RollOut -Pre-Rolled TachoSil in Laparoscopic Utilisation. A Non-Interventional Study
Conditions: Laparoscopy
Sponsor: Takeda



•
Title: RollOut –Pre-Rolled TachoSil in Laparoscopic Utilisation. A Non-Interventional Study 
NCT Number: NCT02685007
Protocol Approve Date: 20th August 2015
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
Page 1 of 27 
Non-Interventional Study Protocol 
Short title: 
RollOut –Pre-Rolled TachoSil in Laparoscopic Utilisation. A Non-
Interventional Study 
Title: 
RollOut –Pre-Rolled TachoSil in Laparoscopic Utilisation. A Non-
Interventional Study 
Study ID: 
TachoSil-4001 
Sponsor: 
Takeda Pharma Vertrieb 
Takeda Pharma Ges.m.b.H. 
GmbH & Co. KG 
EURO PLAZA, Gebäude F 
Jägerstraße 27 
Technologiestraße 5 
D-10117 Berlin
A-1120 Wien
Germany 
Austria 
Study phase:  Medical Affairs, Non-registration Company Sponsored (Observational) 
Date of version of protocol: 20th August 2015 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
the agreement by the recipient that no information contained herein will be published or disclosed 
without written authorization from Takeda except to the extent necessary to obtain informed consent 
from those persons to whom the drug may be administered. Furthermore, the information is only 
meant for review and compliance by the recipient, his or her staff, and applicable institutional review 
committee and regulatory agencies to enable conduct of the study. 

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TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
Page 4 of 27 
2 
Summary 
The aim of this NIS is to collect further knowledge on the routine use of pre-rolled TachoSil® 
in laparoscopic surgery, especially in the field of gynecology, urology and visceral surgery 
where its hemostatic and sealing properties [see Summary of Product Characteristics 
(SmPC)] help to reduce the rate of postoperative complications, especially of postoperative 
bleeding and lymph leakage. 
Short Title of Study 
RollOut –Pre-Rolled TachoSil in Laparoscopic Utilisation. A Non-Interventional Study 
Study sites 
Up to 50 German and 10 Austrian hospitals performing laparoscopic surgery, from 
departments of gynecology, urology and visceral surgery. The number of centres is subject 
to adjustment. 
Objectives 
•
To describe ease of use and satisfaction with application of pre-rolled TachoSil in
laparoscopic procedures within approved therapeutic indication (SmPC).
•
To assess whether pre-rolled TachoSil is valuable from the surgeon's view for reducing
post-surgical complications, especially bleeding and lymph leakage.
•
To perform a costs analysis (length of hospital stay, avoidance of complications, cost
savings etc.) based on information given by physicians and pecuniary considerations.
•
To describe safety in the routine use of pre-rolled TachoSil in laparoscopic use.
Methodology 
Observational Model: Cohort, Time Perspective: Prospective 
Number of patients 
A sample size estimation resulted in a total number of 465 patients (please refer to Chapter 
11.3). The final number of enclosed patients is determined by the number of available 
patients with pre-rolled TachoSil. It is planned to include up to 105 Austrian and 360 
German patients who will have laparoscopic surgery, especially in the field of gynecology, 
urology and visceral surgery and pre-rolled TachoSil is used. 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
Page 5 of 27 
Diagnosis/Disease/Condition and main criteria for inclusion 
Inclusion Criteria:  
-
Inpatients planned for laparoscopic surgery, in the field of gynecology, urology and
abdominal surgery where pre-rolled TachoSil was applied, 18 years or older.
Exclusion Criteria: 
-
Contraindications, such as hypersensitivity to the active pharmaceutical ingredients
or to other components of pre-rolled TachoSil®, according to the current SmPC.
-
Patient participates in another clinical trial.
Duration of data collection per patient 
Observational period for individual patient: from surgery (V0: Baseline) until date of 
discharge from hospital (V1: Final visit). 
Criteria for evaluation 
Population descriptors 
Inpatients planned for laparoscopic surgery, in the field of gynecology, urology and visceral 
surgery where pre-rolled TachoSil was applied and at least 18 years of age.  
Main outcome variables 
Primary 
-
Assessment by the surgeon with respect to ease of use and overall satisfaction in
the application with pre-rolled TachoSil®, using 5-Point-Likert-Scales (1 =
easy/satisfied, 5 = difficult/ not satisfied)
[Time Frame: intra- and post-surgery until hospital discharge]
Secondary 
-
Length of hospital stay (ICU and normal hospital station)
[Time Frame: Date of surgery until hospital discharge]
-
Pharmaco-economic evaluation as assessed by the surgeon
[Time Frame: intra- and post-surgery until hospital discharge]
-
Intra- and post-operative adverse events, especially including bleeding and lymph
leakage
[Time Frame: from study start to study end]

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TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
Page 7 of 27 
Table of Contents 
1 
Administrative information................................................................................................ 2 
1.1 
Contacts ................................................................................................................. 2 
1.2 
Approval ................................................................................................................. 3 
2 
Summary ......................................................................................................................... 4 
3 
Introduction .................................................................................................................... 10 
4 
Study Objective(s) ......................................................................................................... 10 
5 
Study Administrative Structure ....................................................................................... 11 
5.1 
Study Sites ........................................................................................................... 11 
5.2 
Sponsor Personnel ............................................................................................... 11 
5.3 
Contract Research Organisation (CRO) ............................................................... 11 
5.4 
Essential Documents ............................................................................................ 11 
6 
Ethics ............................................................................................................................ 11 
6.1 
Ethical conduct of the Study ................................................................................. 12 
6.2 
Independent Ethics Committee / Institutional Review Board and Authorities ......... 12 
6.3 
Patient Information and Written Informed Consent ............................................... 12 
7 
Study Design and Plan .................................................................................................. 13 
7.1 
Study Schedule .................................................................................................... 14 
7.2 
Discussion of Study Design .................................................................................. 14 
7.3 
Selection of Study Population ............................................................................... 15 
7.4 
Treatments ........................................................................................................... 15 
8 
Conduct ......................................................................................................................... 16 
9 
Management and Reporting of Adverse Events ............................................................. 18 
9.1 
Definitions............................................................................................................. 18 
9.2 
Classifications ...................................................................................................... 18 
9.3 
Reporting of Adverse Events ................................................................................ 20 
9.3.1 Reporting of Pregnancies and Breast-feeding .............................................. 21 
9.3.2 Reporting of Misuse and Medication Error ................................................... 21 
10 Data Quality Control and Assurance .............................................................................. 21 
10.1 Quality Control ...................................................................................................... 21 
10.2 Audit from Quality Assurance Unit ........................................................................ 21 
10.3 Inspection by IRB/IEC or Competent Authority ..................................................... 21 
10.4 Data Management ................................................................................................ 22 
10.4.1 
Data Collection Tools and Flow ............................................................... 22 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 8 of 27 
 
 
10.4.2 
Query management ................................................................................ 23 
11 Statistical Methods and Determination of Sample Size .................................................. 23 
11.1 Statistical Analysis Plan ........................................................................................ 23 
11.2 Interim Analyses ................................................................................................... 24 
11.3 Determination of Sample Size .............................................................................. 24 
12 Reports .......................................................................................................................... 26 
13 Publications ................................................................................................................... 26 
14 Archiving of Study Documentation ................................................................................. 26 
15 References .................................................................................................................... 26 
 
APPENDICES 
1. 
SmPC, TachoSil® sealant matrix, German language 09/2014 
 
 
 
 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 9 of 27 
 
 
List of Abbreviations and Definition of Terms 
AE: 
 
Adverse Event 
ADR:  
Adverse Drug Reaction 
CA: 
 
Competent Authority 
CCSI:  
Core Company Safety Information 
CRF:  
Case Report Form 
CRO:  
Contract Research Organisation 
CV: 
 
Curriculum Vitae 
GCP:  
Good Clinical Practice 
GPP:  
Good Pharmacoepidemiology Practices 
ICH: 
 
International Conference on Harmonisation 
ICU:   
Intensive care unit 
IDS: 
 
International Drug Safety 
IEC: 
 
Independent Ethics Committee 
IRB: 
 
Institutional Review Board 
NIS: 
 
Non-interventional study 
PP:  
 
Per Protocol 
PSUR:  
Periodic Safety Update Report 
SAE:  
Serious Adverse Event 
SAF:  
Safety Population 
SAP:  
Statistical Analysis Plan 
SADR:  
Serious Adverse Drug Reaction 
SmPC: 
Summary of Product Characteristics 
 
 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 10 of 27 
 
 
3 
Introduction 
TachoSil® consists of a collagen sealant matrix coated with human fibrinogen and human 
thrombin for use as a local haemostatic and tissue sealing. This fixed combination is applied 
directly to the wound surface. Upon contact with blood, body fluids, or physiological saline, 
the components of the coating dissolve and diffuse into the wound surface. Thrombin 
converts fibrinogen into fibrin, mimicking the final stage of the coagulation cascade, and 
forming a cross-linked fibrin clot, which holds the collagen matrix tightly to the wound surface 
providing local haemostasis and tissue sealing. The active side of the coating sealant matrix 
is marked in yellow.  
Extensive experience on the use of TachoSil® in open invasive surgery5 and its relevant 
results in respect to reduction of time to hemostasis5,7,8, change in length of hospital stay5,9,10 
and decrease in postoperative complications5,9,11 encouraged surgeons to apply TachoSil® in 
minimal invasive (laparoscopic) surgery as well6. As laparoscopic techniques require the 
application of TachoSil® through a trocar, surgeons started preparing TachoSil® themselves 
raising the need to develop a pre-rolled form which was approved by the European 
Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) in 
September 2014. 
No clinical trials using pre-rolled TachoSil have been performed. This real-world 
observational study is conducted to obtain an overview on the ease of use of pre-rolled 
TachoSil® in laparoscopic use, especially when performing gynaecological, urological and 
visceral surgery. Additionally, users’ satisfaction with the product will be evaluated to 
confirm procedural advantages of the pre-rolled form in laparoscopic use. 
 
4 
Study Objectives 
• 
To describe ease of use and satisfaction with application of the pre-rolled TachoSil in 
laparoscopic procedures within approved therapeutic indication (SmPC). 
  
• 
To assess whether pre-rolled TachoSil is a valuable tool from the surgeon's view for 
reducing post-surgical complications, especially bleeding and lymph leakage. 
 
• 
To perform a costs analysis (length of hospital stay, avoidance of complications, cost 
savings etc.) based on information given by physicians and pecuniary considerations 
(Euro)  
 
• 
To describe safety in the routine use of pre-rolled TachoSil in laparoscopic surgery. 

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TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 12 of 27 
 
 
 
6.1 Ethical conduct of the Study 
This study will be conducted in accordance with the protocol, the current version of the 
Declaration of Helsinki, Good Pharmacoepidemiology Practices (GPP), ISPE GPP guideline 
and any local regulations. Special attention will be paid to data protection as described in 
Directive 95/46/EC. 
Takeda will ensure that the protocol, any amendments and the Patient Information 
Sheet/Informed Consent Form are submitted to the relevant Independent Ethics Committees 
(IECs) according to local requirements. 
Takeda as the sponsor is responsible for meeting the ICH requirement for yearly updates to 
the IECs, if applicable. 
 
6.2 Independent Ethics Committee  
According to all relevant local regulations, the Sponsor will: 
• 
notify or obtain approval from the relevant IEC of the protocol, any amendments and the 
Patient Information Sheet / Informed Consent Form 
The Sponsor will submit required documents to the IEC, such as: 
• 
notification of substantial changes of the study documents 
• 
notification of the end-of-study 
• 
a summary of the study results 
 
Sponsor/CRO will keep an updated list of all submission and approval dates of all 
documents submitted to the IEC and will provide the Site Responsible with a copy of this list. 
Copies of the documents will be distributed upon request. 
 
Authorities 
Sponsor will send required documents to the competent authority (CA) and/or other national 
or regional authorities. Sponsor will keep an updated list of submission and approval dates 
and a copy of all documents submitted. 
 
6.3 Patient Information and Written Informed Consent 
The Site Study Responsible must give the patient (and if applicable, legal guardian) oral and 
written information about the study in a form that the patient (legal guardian) can understand, 
and obtain the patient’s (and if applicable, the patient’s assent and the legal guardian’s) 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 13 of 27 
 
 
written consent before collection of identifiable patient information (hereinafter referred to as 
personal data). Before consenting, the patient (and if applicable, legal guardian) must be left 
with ample time to consider and to pose questions.  
Since the study is observational the consent only concerns the data collection per se and is 
no consent to any experimental procedure or treatment. 
As patients will only be eligible for study participation in case pre-rolled TachoSil® has been 
applied during surgery, information regarding the study will be provided to potential 
participants before the surgery, but consent will be collected only after the surgery. 
 
The patient must agree that sponsor personnel, their representatives or IEC or CA personnel 
(national or other) may require direct access to the patient’s data / personal records which 
were collected, processed and stored in an anonymized form. 
 
The patient must agree that his / her data will be processed and stored in an anonymized 
form for evaluation of this study and any later overviews. Data may also be transferred in 
anonymized form to third parties, e.g. other companies or authorities, that may be located in 
other countries with potentially different regulations for data.  
The patient and legal guardian, if applicable, has the right to withdraw his/her consent at any 
time without prejudice. In the Informed Consent Form it is stated that if consent is withdrawn, 
any data collected before withdrawal of consent will be kept unless its deletion is actively 
requested by the patient. The original, signed Informed Consent Forms must be kept on the 
Site. 
For details, see the Patient Information Sheet and Informed Consent Form. 
 
7 
Study Design and Plan 
This study is a ‘non-interventional study’ as defined in: G-STND-PV-006, Directive 
2001/83/EC (4) and will follow the guidelines for GPP (2). Additional applicable sponsor 
SOPs are: 1410A-SOP-0000001.03, DE-BE-MED-ALL-025. 
 
This means that: 
• 
The assignment of a patient to a particular therapeutic strategy is not decided in advance 
by the study protocol but falls within current practice 
• 
No additional diagnostic or monitoring procedures shall be applied to the patients 
• 
Epidemiological methods shall be used for the analysis of collected data 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 14 of 27 
 
 
• 
Pre-rolled TachoSil® is prescribed in accordance with the terms of the marketing 
authorisation(s) 
• 
The prescription of pre-rolled TachoSil® is clearly separated from the decision to include 
the patient in the study 
 
7.1 Study Schedule 
Planned Start of Study: 
 
 
 
October 2015 
Planned collection of first data point: 
 
October 2015 
Planned collection of the last data point: 
 
November 2016 
Planned End of Study: 
 
 
 
February 2017 
Planned completion of the Study Report: 
 
May 2017 
 
The Start of Study is defined as country specific IEC votes are available.  
The End of study is defined as database lock. 
 
Sponsor will ensure that End-of-Study notification is submitted to the concerned authorities 
and IEC for each site, for each country and for the complete study, as locally required. 
 
Global Research will ensure that results are posted on “clinicaltrials.gov” and Sponsor will 
ensure that results are posted as required by local authorities.  
 
Based on upcoming knowledge, Takeda might choose to terminate the study prematurely. In 
such case the Committee(s), study sites, IECs and authorities will be informed promptly. 
 
7.2 Discussion of Study Design 
This study is a non-interventional, international, prospective, multi-site cohort study in 
patients planned for laparoscopic surgery in the field of gynecology, urology or visceral 
surgery. A patient can be included in the study when the physician has decided to use pre-
rolled TachoSil® according to the local SmPC.  
There are no treatment groups or interventions to which the patients can be randomly 
assigned. Data will be collected in a routine setting. Participating physicians will not perform 
any medical procedures that are outside of their normal routine. All treatment decisions are 
at the sole discretion of the participating physicians and reflect their current standard of care. 
The decision to apply pre-rolled TachoSil® must be made independently from the decision to 
include a patient in this study. 

TachoSil-4001 
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Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 15 of 27 
 
 
Results from this study are prone to selection bias, e.g. by selecting sites experienced in 
using pre-rolled TachoSil® in laparoscopic surgery, or by including patients with known 
surgical outcome. Also confounding factors prevail in patients in a real-world setting, e.g. by 
indication, concurrent disease, concomitant drugs, or differing surgical procedures among 
sites. 
It is acknowledged that such biases are present in any observational study. These limitations 
of the study design are inherent and result from the non-interventional character and the 
voluntary participation of physicians and patients. 
 
7.3  Selection of Study Population 
It is planned to include up to 105 Austrian and 360 German inpatients who have undergone 
laparoscopic surgery in the field of gynecology, urology and visceral surgery where pre-
rolled TachoSil® was applied and who are 18 years or older. 
Contraindications, such as hypersensitivity to the active pharmaceutical ingredient or to 
another ingredient of pre-rolled TachoSil®, are to be observed according to the current 
SmPC. 
The observational period for individual patient will last from surgery (V0: Baseline) until date 
of discharge from hospital (V1: Final visit). 
Data will be collected from patient files as well as study specific questions answered by the 
treating physician. 
Written informed consent to use of collected data must always be obtained before collection 
of any study specific personal, sensitive data. 
Subjects should be included in the study only once.  
Data erroneously collected from subjects for which written consent is not available, will not 
be included in or will be deleted from the database. 
 
7.4 Treatments 
Non-interventional/observation – no experimental treatments/pharmacotherapy are 
applicable.  
A patient can be included in the study when the physician has decided to use pre-rolled 
TachoSil® according to the local SmPC.  
There are no treatment groups or interventions to which the patients can be randomly 
assigned. Data will be collected in a routine setting. Participating physicians will not perform 
any medical procedures that are outside of their normal routine. All treatment decisions are 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 16 of 27 
 
 
at the sole discretion of the participating physicians and reflect their current standard of care. 
The decision to apply pre-rolled TachoSil® must be made independently from the decision to 
include a patient in this study. 
 
8 
Conduct 
Data collection overview: 
Type of data point 
Timing of data point 
 
Before 
diagnosis/ 
treatment 
At time of 
surgery 
Time interval 1 
(After surgery 
until discharge 
from hospital) 
End of data 
collection (day of 
discharge from 
hospital) 
Investigator contract 
signed 
x 
 
 
 
ICF signed 
 
 
x 
 
Inclusion/Exclusion 
criteria 
 
 
x 
 
Demographics 
 
x 
 
 
Medical history 
x 
x 
 
 
Surgery parameters 
 
x 
 
 
Adverse events after 
application of pre-
rolled TachoSil® 
 
x 
x 
x 
Post-operative 
parameters 
 
 
x 
x 
Assessment by the 
surgeon (5-Point-
Likert-Scales)  
 
 
x 
x 
Cost-effectiveness 
 
 
 
x 
 
Demographics: 
- 
Age, gender (if gender is female, pregnancy/breast-feeding (yes/no) should be 
documented), height, weight 
 

TachoSil-4001 
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Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 17 of 27 
 
 
Inclusion criteria: 
- 
Inpatient planned for laparoscopic surgery, in the field of gynecology, urology and 
visceral surgery where pre-rolled TachoSil® was applied and at least 18 years of age 
 
Exclusion Criteria:  
- 
Contraindications, such as hypersensitivity to the active pharmaceutical ingredient or 
to another ingredient of pre-rolled TachoSil®, according to the current SmPC. 
- 
Patient participates in another clinical trial. 
 
Medical history: 
- 
Concomitant diseases  
- 
Evaluation of haemorrhage risk 
- 
Coagulation status 
 
Intra-operative parameters: 
- 
Coagulation status 
- 
Diagnosis underlying surgery, including type of surgery (gynecology, urology or 
visceral surgery) 
- 
Indication for use of pre-rolled TachoSil® (hemostasis, tissue sealing or suture 
support) 
- 
Description of surgery (Type of minimal-invasive surgical technique, duration) 
- 
Description of TachoSil application (diameter of trocar, dry/wet, localisation, number 
of pre-rolled TachoSil® applied during surgery, time of compression) 
- 
Primary techniques used for tissue sealing/hemostasis 
- 
Intra-operative adverse events after application of pre-rolled TachoSil® 
- 
Assessment of pre-rolled TachoSil® by the surgeon:  
- 
      -    ease of use (5-Point-Likert-Scale) 
- 
      -    satisfaction with the application of pre-rolled TachoSil (5-Point-Likert-Scale) 
 
Post-operative parameters: 
- 
Post-operative adverse events, especially including bleeding and lymph leakage 
- 
length of ICU and overall hospital stay 
 
Overall assessment of pre-rolled TachoSil® by the surgeon:  

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 18 of 27 
 
 
      -    overall satisfaction with the application of pre-rolled TachoSil (5-Point-Likert-Scale 
      -    cost-effectiveness, based on subjective assessment of the surgeon, shortening of 
surgery time and hospital stay.  
 
Adverse events, exposure of a pregnant patient to pre-rolled TachoSil® or pregnancy/breast-
feeding after application of pre-rolled TachoSil®, as well as medication error, suspected 
transmission of an infectious agent and lack of effect.  
 
Informed Consent will be obtained before collection of the first data point. 
 
9 
Management and Reporting of Adverse Events 
 
9.1 Definitions 
Adverse Event 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not the event is considered causally related to the use of the product.  
All AEs (Serious adverse events (SAEs) and adverse events which do not meet the criteria 
of a SAE), will be recorded and reported in this study. SAEs are defined below in Section 
9.2.  
 
9.2 Classification 
Serious Adverse Events 
A Serious Adverse Event (SAE) is an AE that meets any of the following criteria: 
• 
Is fatal or life threatening, i.e., in the view of the Investigator, places the patient at 
immediate risk of death from the reaction as it occurred. An event would not be 
classified as life threatening solely because, had it occurred in a more serious form, it 
might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening, even though 
drug-induced hepatitis can be fatal.  
• 
Results in persistent or significant disability or incapacity. Disability is defined as a 
substantial disruption of a person's ability to conduct normal life functions. 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization.  
• 
Is a congenital anomaly/birth defect.  

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 19 of 27 
 
 
• 
Any other important medical event that may not result in death, be life-threatening or 
require hospitalization, but based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed above.   
 
Hospitalization for underlying disease progression will constitute an SAE. Hospitalization for 
an elective or planned procedure to treat a pre-existing condition is not considered an SAE, 
unless it results in one of the other outcomes listed above. 
 
Severity  
The Investigator will use the following definitions of severity in the evaluation of AEs: 
• Mild: An AE that is easily tolerated and does not interfere with daily activities. 
• Moderate: An AE that is sufficiently discomforting so as to interfere with daily activities. 
• Severe: An AE that prevents normal everyday activity. 
Note that “severe” is not synonymous with “serious”: an AE may be assessed as severe 
without meeting the criteria for an SAE (see above) 
 
Assessment of Relationship to Study Drug  
The following definitions of relationship should be used to characterize the suspected 
causality of each AE as either related or not related to pre-rolled TachoSil®. This assessment 
should be based on the Investigator's consideration of all available information about the 
event, including temporal relationship to drug administration, recognized association with 
drug product/class, pharmacological plausibility, and alternative etiology (e.g., underlying 
illness, concurrent conditions, concomitant treatments): 
• Related: There is a reasonable possibility that the drug caused the event.  
• Not related: There is not a reasonable possibility that the drug caused the event 
 
Adverse Reactions 
For the purposes of this study, an adverse reaction is an AE that is considered related to 
pre-rolled TachoSil® according to the definition above. 
 
Outcome 
• 
Fatal: The patient died due to the event. If the patient died due to other circumstances 
than the event the outcome should be stated as ‘Not recovered’ or ‘Recovering’. 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 20 of 27 
 
 
• 
Recovered/Resolved: The patient has fully recovered from the event or the condition 
has returned to the level observed at baseline. 
• 
Recovering/Resolving: The event is improving but the patient is still not fully 
recovered. 
• 
Not Recovered/Not Resolved: The event is ongoing at the time of reporting and the 
patient has still not recovered. 
• 
Recovered with Sequelae/Resolved with Sequelae: As a result of the event, the 
patient suffered persistent and significant disability/incapacity (e.g. became blind, deaf 
or paralysed). 
• 
Unknown: If Outcome is not known or not reported. 
 
9.3 Reporting of Adverse Events 
Documentation of AEs will commence after a patient has provided informed consent 
and pre-rolled TachoSil® was applied in that patient. AEs and SAEs (which include all 
deaths) must be reported, whether or not considered causally related to pre-rolled 
TachoSil®. 
In case of a SAE, the Investigator will notify the Sponsor through use of the SAE form, 
within 24 hours after the Investigator becomes aware of the event. The event must be 
documented in source documentation. 
 
AEs which do not meet the criteria of SAEs are documented through use of the AE 
form within the study CRF.  
 
After receipt of the initial report, the information will be reviewed, and the Investigator 
might be contacted to request additional information or for data clarification. If required, 
a follow-up report, including all new information obtained on the event, must be 
prepared and sent to the designated contact of the Sponsor.  
 
The Sponsor assumes responsibility for reporting of AEs/SAEs occurring in patients 
exposed to pre-rolled TachoSil® to regulatory authorities according to legal 
requirements. 
 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 21 of 27 
 
 
  9.3.1 Reporting of Pregnancy and Breast-feeding 
Any case in which a pregnant patient or a patient that is breast-feeding is exposed to pre-
rolled TachoSil® this information needs to be forwarded to the Sponsor using the SAE form 
regardless whether an AE results or not. 
 
  9.3.2 Reporting of Medication Error 
All information of medicinal product medication error, suspected transmission of an 
infectious agent or lack of effect relating to pre-rolled TachoSil® regardless of whether an 
SAE results or not, need to be forwared to the Sponsor using the SAE form. 
 
10 Data Quality Control and Assurance 
 
10.1 Quality Control 
The quality of data and adherence to the NIS protocol, to legal and ethical requirements will 
be overseen by the CRO applying a combination of centralized and on-site monitoring.  
All CRFs will be reviewed for pre-defined criteria (e.g. ICF, AEs and study treatment), and 
queries will be raised in case of deviations. 
On-site visits will be scheduled in approx. 5% of sites (1 Austrian and 3 German sites), 
including source data verification of pre-defined items (e.g. ICF, AE data and Patient 
Identification List). 
The extent and nature of quality assurance will be described in detail in the monitoring plan. 
If applicable, for further information see sponsor SOPs: G-SOP-MA-005, C-GUID-DO-354 
and C-GUID-DO-333. 
 
10.2 Audit from Quality Assurance Unit 
The Quality Assurance (QA) unit may audit the study to ensure that study procedures 
comply with the protocol and standard operating procedures, and that collected data is 
correct and complete. 
 
10.3 Inspection by IEC or Competent Authority 
Representatives from EC or Competent Authority may in rare cases wish to inspect the 
study on site. Upon receiving notification of such inspection, the Study Site Responsible 
must immediately contact the Sponsor and must make the records available as requested.  

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TachoSil-4001 
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Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 24 of 27 
 
 
[Time Frame: intra- and post-surgery until hospital discharge] 
 
Secondary 
- Length of hospital stay (ICU and normal hospital station) 
[Time Frame: Date of surgery until hospital discharge]  
 
- Pharmaco-economic evaluation as assessed by the surgeon  
[Time Frame: intra- and post-surgery until hospital discharge]  
 
- Safety intra- and post-operative adverse events 
[Time Frame: from study start to study end]  
 
Health economics 
Cost analysis (length of hospital/ICU stay, avoidance of complications, cost savings) based 
on information given by physicians and pecuniary considerations (cost per minute of 
surgery/day in ICU/day in normal ward) 
 
AEs/SAEs reported in the study as well as AEs/SAEs reported directly to authorities and to 
Takeda Drug Safety according to section 9.3 and not captured in the study database will be 
extracted from the overall safety database and the study database and listed or tabulated in 
the final report in the standard way of presenting such data in a Periodic Safety Update 
Report (PSUR). 
 
11.2 Interim Analyses 
No interim analyses are planned for this study.  
 
11.3 Determination of Sample Size 
It is planned to collect data from up to 50 german hospitals and 10 ustrian hospitals 
performing laparoscopic surgery, from departments of gynecology, urology and visceral 
surgery. Each study centre should document only up to 20 patients. 
 
As primary outcome measures the peri- and post-surgery assessment by the surgeon with 
respect to ease of use and overall satisfaction in the operation, using 5-point-Likert-Scales (1 
= easy/satisfied, 5 = difficult/ not satisfied) are fixed in the study protocol. It is expected that 

TachoSil-4001 
(RollOut) 
Observational/Non-Interventional 
Study Protocol 
 20th August 2015 
 
 
Page 25 of 27 
 
 
the use of pre-rolled TachoSil® is easier than the application of planar TachoSil® 
prepared/rolled by the surgeons themselves. 
No published paper could be found with an identical outcome measure ’ease of use’, which 
could have served as base for sample size calculation. Therefore the results of an older 
study with a specific MIS -applicator as a surrogate approach (Nycomed Arzneimittel GmbH 
1998) were used.  
Amongst others a parameter called ‘Handhabungs-Score’ (handling- score) was considered 
as outcome parameter according to the study protocol. This parameter comes very close to 
the parameter ’ease of use’ intended to be used in the present RollOut-study. This score 
was calculated as the sum of the answers from a questionnaire with 5 AMISA-specific items. 
In the best case, this score takes a value of 5, in the worst case a value of 17. The results for 
the handling score showed that in 82% of cases the score was less or equal 9 points and 
about 18% greater than 9 points. 
 
To show in a 1-group design (NIS) that this rate can be reduced with the use of pre-rolled 
TachoSil® significantly to 9%- points (= 0.05, power = 80%,  two-tailed one group Chi2- test) 
it takes a minimum of 122 patients without any drop-out (see Table 2 below). To investigate 
this hypothesis in 3 fields of surgery (gynecology, urology and visceral surgery) 
independently, a total of 366 patients is needed. Since it is expected to improve the power 
from 80% up to 90% a minimum of 155 patients in each field and a total up to 465 should be 
included into the Study. 
 
Test significance level,  
  0.050 
0,050 
1 or 2 sided test? 
   2 
2 
    Null hypothesis proportion, 0 
 0.180 
0,180 
    Alternative proportion, A 
 0.090 
0,090 
Power (%) 
80 
90 
N 
 122 
155 
Table 2: Comparison of a portion A against a fixed portion 0 (asymptotic Chi2-test); determined with the program N-Query 7.0 
according to Dixon et al. (1983) 
 

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Observational/Non-Interventional 
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 20th August 2015 
 
 
Page 26 of 27 
 
 
12 Reports 
A Non-Interventional Study Report based on the results obtained will be prepared and 
submitted to Global Medical Affairs for distribution. The Final Study Report should be 
available within one year from database lock.  
 
13 Publications 
Takeda aims to have the results of this study published. 
 
Takeda has the right to use the data and results for regulatory purposes and for internal 
presentation within the company and to partners. 
 
14 Archiving of Study Documentation 
During the course of the study the Site Responsible must as a minimum file the essential 
documents (Section 5.4), the protocol, any amendments, the list of participating patients, the 
written informed consents, the CRFs and the progress reports in the Study Site File. After 
final database lock the Site Responsible must as a minimum store the list of participating 
patients and the signed Informed Consent Forms on site for 10 years. The Site Responsible 
should store additional study documentation for a longer period of time as required by any 
local regulations and/or hospital requirement. 
 
15 References 
1. World Medical Association Declaration of Helsinki. Ethical principles for Medical 
Research Involving Human Subjects, Helsinki 1964, amended in Tokyo 1975, Venice 
1983, Hong Kong 1989, South Africa 1996, Edinburgh 2000, and Seoul 2008. 
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