A Disease Registry for Patients With Tenosynovial Giant Cell Tumors (TGCT), Also Known as Pigmented Villonodular Synovitis (PVNS) and Giant Cell Tumor of the Tendon Sheath (GCT-TS)
Conditions: Giant Cell Tumors
Sponsor: Daiichi Sankyo

OBSERVATIONAL PLAN
TGCT Observational Platform Project
A Disease Registry for patients with tenosynovial giant cell tumors 
(TGCT), also known as pigmented villonodular synovitis (PVNS) 
and giant cell tumor of the tendon sheath (GCT-TS) 
DS-ONC-01-15-EU
Sponsor: 
Daiichi Sankyo Europe GmbH 
Zielstattstrasse 48
81379 Munich 
Germany
Version Number:   4.0 VALID ONLY FOR US
Date of Version: 15 OCT 2020 
Confidentiality Statement
The information in this document is confidential and is not to be disclosed without the 
written consent of Daiichi Sankyo Europe GmbH  
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CONTENTS: 
1. 
SIGNATURES ........................................................................................... 4 
1.1. 
Daiichi Sankyo ........................................................................................... 4 
1.2. 
Steering Committee ................................................................................... 5 
2. 
SUMMARY OF CHANGES ..................................................................... 6 
3. 
GLOSSARY .............................................................................................. 8 
4. 
RESPONSIBLE PARTIES ........................................................................ 9 
4.1. 
Steering Committee (if applicable) .......................................................... 10 
4.2. 
List of participating centres...................................................................... 10 
5. 
SUMMARY ............................................................................................. 12 
6. 
AMENDMENTS TO THE OBSERVATIONAL PLAN ........................ 15 
7. 
MILESTONES ......................................................................................... 16 
7.1. 
Study Flow Chart ..................................................................................... 16 
8. 
RATIONALE AND BACKGROUND .................................................... 17 
8.1. 
Background .............................................................................................. 17 
8.2. 
Study Rationale ........................................................................................ 18 
9. 
RESEARCH QUESTION AND OBJECTIVES OF THE 
OBSERVATION ..................................................................................... 19 
9.1. 
Primary Objective .................................................................................... 19 
9.2. 
Secondary Objectives ............................................................................... 19 
10. 
RESEARCH METHODS ........................................................................ 20 
10.1. 
Study Design ............................................................................................ 20 
10.2. 
Settings ..................................................................................................... 20 
10.2.1. 
Participating Centres ................................................................................ 20 
10.2.2. 
Eligibility Criteria .................................................................................... 20 
10.2.3. 
Schedule ................................................................................................... 20 
10.3. 
Variables .................................................................................................. 21 
10.4. 
Data Sources ............................................................................................ 21 
10.4.1. 
Baseline/Enrolment .................................................................................. 22 
10.4.2. 
12 month, 24 month and any further data collection points .................... 24 
10.4.3. 
Patient Reported Outcomes (optional) ..................................................... 26 
10.4.4.  
Adverse Drug Reaction Reporting ........................................................... 26 

 
 
 
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10.5. 
Sample Size Calculation .......................................................................... 26 
10.6. 
Data Management .................................................................................... 26 
10.7. 
Data Analysis ........................................................................................... 27 
10.8. 
Quality Control/Monitoring ..................................................................... 27 
10.9. 
Limitations of the Research Methods ...................................................... 28 
11. 
MANAGEMENT AND REPORTING OF ADVERSE DRUG 
REACTIONS ........................................................................................... 29 
11.1 
Definitions ................................................................................................ 29 
11.2 
Reporting of Suspected ADRs by the Investigator .................................. 30 
11.3. 
Pregnancy ................................................................................................. 31 
12. 
PROTECTION OF HUMAN SUBJECTS .............................................. 32 
12.1. 
Review by Independent Ethics Committees/Competent Authorities ....... 32 
12.2. 
Insurance and Liability ............................................................................ 32 
12.3. 
Patient Information, Informed Consent ................................................... 32 
12.4. 
Data Protection ......................................................................................... 32 
12.5. 
Numbering and Identification of Patients ................................................ 32 
12.6. 
Assessments (according to the study type) .............................................. 33 
12.6.1. 
Patient Reported Outcomes ...................................................................... 33 
13. 
DOCUMENTATION AND ARCHIVING ............................................. 34 
14. 
LEGAL REQUIREMENTS ..................................................................... 35 
14.1. 
Reimbursement ........................................................................................ 35 
14.2. 
Registration .............................................................................................. 35 
15. 
FINAL REPORT ..................................................................................... 36 
16. 
PUBLICATION ....................................................................................... 37 
17. 
PREMATURE TERMINATION OF THE REGISTRY ......................... 38 
18. 
APPENDICES ......................................................................................... 39 
18.1. 
EQ-5D-5L ................................................................................................ 39 
18.2. 
Brief Pain Inventory Short Form ............................................................. 42 
18.3. 
Worst Stiffness NRS item ........................................................................ 44 
18.4. 
PROMIS Physical Function Scale ........................................................... 45 
19. 
REFERENCES ........................................................................................ 47 
 
 

 
 
 
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1. 
SIGNATURES 
1.1. 
Daiichi Sankyo 
 
 
 
 
 
 
 
 
 
 
Daiichi Sankyo Europe GmbH 
 
 
Date 
 
 
 
 
 
 
 
Daiichi Sankyo Europe GmbH 
 
 
Date 
 
 
 
 
 
 
 
Daiichi Sankyo Europe GmbH 
 
 
 
Date 
 
 
 
 
 
 
 
Daiichi Sankyo Europe GmbH 
 
 
 
Date 
 
 
 
 
 
 
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1.2. 
Steering Committee 
 
 
 
 
 
 
 
Leiden University Medical Center 
Date 
 
 
 
 
 
 
 
Leiden University Medical Center 
Date 
 
 
 
 
 
 
 
Istituto Ortopedico Rizzoli 
Date 
 
 
 
 
 
 
 
Istituto Ortopedico Rizzoli 
Date 
 
 
 
 
 
 
 
Date 
Istituto Nazionale Tumori-Fondazione IRCCS 
 
 
 
 
 
 
 
 
Date 
West German Cancer Center 
 
 
 
 
 
 
 
 
Date 
Memorial Sloan Kettering Cancer Center 
 
 
 
 
 
 
 
 
Date 
University Castilla-La Mancha 
 
 
 
 
 
 
 
 
 
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2. 
SUMMARY OF CHANGES 
 
New Version 
Previous version 
Change 
4.0 dated 15 Oct 2020 
3.0 dated 18 Jul 2017 
Documentation of Adverse Drug 
Reactions updated following 
approval of pexidartinib in the US 
on 02Aug2019; 
Administrative changes: change in 
study statistician, data manager to 
sign protocol; glossary updated; 
dates for milestones and final report 
updated  
3.0 dated 18 Jul 2017 
2.0 dated 14 Oct 2016 
Country list updated to add the US 
3.0 dated 18 Jul 2017 
3.0 dated 18 Jul 2017 
Total Patient Number required for 
the study changed from 100 to 200 
3.0 dated 18 Jul 2017 
2.0 dated 14 Oct 2016 
Overall site number increased from 
“approximately 15” to “up to 20” 
3.0 dated 18 Jul 2017 
2.0 dated 14 Oct 2016 
added to the lists 
of the steering committee members 
and national coordinators 
3.0 dated 18 Jul 2017 
2.0 dated 14 Oct 2016 
excluded from 
Steering Committee members list 
3.0 dated 18 Jul 2017 
2.0 dated 14 Oct 2016 
and 
 
added to the list of the national 
coordinators for Spain and Austria 
respectively 
2.0 dated 14 Oct 2016 
1.0 dated 23 May 2016 
Inclusion criteria updated to 
confirm patients must be diagnosed 
histologically 
2.0 dated 14 Oct 2016 
1.0 dated 23 May 2016 
Inclusion criteria updated to remove 
the restriction on patients in an 
interventional study 
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2.0 dated 14 Oct 2016 
1.0 dated 23 May 2016 
Section 10.4 updated to reflect that 
co-morbidities, employment status 
and MRI results will be collected 
throughout the observational period 
not just at baseline 
2.0 dated 14 Oct 2016 
1.0 dated 23 May 2016 
Addition that the site needs to 
confirm the patient is not 
participating in the registry at 
another site 
2.0 dated 14 Oct 2016 
1.0 dated 23 May 2016 
Removal of question regarding the 
patients race 
2.0 dated 14 Oct 2016 
1.0 dated 23 May 2016 
The entire Brief Pain Inventory 
Questionnaire shall be completed 
not just the worst pain scale item. 
 

 
 
 
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3. 
GLOSSARY 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
CA 
Competent Authority 
CRO 
Contract Research Organisation 
DB 
Database  
DM 
Data Management 
DS 
Daiichi Sankyo 
DSE 
Daiichi Sankyo Europe GmbH 
eCRF 
Electronic Case Report Form 
FPI 
First Patient In 
GCT-TS Giant cell tumor of the tendon sheath 
GEP 
Good Epidemiological Practice 
HEOR Health Economic Outcome Research 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
LPO 
Last Patient Out 
NIS  
Non-interventional Study 
PRO 
Patient Report Outcome 
PVNS Pigmented villonodular synovitis 
SADR Serious Adverse Drug Reaction  
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SAS® Statistical Analysis Software 
SDTM Study Data Tabulation Model (CDISC) 
TGCT Tenosynovial Giant Cell Tumor 
 
 
 

 
 
 
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4. 
RESPONSIBLE PARTIES 
Project Leader  
Daiichi Sankyo Europe GmbH 
 
 
 
 
 
 
Coordinating Investigator/Chair of 
Steering Committee 
Leiden University Medical Center 
 
 
 
 
 
 
 
Study Statistician 
 
 
 
 
Contract Research Organisation  
Project Leader  
SSS International Clinical Research 
 
 
 
 
 
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4.1. 
Steering Committee (if applicable) 
The Steering Committee is the primary group with supervisory responsibility for all aspects of 
the conduct of the T.O.P Project (DS-ONC-01-15-EU).  It has contributed to the design of the 
registry, is ensuring the maintenance of the scientific quality and integrity of conduct and will 
support the Daiichi Sankyo project team during the course of the study.  The Steering 
Committee will evaluate the results together with the Daiichi Sankyo project team and will 
review the study report as well as publications based on the results of the registry. 
The Steering Committee (SC) consists of external renowned members of the scientific 
community with a strong medical background in the treatment of TGCT. The responsibilities 
of the SC are: 
o 
Participation in Steering Committee meetings 
o 
Scientific and medical advice prior, during and after the Registry, including 
evaluation and interpretation of the results of the Registry 
o 
Advice in observational plan & eCRF development 
o 
Support the performance of the Registry as a contact person for sites and other 
personnel involved in the Registry 
o 
Scientific and medical advice regarding the Registry results  
o 
Support and advice on publication, abstracts, posters, journals and congresses in 
connection with the Registry. 
In addition, selected persons of the Daiichi Sankyo Project Team were specially assigned as 
Steering Committee members from the following functions: Clinical Operations, Health 
Economics and Outcome Research (HEOR), Biostatistics.  These members will participate in 
the meetings as non-voting members. 
 
4.2. 
List of participating centres  
A list of the principal investigators and all collaborating institutions and investigators is kept 
in a stand-alone document and can be made available upon request. Listed below are the 
details of the coordinating investigators for each country. 
 
 

 
 
 
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Chair of Steering 
Committee and National 
Coordinator for 
Netherlands 
 
National Coordinator for 
France 
 
National Coordinator for 
Germany 
 
National Coordinator for 
Italy 
 
National Coordinator for 
Spain 
 
National Coordinator for  
the United Kingdom 
 
National Coordinator for  
Austria 
 
National Coordinator for  
the United States of 
America 
 
 
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5. 
SUMMARY 
Study/Registry Title 
TGCT Observational Platform Project: A Disease Registry for 
patients with tenosynovial giant cell tumors (TGCT), also known as 
pigmented villonodular synovitis (PVNS) and giant cell tumor of the 
tendon sheath (GCT-TS) 
Protocol version 
identifier 
DS-ONC-01-15-EU 
Date of last protocol 
version 
18-Jul-2017 
Centres/Study 
Sites/Countries 
Up to 20 sites located in the Netherlands, Germany, Italy, France, 
Austria, Spain, the UK and US. 
Milestones  
First Patient In (FPI) / Start of Data Collection: Nov 2016 
Last Patient Out (LPO) / End of data Collection: Apr 2021 
Snapshot Report: Dec 2017 
Final  Report 
Q3 2021 
Rationale and 
Background 
The purpose of the TGCT Disease Registry is to explore the real 
world management of patients diagnosed with diffuse TGCT, to 
understand the management of TGCT patients, the patient flow and 
to understand the relapse rates of the surgical series.  
 
Scientific Background: Tenosynovial giant cell tumor (TGCT) is a 
rare, benign, but potentially locally aggressive and recurrent disease. 
It is characterized by synovial hyperplasia and pigment deposition 
inside the joints, tendon sheaths and bursae. Evidence shows that it 
mainly affects large joints such as the knee and the hip and is 
extremely rare in the temporomandibular joint and spine.  There are 
two forms of TGCT, localized and diffuse. When the tumor involves 
the tendons that support the joint, or occurs in just one area of the 
joint, it is called localized TGCT. This type usually responds well to 
surgical treatment. The diffuse type is more widespread and involves 
an entire joint. It tends to be more destructive and is more difficult to 
treat.  
 
TGCT is rare, with an estimated annual incidence of 1.8 cases per 
million for PVNS and 9.2 cases per million for GCT-TS, in the 
United States (Myers 1980). TGCT is a challenging disease to 
manage and the aggressiveness of the tumour is often 
underestimated. The current standard of care is surgical resection of 
the tumor as completely as possible in order to: (1) reduce pain, 
stiffness, and joint destruction caused by the disease process; (2) 
improve function; and (3) minimize the risk of recurrence. Patient 
outcome following surgery depends on multiple factors including the 
location and extent of disease as well as on a thorough diagnostic 
evaluation and quality of surgery.  Currently, there are no systemic 

 
 
 
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agents approved for the treatment of TGCT. Currently studies in 
TGCT mainly focus on its radiological and pathological 
characteristics and surgical outcomes. Little effort has been made to 
address its clinical characteristics and natural history. Therefore, this 
prospective registry will be conducted to evaluate the clinical profile 
and management of the disease in Europe. 
Research Question and 
Objectives 
To gain detailed insight on the characteristics and management 
patterns of patients with diffuse TGCT (including functional details 
measured pre and post treatment), to explore the patient pathway in a 
real world setting and collect data on patients’ quality of life. 
Study Design  
Multinational, multicentre, prospective, non-interventional 
observational disease registry. 
Setting 
• 
2 year recruitment period 
• 
2 year follow up per patient  
• 
Electronic data capture  
• 
Number of recommended data collection points:  1 baseline and 
 
2 follow up data collections at 12 and 24 months  
Population/Patients  
It is the aim to document 200 patients with TGCT. However, the 
enrolment of patients will be stopped at the latest 24 months after 
enrolment of the first patient regardless of the total number of 
patients enrolled. 
Inclusion/exclusion 
criteria 
As this is a non-interventional study, there are no explicit selection 
criteria besides:  
- Written informed consent for participation in the study (ICF) 
- Age ≥ 18 years 
- Patients with diffuse TGCT (diagnosed histologically) confirmed 
naïve or recurrent case 
Variables 
(Observation Criteria) 
Data on the patients’ TGCT (both current status and history) will be 
collected at an initial baseline data collection point. Patient reported 
outcomes on TGCT symptoms and quality of life will also be assessed 
at this time as well as health resources used in the past 24 months.  
The patient will also attend two further data collections at 12 months 
and 24 months (as this is routine clinical practice). Details of the 
patients’ TGCT will be recorded and associated patient reported 
outcomes and health resource utilization will be assessed again. This 
will also be done at any time the patient attends the site. 
Optionally, the patients may also complete the PRO questionnaires on 
pain, stiffness, physical function, quality of life and health resource 
utilization between the data collection points at 6 and 18 months. 
Data Sources 
As this is a non-interventional observational study, only data from 
routine clinical practice will be documented. To facilitate accurate 
recording of data, patients can fill in a memory aid to note important 
details. This can then serve also as a memory aid during the visits. 
Patients can also optionally complete patient reported outcome 

 
 
 
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questionnaires to report on the details of their TGCT and Quality of 
Life.  
Planned Sample Size, 
Data analysis 
As this is a rare disease the recruitment of patients within the 
scheduled 2-years treatment period will be difficult. Therefore, no 
formal sample size consideration has been performed. All collected 
variables will be used in the statistical analysis.  
Binary, categorical, and ordinal parameters will be summarised by 
means of absolute and percentage numbers within the various 
categories. Numerical data will be summarised by means of standard 
statistics. In addition, adequate graphs (e.g. bar charts, box-whisker 
plots) may be presented. The purpose of all analyses will be purely 
descriptive/exploratory. 
Quality Control 
This study will be conducted according to the rules Good 
Epidemiological Practice (GEP) and STROBE guidelines. Related 
quality control mechanisms (e.g. data plausibility checks, monitoring 
of data) will be performed accordingly 
 
 

 
 
 
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6. 
AMENDMENTS TO THE OBSERVATIONAL PLAN 
In case of essential changes to the existing Observational Plan the investigators have to be 
informed as well as the respective local and/or competent authorities and Independent Ethics 
Committees (IEC) if required by local laws or regulations. 
 

 
 
 
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7. 
MILESTONES 
 
Table 1: Study milestones 
FPI / Start of data collection 
Q4 2016 
LPI 
Q1 2019 
LPO/ Planned end of data collection 
Q2 2021 
Data Snapshot 
Q4 2017 
Final Study Report 
Q3 2021 
 
7.1. 
Study Flow Chart 
* Additional Data Collection points may occur at any time the patient visits the site, even if it 
is outside this schedule 
Baseline data 
collection 
point at site, 
patient 
completes 
questionnaires 
6 months  
Patient 
optionally 
completes 
questionnaires 
at home 
18 months 
Patient 
optionally 
completes 
questionnaires 
at home 
12 month data 
collection 
point at site, 
patient 
completes 
questionnaires 
24 month data 
collection 
point at site, 
patient 
completes 
questionnaires 

 
 
 
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8. 
RATIONALE AND BACKGROUND 
8.1. 
Background 
Pigmented villonodular synovitis (PVNS) and giant cell tumors of the tendon sheath (GCT-
TS) are members of a single condition referred to as tenosynovial giant cell tumor (TGCT), 
localized and diffuse type, and have a common pathogenesis.1 They are proliferative 
neoplasms involving the synovium and tendon sheaths that typically present in young and 
middle-aged adults of both sexes. Diffuse-type TGCT tends to be more aggressive, often 
recurring locally (8%–56%) after surgery, and is capable of malignant transformation.2 In a 
retrospective analysis of 49 previously untreated patients with PVNS of the knee (12 
localized, 37 diffuse), the overall relapse rate after surgery was 43%, with 52% of diffuse-type 
relapsing within 5 years.3  
Although rare, TGCTs are likely underreported and underdiagnosed, with an estimated overall 
annual incidence in the United States of 11 cases per million, including 1.8 cases per million 
for PVNS, and 9.2 cases per million for GCT-TS.4 More recent nationwide pathology data 
from the Netherlands estimate the annual incidence of TGCTs to be 49.7 cases per million.5 
The current standard of care for TGCT is surgical resection of the tumor as completely as 
possible to reduce symptoms and joint destruction, improve function, and minimize the risk of 
recurrence.6 Although surgery is the standard of care, it has been observed that expression of 
the colony-stimulating factor 1 gene is elevated in most TGCT tumors7 and may, in many 
cases, be driven by a gene translocation.8,9 This possibility has led to the development of 
therapies targeting the colony-stimulating factor 1 receptor for which regression in tumor 
volume is the primary indicator of response.10 
Treatments for rare diseases, especially innovative treatments must now also compete with 
technologies for other indications, in terms of their benefits and risks for the patients and 
resources needed. A range of access hurdles are already in use by payers/budget holders to 
curb physicians’ prescriptions. At their heart is the goal of improving effectiveness and value 
in healthcare as a way of balancing growing costs and increasingly limited resources. 
Constantly higher levels of performance are demanded in terms of improved patient-relevant 
outcomes without additional risks. The need for proven evidence of effectiveness and cost-
effectiveness has become imperative. 
Current studies in TGCT focus on its radiological and pathological characteristics and 
surgical outcomes. Little effort has been made to address its clinical characteristics and 
natural history.  
Therefore, this prospective registry will be conducted to evaluate the routine clinical care the 
clinical profile, management of the disease, clinical and patient-reported outcomes and 
resource usage in Europe. This registry will be the first comprehensive European disease 
registry to increase transparency on TGCT patients’ pathways, treatment patterns, health 
outcomes and health economics. Data collected through this registry could also be used to 
assess the unmet medical need. 
 

 
 
 
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8.2. 
Study Rationale 
As previously noted TGCT is a rare disease that is difficult to manage, surgical resection is 
the primary treatment currently available. To date no disease registry exists and there is little 
data available detailing the management of patients with TGCT, the burden of TGCT for 
patients (including pain, joint stiffness, swelling, reduced mobility and quality of life) or the 
economic impact of TGCT. This study aims to collect data by an observational disease 
registry involving no intervention to the patient or changes to investigators treatment 
decisions.  

 
 
 
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9. 
RESEARCH QUESTION AND OBJECTIVES OF THE 
OBSERVATION 
9.1. 
Primary Objective  
The primary objective of this disease registry is to gain detailed insight on the characteristics 
and management patterns of patients with diffuse TGCT. Specifically this registry will 
explore the following: 
• Patient pathway to diagnosis 
• To provide insight into the routine clinical care for patients with TGCT 
• Requirement for surgery 
• Severity of disease on MRI 
• Rate of complications due to surgery 
• Rate of recurrence 
• Patient reported outcomes on pain, stiffness and physical function 
9.2. 
Secondary Objectives 
The secondary objective is to assess the economic health and quality of life burden for patients 
with diffuse TGCT. Specifically this registry will collect information on the following: 
• Patient Reported Outcomes on Quality of Life 
• Health Resource Utilization   
• Patient daily life activity 
• Collection of ADR for those patients treated with Pexidartinib after 02 Aug 2019  
 
 

 
 
 
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10. 
RESEARCH METHODS 
10.1. 
Study Design 
Multinational, multicentre, prospective, observational disease registry. 
10.2. 
Settings 
TGCT is a rare, benign, but potentially locally aggressive and recurrent disease. Treatment 
pattern and treatment initiation, continuation or changes are solely at the discretion of the 
physician and the patient. There will be no attempt to influence the prescribing patterns of any 
individual treating physician. All medication will be prescribed in the usual standard of care 
and will not be provided by the study sponsor. Participation in the study will in no way 
influence payment or reimbursement for any treatment received by patients during the study. 
It is the responsibility of the investigator and his study staff to enter all relevant patient data 
required for this registry in the eCRF and in the patients’ medical records. 
Patients from several European countries and care settings will be enrolled and followed up for 
2 years. A 2-year patient recruitment period is planned. 
10.2.1. 
Participating Centres 
Up to 20 sites located in France, Germany, Austria, Italy, the Netherlands, Spain, the United 
Kingdom and US) are planned to participate in the study.  The sites will be specialized sites 
that treat TGCT regularly; no referral sites will be used.  
10.2.2. 
Eligibility Criteria 
As this is a non-interventional study, there are no explicit selection criteria besides:  
• Written informed consent for participation in the study (ICF) 
• Age ≥ 18 years 
• Patients with diffuse TGCT (diagnosed histologically ) confirmed naïve or 
recurrent case 
10.2.3. 
Schedule 
The total study period from FPI to LPO is 48 months. The patient recruitment period is 24 
months. The follow up period for each patient is 24 months.  
The patients will have a baseline data collection point and follow up data collection points 
performed at 12 and 24 months as this is routine clinical practice. Patients will be followed up 
according to normal clinical practice; therefore if they attend the site more frequently then this 
data will also be documented in the clinical notes and entered in the eCRF. Patients will be 
given questionnaires to optionally complete at the 6 month and 18 month point allowing them 
to report on their TGCT symptoms and quality of life regularly without the need to visit the 
site.  

 
 
 
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• Insurance status 
• Vital Signs: 
• Blood Pressure 
• Heart rate 
• Height 
• Weight 
• Medical History 
• General clinical history 
• Trauma 
• Auto-immune disease 
• Auto-immune disease in family members 
• TGCT History, diagnosis: 
• Date of first symptoms 
• Date of first diagnosis 
• Tumor details (side, joint affected) 
• MRI  
• Diagnosis confirmation 
• Histology 
• Primary diagnosis or Recurrence 
• Current status of TGCT: 
• Current status 
• Current symptoms 
• Most disturbing symptom   
• TGCT past treatment 
• Surgery required 
 Date  
 Type of resection performed  
 Adjuvant therapy received  
 Outcome of the surgery  
 Complications experienced  
• TGCT current treatment 

 
 
 
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• Current treatment plan 
• Concomitant therapies for managing TGCT related symptoms 
• Health Resource utilization 
• Number of referrals/specialist visits prior to diagnosis (to identify the pathway 
to diagnosis) 
• Number of health appoints due to TGCT in the previous 12 and 24 months 
including: 
 Number of office visits due to TGCT  
 Number of emergency room visits due to TGCT  
 Number of hospitalizations due to TGCT  
 Number of days in hospital due to TGCT 
 Number of days in rehabilitation / physical therapy due to TGCT 
• Number of days of work missed due to TGCT symptoms or treatment in the 
last 12 and 24 months 
• Domestic help required 
• Patient Reported Outcomes 
• Brief Pain Inventory 
• Worst Stiffness Scale 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
10.4.2. 
12 month, 24 month and any further data collection points 
As part of standard of care patients will attend a 12 month and 24 month data collection point. 
Patients may also attend further data collection points at any time as part of their usual care. 
At these follow up points the following data will be collected: 
• Date of visit 
• Vital signs: 
• Blood pressure 
• Heart rate 
• Weight 
• Any changes in employment status 
• Any new comorbidities diagnosed 
• Any change in the current status of TGCT including: 

 
 
 
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• Current status (for example: stable, resolved, any recurrence) 
• If recurrence, date of recurrence 
• Current symptoms 
• Most disturbing symptom   
• Any changes in TGCT treatment including 
• Hospitalization since last visit? (including number of days) 
• Surgery occurred since last visit?  
 Date  
 Type of resection performed  
 Adjuvant therapy received  
 Outcome of the surgery  
 Complications experienced 
• Changes to current treatment plan 
• Changes to Concomitant therapies for managing TGCT related symptoms 
• Changes in MRI 
• ADR for patients on pexidartinib after 02 Aug 2019 
• Health Resource utilization 
• Number of health appointments due to TGCT since the previous visit 
including: 
 Number of office visits due to TGCT  
 Number of emergency room visits due to TGCT  
 Number of hospitalizations due to TGCT  
 Number of days in hospital due to TGCT 
 Number of days in rehabilitation/physical therapy due to TGCT 
• Number of days of work missed due to TGCT symptoms or treatment since 
last visit 
• Changes in amount of domestic help required 
• Patient Reported Outcomes 
• Brief Pain Inventory 
• Worst Stiffness Scale 
• PROMIS Physical Function Scale 

 
 
 
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• EQ-5D-5L 
The patient may be provided with a memory aid to facilitate them recording and recalling data 
between data collection points.  
10.4.3. 
Patient Reported Outcomes (optional) 
Questionnaires may be completed by the patient at 6 months and 18months to give the patient 
the opportunity to report on their TGCT symptoms and Quality of Life  
• Brief Pain Inventory 
• Worst Stiffness Scale 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
10.4.4.  
Adverse Drug Reaction Reporting 
In case a patient experiences an adverse drug reaction that the investigator judges to be related 
to pexidartinib, this needs to be documented independent from the data collection point, in the 
respective eCRF section. ADRs will be collected starting from August 02, 2019, which is the 
date pexidartinib became available on the US market. ADRs occurred prior this date, were 
collected within the follow-up phase of the ENLIVEN study in which all study patients who 
were treated with pexidartinib, were participating.  
The ADR documentation and processing follows the Guideline on Good Pharmacovigilance 
Practices (GVP) Module VI (Collection, management and submission of reports of suspected  
adverse reactions to medicinal products) 
10.5. 
Sample Size Calculation 
As this is a rare disease the recruitment of patients within the scheduled 2-years treatment 
period will be difficult. Therefore, no formal sample size consideration has been performed. 
All collected variables will be used in the statistical analysis.  
10.6. 
Data Management 
Data will be collected on standardised electronic CRFs (eCRF, Clincase) in English. During 
data entry performed at the investigational sites automated plausibility checks (e.g., range 
checks, conditional checks, etc.) will be performed. Additional manual queries resulting from 
medical/manual data review may be raised by Data Management. 
All patient reported outcome questionnaires will be completed on paper forms in local language 
and will be entered in the clinical database directly by Data Management. 
Data from the project specific database will be exported into SAS data sets for further validation 
and analysis. Data Management details will be described in a separate Data Management Plan. 
For (S)ADRs a reconciliation between the data available in the Daiichi Sankyo safety database 
and the data in the eCRF will be performed as described in the separate (S)ADR Reconciliation 
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10.7. 
Data Analysis 
All statistical methodology will be described in detail in the Statistical Analysis Plan (SAP) 
which will be finalised at the latest prior to data snapshot. All variables collected in the eCRF 
as well as the data obtained from the patient reported outcomes assessments and all derived 
parameters will be used in the statistical analysis.  
Binary, categorical, and ordinal parameters will be summarised by means of absolute and 
percentage numbers within the various categories (including ‘missing data’ as valid category 
at baseline). Numerical data will be summarised by means of standard statistics. In addition, 
adequate graphs (e.g. bar charts, box-whisker plots) may be presented. The purpose of all 
analyses will be purely descriptive/exploratory. Adverse drug reactions will be analysed 
overall and by type of ADR, based on MedDRA preferred terms and primary system organ 
class. 
 
10.8. 
Quality Control/Monitoring 
This study will be performed according to Good Epidemiological Practice and the STROBE 
guidelines, specifically following the RECORD statement (http://www.record-statement.org).  
Remote monitoring will be performed on regular basis. The purpose is to ensure that the 
rights of the patients are protected, that the reported data is complete and that the conduct of 
the study is in compliance with the Observational Plan and applicable regulatory 
requirements. 
Onsite monitoring may be performed at the sponsor’s discretion (e.g. at sites that have 
enrolled a pre-specified number of patients or depending on findings during remote 
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10.9. 
Limitations of the Research Methods 
As this study aims at collecting and evaluating real world evidence, some limitations common 
to non-interventional studies apply. In addition to this, the following aspects need to be 
considered: 
• Only specialized centres will be used for the study which limits the number of sites per 
country. This may influence the sites’ representativeness for this specific patient 
population. 
• Eligible patients may choose not to participate in the Registry. Therefore, this may 
impact the consecutive enrolment at a site. To be able to assess the consecutiveness of 
enrolment, eligible patients will be listed in the patient screening log. 
• At the follow up documentation time point all relevant changes/events since the last 
documentation time point need to be entered. Due to the long time between data 
collection an underreporting of data might occur that are not considered essential or 
that are difficult to remember. The patient memory aid and the patients’ medical 
records at the site shall support the precise documentation of the time between two 
data documentation time points. The utility of both records is however influenced by 
the precision and accuracy with which the memory aid and the medical records have 
been completed in the meantime. It is expected that possible underreporting will not 
appear in case of severe events and hospitalizations and that this data is considered to 
be representative for the whole study population.  
• Due to the nature of the disease the number of patients enrolled in this study is limited. 
• As the study is non-interventional, only data from the clinical routine treatment can be 
obtained. Therefore, some information may be missing or unavailable. This needs to 
be taken into account when data is analysed and reported.  
• No explicit non-eligibility criteria are defined to avoid selection of patients and thus 
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11. 
MANAGEMENT AND REPORTING OF ADVERSE DRUG 
REACTIONS 
In case a patient experiences an adverse drug reaction that the investigator judges to be related 
to pexidartinib, this needs to be documented independent from the data collection point, in the 
respective eCRF section. ADRs will be collected starting on August 02, 2019, which is the 
date pexidartinib became available on the US market (please refer to section 10.4.4)  
 
In the US, Turalio (pexidartinib) was approved by the FDA with a boxed warning for 
hepatotoxicity and is available only through a restricted program called the TURALIO Risk 
Evaluation and Mitigation Strategy (REMS) program Safety reporting of initial hepatotoxicity 
event(s) will occur through the REMS program (i.e., REMS Liver Adverse Event form) 
and/or through routine pharmacovigilance. Reporting of non-hepatic, TURALIO-related 
safety events will occur only through routine pharmacovigilance, regardless of seriousness. 
 Safety reporting of initial hepatotoxicity event(s) will occur through the REMS program (i.e., 
REMS Liver Adverse Event form) and/or through routine pharmacovigilance. Reporting of 
non-hepatic, TURALIO-related safety events will occur only through routine 
pharmacovigilance, regardless of seriousness. 
 
All Adverse Drug Reactions will need to be documented in the eCRF, independently whether 
they have already been reported through the REMS program or not. 
 
Adverse drug reactions that occurred from August 022019 onwards are to be collected as 
pexidartinib has become commercially available in the US on that date. The documentation and 
reporting follows the Guideline on Good Pharmacovigilance Practices (GVP Module VI). 
The ADR documentation and processing follows the Guideline on Good Pharmacovigilance 
Practices (GVP) Module VI (Collection, management and submission of reports of suspected  
adverse reactions to medicinal products). 
 
11.1 Definitions  
Adverse Drug Reaction (ADR) 
A response to a medicinal product which is noxious and unintended and which occurs at doses 
normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, 
correction or modification of physiological function. 
Response in this context means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility. 
Adverse reaction also includes adverse clinical consequences associated with use of the product 
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11.3. 
Pregnancy 
Daiichi Sankyo must be notified of those patients only who become pregnant while receiving 
or within 30 days of discontinuing pexidartinib. The patient should discontinue pexidartinib 
upon confirmation of pregnancy. 
Although pregnancy is technically not an adverse reaction, pregnancies for patients treated with 
pexidartinib must be followed to conclusion to determine their outcome.  This information is 
important for both drug safety and public health concerns.  It is the responsibility of the 
Investigator, or designee, to report any pregnancy in a female patient using the Exposure In 
Utero (EIU) Reporting form.  
Please contact your study monitor to receive the EIU Reporting Form upon learning of a 
pregnancy.  The Investigator should make every effort to follow the patient until completion of 
the pregnancy and complete the EIU Reporting Form with complete pregnancy outcome 
information, including normal delivery and induced abortion.  
The adverse pregnancy outcome, either serious or non-serious, should be reported in accordance 
with study procedures.  If the outcome of the pregnancy meets any criteria for immediate 
classification as a SADR (e.g., post-partum complications, spontaneous or induced abortion, 
stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
Investigator should follow the procedures for reporting ADRs outlined in Section 11.2.  
 

 
 
 
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12. 
PROTECTION OF HUMAN SUBJECTS 
12.1. 
Review by Independent Ethics Committees/Competent Authorities 
Notification to or approval by IECs and CAs or other organizations will be performed as 
required by national regulations in the participating countries before commencement of 
enrolment at a study centre. 
12.2. 
Insurance and Liability 
All treatments of patients included in this disease registry are local standard of care and occur 
as part of the daily routine practice. Claims of the patient upon his physician will not be 
covered by Daiichi Sankyo. A specific patient’s insurance for disease registry is not 
necessary. 
12.3. 
Patient Information, Informed Consent  
It is the responsibility of the investigator to inform the patient about his/her disease, 
possibilities for diagnostic and therapeutic measures, independent of a possible participation 
in any survey and therefore this information will not be part of the ICF.  
The written ICF will be provided to the study centres in the local language(s). The ICF and 
any revision(s) should be approved by the Independent Ethics Committee (IEC) prior to being 
provided to potential patients. 
The patient’s written informed consent will be documented in the patient’s medical records of 
the investigator. The ICF should be signed and personally dated both by the patient and by the 
investigator who conducted the informed consent discussion. The original signed ICF should 
be retained at the study site (preferably in the patient’s medical records). A copy of the signed 
consent form should be provided to the patient. The date of informed consent will also be 
recorded in the electronic CRF (eCRF). 
12.4. 
Data Protection 
The patients' privacy will be kept according to the requirements of Directive 95/46 EC and 
national legislation for data protection. Data will be collected in a pseudonymous way. An 
identification number assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting study-related data.  
Only authorised personnel such as hospital staff, representatives of the sponsor and contract 
research organisation (CRO), and Competent Authorities (CAs) should have access to 
personalised patient data e.g. in original source documents (medical records). The patient will 
agree to this by signing a respective statement on the ICF.  
12.5. 
Numbering and Identification of Patients 
A unique identification number will be assigned to each patient, for the eCRF. 
At each study site a patient identification list (‘Enrolment log’) will be kept linking the 
identification number to the patient’s identity.  

 
 
 
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12.6. 
Assessments (according to the study type) 
The investigators will be instructed about the correct documentation of the required data for 
each patient in the CRF. These data are available as part of the routine treatment. No 
diagnostic or monitoring procedures are applied to the patients in the study other than those 
performed as standard of care. 
12.6.1. 
Patient Reported Outcomes 
While physicians in daily routine assess health-related quality of life (QoL) in a non-
standardised manner (usually by questioning the patient), in the context of this registry they 
will be provided with validated questionnaires (EQ-5D-5L, Brief Pain Inventory (BPI), Worst 
Stiffness NRS item and PROMIS Physical Function Scale), these will be available in the local 
language. 
Generally, questions in quality-of-life questionnaires are not more upsetting than those posed 
by a patient’s physician or by friends and family members on a day-to-day basis. The use of 
the questionnaires is considered to be non-interventional, as the questions raised are similar to 
those asked in routine care. Patients are free to accept or refuse to fill in the proposed 
questionnaires in this registry. 
12.6.1.1. EQ-5D-5L 
The EQ-5D-5L is a preference-based general health status or health-related quality of life 
instrument consisting of two parts (Appendix 16.1). The first part comprises five domains 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each of which can 
have five levels ranging from no problems through profound difficulties. Accordingly, 3125 
potential health profiles can be generated to which public preferences or utilities are applied. 
These data can subsequently be used in an economic evaluation or cost-utility analysis. The 
second part of the EQ-5D-5L is a Visual Analogue Scale on which the subject rates their 
current health, with 0 representing the “worst health you can imagine” and 100 representing 
the “best health you can imagine.” 
12.6.1.2. Brief Pain Inventory (BPI) short form 
The BPI short form is a 5 minutes self-administered questionnaire that assesses severity of 
pain, impact of pain on daily function, location of pain, pain medications and amount of pain 
relief in the past 24 hours or the past week. 
12.6.1.3. Worst Stiffness NRS item 
The Worst Stiffness NRS item is a one-item self-administered questionnaire assessing the 
“worst” stiffness in the last 24 hours (Appendix 16.3). The NRS for this item ranges from 0 
(“no stiffness”) to 10 (“stiffness as bad as you can imagine”). 
12.6.1.4. PROMIS Physical Function Scale 
Physical function items relevant to the assessment of lower and upper limb function are to be 
selected from the PROMIS physical function item bank (Appendix 16.4). Items assessing 
lower limb function will be administered to subjects with the lower extremity tumors, and 
items assessing upper limb function will be administered to subjects with upper extremity 
tumors. The results from both sets of items will be combined and analysed together. 

 
 
 
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13. 
DOCUMENTATION AND ARCHIVING 
The sponsor is responsible for archiving study specific documentation (Observational Plan, 
potential amendments, Final Report and Database) for at least 10 years. Archived data may be 
held on electronic record, provided that a back-up exists and that hard copies can be obtained, 
if required. 
The investigator is responsible for archiving the patient identification list, all signed ICFs and 
his contract for at least 10 years and in accordance with local legislation, if applicable. 
Physicians are obliged to keep patient files according to national requirements. 
 

 
 
 
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14. 
LEGAL REQUIREMENTS 
This NIS fulfils the requirements of the Directive 2001/83 EC, Module VIII of Guidelines on 
Good Pharmacovigilance Practices (GVP), Directive 95/46 EC, the Declaration of Helsinki 
and will be conducted in accordance with the respective SOPs of DSE. 
14.1. 
Reimbursement 
Compensation according to local regulations and to the time spent to inform patients and to 
document patient data will be paid. This compensation also includes the honorarium for 
responding to queries and for monitoring. 
14.2. 
Registration 
This NIS/registry will be listed in a public registry which meets International Committee of 
Medical Journal Editors (ICJME) requirements, before the onset of patient enrolment. 
 

 
 
 
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15. 
FINAL REPORT  
A final NIS report will be presented latest one year after data base lock, if not required earlier 
by local legislation. 
 

 
 
 
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16. 
PUBLICATION 
CCI

 
 
 
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17. 
PREMATURE TERMINATION OF THE REGISTRY 
The physician may withdraw his/her participation in this registry at any time. In the case of a 
premature termination of the entire NIS/registry by the sponsor, the project leader has to 
inform all participating sites, Ethics Committees, and authorities. 
 
 

 
 
 
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18. 
APPENDICES 
18.1. 
EQ-5D-5L 
 
 

 
 
 
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18.2. 
Brief Pain Inventory Short Form 
 

 
 
 
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18.3. 
Worst Stiffness NRS item 
 
 
 
 
 
 

 
 
 
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18.4. 
PROMIS Physical Function Scale 
 
 
   
 
 

 
 
 
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19. 
REFERENCES 
 
 
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IARC Press; 2013. 
2 Murphey MD, Rhee JH, Lewis RB, etal. Pigmented villonodular synovitis: radiologic-pathologic correlation. 
Radiographics. 2008; 28: 1493–1518. 
3 Sharma V, Cheng EY. Outcomes after excision of pigmented villonodular synovitis of the knee. Clin Orthop Relat Res. 
2009; 467: 2852–2858. 
4 Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical epidemiologic study of 166 cases and 
literature review. Medicine (Baltimore). 1980; 59: 223–238. 
5 Verschoor AJ, Bovee JVMG, van de Sande MAJ, Gelderblom H. Incidence and demographics of giant cell containing 
tumors in the Netherlands: a nationwide pathology database study. Paper presented at: Connective Tissue Oncology Society 
Annual Meeting; 2015; Salt Lake City, UT. 
6 Ravi V, Wang WL, Lewis VO. Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr Opin 
Oncol. 2011; 23: 361–366. 
7 Molena B, Sfriso P, Oliviero F, etal. Synovial colony- stimulating factor-1 mRNA expression indiffuse pigmented 
villonodular synovitis. Clin Exp Rheumatol. 2011; 29: 547–550. 
8 West RB, Rubin BP, Miller MA, etal. A landscape effect in tenosynovial giant – cell tumor from activation of CSF1 
expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci USA. 2006; 103: 690–695. 
9 Cupp JS, Miller MA, Montgomery KD, etal. Translocation and expression of CSF1 in pigmented villonodular synovitis, 
tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol. 2007; 31: 970–976. 
10 Tap WD, Wainberg ZA, Anthony SP, etal. Structure- guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. 
N Engl J Med. 2015; 373: 428–437.