicable laws, including laws related to the implementation of 
organizational and technical measures to ensure the protection of patient's personal data. Such 
measures will include the omission of patient names or other directly identifiable information in 
reports, publications or other media, except when required by current laws. 
Personal data will be kept in the study centre in paper format and will be in a closed room to 
ensure access to only authorized study personnel. The study centre will apply the appropriate 
technical and organizational measures to ensure that personal data can be recovered in the event 
of a disaster. 
In case of a possible breach in the personal data security, the study centre will be responsible for 
determining if a personal data security breach has actually occurred and, in such case, to notify 
the incident as required by law. 
To protect the rights and freedoms of natural persons with respect to the processing of personal 
data, when the study data is compiled for transfer to Pfizer and other authorized parties, patient 
names will be deleted and replaced by a unique numeric code specific based on a numbering 
system defined by Pfizer. All other identifiable data transferred to Pfizer or other authorized 
parties will be identified by this unique code specific to the patient.  
The investigators centre will keep a confidential list of patients who have participated in the 
study, linking the numerical code of each patient with their real identity. In case of transfer of the 
data, Pfizer will maintain high standards of confidentiality and protection of the personal data of 
patients in accordance with the clinical study agreement and the applicable privacy laws. 

 
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9.2. Patient consent 
9.3. Withdrawal of patients 
9.4. Independent Ethics Committee (IEC) 
The coordinator/investigator is responsible for obtaining the prospective approval of the study 
protocol, the protocol amendments and other relevant documents, as applicable, of the IEC. All 
correspondence with the IEC must be kept in the Investigator Files. Copies of IEC approvals 
must be sent to Pfizer. 
9.5. Ethical aspects of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with purpose, value and scientific rigor, 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 International Epidemiological Association (IEA), Good Practices for 
Outcomes Research published by International Society for Pharmacoeconomics and Outcomes 
Research (ISPOR), International Ethical Guidelines for Epidemiological Research published by 
Council for International Organizations of Medical Sciences (CIOMS), European Medicines 
Agency 
(EMA), 
European 
Network 
of 
Centers 
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 Labeling Claims and/or equivalent.Interference with doctor's 
prescription habits 
In no case will the investigator's decision be interfered with regarding the most appropriate 
treatment for the patient. 
It is a non-interventional study, therefore decisions to indicate treatment and inclusion in the 
study should be independent and always based on daily clinical practice. 
10. HANDLING AND COMMUNICATION OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study protocol requires a manual review of unstructured patient data; the term unstructured 
data refers to literal medical data, including descriptions based on texts and visual 
representations of medical information, such as medical records, images of doctor's notes, 

 
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neurological images, radiographs, or narrative fields of a database. The reviewer must report the 
adverse events (AE) explicitly attributable to any Pfizer medication that appear in the revised 
information (defined according to the study population and the study period specified in the 
protocol). Explicit attribution should not be deducted by a temporal relationship between the 
administration of the drug and an AE, but should be based on a definitive causality statement by 
a healthcare professional, linking the administration of the drug to the AE. 
The requirements for reporting safety events in the non-interventional study (NIS) adverse event 
monitoring (AEM) Report Form to the Pfizer Department of Drug Safety are as follows: 
All serious and non-serious AEs with explicit attribution to any Pfizer product that appears in the 
revised information must be recorded in the CRF and notified within 24 hours of its knowledge 
to the Department of Drug Safety of Pfizer using the NIS AEM Report Form. 
Situations involving exposure to a drug, including exposure during pregnancy, exposure during 
lactation, medication error, overdose, incorrect use of the drug, extravasation, lack of efficacy 
and occupational exposure associated with the use of a Pfizer product, should be reported to the 
Pfizer Medication Safety Department within 24 hours of your knowledge through the NIS AEM 
Report Form. 
In the case of these safety events with explicit attribution or associated with the use, respectively, 
of a Pfizer product, the data reflected in the clinical record will constitute all known information 
regarding these adverse events. There will be no follow-up of these related adverse events. 
All research staff will have to complete the mandatory training in: "Your Reporting 
Responsibilities: Monitoring the Safety, Performance and Quality of Pfizer Products (Multiple 
Languages)" and any additional training from Your Reporting Responsibilities that is considered 
relevant. This training will be provided to the research staff before the start of the study. All 
training modules include a "Confirmation of Training Certificate" (which must be signed by the 
person who has received the training) as a record of the training, and must be kept in a 
retrievable format. Copies of all signed training certificates will be delivered to Pfizer. 
The training must be completed annually using the most recent version of: "Your Reporting 
Responsibilities". 
10.1. Single reference safety document 
The Investigator will use the drug Summary of Product Characteristics as a single reference 
safety document (SRSD) during the development of the study, which will be used by the Pfizer 
Safety Department to evaluate any safety event reported to Pfizer during the course of the study. 

 
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The SRSD must be used by the investigator as a guide for the prescription, as well as evaluation 
of any event with the safety of the patients in relation to the received drug. 
11. DISSEMINATION OF RESULTS 
The registry results will be published in appropriate scientific forums after the preparation of the 
final report. 
INCIDENT COMMUNICATION 
In the event that a competent authority anywhere in the world imposes a prohibition or restriction 
(eg, temporary suspension), or if the investigator is aware of any new information that could 
influence the evaluation of the benefits and risks of a Pfizer product, you must inform Pfizer 
immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
adopted by him to protect the patients of the study from any danger, and any protocol violation 
of which he or she knows. 
12. REFERENCES 
13. TABLES LISTING  
14. GRAPHICS LISTING 
15. ANNEX 1. LISTING OF INDEPENDENT DOCUMENTS