Non-Interventional Study Report - vfa · TC-2402-401-DE Non-Interventional Study Report Takeda GCP-602-S087 Version 01.0 Effective date: 15 Oct 2008 Non-Interventional Study Report

TC-2402-401-DE Non-Interventional Study Report

Takeda

GCP-602-S087 Version 01.0 Effective date: 15 Oct 2008

Non-Interventional Study Report Document ID: <<<>>>

Page 1 of 51 Date: 16 February 2015

Non-Interventional Study Report

Short title: SEAL

Title: Use of TachoSil for lymph sealing during surgery

(German title: TachoSil in der Lymphversiegelung)

Study ID: TC-2402-401-DE

Sponsor: Takeda Pharma Vertrieb GmbH & Co. KG

Jägerstraße 27, D-10117 Berlin

Germany

Phone: +49-0-800 295-3333

Fax: +49-0-800 295-5555

Study phase: Therapeutic use

Date of study initiation: 30-Sep-2012 (first patient in)

Date of study completion: 27-Mar-2014 (last patient out)

Date of draft/final version of report: 16 December 2014 (final)

This study was conducted in accordance with Good Pharmacoepidemiology Practices.

This document is the property of Takeda and should be kept confidential by the involved

parties.


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List of Abbreviations and Definition of Terms

ADR: Adverse drug reaction

AE: Adverse event

AMG: German Drug Law (‘Arzneimittelgesetz’)

BfArM: Bundesinstitut für Arzneimittel und Medizinprodukte

BMI: Body mass index

CRF: Case report form

CRO: Contract research organisation

EC: Ethics committee

ECOG: Eastern Cooperative Oncology Group

FIGO: International Federation of Gynaecological Oncologists

GKV: (German) Central Federal Association of the Health Insurance Funds

GMP: Good Manufacturing Practices

GPP: Good Pharmacoepidemiology Practices

ICSR: Individual case safety report

ICU: Intensive care unit

INR: International normalised ratio

ITT: Intention-to-treat

KBV: (German) Association of Statutory Health Insurance Physicians

LN: Lymph node

MedDRA: Medical Dictionary for Regulatory Activities

N: Number (of patients)

PEI: Paul-Ehrlich-Institute

pTT: Partial thromboplastin time

SAE: Serious adverse event

SADR: Serious adverse drug reaction

SAP: Statistical analysis plan

SD: Standard deviation

SPC: Summary of Product Characteristics

TNM: Tumour-node-metastasis (classification)


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Table of Contents

Non-Interventional Study Report ............................................................................................ 1

List of Abbreviations and Definition of Terms ......................................................................... 3

Table of Contents ................................................................................................................... 4

1 Ethics .............................................................................................................................. 7

1.1 Ethics Committees .................................................................................................. 7

1.2 Ethical Conduct of the Study .................................................................................. 7

1.3 Patient Information and Consent ............................................................................ 7

1.4 Critical Documents ................................................................................................. 8

2 Introduction ...................................................................................................................... 8

3 Study Objective(s) ........................................................................................................... 9

4 Study Design and Plan .................................................................................................. 10

4.1 Discussion of Study Design Including Use of Comparator Medication .................. 11

4.2 Selection of Study Population ............................................................................... 12

4.3 Treatments ........................................................................................................... 12

5 Conduct ......................................................................................................................... 13

5.1 Study Schedule .................................................................................................... 13

5.2 Assessments ........................................................................................................ 14

5.2.1 ECOG Performance Status ..................................................................... 14

5.2.2 TNM Staging System .............................................................................. 15

5.2.3 FIGO Classification ................................................................................. 15

5.2.4 Evaluation of TachoSil........................................................................... 15

6 Safety Reporting ............................................................................................................ 16

6.1 Definitions............................................................................................................. 16

6.2 Documentation of Adverse Events / Adverse Drug Reactions ............................... 16

7 Data Quality Assurance ................................................................................................. 17

7.1 Monitoring and Source Document Verification ...................................................... 17

7.2 Audit by International Quality Assurance Unit ....................................................... 17

7.3 Inspection by Competent Authority ....................................................................... 17

7.4 Data Management and Data Handling .................................................................. 17

8 Statistical Methods and Determination of Sample Size .................................................. 17

8.1 Statistical Plan ...................................................................................................... 18

8.1.1 Definition of Analysis Set ........................................................................ 18

8.1.2 Endpoints ................................................................................................ 18


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8.1.3 Descriptive Statistics ............................................................................... 19

8.1.4 Inferential Statistics ................................................................................. 19

8.2 Determination of Sample Size .............................................................................. 19

8.3 Interim Analyses ................................................................................................... 19

8.4 Handling of Missing Data and Withdrawals ........................................................... 20

8.5 Baseline Comparability of Treatment Groups ....................................................... 20

8.6 Software ............................................................................................................... 20

9 Changes in the Planned Analyses ................................................................................. 20

10 Patients ......................................................................................................................... 20

10.1 Disposition of Patients .......................................................................................... 20

10.2 Protocol Deviations ............................................................................................... 21

11 Results .......................................................................................................................... 21

11.1 Data Sets Analysed .............................................................................................. 21

11.2 Demographic and Baseline Features .................................................................... 21

11.2.1 Experience in the Use of TachoSil® ......................................................... 21

11.2.2 Demographic Data .................................................................................. 22

11.2.3 Main Diagnosis and Baseline Characteristics of the Primary Disease ..... 23

11.2.4 Previous Treatment of the Underlying Disease ....................................... 26

11.2.5 Concomitant Diseases ............................................................................ 26

11.2.6 Assessment of Bleeding Risk, Coagulation Parameters, and Management

of Bleeding .............................................................................................. 27

11.3 Details of the Operation ........................................................................................ 28

11.3.1 Type of Surgery ...................................................................................... 28

11.3.2 Haemostatic Measures Taken prior to the Application of TachoSil® ........ 30

11.4 Extent of Exposure ............................................................................................... 31

11.4.1 Number of TachoSil® Patches Used ........................................................ 31

11.4.2 Mode of Application ................................................................................ 32

11.4.3 Purpose of TachoSil® Application ............................................................ 33

11.5 Efficacy and Safety Evaluation ............................................................................. 34

11.5.1 Variable of Primary Interest ..................................................................... 34

11.5.1.1 Incidence of Postoperative Seroma Formation ................................... 34

11.5.2 Variables of Secondary Interest .............................................................. 34

11.5.2.1 Incidence of Postoperative Complications .......................................... 34

11.5.2.2 Usage of Drainage and Changes in Drainage Management ............... 35


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11.5.2.3 Postoperative Thrombosis Prophylaxis ............................................... 37

11.5.2.4 Length of Hospital Stay ...................................................................... 37

11.5.2.5 Previously used Techniques, Methods, or Products in Similar Cases . 37

11.5.2.6 Evaluation of the Benefit of TachoSil® for Lymph Sealing Compared to

Alternative Techniques, Methods or Products .................................... 38

11.5.2.7 Evaluation of TachoSil® (Handling, Usefulness, Satisfaction) ............. 40

11.5.2.8 Pharmacoeconomic Evaluation .......................................................... 42

11.5.2.9 Requirement of Additional Sizes of TachoSil® .................................... 44

11.5.2.10 Adverse Events .................................................................................. 44

12 Discussion ..................................................................................................................... 45

13 Conclusion ..................................................................................................................... 49

14 References .................................................................................................................... 50

APPENDICES

1. Study Protocol and Case Report Form (in German)

2. Patient Information Sheet/Informed Consent Form (in German)

3. Summary of Product Characteristics (German version, June 2010)

4. Statistical Analysis Plan

5. End-of-text Tables

6. Patient Listings


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1 Ethics

1.1 Ethics Committees

The study-relevant documents (study protocol and case report form, Appendix 1, and patient

information sheet/informed consent form, Appendix 2) were submitted to the responsible

ethics committee (‘Ethikkommission, Universitätsmedizin Greifswald, Institut für

Pharmakologie’) for ethical advice. This EC provided a positive opinion during the session on

27 November 2012.

According to § 67 (6) of the German drug law, the Paul-Ehrlich-Institute (i.e. the competent

higher federal authority for blood preparations and blood components, among others), the

Central Federal Association of the Health Insurance Funds (GKV), and the National

Association of Statutory Health Insurance Physicians (KBV) were notified of this non-

interventional study.

In addition, the study was registered in a publicly accessible clinical trials registry

(www.clinicaltrials.gov).

1.2 Ethical Conduct of the Study

This study was conducted in accordance with the Declaration of Helsinki (Ref. 1) and Good

Pharmacoepidemiology Practices (GPP) (Ref. 2), and applicable local requirements.

1.3 Patient Information and Consent

In agreement with local regulations, the physician (surgeon) gave the patient oral and written

information about the study in a form that the patient could understand before the collection

of personal data1.

The physician obtained the patient’s voluntary consent for the collection of personal data and

transfer of the data in pseudonymous form before the start of the documentation. The patient

had the right to withdraw his/her consent at any time without prejudice. The original, signed

informed consent forms are kept in the physician file.

For details, see the patient information sheet and informed consent form (Appendix 2).

1 There were 13 patients who have had the documented lymph node resection prior to the start of this study;

these patients provided their informed consent after study start and data were then collected retrospectively from

the patients’ medical files (see also Section 5.1).


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1.4 Critical Documents

Before the study was initiated at a site, the following documents from the site were in the

hands of Takeda:

Written agreement between Takeda and the Physician(s)

Written notification of the study to the Competent Authority (Paul-Ehrlich-Institute)

according to local regulations;

Written notification of the study to the Central Federal Association of the Health

Insurance Funds (GKV) according to local regulations;

Written notification of the study to the National Association of Statutory Health Insurance

Physicians (KBV) according to local regulations;

Written opinion of the EC confirming no ethical concerns regarding the study according

to local regulations;

Patient Information Sheet and Informed Consent Form in local language according to

local regulations.

Participating physicians were reported to the Paul-Ehrlich-Institute, the GKV and KBV upon

agreement for participation in this non-interventional study.

2 Introduction

Lymphadenectomy (lymph node dissection), i.e. the surgical removal of lymph glands, is

principally performed to determine whether a cancer has started to metastasise or prevent

further spread of cancer cells in the body. Among the postoperative complications that may

occur after lymphadenectomy are the formation of lymphocysts, lymphoceles (cavity without

an epithelial lining filled with lymph fluid) and seroma (accumulation of lymph fluid or ichor in

a tissue or organ). A variety of approaches may be used to prevent leakage of blood or

lymph fluid from capillaries or lymph channels, including ultrasonic dissection,

electrocoagulation, infrared coagulation, and fibrin sealants.

TachoSil is a fixed combination of tissue-adhering components in solid form and a collagen

patch. It is indicated in adults for supportive treatment in surgery for improvement of

haemostasis, to promote tissue sealing, and for suture support in vascular surgery where

standard techniques are insufficient.

The yellow side of the TachoSil patch contains the active components: human fibrinogen

and human thrombin. When this side comes in contact with physiological fluids, e.g. blood,


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lymph or physiological saline solution, the components of the coating dissolve and partly

diffuse into the wound surface. This is followed by the fibrinogen-thrombin reaction which

initiates the last phase of physiological blood coagulation. Fibrinogen is converted into fibrin

monomers which spontaneously polymerise to a fibrin clot, which binds the collagen patch

tightly to the wound surface. The fibrin is then cross linked by endogenous factor XIII,

creating a firm, mechanically stable network with good adhesive properties and therefore

provides sealing as well.

Intra-operative application of TachoSil has been shown to reduce the rate of lymphocysts

and prevent the development of lymphoceles after pelvic lymphadenectomy (Ref. 3, 4).

For further information on efficacy and safety of TachoSil see the Summary of Product

Characteristics (SPC) (Appendix 3).

3 Study Objective(s)

The aim of this non-interventional study was to collect further knowledge on the routine use

of TachoSil® in lymph node surgery where its sealing property (see SPC) helps to reduce the

rate of postoperative complications, especially of seroma formation. Some data were already

available from gynaecology, urology and thoracic surgery (Ref. 3-5).

In particular, the following aspects were examined in this study:

Knowledge was to be gathered with respect to the application of TachoSil for lymph

sealing after lymphadenectomy;

Acceptance and practicability of the product were to be evaluated in both open and

minimally invasive interventions;

The precise experiences of TachoSil users during application were to be examined and

evaluated;

Pharmacoeconomic aspects that the applying surgeon could deduce from the use of the

medicinal product were to be recorded and evaluated.

Adverse events (AEs) were to be observed and recorded.

Upon consideration of the results of this investigation, Takeda will decide whether

modifications to the product should be or must be undertaken to better meet the needs and

requirements during use.


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4 Study Design and Plan

This study, which is a single-arm, prospective, observational cohort study, was conducted as

a “non-interventional study” as defined in Directive 2001/20/EC (Ref. 6) and followed the

guidelines for GPP (Ref. 2), the applicable German regulations (§67 Abs. 6 AMG), the

recommendations of the Federal Institute for Drugs and Medical Devices (BfArM) and the

Paul-Ehrlich-Institute (PEI) on the planning, implementation, and evaluation of observational

studies (7 July 2010) (Ref. 7), and the recommendations of the ‘Verband der Forschenden

Arzneimittelhersteller’ (Ref. 8). In practice, this means that:

TachoSil® was prescribed in accordance with the terms of the marketing authorisation;

The assignment of the patient to a particular therapeutic strategy was not decided in

advance by the study protocol but fell within current practice;

The prescription of TachoSil® was clearly separated from the decision to include the

patient in the study;

No additional diagnostic or monitoring procedures were applied to the patients;

Epidemiological methods were used for the analysis of collected data.

Due to the observational design of the study, patient visits (i.e. documentation times)

followed the usual clinical practice, i.e. one baseline visit (including surgery) and one follow-

up visit (hospital discharge). All patient-care decisions, including diagnostic and therapeutic

interventions, were at the discretion of the participating surgeons according to their clinical

judgement and the local standard of medical care.

After the decision to use TachoSil® had been made, informed consent was to be obtained

from the patients (before or after the application of TachoSil®) for the pseudonymous

evaluation of their data. Data on the patient’s medical history and treatment were to be

transcribed to the case report form (CRF) from the patient’s medical record. Data were

collected at the patients’ scheduled standard visits.

Visit 1: Baseline (including surgery)

The following data were recorded in the ‘baseline’ section of the CRF:

Patient data: age, sex, weight, height;

Medical history;

Previous treatments;

Preoperative coagulation parameters;

Details of the performed surgery;


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Application of TachoSil®;

Adverse events.

Visit 2: End-of-Study (upon discharge from the hospital).

The following data were recorded in the ‘end-of-study’ section of the CRF:

Intra-operative complications;

Postoperative course (drainage, thrombosis prophylaxis, complications);

Comparison of TachoSil® with other techniques used for lymph sealing by the physician;

Physicians’ assessment of TachoSil® (handling, satisfaction, usefulness, and pharmaco-

economic aspects);

Adverse events.

4.1 Discussion of Study Design Including Use of Comparator Medication

A prospective, non-interventional study was considered an appropriate tool to assess

effectiveness and reliability of TachoSil® as well as tolerability, including rare adverse drug

reactions, in a large and heterogeneous group of individuals under conditions of everyday

clinical practice.

The limitations of this study are those associated with the non-experimental character of the

study and include the lack of a control or comparator with regard to the evaluation of

treatment effects.

Lymph nodes are often removed during other surgery as a secondary operation, e.g. axillary

lymphadenectomy during the surgical treatment of breast cancer. In these cases, the results

would have depended on the primary as well as the secondary operation. To avoid such

bias, only data on the actual lymphadenectomy were to be documented.

Restrictions on the use of TachoSil were determined exclusively on the basis of the

contraindications described in the SPC (cf. SPC Section 4.3, Appendix 3).

The risk of distortion of the overall results through incorrect application of TachoSil® was

minimised by inviting only specialised departments to participate in this non-interventional

study, where it was known that lymph node dissections were being performed as part of

surgical cancer management and TachoSil had already been in use for some time.


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4.2 Selection of Study Population

It was planned to recruit up to 600 patients by approximately 100 surgeons experienced in

lymphadenectomy in Germany.

Inclusion Criteria

Male and female patients ≥ 18 years of age;

Stationary patients undergoing lymphadenectomy;

TachoSil was used during the documented surgery;

Written informed consent was given by the patient before starting data collection and

data processing.

Exclusion Criteria

Contraindications, such as hypersensitivity to the active pharmaceutical ingredient or to

other ingredients, as described in the SPC.

4.3 Treatments

Trade ware of TachoSil was used in this study. Dosage and application was to follow the

recommendations given in the SPC (Appendix 3).

TachoSil is a sterile, ready-to use, absorbable patch for intra-operative topical application. It

consists of an equine collagen patch coated with fibrin glue components human fibrinogen

(5.5 mg/cm2) and human thrombin (2.0 IU/cm2). The active side is coloured yellowish with

riboflavin. TachoSil is manufactured, packed and labelled according to Good Manufacturing

Practice (GMP). TachoSil patches are available in three sizes: 3.0 cm x 2.5 cm, 4.8 cm x

4.8 cm and 9.5 x 4.8 cm.

According to the SPC, the number of TachoSil® patches to be applied is governed by the

size of the wound area. In animal studies TachoSil® shows a progressive biodegradation.

The fibrin clot is metabolised in the same way as endogenous fibrin by fibrinolysis and

phagocytosis. The collagen patch is degraded by resorptive granulation tissue.

Approximately 24 weeks after application only a few remnants were present without any

signs of local irritation.


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5 Conduct

5.1 Study Schedule

This non-interventional study started officially on 15 December 2012. Documentation of

cases started in February 2013 (the first enrolment fax was received on 15 February 2013).

However, there were 13 patients with baseline (visit 1) dates and surgery dates prior to the

official study start date: the earliest baseline date being 30 September 2012 (surgery date

was 01 October 2012). These patients provided their informed consent to the documentation

and processing of their data after the official study start, as confirmed in writing by the

concerned study centre. Therefore, although their data had been collected retrospectively,

these 13 patients were included in the intention-to-treat population (see Section 8.1.1 for

definition) on which the data analysis was based. A study duration of approximately 1 year

was planned. Due to the insufficient number of recruited patients at the end of the planned

recruitment period (30 November 2012) the period was extended. The study was completed

in March 2014; the last documented date was 27 March 2014.

Selection of the patients was undertaken exclusively by the surgeon and TachoSil was

applied only where required. In addition to routine procedures, no further diagnostic or

monitoring procedures were to be applied to the patients.

Written informed consent from the patient was obtained by the physician prior to starting any

documentation in the CRF for this study.

An overview of the study schedule is given in T-Table 1.


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T-Table 1: Study schedule

Procedure

Visit 1 (Baseline)

Visit 2 (End-of-Study)

Informed consent ●

Demographic data ●

Main diagnosis / underlying disease ●

Previous treatment ●

ECOG status ●

Tumour classification ●

Concomitant diseases ●

Assessment of bleeding risk / coagulation parameter ●

Pre- and postoperative measures ●

Description of surgery ●

Use of TachoSil® ●

Intra-operative complications ●

Comparison with other techniques used for lymph sealing ●

Postoperative course: drainage, thrombosis prophylaxis, complications

●

Assessment of TachoSil® by the surgeon ●

Pharmacoeconomic aspects ●

Discharge of the patient ●

Requirements of TachoSil® (additional sizes) for

lymphadenectomy / suggestions by the surgeon ●

Monitoring of adverse events (AEs)a ● ●

a AEs are understood in this report as those AEs or intra- and postoperative complications which were treated

as AEs by the Sponsor’s Drug Safety Department (see Section 6.2).

5.2 Assessments

5.2.1 ECOG Performance Status

The Eastern Cooperative Oncology Group (ECOG) performance status is a 5-point rating

scale (see below) used by doctors and researchers to assess how a patient's disease is

progressing, to assess how the disease affects the daily living abilities of the patient, and to

determine appropriate treatment and prognosis (Ref. 9).

Grade 0 = Fully active, able to carry on all pre-disease performance without restriction.

Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.

Grade 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours.


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Grade 3 = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours

Grade 4 = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair

5.2.2 TNM Staging System

The TNM Classification of Malignant Tumours (TNM) describes the stage of cancer by

means of codes based on tumour size, lymph node involvement, and presence or absence

of metastases (Ref. 10):

T: describes the size of the primary tumour and whether it has invaded nearby tissue.

N: describes the involvement of lymph nodes.

M: describes the presence of distant metastasis.

5.2.3 FIGO Classification

The tumour classification system according to the International Federation of Gynaecological

Oncologists (FIGO) consists generally of 5 stages (Ref. 11):

Stage 0 = carcinoma in situ (common in cervical, vaginal, and vulval cancer);

Stage I: confined to the organ of origin;

Stage II: invasion of surrounding organs or tissue;

Stage III: spread to distant nodes or tissue within the pelvis;

Stage IV: distant metastasis(es).

The FIGO classification applies only to female patients with cancers of the vulva, cervix,

endometrium or sarcomas, respectively.

5.2.4 Evaluation of TachoSil

Handling of TachoSil, its usefulness as a surgical tool and the surgeon’s satisfaction with

TachoSil in the documented operation were assessed on numerical rating scales ranging

from 1 (very good, very useful, very satisfied) to 10 (very poor, not useful at all, totally

dissatisfied).

http://en.wikipedia.org/wiki/Lymph_nodes

http://en.wikipedia.org/wiki/Metastasis


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6 Safety Reporting

6.1 Definitions

Adverse Event (AE): Any untoward medical occurrence in a patient administered a

medicinal product and which does not necessarily have a causal relationship with this

treatment.

Adverse Drug Reaction (ADR): Any untoward and unintended response to a medicinal

product related to any dose administered.

Serious Adverse Event / Adverse Drug Reaction (SAE / SADR): Any untoward medical

occurrence at any dose, which results in death, is life-threatening, requires inpatient

hospitalisation or prolongs existing hospitalisation, results in persistent or significant

disability or incapacity, or is a congenital anomaly or birth defect. Important AEs or ADRs

that are not immediately life-threatening or do not result in death or hospitalisation but may

jeopardise the patient and may require medical or surgical intervention to prevent one of the

outcomes listed in this definition were also considered as serious.

6.2 Documentation of Adverse Events / Adverse Drug Reactions

The following information was collected and processed as individual case safety reports

(ICSR) in the Sponsor’s Drug Safety database:

AEs, SAEs, ADRs and SADRs documented as such by the surgeon;

All postoperative complications assessed by the surgeon as being related to the

application of TachoSil;

All postoperative complications assessed as being medically relevant by Takeda

Drug Safety (e.g. lymphocele puncture, administration of erythrocyte concentrates)

irrespective of causality.

The surgeon was responsible for the documentation of AEs / ADRs. Any AE observed during

the study was to be recorded on the “Adverse Event Form” of the CRF, including date of

onset, intensity, outcome, and causal relationship to TachoSil.

Serious AEs / ADRs (SAEs / SADRs) had to be documented on the “Serious Adverse Event

Form” of the CRF. The surgeons had to forward all SAEs / SADRs observed during the

study immediately (i.e. within 24 hours at the latest) to the Drug Safety Department of

Takeda Pharma Vertrieb GmbH & Co. KG by fax or telephone.


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7 Data Quality Assurance

After receipt of the CRFs, the data management department of the responsible contract

research organisation (CRO) syneed medidata GmbH checked the mandatory items of the

CRF for completeness and performed a validation process. In case of missing mandatory

data or inconsistent entries regarding safety information (AEs / SAEs, ADRs / SADRs),

queries were sent to the respective surgeon.

7.1 Monitoring and Source Document Verification

No monitoring visits at the study centres were performed.

7.2 Audit by International Quality Assurance Unit

Audits were not performed.

7.3 Inspection by Competent Authority

Inspections were not performed.

7.4 Data Management and Data Handling

After informing the responsible Takeda representative, the surgeons sent the completed

paper CRFs to the designated CRO. Data management was performed by the CRO syneed

medidata GmbH.

Patients were identified in the database by patient ID (consecutive number assigned to a

CRF/patient starting with “1” based on the date of CRF receipt), sex, and age. The list of all

intra- and postoperative AEs (Listing 11.5.2.4) contains a case number (provided by the

Sponsor’s Drug Safety Department) in addition to the patient ID.

Data were validated and pre-processed as described in the Statistical Analysis Plan (SAP)

(Appendix 4).

The documentation relating to this study will be archived for at least 10 years according to

local regulations.

8 Statistical Methods and Determination of Sample Size

Statistical analysis was performed by the CRO syneed medidata GmbH.


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8.1 Statistical Plan

In the following, statistical methods are summarised as described in the Statistical Analysis

Plan (SAP, Appendix 4). Statistical analysis was purely exploratory.

8.1.1 Definition of Analysis Set

Data analysis was based on the intention-to-treat (ITT) population. The ITT population

consisted of all patients,

who received a patient information and who had consented to the collection,

transmission and evaluation of their data (Comment: this had not to be documented in

the CRF but it is assumed that the consent forms are available for all patients in the

corresponding study centre.), and

who underwent lymph node resection with TachoSil applied during surgery as

documented in the CRF.

The ITT was used for summaries of demographic and baseline characteristics, all tolerability

and safety related variables and all summaries of effectiveness data. No per-protocol- set

analysis was done.

8.1.2 Endpoints

Primary endpoints:

Incidence of postoperative seroma formation

Secondary endpoints:

Assessment of TachoSil® by the surgeon with respect to handling, utility and

satisfaction in the operation, documented using 10 point Numerical Rating Scales;

Usage/duration/volume of drainage;

Length of hospital stay (ICU and normal hospital station);

Pharmacoeconomic evaluation as assessed by the surgeon. According to the Non-

Interventional study protocol (version 1.0, 05-Dec-2012), it was planned to describe

the pharmacoeconomical aspects in terms of money (€); for doing this the numbers

shown in the following table were to be used;

Parameter Costs (2012) Source/comment

OP-time 12-15 €/min Web

Stay on ICU 2000 €/day =€ 1334 * 1.0414^10#

Stay on normal hospital unit 512 €/ day =€ 436 * 1.0414^4#

# from Felder et al. (Ref. 12): IUC € 1.334/day in 2002, normal station €436/day in 2008, each extrapolated to 2012 with an annual cost increase factor of 4.14% according to the average annual increase in hospital costs


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Safety/intra- and postoperative complications/AEs;

8.1.3 Descriptive Statistics

All collected data were analysed descriptively.

In general, numerical continuous or ‘quasi’- continuous data were summarised with standard

descriptive statistics including number of patients with valid data, arithmetic mean, standard

deviation, minimum, median and maximum. For categorical variables, absolute frequencies

and (column) percentages were determined. The percentages were based on the number of

patients in the column heading unless otherwise stated. The number of patients with missing

values was included in the calculation of the percentages.

8.1.4 Inferential Statistics

No statistical tests were performed.

8.2 Determination of Sample Size

The incidence of seroma described in the literature varies very much due to numerous

factors influencing the development of seroma, including age of the patient, duration of

drainage, method of dissection, use of fibrin sealant, amongst others (Ref. 13-17). In

addition, the studied patient collectives have usually been heterogeneous and the sample

sizes small, which may have led to bias in the estimation of the rates of seroma formation.

The rationale for the sample size calculation for this study is presented in a separate

document (Ref. 18). For the determination of the sample size, a seroma rate of 30% was

assumed in a conservative approach. The sample size required to demonstrate that with the

use of TachoSil® this rate could be significantly reduced to 20% (alpha = 0.05, power = 80%,

two-sided test) was estimated as 150 patients in a single group design. To test this

hypothesis in a scenario with 4 types of lymph node surgery, a sample size of 600 patients

was estimated.

8.3 Interim Analyses

An interim analysis was not performed.


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8.4 Handling of Missing Data and Withdrawals

All data were analysed as they appeared in the data base. Missing data were displayed in

patient data listings and were declared in tables as appropriate. For continuous data,

missing data were handled by either leaving the respective field blank or inserting the phrase

‘missing’. In frequency tables of categorical data a category ‘missing’ was provided

whenever there were data missing. A proportion was calculated based on the number of all

cases (including missing values). As a rule, missing values were not imputed beside cases

explicitly mentioned in Section 14.2 in the SAP (Appendix 4).

8.5 Baseline Comparability of Treatment Groups

Not applicable. There were no different treatment groups in this study.

8.6 Software

Data analysis was performed using the software system SAS version 9.1.3.

9 Changes in the Planned Analyses

In the study protocol (Appendix 1) it was planned to perform subgroup analyses with respect

to the type of surgical access at the time of the application of TachoSil® (open vs. minimally

invasive), to the resection/application area and to different types of lymph node surgery

including several inferential tests to test for differences between subgroups (e.g. the

asymptotic Mann-Whitney-U-test and the asymptotic Chi square-test). In prefinal versions of

the SAP this idea was worked out in detail for the comparison of the open vs. minimally

invasive approach. Due to the small number of patients operated upon using a minimally

invasive approach, this idea was abandoned in the final version of the SAP (Appendix 4).

10 Patients

10.1 Disposition of Patients

A total of 233 patients were enrolled by 39 study centres (22 gynaecological, 15 urological

and 2 general surgery centres) in Germany. Five of these patients were excluded from the

ITT population, because they did not fulfil the inclusion criteria (patient underwent

lymphadenectomy and TachoSil® was used during surgery). Thus, the ITT population

comprised 228 patients (End-of-text Table 11.3.0b).


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None of the patients discontinued the study prematurely.

The numbers of patients (ITT population) documented by each centre are presented in End-

of-text Table 11.3.1. The majority of the centres, i.e. 21 centres, documented data of 2-4

patients. Overall, the number of documented cases ranged between 1 and 27.

10.2 Protocol Deviations

Protocol deviations were not analysed due to the non-interventional character of the study.

For 2 patients, the statement whether lymphadenectomy was performed and TachoSil® was

used during surgery in the section ‘Inclusion criteria’ of the CRF was missing (End-of-text

Table 11.3.0b). However, these patients were not excluded from the ITT population based

on the data derived from the description of the surgery and the application information of

TachoSil® provided on page 5 of the CRF.

11 Results

The following sections summarise the results of the statistical analysis. Original analysis

results can be found in End-of-text Tables in Appendix 5. Descriptions, comments, and

details on postoperative complications and AEs are provided in Listings in Appendix 6.

11.1 Data Sets Analysed

All analyses were based on the ITT population (N=228; for definition see Section 8.1.1).

11.2 Demographic and Baseline Features

11.2.1 Experience in the Use of TachoSil®

In accordance with the study protocol, almost all surgeons already had experience in the use

of TachoSil® (T-Table 2). For 3 patients (1.3%), the treating surgeon stated that he/she had

used TachoSil® for the first time and for 16 patients (7.0%) it was stated that TachoSil® was

used for the first time for this type of surgery. The surgeons reported experience with

TachoSil® from more than 50 previous operations for 102 patients (44.7%), referring to

previous experience in general, and for 13 patients (5.7%), referring to the type of surgery

documented in this study. It has to be noted that the analysis was done on the patient level,

i.e. the same surgeon may have provided answers for more than one patient.


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T-Table 2: Experience in the use of TachoSil®

Characteristic [number (%) of patients] Experience in general

Experience in the documented type of surgery (lymphadenectomy)

Use of TachoSil®:

First time 3 (1.3) 16 (7.0)

1-10 times 47 (20.6) 85 (37.3)

11-50 times 73 (32.0) 109 (47.8)

More than 50 times 102 (44.7) 13 (5.7)

Missing data 3 (1.3) 5 (2.2)

Percentages relate to the total number of patients in the ITT population (N=228) Data source: End-of-text Table 11.3.2.

11.2.2 Demographic Data

Demographic data of the ITT population are summarised in T-Table 3. Of the 228 patients in

the ITT population, 110 (48.3%) were men and 111 (48.7%) were women. No information on

the sex of the patient was provided for 7 patients (3.1%). One case of pregnancy2 was

documented. Generally, TachoSil® may be administered to pregnant and breastfeeding

women if clearly needed. Information on whether a patient was pregnant or not was missing

for 7 (6.3%) female patients.

None of the patients with documented age (N=226) were younger than 18 years. The mean

age was 63.6 10.8 years (median: 65 years). The mean BMI, calculated from 216 patients,

was 27.6 5.1 kg/m2. Details of demographic characteristics are given in End-of-text Tables

11.3.3a, 11.3.3b, and 11.3.3c.

2 As the patient’s age was reported to be 78 years, a pregnancy is unlikely. Presumably, the surgeon

inadvertently ticked the wrong box on the CRF, i.e. ‘yes’ instead of ‘no’ for existence of pregnancy. No AEs were

reported for this patient.


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T-Table 3: Demographic data

Characteristic ITT (N=228)

Age [years] n 226

Mean ± SD 63.6 ± 10.8

Median (min; max) 65 (33; 90)

Weight [kg] n 216

Mean ± SD 79.6 ± 15.8

Median (min; max) 80 (45, 161)

Height [cm] n 216

Mean ± SD 169.9 ± 9.1

Median (min; max) 170 (146; 198)

BMI [kg/m

2] n 216

Mean ± SD 27.6 ± 5.1

Median (min; max) 27 (18; 60)

Sex [n (%)] Male 110 (48.3)

Female 111 (48.7)

Missing data 7 (3.1)

Percentages relate to the total number of patients in the ITT population. BMI = body mass index (derived from documented data of weight and height), SD = standard deviation. Data source: End-of-text Tables 11.3.3a and 11.3.3b.

11.2.3 Main Diagnosis and Baseline Characteristics of the Primary Disease

Main Diagnosis

The frequencies of the main diagnoses are shown in T-Table 4. The most frequent

underlying disease (main diagnosis) was prostate cancer in 44.7% of the patients (N=102).

Other frequent diagnoses were endometrial cancer in 12.3% (N=28), breast cancer in 10.1%

(N=23), cervical cancer in 9.2% (N=21), ovarian cancer in 8.3% (N=19), and vulvar cancer in

4.8% (N=11) of the patients. One patient had pancreatic cancer. For 11.4% (N=26) of the

patients, the category ‘other’ was ticked in the CRF with regard to the underlying disease

(type of cancer) – for 2 of these patients also one of the predefined diagnoses were ticked3.

All documented ‘other’ cancer diagnoses are listed in Listing 11.3.4a and presented by

frequency in End-of-text Table 11.3.4a. These ‘other’ cancer diagnoses affected the

3 One patient with ′other′ diagnosis ′adenocarcinoma of the pancreatic tail’ also had the diagnosis ′pancreatic

cancer′; a second patient with ′other′ diagnosis ′bladder cancer′ also had the diagnosis ′prostate cancer′.


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bladder/ureter (N=9), rectum/anus (N=4), penis/testicles (N=4), vagina (N=2), and other

organs or body regions including the appendix, peritoneum, fallopian tubes, and pancreatic

tail (N=7).

T-Table 4: Underlying disease

Characteristic [number (%) of patients] ITT (N=228)

Main diagnosis [n (%)]a

Prostate cancer 102 (44.7)

Endometrial cancer 28 (12.3)

Breast cancer 23 (10.1)

Cervical cancer 21 (9.2)

Ovarian cancer 19 (8.3)

Vulvar cancer 11 (4.8)

Pancreatic cancer 1 (0.4)

Otherb 26 (11.4)

Missing data 0

Percentages relate to the total number of ITT patients. a

Multiple answers were possible. b

Specifications of other diagnoses (free text entries) are provided in end-of-text Table 11.3.4a. Data source: End-of-text Table 11.3.4a.

Disease Classifications

As shown in T-Table 5, the vast majority of the patients, i.e. 87.7% (N=200) were fully active

and were able to carry on all pre-disease performance without restriction (ECOG grade 0),

10.1% (N=23) were restricted in physically strenuous activity but ambulatory and able to

carry out work of a light or sedentary nature (ECOG grade 1), and 1.3% (N=3) were

ambulatory and capable of all selfcare but unable to carry out any work activities and were

up and about more than 50% of waking hours (ECOG grade 2). One patient was capable of

only limited selfcare and confined to bed or chair more than 50% of waking hours (ECOG

grade 3). Data on the performance status was missing for 1 patient.

T-Table 5 also summarises the most frequently reported codes according to the TNM

classification. The most frequent code was T2 N0 M0, reported in 24.1% (N=55) of the

patients, meaning a tumour size between 2 and 5 cm, absence of tumour cells from regional

lymph nodes, and no distant metastasis. As presented in End-of-text Table 11.3.5a, lymph

nodes were not affected by tumour cells (N0) in 58.3% (N=133) of the patients, whereas

regional lymph node metastasis was present (N1) in 23.3% (N=53), the tumour had spread

to an extent between N1 and N3 (N2) in 5.3% (N=12), and the tumour had spread to more


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distant or numerous regional lymph nodes (N3) in 0.9% (N=2) of the patients. Lymph nodes

could not be evaluated (Nx) in 3.5% (N=8) and an assessment of lymph node involvement

was missing in 8.8% (N=20) of the patients.

T-Table 5: Baseline characteristics of the primary disease


ECOG grade prior to surgery [n (%)]a

0 200 (87.7)

1 23 (10.1)

2 3 (1.3)

3 1 (0.4)

4 0


Tumour classification [n (%)]

TNM classificationb (most frequently reported codes)

T2 N0 M0 55 (24.1)

T1 N0 M0 18 (7.9)

T3 N0 M0 18 (7.9)

T3 N1 M0 15 (6.6)

T2 N0 M0 7 (3.1)

T3 N1 Mx 7 (3.1)

T2 N0 Mx 6 (2.6)

T1a N0 M0 5 (2.2)

T2 N2 M0 5 (2.2)

Other combinations 80 (35.1)


FIGO stage

c,d

0 0

I 27 (11.8)

II 17 (7.5)

III 6 (2.6)

IV 2 (0.9)



For definition of ECOG stage see Section 5.2.1. b For definition of the TNM classification see Section 5.2.2.

c For definition of the FIGO staging system see Section 5.2.3.

d Only female patients with cancers of the vulva, cervix, endometrium or sarcomas, respectively.

Data source: End-of-text Tables 11.3.5a and 11.3.5b.


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There was no distant metastasis in 70.2% (N=160) of the patients, whereas distant

metastasis was present in 4.8% (N=11); an assessment was not possible or was missing in

12.3% (N=28) or 12.7% (N=29) of the patients, respectively (see End-of-text Table 11.3.5b).

Any data on TNM classification were missing for 5.3% (N=12) of all patients.

According to the FIGO classification, 11.8% (N=27) of the female patients with cancers of

the vulva, cervix, endometrium, or sarcomas (i.e. leiomyosarcoma of the vagina),

respectively, had a tumour confined to the organ of origin (stage I), 7.5% (N=17) had

invaded cancer cells in surrounding organs or tissue (stage II), 2.6% (N=6) had cancer cells

spread to distant nodes or tissue (stage III), and 0.9% (N=2) had distant metastasis (stage

IV); an assessment according to the FIGO system was missing for 4.4% (N=10) of the

female patients with gynaecological cancers (T-Table 5).

11.2.4 Previous Treatment of the Underlying Disease

Approximately one third of the patients, i.e. 29.4% (N=67), had previously been treated for

the underlying disease, whereas 68.4% had not been treated; data on previous treatment

were missing for 2.2% (N=5) of the patients. Of the patients with documented previous

treatment, 50 patients had undergone surgery (21.9% of all ITT patients), 10 patients (4.4%)

had received systemic treatment, 3 patients (1.3%) had received surgical and systemic

therapy, and no information on the kind of applied treatment was provided for the remaining

9 patients (4.0%). The data relating to previous treatment are summarised in End-of-text

Table 11.3.4b.

11.2.5 Concomitant Diseases

Concomitant diseases were reported in 71.5% (N=163) of the patients: 30.7% (N=70) had

one concomitant disease, 27.6% (N=63) had two concomitant diseases, and 13.2% (N=30)

had between three and ten concomitant diseases. Absence of concomitant diseases was

reported in 24.1% (N=55); data were missing for 4.4% (N=10).

The most frequently reported concomitant diseases were those affecting the cardiovascular

system (50.0%, N=114) and the metabolism or endocrine system (26.3%, N=60). The

frequencies of concomitant diseases are presented by category in End-of-text Table 11.3.6.


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Documentations made under the category ‘other’ comorbidities4 are presented in Listing

11.3.6.

11.2.6 Assessment of Bleeding Risk, Coagulation Parameters, and Management of

Bleeding

Use of Blood Thinners and Presence of Coagulation Disorders

As shown in End-of-text Tables 11.3.7a, 11.3.7b, and 11.3.7c, 193 patients (84.7%) had no

risk of bleeding, i.e. they were not taking blood thinning medications and had no coagulation

disorders. Thirty-one patients (13.6%) were taking blood thinning medications around the

time of surgery. One of these patients (0.4%) also was reported with a coagulation disorder

(‘marcumar patient’; see also Listing 11.3.7c).5 For 4 patients (1.8%), data on the use of

blood thinning medications and/or coagulation disorders were missing.

The most frequently reported blood thinning medication that was used by patients around

the time of surgery was heparin (5.3%, N=12), followed by acetylsalicylic acid (4.8%, N=11),

and other medications (4.4%, N=10), of which all but 1 medication (dabigatran etexilate)

were low-molecular-weight heparins (see Listing 11.3.7b). None of the patients were treated

with phenprocoumon (although one of the patients was reported to be a ‘marcumar patient’)

or clopidogrel sulphate before surgery. A patient could have been treated with more than

one blood thinning medication.

Preoperative Coagulation Parameters

The results of the coagulation parameters measured prior to surgery are summarised in T-

Table 6. The mean international normalised ratio (INR) was 0.98 ± 0.08, the mean Quick

value was 101.2 ± 12.1%, the mean partial thromboplastin time (pTT) was 29.9 ± 4.7 s, and

the mean platelet count was 260,900 ± 92,800 per µL.

Preoperative platelet activity was normal in 190 patients (83.3%); data on platelet activity

were missing for the remaining 38 patients (16.7%) (End-of-text Table 11.3.8b).

4 Comorbidities documented in the category 'other′ were not further analysed, i.e. such comorbidities that would

also have qualified for one of the other predefined categories in the CRF were not assigned to and counted in

another category except for the category 'other′ in the context of the analysis.

5 The entry 'marcumar patient′ was most likely erroneously made in the CRF section 'coagulation disorder′ by the

surgeon. 'Phenprocoumon′ was not ticked on the CRF as blood thinning medication around the time of surgery

for this patient.


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T-Table 6: Perioperative coagulation parameters

Parameter N Mean ± SD Median Min Max

INR 206 0.98 ± 0.08 1.0 0.8 1.5

Quick value [%] 226 101.2 ± 12.1 100.0 61 142

pTT [s] 220 29.9 ± 4.7 29.0 21 58

Platelets [1000/µL] 226 260.9 ± 92.8 245 96 975a

INR = international normalised ratio; pTT = partial thromboplastin time a

All other perioperative coagulation parameters were normal in this patient (patient ID #232). Data source: End-of-text Table 11.3.8a.

Pre- and Perioperative Measures Taken to Improve Coagulation

In 204 patients (89.5%) no measures to improve coagulation were taken prior and/or during

surgery, whereas blood clotting was promoted in 21 patients (9.2%), and data regarding pre-

or perioperative measures were missing for 3 patients (1.3%) (End-of-text Table 11.3.8c).

Only one type of measure was taken in 13 patients (5.7%), two different measures were

taken in 6 patients (2.6%), and 3 measures were taken in 2 patients (0.9%). As shown in

End-of-text Tables 11.3.8d-k, the most frequently reported measure was the administration

of red blood cell concentrate (5.3%, N=12; between 1 and 5 units were administered),

followed by fresh frozen plasma (4.4%, N=10; between 2 and 9 units were administered).

One patient (0.4%) received platelet concentrate and 8 patients (3.5%) were treated with

other measures (including low-molecular-weight heparin, N=4), which are listed in End-of-

text Table 11.3.8k.

11.3 Details of the Operation

11.3.1 Type of Surgery

The initial approach was open surgery in the vast majority of the patients (88.6%, N=202);

21 patients (9.2%) had minimally invasive surgery as initial approach, and 2 patients (0.9%)

were reported with both types of surgery (as this implausible, inadvertent incorrect entries in

the CRF are assumed). Data on the type of surgery were missing for 3 patients (1.3%; End-

of-text Table 11.5.1.1). In 2 patients who underwent minimally invasive lymphadenectomy

and 1 patient who was reported with both types of surgery as initial approach, a conversion

of the minimally invasive approach to open surgery was necessary because of technical

problems (N=1), or other reasons (N=2; see Listing 11.5.1.3b) (End-of-text Table 11.5.1.5f).

Visual identification of nerves was performed in 2 patients (0.9%).


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The mean duration of the operation, calculated for 222 patients with data available, was

192.2 ± 107.2 min (median: 170 min). The shortest duration was 15 min and the longest

duration was 687 min (patient with pancreatic cancer/adenocarcinoma of the pancreatic tail,

patient ID #197).

Details on the type and duration of surgery are presented in End-of-text Tables 11.5.1.1,

11.5.1.3a, and 11.5.1.3b. Brief descriptions of the operations are provided in Listing 11.5.1.1.

T-Table 7 summarises the main characteristics of the operation by resection site. Lymph

nodes may have been removed from more than one body area in a patient. In the vast

majority of the patients, lymph nodes were removed from the pelvic area (N=187). In

addition, lymph nodes were removed from the paraaortal area in 51 patients, the armpits

(axillary) in 24 patients, the inguinal (groin) area in 23 patients, and the cervical (neck) area

in 3 patients. Radionuclide labelling for sentinel lymph node detection was reported in 7

patients (29.2% of 24 patients) with axillary lymphadenectomy and in 2 patients (8.7% of 23

patients) with inguinal lymphadenectomy. Open surgery was overall the predominant

approach. Minimally invasive surgery was used in 21 cases (11.2% of 187 patients) of pelvic

lymphadenectomy, in 6 cases (11.8% of 51 patients) of paraaortal lymphadenectomy, and in

2 cases (66.7% of 3 patients) of cervical lymphadenectomy. In ≥ 90% of the cases of pelvic

and paraaortal lymphadenectomy (93.6% and 90.2%, respectively) and in 52.2% of the

cases of inguinal lymphadenectomy, lymph nodes were removed from both body sides. The

mean numbers of removed lymph nodes, calculated from those patients with respective data

available, ranged between 1 lymph node (N=1) in the cervical area and 19.2 ± 11.4 lymph

nodes (N=166) in the pelvic area.

None of the patients had lymph nodes removed from the mediastinal, peribronchial, or

parasternal area. One patient had 7 lymph nodes removed from another (not named) area.

Summaries of all documented details by resection site, including additional details on

cervical and axillary lymphadenectomy, can be found in End-of-text Table 11.5.1.2a. All

documented details by resection site and patient are provided in Listing 11.5.1.2a.


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T-Table 7: Details of the operation

Resection sitea

Characteristic Pelvic (N=187)

Paraaortal (N=51)

Axillary (N=24)

Inguinal (N=23)

Cervical (N=3)

Marker (LN detection) [n (%)]b n.a.

No marker used 27 (52.9) 6 (25.0) 11 (47.8) 0

Radionuclide labellingc 0 7 (29.2) 2 (8.7) 0

Colour markingc 0 1 (4.2) 0 0

Other 1 (2.0) 0 0 0

Missing data 23 (45.1) 10 (41.7) 10 (43.5) 3 (100.0)

Approach [n (%)]a

Open 163 (87.2) 45 (88.2) 23 (95.8) 22 (95.7) 1 (33.3)

Minimally invasive [n (%)]b 21 (11.2) 6 (11.8) 0 0 2 (66.7)

Missing data 3 (1.6) 0 1 (4.2) 1 (4.4) 0

Body side [n (%)]b

Left 4 (2.1) 0 11 (45.8) 7 (30.4) 0

Right 2 (1.1) 0 12 (50.0) 3 (13.0) 0

Both sides 175 (93.6) 46 (90.2) 0 12 (52.2) 0

Missing data 6 (3.2) 5 (9.8) 1 (4.2) 1 (4.4) 3 (100.0)

Number of removed LNs

N 166 44 19 18 1

Mean ± SD 19.2 ± 11.4 15.6 ± 8.8 8.6 ± 6.2 7.0 ± 5.2 1.0

Median (min; max) 18 (0; 58) 14 (1; 36) 8 (1; 20) 7 (1; 24) 1 (1; 1)

a More than one resection site was possible per patient.

b Percentages relate to the total number of ITT patients per resection site

c Sentinel lymphonodectomy

LN = lymph node, n.a. = not applicable Data source: End-of-text Table 11.5.1.2a.

11.3.2 Haemostatic Measures Taken prior to the Application of TachoSil®

Prior to the application of TachoSil®, at least one primary haemostatic measure was taken

during the documented surgery in 221 patients (96.9%). As shown in T-Table 8, bipolar

electrocoagulation (67.1%, N=153) was the most frequently used haemostatic measure,

followed by monopolar electrocoagulation (49.6%, N=113), clipping (45.6%, N=104), and

ligature (41.7%, N=95). Suturing and ultrasound techniques were used less frequently. More

than one measure could have been taken in a patient.

The most frequently reported (≥ 5% of patients) single measures (i.e. no other measures

were taken in the respective patients) or combinations of measures were bipolar coagulation

(16.2%, N=37), a combination of ligature, clipping, bipolar and monopolar

electrocoagulation, and suturing (7.0%, N=16), and a combination of ligature and bipolar


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electrocoagulation (6.6%, N=15). The frequency counts of all single measures and

combinations of measures are presented in End-of-text Table 11.5.1.4.

T-Table 8: Haemostatic measures during surgery prior to TachoSil® application


Measure taken [n (%)]a

Electrocoagulation bipolar 153 (67.1)

Electrocoagulation monopolar 113 (49.6)

Clipping 104 (45.6)

Ligature 95 (41.7)

Suturing 57 (25.0)

Ultrasound techniques 30 (13.2)

Other 0

None 7 (3.1)


Multiple answers were possible. Data source: End-of-text Table 11.5.1.4.

No haemostatic measures prior to the application of TachoSil® were taken in 7 patients

(3.1%). In these patients, TachoSil® was used ‘off-label’, as according to the SPC it is

indicated in adults for supportive treatment in surgery for improvement of haemostasis, to

promote tissue sealing, and for suture support in vascular surgery where standard

techniques are insufficient.

11.4 Extent of Exposure

11.4.1 Number of TachoSil® Patches Used

TachoSil® was applied locally once per patient during surgery. Irrespective of the size of the

TachoSil® patch, up to 8 patches (of different sizes) were used in a patient. In more than half

of the ITT population (55.3%, N=126), 1 patch was used during surgery. Only half a patch

was used in 6.1% (N=14), 2 patches were used in 28.5% (N=65), 3 patches were used in

6.1% (N=14), 4 patches were used in 3.1% (N=7), and 8 patches were used in 0.4% (N=1)

of the patients. For 1 patient, information on the application of TachoSil® was missing. Of the

three available sizes, the largest patch (9.5 x 4.8 cm) was the most frequently used, i.e. in

61.0% (N=139) of the patients, followed by the medium size patch (4.8 x 4.8 cm) and the

small patch (3.0 x 2.5 cm), which were used in 35.1% (N=80) and 10.5% (N=24),

respectively. The frequency counts of TachoSil® patches by size and number of patches

applied are presented in End-of-text Table 11.5.1.5a and Figure 1.


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Figure 1: Frequency of TachoSil® patches used (by patch size and number of patches

used)

Percentages relate to the total number of ITT patients (N=228). Data source: End-of-text Table 1.5.1.5a.

T-Table 9 summarises the number of TachoSil® patches used by size and overall.

Irrespective of size, a mean number of 1.5 ± 0.9 patches were used per patient.

T-Table 9: Number of TachoSil® patches used

Characteristic N Mean ± SD Median Min Max

TS-patches total 227 1.5 ± 0.9 1 1 8

TS-patches 9.5 x 4.8 cm 227 0.8 ± 0.9 1 0 4

TS-patches 4.8 x 4.8 cm 227 0.5 ± 0.8 0 0 4

TS-patches 3.0 x 2.5 cm 227 0.2 ± 0.7 0 0 4

TS = TachoSil®

Data source: End-of-text Table 11.5.1.5b.

The frequency counts per number of patches used at a given application site (as

documented by the surgeons in the CRF) are presented in End-of-text Table 11.5.1.5c.

11.4.2 Mode of Application

In half of the patients (50.0%, N=114), the patches were used in the available sizes,

whereas in 45.6% (N=104), at least one of the applied patches was cut to shape; data were

missing for 4.4% (N=10) of the patients (End-of-text Table 11.5.1.5d). In most cases, i.e. in


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63 out of 104 patients, only 1 patch was cut to the correct size; 2 patches were cut in 27

patients, 3 patches in 2 patients, and 4 patches in 3 patients. For 9 patients, the number of

patches cut to shape was not named.

TachoSil® patches were applied moist or dry in approximately the same number of patients,

i.e. moist in 113 patients (49.6%) and dry in 112 patients (49.1%); for 3 patients (1.3%) the

respective information was not provided (End-of-text Table 11.5.1.5e). In most cases, i.e.

175 patients (76.8%), a moistened compress was used to press on the patch; a dry

compress was used in 16 patients (7.0%), another method (not further specified) was used

in 20 patients (8.8%), a moistened compress in combination with another method was used

in 3 patients (1.3%), and the method was not named in 14 patients (6.1%).

Overall, the most frequently used application mode was moistened TachoSil® patch pressed

on with a moistened compress (43.9%, N=100), followed by dry TachoSil® patch pressed on

with a moistened compress (32.9%, N=75). All frequency counts by application mode are

presented in End-of-text Table 11.5.1.5e.

The modes of insertion of the TachoSil® patch through the trocar in the 19 patients with

minimally invasive surgery and without conversion to open surgery are presented by

frequency in End-of-text Table 11.5.1.5f and comments made under ‘other way’ of insertion

in these patients are listed in Listing 11.5.1.5f.

11.4.3 Purpose of TachoSil® Application

More than one reason for the application of TachoSil® was given in 49 patients (21.5%),

while only one reason was named in 178 patients (78.1%): prevention of a lymph fistula,

lymphocele or seroma in 170 patients (74.6%) and haemostasis in 8 patients (3.5%). No

reason was provided for 1 patient. The frequency counts of all documented single reasons

and combination of reasons are presented in End-of-text Table 11.5.1.6. Comments made

under ‘other’ reasons are provided in Listing 11.5.1.6.

Overall, as shown in End-of-text Table 11.5.1.6, the predominant purpose of the application

of TachoSil® was the prevention of a lymph fistula, lymphocele or seroma, i.e. this was

named as a reason for the application in 219 patients (96.1%). The second most frequent

purpose was haemostasis, which was named in 51 patients (22.4%). Other reasons were

considerably less frequently named, i.e. tissue sparing in 4 patients (1.8%), suture support in

2 patients (0.9%), augmentation of vulnerable tissue and adhesion prophylaxis in 1 patient

each, and other reasons (securing of an aneurysm, prevention of bleeding) in 4 patients.


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11.5 Efficacy and Safety Evaluation

11.5.1 Variable of Primary Interest

11.5.1.1 Incidence of Postoperative Seroma Formation

Postoperative seroma formation was reported in 6 (2.6%) of 228 patients (T-Table 10).

Seroma formation was not observed in 213 patients (93.4%); data on seroma formation were

missing for 9 patients (4.0%). Formation of seroma was observed on postoperative day 2

(N=1), 9 (N=1), and 14 (N=2) in patients for whom the respective information was available.

A causal relationship with the application of TachoSil® was assumed in one case (0.4%).

Further details on seroma formation, including the site of seroma formation, whether the

seroma was punctured, and punctured volume, are summarised in End-of-text Table

11.5.2.3c. Results on other postoperative complications are described in Section 11.5.2.1.

Details of all postoperative complications are provided by patient in Listing 11.5.2.3.

11.5.2 Variables of Secondary Interest

11.5.2.1 Incidence of Postoperative Complications

Postoperative complications were observed in 42 patients (18.4%), none were observed in

177 patients (77.6%), and information was not provided for 9 patients (4.0%) (End-of-text

Table 11.5.2.3a). Postoperative complications were collected and processed as ICSRs

(Section 6.2) in 27 of the 42 patients (these cases are presented in the AE Listing 11.5.2.4,

which also includes 4 additional patients with AEs that were not postoperative complications;

see also Section 11.5.2.10); in 15 patients, postoperative complications were not classified

as safety cases (AEs) by the Drug Safety Department. Thirty two patients had 1 and 10

patients had 2 or 3 postoperative complications (Listing 11.5.2.3).

Frequencies of postoperative complications, overall and by relationship with the application

of TachoSil® are presented in T-Table 10. The most frequently observed postoperative

complication was the formation of lymphoceles, which was reported in 27 patients (11.8%),

followed by the formation of seroma (2.6%, N=6, see Section 11.5.1.1), necessary

postoperative insertion of drainage (2.6%, N=6), formation of lymph fistulae (1.3%, N=3),

postoperative haemorrhage necessitating administration of red blood cell concentrate (1.3%,

N=3), thrombosis (1.3%, N=3), lymphoedema (0.9%, N=2), and postoperative haemorrhage

necessitating revision (0.9%, N=2). In total, 33 patients (14.5%) were reported with

postoperative lymphoceles and/or seroma.


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Further details, including the day of onset and affected body area are provided by type of

complication in End-of-text Tables 11.5.2.3b-h.

T-Table 10: Postoperative complications


Complication [n (%)]a Total Related Not related

Lymphocele 27 (11.8) 7 (3.1) 13 (5.7)

Seroma 6 (2.6) 1 (0.4) 5 (2.2)

Insertion of drainage 6 (2.6) 2 (0.9) 4 (1.8)

Lymph fistula 3 (1.3) 0 3 (1.3)

Haemorrhage necessitating RBC 3 (1.3) 0 2 (0.9)

Thrombosis 3 (1.3) 0 2 (0.9)

Lymphoedema 2 (0.9) 1 (0.4) 1 (0.4)

Haemorrhage necessitating revision 2 (0.9) 0 2 (0.9)

Percentages relate to the total number of ITT patients. a Causal relationship between the event and the application of TachoSil

® as assessed by the surgeon

(assessments were not provided for all documented complications). A patient could have had more than 1 postoperative complication. RBC = red blood cell concentrate Data source: End-of-text Tables 11.5.2.3b-h.

11.5.2.2 Usage of Drainage and Changes in Drainage Management

At least 1 drainage was inserted during surgery in 81.1% (N=185) of the patients, whereas

no drainage was used in 18.4% (N=42); data were missing for 1 patient (End-of-text Table

11.5.2.1a). Only 1 drainage was used in 81 patients (35.5%), 2 drainages were used in 93

patients (40.8%), 3 drainages were used in 8 patients (3.5%); 1 patient (0.4%) required 4

drainages and data on the number of inserted drainages were missing for 3 patients (1.3%).

The mean number of inserted drainages was 1.3 ± 0.8 and the mean maximum duration of

wound drainage (i.e. time until removal of the last drain) was 5.6 ± 4.6 days (T-Table 11).

T-Table 11: Number of drainages inserted during surgery and maximum duration of drainage


Number of drainages 225 1.3 ± 0.8 1 0 4

Maximum duration of drainage [days] 177 5.6 ± 4.6 4 1 42

Data source: End-of-text Table 11.5.2.1b.

The results relating to the questions on changes in drainage management due to the use of

TachoSil® are presented in T-Table 12.


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T-Table 12: Changes in drainage management due to TachoSil®

Characteristic [number (%) of patients]

ITT (N=228)

At least 1 drainage inserted (N=185)

No drainage inserted (N=42)

Was the drainage management changed due to the use of TachoSil

®?

No 83 (44.9) 28 (66.7)

Yes 98 (53.0) 10 (23.8)

Missing data 4 (2.2) 4 (9.5)

If management changed (if ‘yes’):

Improved 94 (50.8) 10 (23.8)

Worsened 1 (0.5) 0

Missing data 3 (1.6) 0

Has the duration of the drainage changed?a,b

No 89 (48.1) 29 (69.1)

Yes 90 (48.7) 7 (16.7)

Missing data 6 (3.2) 6 (14.3)

Has the drainage volume changed?a,b

No 71 (38.4) 29 (69.1)

Yes 107 (57.8) 5 (11.9)

Missing data 7 (3.8) 8 (19.1)

Percentages relate to the total number of ITT patients in each subgroup. a Compared to a similar case where TachoSil

® had not been used.

b Changes in the duration of drainage or drainage volume are implausible in patients without applied

drainage; data are presented as documented by the surgeons. Data source: End-of-text Tables 11.5.2.1c and 11.5.2.1d.

In 98 (53.0%) of 185 patients in which at least one drainage was inserted during surgery, the

surgeon stated that he/she had changed the drainage management due to TachoSil®. In

almost all cases (50.8%, N=94), the management was improved; only in 1 patient, the

drainage management worsened (no details were provided for 3 patients). In the subgroup

of patients without drainage, drainage management was changed in 10 (23.8%) of 42

patients. In all 10 cases drainage management was improved.

In patients with at least 1 drainage inserted during the current surgery, the duration of the

drainage had changed in 90 (48.7%) of 185 patients and the drainage volume had changed

in 107 patients (57.8%) in the opinion of the surgeons and compared to a similar case where

TachoSil® had not been used. Although not plausible, as no drainage was inserted during

the current surgery in these patients, the surgeons reported a change in the duration of the


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drainage in 7 (16.7%) and a change in drainage volume in 5 (11.9%) of 42 patients without

drainage (T-Table 12).

11.5.2.3 Postoperative Thrombosis Prophylaxis

Most patients (98.7%, N=225) received postoperative thrombosis prophylaxis with low-

molecular-weight heparin. Only 3 patients (1.3%) did not receive thrombosis prophylaxis

(End-of-text Table 11.5.2.2).

11.5.2.4 Length of Hospital Stay

Data on the length of hospital stay were available for 225 patients (T-Table 13). The patients

remained in the hospital between 2 and 50 days. The mean length of hospital stay was 12.2

± 6.6 days (median: 11 days; N=225). The mean length of stay in the intensive care unit

(ICU) was 2.8 ± 1.9 days (median: 2 days), calculated from 100 patients with data available

(no date of discharge from the ICU was specified in the CRFs of the remaining 128 patients)

(T-Table 13). ICU stays lasted between 1 and 13 days. Frequency counts by days of hospital

stay and ICU stay are presented in End-of-text Table 11.5.2.5a.

T-Table 13: Length of hospital stay


Stay in hospital (overall) [days] 225 12.2 ± 6.6 11 2 50

Stay in ICU [days] 100 2.8 ± 1.9 2 1 13

ICU = intensive care unit Data source: End-of-text Table 11.5.2.5b.

11.5.2.5 Previously used Techniques, Methods, or Products in Similar Cases

As presented in End-of-text Table 11.5.3.1, the most frequent technique, method, or product

that was used in cases that were similar to the current surgery was electrocoagulation

(77.2%, N=176), followed by hand suture/suturing/ligature (48.7%; N=111), compression/

tamponade (20.2%, N=46), ultrasound techniques (14.5%, N=33), conventional

haemostyptics (8.3%, N=19), fibrin glue (6.1%, N=14), argon beamer (4.4%, N=10), and

fibrin glue and patch (4.0%, N=9). Data were missing for 4 cases (1.8%). Other techniques

or methods were named in 39 cases (17.1%), the frequencies of which are presented in

End-of-text Table 11.5.3.1 (details are also given in Listing 11.5.3.1).


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11.5.2.6 Evaluation of the Benefit of TachoSil® for Lymph Sealing Compared to

Alternative Techniques, Methods or Products

The surgeons subjectively assessed the benefit of TachoSil® for lymph sealing in

comparison to other techniques, methods, or products, based on their experience in lymph

node dissection. Overall, at least one benefit of TachoSil® for lymph sealing was seen by the

surgeons in 187 patients (82.0%), no benefit was seen in 23 patients (10.1%), and data on

benefits were missing or unknown in 18 patients (7.9%) (End-of-text Table 11.5.3.2a).

The participating surgeons assessed the application of TachoSil® as being faster in

comparison with hand suture/suturing/ligature (45.2%, N=103), but as being slower in

comparison with electrocoagulation (50.9%, N=116), ultrasound techniques (16.2%, N=37),

and argon beamer (10.1%, N=23) (Figure 2). According to the surgeons, the application of

TachoSil® was predominantly equally fast or faster compared to most other techniques,

methods or products (Figure 2).

As shown in Figure 3, the handling of TachoSil® was assessed as being easier compared

with hand suture/suturing/ligature in 44.7% of the cases (N=102). Compared with

electrocoagulation, the handling of TachoSil® was described as being more difficult in 34.2%

of the cases (N=78), but as being easier or equally easy in 50.9% of the cases (N=116).

The surgeons assessed the effect of TachoSil® as being more reliable particularly in

comparison to electrocoagulation (44.7%, N=102), compression/tamponade (30.7%, N=70),

and conventional haemostyptics (18.4%, N=42) (Figure 4). Compared with hand

suture/suturing/ligature, the effect of TachoSil® was assessed as being equally reliable in

32.9% of the cases (N=75) and more reliable in 14.9% (N=34).


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Figure 2: The speed of application of TachoSil® in comparison with other techniques,

methods, or products

Percentages relate to the total number of ITT patients (N=228). Data source: End-of-text Table 11.5.3.2b-k.

Figure 3: The handling of TachoSil® in comparison with other techniques, methods, or

products



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Figure 4: The reliability of the effect of TachoSil® in comparison with other techniques,

methods, or products


Other Benefits of TachoSil® for Lymph Sealing

When asked about further advantages of TachoSil® in the documented case, the surgeons

stated that in 55.7% of the cases (N=127) postoperative complications were less likely to

occur due to the use of TachoSil® (End-of-text Table 11.5.3.3). Another named benefit was

nerve sparing due to atraumatic procedure in 21.1% of the cases (N=48). No answers were

provided in 23.7% (N=54), and other advantages were named in 33.8% (N=77) of the cases.

Details on other advantages are presented in Listing 11.5.3.3. These other advantages were

mainly the prevention of lymphoceles, seroma, or lymphocysts, or the reduction of the rate of

lymphoceles or lymphoceles and haematoma (N=37), the reduction of the risk of

lymphoceles (N=14), the prevention of lymph fistulae, lymphorrhea, lymphoedema, or lymph

secretion (N=6), and other advantages (N=16). For 4 patients, there was currently no

advantage noticeable.

11.5.2.7 Evaluation of TachoSil® (Handling, Usefulness, Satisfaction)

On rating scales ranging from 1 (best score) to 10 (worst score), handling of TachoSil®, its

usefulness, and the surgeon’s satisfaction with TachoSil® in the documented operation were

assessed as being rather good. The median score was 2 for all three variables (T-Table 14).


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T-Table 14: Evaluation of TachoSil®


Handling 225 2.2 ± 1.0 2 1 6

Usefulness (as a surgical tool) 225 2.3 ± 1.3 2 1 8

Satisfactiona 225 2.3 ± 1.4 2 1 8

a With regard to the current operation (lymphadenectomy)

Variables were assessed on 10-point scales (1 = very good/satisfied/useful; 10 = very poor/totally dissatisfied/not useful at all). Data source: End-of-text Table 11.5.3.4b.

Very good or good scores (score = 1, 2, or 3) were observed for the handling of TachoSil® in

205 patients (89.9%), for the usefulness of TachoSil® in 190 patients (83.3%), and for the

satisfaction with TachoSil® in 191 patients (83.8%). A score = 4 was observed for the

handling in 14 patients (6.1%), for the usefulness in 26 patients (11.4%), and for the

satisfaction in 17 patients (7.5%). Scores < 5 were provided for the handling in 6 patients

(2.6%), for the usefulness in 9 patients (3.9%), and for the satisfaction in 17 patients (7.5%).

Frequency counts by score and variable are presented in End-of-text Table 11.5.3.4a. Data

on handling, usefulness, and satisfaction were missing for 3 patients.

The results of the subgroup analyses based on the surgeon’s level of experience with

TachoSil® in the type of surgery documented in this study suggest that handling, usefulness,

and satisfaction were more favourably assessed with increasing experience (End-of-text

Table 11.5.3.4c) (Figure 5). It has to be noted that the analyses were done on the patient

level, i.e. the same surgeon may have provided answers for more than one patient.

The mean scores in the subgroup of surgeons who had used TachoSil® 11-50 times (N=109)

were numerically lower (better) than those in the subgroup of surgeons who had used

TachoSil® only 1-10 times (N=85): 1.9 ± 0.8 vs. 2.4 ± 1.0 (handling), 2.0 ± 1.0 vs. 2.3 ± 1.5

(usefulness), and 2.0 ± 1.2 vs. 2.7 ± 1.6 (satisfaction). However, the median scores were 2.0

in both subgroups and for all variables. The sample sizes of the subgroups of first time users

and surgeons who had used TachoSil® > 50 times in this type of surgery were smaller (i.e.

the evaluations were made for 16 and 13 patients, respectively); thus, results should be

interpreted with caution when comparing them to those of the other two subgroups. The

mean scores in the first time users and experienced users (> 50 times) were 2.8 ± 1.7 and

2.2 ± 0.6 (handling), 2.4 ± 0.9 and 4.0 ± 0.0 (usefulness), and 2.8 ± 1.7 and 2.2 ± 0.6,

respectively (End-of-text Table 11.5.3.4c).


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Figure 5: Evaluation of TachoSil® by the surgeon’s experience level with TachoSil

®

(mean score values)

Handling, usefulness and satisfaction (regarding the documented surgery) were assessed on 10-point scales (1 = very good/satisfied/useful; 10 = very poor/totally dissatisfied/not useful at all). Assessments were performed on the patient level, i.e. the same surgeon may have provided answers for more than one patient. Data are presented as mean scores and standard deviation. Data source: End-of-text Table 11.5.3.4c.

11.5.2.8 Pharmacoeconomic Evaluation

The surgeons subjectively assessed potential benefits or advantages of TachoSil® in terms

of pharmacoeconomy, based on their experience and recollection of cases similar to the

current case documented in this study. The results of the assessments of

pharmacoeconomic parameters are summarised in T-Table 15. The surgeons saw a benefit

of TachoSil® for lymph sealing most frequently with regard to the reduction of drainage

volume (89 of 228 cases, 39.0%) and drainage time (82 cases, 36.0%). A benefit was seen

in 62 cases (27.2%) with regard to the reduction in the length of the hospital stay, in 41

cases (18.0%) with regard to the reduction in the duration of surgery, and in 20 cases (8.8%)

with regard to the reduction in the time spent in the ICU. Data on the benefit evaluation were

missing for up to 32 patients.

For all pharmacoeconomic parameters, data on the current (documented) case as wells as

on previous similar cases were available for comparison only for a small number of patients

(T-Table 15). The results of the comparisons (current vs. similar cases) based on these

patients showed that with TachoSil® the duration of surgery was reduced by a mean of 25.6

± 19.6 min (N=23), the time spent in the ICU was reduced by a mean of 1.0 ± 0 days (N=10),

the time spent in hospital was reduced by a mean of 2.7 ± 3.4 days (N=30), the drainage


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time was reduced by a mean of 1.9 ± 1.1 days (N=48), and the drainage volume was

reduced by a mean of 483 ± 345 mL (N=52).

T-Table 15: Pharmacoeconomic aspects

Characteristic

Parameter: Reduction of…

Duration of surgery

[min]

Time spent in the ICU [days]

Time spent in hospital [days]

Drainage time

[days]

Drainage volume

[L]

Benefit [n (%)]a,b

Yes 41 (18.0) 20 (8.8) 62 (27.2) 82 (36.0) 89 (39.0)

No 169 (74.1) 183 (80.3) 147 (64.5) 122 (53.5) 107 (46.9)

Missing data 18 (7.9) 25 (11.1) 19 (8.3) 24 (10.5) 32 (14.0)

Comparison to similar cases

N 23 10 30 48 52

Mean ± SD (similar cases) 197 ± 118 1.5 ± 0.7 13.1 ± 4.6 5.2 ± 2.1 1.03 ± 1.27

Mean ± SD (current case) 172 ± 115 0.5 ± 0.7 10.4 ± 4.1 3.3 ± 1.8 0.55 ± 1.17

Difference (similar-current)

Mean ± SD 25.6 ± 19.6 1.0 ± 0 2.7 ± 3.4 1.9 ± 1.1 0.48 ± 0.34

Median (min; max) 20 (5; 80) 1 (1; 1) 2 (1; 15) 2 (1; 7) 0.5 (0.0; 0.1)

a Percentages relate to the total number of ITT patients (N=228).

b Benefit of the usage of TachoSil

® for lymph sealing in the current case (documented surgery).

ICU = intensive care unit Data source: End-of-text Tables 11.5.3.5a1-11.5.3.5e2.

The complete analysis results of the pharmacoeconomic parameters, including frequency

count distributions can be found in End-of-text Tables 11.5.3.5a1-11.5.3.5e2).

Besides the pharmacoeconomic parameters described below, the surgeons also stated

other benefits of TachoSil® in 19 patients (8.3%), e.g. prevention of lymphoceles or no

drainage necessary, which are presented by frequency in End-of-text Table 11.5.3.5g and

listed by patient in Listing 11.5.3.5g.

Benefit of TachoSil® Expressed in EURO

Based on the comparisons current vs. similar cases (see section above), the favourable

reductions in the duration of surgery, ICU stay, and hospital stay seen in the current cases

with TachoSil® were converted into savings expressed in EURO (€) based on the values

presented in Section 8.1.2. The results are presented in End-of-text Table 11.5.3.5f. The

reduction of the duration of surgery translates into a mean saving of 384 ± 293 € (N=23), the


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reduction in the time spent in the ICU translates into a mean saving of 2,000 ± 0 € (N=10),

and the reduction in the time spent in hospital translates into a mean saving of 1,382 ± 1,759

€ (N=30). Overall, the estimated total saving amount ranged between 75 € and 7,680 €

(N=47; mean: 1,496 ± 1,766 €; median: 660 €).

11.5.2.9 Requirement of Additional Sizes of TachoSil®

In most cases (81.1%, N=185), the surgeons stated that in addition to the available sizes of

TachoSil®, no other sizes were required for use in lymphadenectomy (End-of-text Table

11.5.3.6). In 4.8% of the patients (N=11), the surgeon stated that additional sizes were

required; data were missing for 14.0% of the patients (N=32). Additional sizes that were

considered essential were the following: 10.0 x 10.0 cm in 3 cases (1.3%) and 2.5 x 2.5 cm

in 2 cases (0.9%).

11.5.2.10 Adverse Events

A total of 39 AEs were reported in 31 of 228 patients (13.6%) (End-of-text Table 11.5.2.4).

Twenty seven of these patients had postoperative complications which were collected and

processed as ICSRs (see also Section 6.2 and Section 11.5.2.1), 4 patients had only AEs

that were not postoperative complications (leg pain, neurological disorder, effusion pleural,

wound infection, micturition disorder, wound erythema).

Ten AEs in 7 patients (3.1%) were serious (SAEs), and 10 AEs in 8 patients (3.5%) were

assessed by the surgeons as being causally related to the application of TachoSil®. Two

SAEs (lymphocele formation, inguinal abscess) in 2 patients were among the AEs that were

assumed causally related to TachoSil® application.

Details of all AEs, including duration, severity, outcome, and causal relationship, are listed

by patient in Listing 11.5.2.4.


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12 Discussion

The aim of this single-arm, prospective, non-interventional study was to gain further

knowledge on the routine use of TachoSil® in lymph node surgery where its sealing property

helps to reduce the rate of postoperative complications, especially of seroma formation.

The planned sample size of 600 patients was not achieved. Thus, due to the lower sample

size of 228 patients, subgroup analyses including inferential tests as originally planned in the

observational plan were considered inappropriate and were not planned in the final version

of the SAP. However, the actual sample size was considered sufficient to draw meaningful

conclusions with regard to the objectives and endpoints of this study.

The limitations of this study are those associated with its observational and non-

interventional character, including the lack of a comparator group, and missing data.

Information bias may have occurred due to incorrect recall of information by the surgeons,

with regard to similar cases in the past.

The observational plan required that TachoSil had already been in use for some time at the

participating centres. This was true for most participating surgeons, i.e. in 52.6% of the

cases, the surgeons had used TachoSil between 1 and 50 times and in 44.7% cases they

had used the product more than 50 times. Only in the cases of 3 patients (all 3 enrolled by

different surgeons), the surgeons stated that the current operation was the first time they

were using TachoSil. In addition, data on the previous use of TachoSil was missing for

another 3 patients.

Patient Population, Bleeding Risk, Type of Surgery, and TachoSil Application

The mean age was 63.6 10.8 years. For 2 study patients, information on age was not

provided; all other patients were between 33 and 90 years old (median: 65 years). The male

to female ratio was balanced (48.3% men and 48.7% women). The most frequent underlying

diseases were prostate cancer (44.7%), endometrial cancer (12.3%), breast cancer (10.1%),

cervical cancer (9.2%), and ovarian cancer (8.3%). The vast majority of the patients (87.7%)

were fully active and were able to carry on all pre-disease performance without restriction

(corresponding to ECOG grade 0). According to the TNM- classification, lymph nodes were

not affected by tumour cells in more than half of the patients (58.3%) and the majority of the

patients (70.2%) was not affected by distant metastasis.

Based on the use of blood thinning medications and the presence of coagulation disorders,

13.6% of the patients had an increased risk of bleeding. The mean values of preoperative


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coagulation parameters (INR, Quick value, pTT, and platelet count) in the total study

population were within the normal ranges.

The vast majority of the patients had open surgery (88.6%); only 8.3% had minimally

invasive surgery without conversion to the open surgery approach. Lymph nodes were most

frequently removed from the pelvic area (82.0% of 228 patients).

At least one primary haemostatic measure was taken in most patients (96.9%) prior to the

application of TachoSil® in the current documented surgery. These measures were mainly

bipolar electrocoagulation (67.1%), monopolar electrocoagulation (49.6%), clipping (45.6%),

and/or ligature (41.7%).

It appears that in the documented cases of lymphadenectomy, the predominant reason for

the application of TachoSil® was the prevention of a lymph fistula, lymphocele or seroma

(96.1%). Haemostasis was named as a reason for TachoSil® application in only 22.4% of the

cases.

Irrespective of size, a mean number of 1.5 ± 0.9 TachoSil® patches were used per patient.

Of the three available sizes, the largest patch (9.5 x 4.8 cm) was the most frequently used

(61.0%), followed by the 4.8 x 4.8 cm size patch (35.1%) and the 3.0 x 2.5 cm size patch

(10.5%). Although in 45.6% of the patients at least one of the applied patches was cut to

shape, surgeons stated in only 4.8% of all cases that additional sizes of TachoSil® patches

should be available on the market. Apparently, surgeons coped well with the available sizes

or with cutting the patches to the correct sizes as needed.

In most cases, a moistened compress was used to press on either a moistened (43.9%) or

dry (32.9%) TachoSil® patch.

Efficacy and Safety Evaluation

Any postoperative complications were reported in 18.4% of the patients, seroma formation

being reported in 2.6% and lymphocele formation in 11.8%. It has to be noted that although

seroma and lymphocele are differently defined they may have been used synonymously in

the literature. Furthermore, rates of seroma and lymphocele formation vary greatly across

studies. Grimm et al. found literature evidence for the occurrence of pelvic lymphoceles in

11-63% of patients undergoing pelvic lymphadenectomy (Ref. 19). Due to the observational

character of this study, no definite evidence for the efficacy of TachoSil® in the documented

types of lymphadenectomy can be provided; however, the rates of seroma and lymphocele

formation are at the lower end of the spectrum of rates reported in the context of lymph node


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dissection in the literature (see Ref. 18 for further literature references). In addition, the

combined rate of seroma and/or lymphocele formation of 14.5% is below the assumed

improved rate of 20% for the formation of seroma in lymphadenectomy with TachoSil® (Ref.

18; see also Section 8.2). According to the assessment of the participating surgeons,

postoperative complications were less likely to occur in 55.7% of the cases due to the use of

TachoSil® in the documented lymphadenectomy.

The mean number of inserted drainages was 1.3 ± 0.8 (N=225) and the mean maximum

duration of wound drainage was 5.6 ± 4.6 days (N=177). According to the statements of the

participating surgeons, drainage management was changed due to TachoSil® in a total of

108 patients (47.4%). Of these, 98 patients with at least 1 drainage inserted and 10 patients

with no drainage inserted. In almost all of these cases, the drainage management improved

(worsening of drainage management was reported in only 1 case, further information was

not provided in 3 cases). In patients with metastatic melanoma undergoing lymph node

dissection, significant reductions in the drainage duration have been shown in the TachoSil®

group compared to the control group in a study by Di Monta et al. (Ref. 20). When asked to

compare the drainage duration of the documented operation with that of a previous similar

case where TachoSil® had not been used, the surgeons stated that the duration of drainage

had changed in 90 of 185 patients with at least 1 drainage inserted (48.7%). For 36.0% of

the patients, the surgeons saw a benefit of TachoSil® in the current case of

lymphadenectomy with regard to the reduction of drainage time. Based on the data of 48

patients, the drainage time was reduced by a mean of 1.9 ± 1.1 days in the current surgery

compared to a similar case without the application of TachoSil®. In the study by Di Monta et

al. (Ref. 20), the difference in drainage duration between the TachoSil® group and the

standard group was approximately 3 days. With regard to drainage volume, the surgeons

saw a change compared to similar cases without TachoSil® application in 107 of 185

patients with at least 1 drainage inserted (57.8%). A benefit of TachoSil® with regard to the

reduction in drainage volume was seen in 39.0% of the cases. Based on the data of 52

patients, the drainage volume was reduced by a mean of 483 ± 345 mL in the documented

cases compared to similar cases without TachoSil® application.

Furthermore, the surgeons assumed a benefit of TachoSil® regarding reductions in the

length of the hospital stay and the time spent in the ICU in 27.2% and 8.8% of the cases,

respectively. The mean length of the hospital stay was 12.9 ± 12.0 days (N=225) and the

mean length of ICU stay was 2.8 ± 1.9 days (N=100). Based on the data of 30 and 10


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patients, respectively, the time spent in hospital was reduced by a mean of 2.7 ± 3.4 days

and the ICU stay was reduced by a mean of 1.0 ± 0 days, when compared to similar cases

without TachoSil® in the past.

When asked to compare the benefit of TachoSil® with alternative techniques, methods, or

products, which had reportedly been used by the surgeons in similar cases of

lymphadenectomy, the participating surgeons saw at least one benefit of TachoSil® for

lymph sealing in 82.0% of the documented cases. Compared with electrocoagulation and

hand suture/suturing/ligature, which were the most frequently named alternative techniques

(named as alternatives in 77.2% and 48.7% of the patients, respectively), TachoSil® was

assessed as being faster than hand suture/suturing/ligature (45.2%) and slower than

electrocoagulation in the majority of the cases (45.2% and 50.9%, respectively). With regard

to the effect, the surgeons considered TachoSil® most frequently as being more reliable than

electrocoagulation (44.7%) and as being equally reliable than hand suture/suturing/ligature

(32.9%).

In line with the results regarding the benefits of TachoSil®, handling and usefulness of

TachoSil®, as well as the surgeon’s satisfaction with TachoSil® in the documented operation

were assessed as being rather good by the participating surgeons. On rating scales ranging

from 1 (best score) to 10 (worst score), the median score was 2 for all three variables.

Surgeons with more experience in the use of TachoSil® (used 11-50 times in the past)

assessed its handling, usefulness and their satisfaction with the product more favourably

than surgeons who had used TachoSil® for the first time or only 1-10 times.

Information on pharmacoeconomic parameters was available only for a small number of

patients. Based on the data provided with regard to reductions in the duration of surgery and

length of hospital and ICU stays, the estimated mean total saving amount, expressed in

EURO, was 1,496 ± 1,766 €. However, due to the small amount of data and the large

variability (range between 75 € and 7,680 €), the estimated saving amount is questionable.

A total of 39 AEs were reported in 31 of 228 patients (13.6%). Most of the AEs were

postoperative complications (including formation of lymphocele, seroma, and lymphatic

fistula). Four patients had AEs that were not postoperative complications, but none of these

AEs were assessed as being related to the application of TachoSil®. In addition, 15 patients

had postoperative complications that were not classified as AEs.


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13 Conclusion

The results of this non-interventional study showed that in a real life population of patients

undergoing lymphadenectomy (mainly in the pelvic area) the main purpose for the

application of TachoSil® was the prevention of a lymph fistula, lymphocele or seroma. The

rates of postoperative seroma or lymphocele formation were lower than anticipated based on

literature data, suggesting that TachoSil® reliably prevents lymphatic leakage and

consequently reduces the incidence of associated complications.

With regard to pharmacoeconomic parameters, the most frequently named benefits of

TachoSil® for lymph sealing according to the surgeons’ assessments were the reduction of

drainage volume, drainage time, and length of the hospital stay.

Handling and usefulness of TachoSil® as well as the surgeon’s satisfaction with TachoSil® in

the documented operation were assessed as being very good or good in the majority of the

cases. The assessment tended to be more favourable in cases where the surgeon already

had been more experienced in the use of TachoSil®.

Although TachoSil® patches were frequently cut to shape, most surgeons coped well with

the available sizes of TachoSil®. In only a few cases, it was stated that additional sizes

would be desirable or essential for use in lymphadenectomy.


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