The Effect of Tinzaparin on Biomarkers in FIGO Stage III-IV Ovarian Cancer Patients Undergoing Neoadjuvant Chemotherapy - A Randomized Pilot Study
Phase: PHASE2
Conditions: Epithelial Ovarian Cancer
Sponsor: University Hospital, Linkoeping

CLINICAL STUDY PROTOCOL 
 
The Effect of tinzaparin on Biomarkers in FIGO Stage III-IV Ovarian 
Cancer Patients Undergoing Neoadjuvant Chemotherapy – A randomized 
pilot study 
 
The TABANETOC-trial 
(Tinzaparin And Biomarkers After Neoadjuvant Treatment of Ovarian Cancer) 
 
 
 
Study code:  
TABANETOC 
EudraCT number:  
2021-000135-31  
Sponsor:  
Preben Kjølhede  
Coordinating Investigators: 
Preben Kjølhede 
Anna-Clara Spetz Holm,  
Gabriel Lindahl, 
Anna Karlsson, 
Tomas Lindahl, 
Maria Jenmalm  
 
 
 
 
 
 

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Table Of Contents 
1 
Synopsis ......................................................................................................................................... 16 
2 
Background and rationale ............................................................................................................. 18 
3 
Benefit-risk evaluation .................................................................................................................. 20 
3.1 
Benefit-risk evaluation with respect to the ongoing Covid-19 pandemic ............................. 21 
4 
Study objectives ............................................................................................................................ 21 
4.1 
Primary objective................................................................................................................... 21 
4.2 
Secondary objective(s) .......................................................................................................... 22 
4.3 
Primary endpoint (variable) .................................................................................................. 22 
4.4 
Secondary endpoints (variables) ........................................................................................... 22 
4.5 
Exploratory endpoints (variables) ......................................................................................... 22 
5 
Study design and procedures ........................................................................................................ 22 
5.1 
Overall study design .............................................................................................................. 22 
5.2 
Procedures and flow chart .................................................................................................... 23 
5.3 
Biological sampling procedures ............................................................................................. 23 
5.3.1 
Handling, storage, and destruction of biological samples ............................................ 23 
5.3.2 
Total volume of blood per subject ................................................................................ 23 
5.4 
Biobank .................................................................................................................................. 23 
5.5 
End of Study .......................................................................................................................... 23 
6 
Subject selection ........................................................................................................................... 24 
6.1 
Inclusion criteria .................................................................................................................... 24 
6.2 
Exclusion criteria ................................................................................................................... 24 
6.3 
Screening ............................................................................................................................... 25 
6.4 
Withdrawal criteria................................................................................................................ 25 
7 
Study treatments ........................................................................................................................... 26 
7.1 
Description of investigational product(s) .............................................................................. 26 
7.2 
Dose and administration ....................................................................................................... 26 
7.3 
Packaging, labeling, and handling of investigational products(s) ......................................... 27 
7.4 
Drug accountability and treatment compliance ................................................................... 27 
7.5 
Randomization....................................................................................................................... 27 
7.6 
Blinding .................................................................................................................................. 28 
7.7 
Concomitant medications ..................................................................................................... 28 
7.7.1 
Background treatment .................................................................................................. 28 
7.7.2 
Other concomitant medications.................................................................................... 28 

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7.8 
Destruction ............................................................................................................................ 28 
7.9 
Treatment after study end .................................................................................................... 28 
8 
Methods for measurement of endpoints for clinical efficacy and safety ..................................... 28 
8.1 
Methods for measurement of endpoints for clinical efficacy ............................................... 28 
8.1.1 
Primary endpoint (variable) .......................................................................................... 28 
8.1.2 
Secondary endpoints (variables) ................................................................................... 29 
8.2 
Methods for measurement of endpoints (variables) for clinical safety ................................ 29 
9 
Handling of Adverse Events ........................................................................................................... 29 
9.1 
Definitions ............................................................................................................................. 30 
9.1.1 
Adverse Event (AE) ........................................................................................................ 30 
9.1.2 
Adverse Reaction (AR) ................................................................................................... 30 
9.1.3 
Serious Adverse Event (SAE) .......................................................................................... 30 
9.1.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .......................................... 30 
9.2 
Assessment of Adverse Events .............................................................................................. 30 
9.2.1 
Assessment of causal relationship ................................................................................ 30 
9.2.2 
Assessment of intensity ................................................................................................. 31 
9.2.3 
Assessment of seriousness ............................................................................................ 31 
9.3 
Reporting and registration of Adverse Events ...................................................................... 31 
9.3.1 
Reporting of Adverse Events (AE) .................................................................................. 33 
9.3.2 
Reporting of Serious Adverse Events (SAE) ................................................................... 33 
9.3.3 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSAR) ................... 33 
9.4 
Follow-up of Adverse Events ................................................................................................. 33 
9.5 
Annual Safety Report (Development Safety Update Report, DSUR) ..................................... 34 
9.6 
Procedures in case of emergencies, overdose or pregnancy ................................................ 34 
9.7 
Reference Safety Information ............................................................................................... 34 
10 Statistics......................................................................................................................................... 34 
10.1 
Analysis population ............................................................................................................... 34 
10.2 
Statistical analyses ................................................................................................................. 34 
10.2.1 
Statistical methods ........................................................................................................ 34 
10.2.2 
Drop-outs ....................................................................................................................... 35 
10.3 
Adjustment of significance and confidence interval ............................................................. 35 
10.4 
Sample size calculations ........................................................................................................ 35 
10.5 
Interim analysis (if relevant) .................................................................................................. 36 
11 Quality Control and Quality Assurance ......................................................................................... 36 

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11.1 
Quality Assurance and Sponsor oversight ............................................................................. 36 
11.2 
Monitoring ............................................................................................................................. 37 
11.3 
Source data ............................................................................................................................ 37 
11.4 
Deviations or serious breaches ............................................................................................. 37 
11.5 
Audits and inspections .......................................................................................................... 37 
12 Ethics ............................................................................................................................................. 38 
12.1 
Compliance to the protocol, GCP and regulations ................................................................ 38 
12.2 
Ethical review of the study .................................................................................................... 38 
12.3 
Procedure for obtaining informed consent ........................................................................... 38 
12.4 
Data protection ..................................................................................................................... 38 
12.5 
Insurances.............................................................................................................................. 39 
12.6 
Publication of results ............................................................................................................. 39 
13 Substantial changes to the study .................................................................................................. 39 
14 Collection, handling, and archiving data ....................................................................................... 39 
14.1 
Case Report Form .................................................................................................................. 40 
15 Notification of study completion, reporting, and publication ...................................................... 40 
16 References ..................................................................................................................................... 40 
 
 
 

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Signature page 
 
Sponsor 
I am responsible for ensuring that this protocol includes all essential information to be able to 
conduct this study. I will submit the protocol and all other important study-related information 
to the responsible investigator(s) so that they can conduct the study correctly. I am aware 
that it is my responsibility to hold the staff members who work with this study informed and 
trained. 
 
 
Sponsor’s signature                                                                  Date 
Preben Kjølhede, MD, PhD; Professor, Senior consultant 
Printed name 
Coordinating Investigators / Principal Investigators 
I have read this protocol and agree that it includes all essential information to be able to 
conduct the study. By signing my name below, I agree to conduct the study in compliance 
with this protocol, the Declaration of Helsinki, ICH GCP (Good Clinical Practice) guidelines 
and the current national and international regulations governing the conduct of this clinical 
trial. 
I will submit this protocol and all other important study-related information to the staff 
members and investigators who participate in this study, so that they can conduct the study 
correctly. I am aware of my responsibility to continuously keep the staff members and 
investigators who work with this study informed and trained.  
I am aware that quality control of this study will be performed in the form of monitoring, 
audit, and possibly inspection. 
 
Coordinating Investigator / Principal Investigator’s signature         Date 
Preben Kjølhede, MD, PhD; Professor, Senior consultant 
Printed name 
 
Coordinating Investigator / Principal Investigator’s signature         Date 
Anna-Clara Spetz Holm, MD, PhD, Associate Professor, Senior Consultant 
Printed name 
 
 

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Coordinating Investigator / Principal Investigator’s signature         Date 
Gabriel Lindahl, MD, PhD, Assistant Professor, Senior Consultant 
Printed name 
 
Coordinating Investigator / Principal Investigator’s signature         Date 
Anna Karlsson, MD, Specialist doctor 
Printed name 
 
Coordinating Investigator / Principal Investigator’s signature         Date 
Tomas Lindahl, MD, PhD, Professor, Senior Consultant 
Printed name 
 
Coordinating Investigator / Principal Investigator’s signature         Date 
Maria Jenmalm, MSc, PhD, Professor 
Printed name 
 
 

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Principal Investigator 
I have read this protocol and agree that it includes all essential information to be able to 
conduct the study. By signing my name below, I agree to conduct the study in compliance 
with this protocol, the Declaration of Helsinki, ICH GCP (Good Clinical Practice) guidelines 
and the current national and international regulations governing the conduct of this clinical 
trial. 
I will submit this protocol and all other important study-related information to the staff 
members and investigators who participate in this study, so that they can conduct the study 
correctly. I am aware of my responsibility to continuously keep the staff members and 
investigators who work with this study informed and trained.  
I am aware that quality control of this study will be performed in the form of monitoring, audit, 
and possibly inspection. 
 
Principal Investigator’s signature                                                    Date 
 
Printed name 
 
 

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Principal Investigator 
I have read this protocol and agree that it includes all essential information to be able to 
conduct the study. By signing my name below, I agree to conduct the study in compliance 
with this protocol, the Declaration of Helsinki, ICH GCP (Good Clinical Practice) guidelines 
and the current national and international regulations governing the conduct of this clinical 
trial. 
I will submit this protocol and all other important study-related information to the staff 
members and investigators who participate in this study, so that they can conduct the study 
correctly. I am aware of my responsibility to continuously keep the staff members and 
investigators who work with this study informed and trained.  
I am aware that quality control of this study will be performed in the form of monitoring, audit, 
and possibly inspection. 
 
Principal Investigator’s signature                                                    Date 
 
Printed name 
 
 

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Principal Investigator 
I have read this protocol and agree that it includes all essential information to be able to 
conduct the study. By signing my name below, I agree to conduct the study in compliance 
with this protocol, the Declaration of Helsinki, ICH GCP (Good Clinical Practice) guidelines 
and the current national and international regulations governing the conduct of this clinical 
trial. 
I will submit this protocol and all other important study-related information to the staff 
members and investigators who participate in this study, so that they can conduct the study 
correctly. I am aware of my responsibility to continuously keep the staff members and 
investigators who work with this study informed and trained.  
I am aware that quality control of this study will be performed in the form of monitoring, audit, 
and possibly inspection. 
 
Principal Investigator’s signature                                                    Date 
 
Printed name 
 
 

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Principal Investigator 
I have read this protocol and agree that it includes all essential information to be able to 
conduct the study. By signing my name below, I agree to conduct the study in compliance 
with this protocol, the Declaration of Helsinki, ICH GCP (Good Clinical Practice) guidelines 
and the current national and international regulations governing the conduct of this clinical 
trial. 
I will submit this protocol and all other important study-related information to the staff 
members and investigators who participate in this study, so that they can conduct the study 
correctly. I am aware of my responsibility to continuously keep the staff members and 
investigators who work with this study informed and trained.  
I am aware that quality control of this study will be performed in the form of monitoring, audit, 
and possibly inspection. 
 
Principal Investigator’s signature                                                    Date 
 
Printed name 
 
 

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Principal Investigator 
I have read this protocol and agree that it includes all essential information to be able to 
conduct the study. By signing my name below, I agree to conduct the study in compliance 
with this protocol, the Declaration of Helsinki, ICH GCP (Good Clinical Practice) guidelines 
and the current national and international regulations governing the conduct of this clinical 
trial. 
I will submit this protocol and all other important study-related information to the staff 
members and investigators who participate in this study, so that they can conduct the study 
correctly. I am aware of my responsibility to continuously keep the staff members and 
investigators who work with this study informed and trained.  
I am aware that quality control of this study will be performed in the form of monitoring, audit, 
and possibly inspection. 
 
Principal Investigator’s signature                                                    Date 
 
Printed name 
 
 
 

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Contact information 
Role 
 
Sponsor 
Preben Kjølhede, MD, PhD, Professor, 
Senior Consultant 
Department of Obstetrics and Gynecology,  
Department of Clinical and Biomedical 
Sciences, Linköping University Hospital 
58185 Linköping 
+46705688201 
Preben.Kjolhede@liu.se  
Preben.Kjolhede@regionostergotland.se  
Coordinating Investigators / Principal 
Investigators Linköping (Linköping 
University Hospital) 
Preben Kjølhede, MD, PhD, Professor, 
Senior Consultant 
Department of Obstetrics and Gynecology,  
Department of Clinical and Biomedical 
Sciences, Linköping University Hospital 
58185 Linköping 
+46705688201 
Preben.Kjolhede@liu.se  
Preben.Kjolhede@regionostergotland.se 
 
Anna-Clara Spetz Holm, MD, PhD, Associate 
Professor, Senior Consultant 
Department of Obstetrics and Gynecology, 
Department of Clinical and Biomedical 
Sciences, Linköping University Hospital 
58185 Linköping 
+4610-1033130 
Anna-Clara.Spetz.Holm@liu.se  
 
Gabriel Lindahl, MD, PhD, Assistant 
Professor, Senior Consultant 
Department of Oncology, Department of 
Clinical and Biomedical Sciences, Linköping 
University Hospital 
58185 Linköping 
+46730958174  
Gabriel.Lindahl@regionostergotland.se   
 
 
 
 
 
 
 

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Role 
 
Anna Karlsson, MD, Phd-student, Specialist 
Doctor 
Department of Obstetrics and Gynecology, 
Department of Clinical and Biomedical 
Sciences, Linköping University Hospital 
58185 Linköping 
+46738366479 
Anna.Karlsson@liu.se  
Anna.Br.Karlsson@regionostergotland.se 
 
Tomas Lindahl, MD, PhD, Professor, Senior 
Consultant 
Department of Clinical Chemistry, 
Department of Clinical and Biomedical 
Sciences, Linköping University Hospital 
58185 Linköping 
+4610-1033227 
+46701479660 
Tomas.Lindahl@liu.se  
 
Maria Jenmalm, MSc, PhD, Professor 
Division of Inflammation and Infection, 
Department of Biomedical and Clinical 
Sciences, Linköping University 
58783 Linköping 
+4613-282418 
Maria.Jenmalm@liu.se  
Clinical monitoring organization 
Forum Östergötland 
Medicinska Fakulteten 
581 85 Linköping 
forumo@regionostergotland.se  
Principal Investigator, Jönköping (Ryhov 
Hospital)  
Laila Falknäs, senior consultant 
Department of obstetrics and gynecology, 
Ryhov hospital 
laila.falknas@rjl.se  
Principal Investigator, Värnamo (Värnamo 
Hospital). 
Shefqet Halili, senior consultant 
Department of obstetrics and gynecology, 
Värnamo Hospital 
shefqet.halili@rjl.se  
Principal Investigator, Eksjö 
(Höglandssjukhuset i Eksjö) 
Malena Tiefenthal Thrane, senior consultant 
Department of obstetrics and gynecology, 
Höglandssjukhuset i Eksjö 
malena.tiefenthal.thrane@rjl.se  
 
 
 
 
 

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Role 
 
Principal Investigator, Kalmar 
(Länssjukhuset i Kalmar) 
Cecilia Molnar, senior consultant 
Department of obstetrics and gynecology, 
Länssjukhuset i Kalmar 
cecilia.molnar@regionkalmar.se  
Principal Investigator, Västervik (Västervik 
Hospital) 
Anders Rosenmüller, senior consultant 
Department of obstetrics and gynecology, 
Västervik Hospital 
anders.rosenmuller@regionkalmar.se  
Central Laboratory 
Klinisk Kemi 
Diagnostikcentrum 
Linköping University Hospital 
58185 Linköping 
Research Laboratory 
Kerstin M Gustafsson, Biomedical Scientist 
Institutionen för biomedicinska och kliniska 
vetenskaper 
Klinisk kemi 
Universitetssjukhuset, hus 420, plan11 
58185 Linköping 
Kerstin.M.Gustafsson@regionostergotland.se  
Olink Laboratory 
Olink Proteomics 
Uppsala Science Park 
75137 Uppsala 
+4618–4443970 
info@olink.com  
 
 
 
 

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List of used acronyms and abbreviations 
Abbreviation 
Term/Explanation 
AE 
Adverse Event = any untoward medical occurrence 
AR 
Adverse Reaction = all noxious and unintended reactions to the 
medicinal product, regardless of dose 
CRF 
Case Report Form  
CRP 
C-reactive protein 
DPDS 
Delayed primary debulking surgery 
DSUR 
Development Safety Update Report = annual safety report 
EOC 
Epithelial ovarian cancer 
EPM 
Etikprövningsmyndigheten (English: Swedish Ethical Review Authority) 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonization  
ITT 
Intention-to-treat = including all data from all subjects who have 
participated in the study 
LMVH 
Low molecular weight heparin 
LVFS 
Läkemedelsverkets författningssamling (English: Swedish Medical 
Products Agency’s statutes) 
NACT 
Neoadjuvant chemotherapy 
OC 
Ovarian cancer 
PP 
Per Protocol analysis = including only data from subjects who have 
completed the study completely in accordance with the protocol, with no 
deviations from the protocol  
SAE  
Serious Adverse Event = serious untoward medical occurrence 
SPC or SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
VEGF 
Vascular endothelial growth factor 
VTE 
Venous thromboembolism 
 
 
 

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1 Synopsis 
EudraCT number: 2021-000135-31 
Title:  
The Effects of tinzaparin on Biomarkers in FIGO Stage III-IV Ovarian Cancer Patients 
Undergoing Neoadjuvant Chemotherapy – A randomized pilot study 
Study code: TABANETOC 
Short background/ Rationale/Aim: 
Previous findings have indicated antineoplastic properties of tinzaparin (Innohep®), a 
commonly used anti-coagulant. Earlier studies have mainly investigated the 
antineoplastic effects of tinzaparin in animal models and in human cell-lines. In this pilot 
study we aim to examine the potential antitumoral effects of tinzaparin in vivo in women 
with epithelial ovarian cancer (EOC).  
Study objectives:  
Primary objective: The primary objective of the study is to evaluate the effects of 
tinzaparin on changes in levels of CA-125 in EOC patients who receive neoadjuvant 
chemotherapy (NACT). 
Secondary objectives: The secondary objective of the study is to explore the impact of 
tinzaparin on the dynamic of a spectrum of immunological and coagulation factors in 
EOC patients who receive NACT. Besides, the compliance of tinzaparin injections and 
adverse events caused by tinzaparin will be described. 
Study design:  
Randomized, open pilot trial 
Study population:  
Women with FIGO stage III-IV EOC receiving NACT 
Number of subjects:  
40 women, 20 in each arm.  
Inclusion criteria:  
• 
The subject has given written consent to participate in the study.  
• 
Age 18 and above 
• 
Epithelial ovarian, fallopian tube or peritoneal cancer, or abdominal cancer 
where a biopsy indicates an origin from the ovary, fallopian tube or peritoneum. 
• 
Histology diagnosis of either high grade serous carcinoma, endometroid 
carcinoma or clear cell carcinoma. 
• 
FIGO stage III-IV disease. 
• 
Selected for NACT with platinum double regimen at a multidisciplinary 
conference at Department of Oncology at Linköping University Hospital 
• 
Receive treatment at either of the University Hospital in Linköping, or the 
hospitals in Jönköping (Ryhov Hospital), Eksjö (Höglandssjukhuset Eksjö), 
Västervik (Västervik Hospital), Kalmar (Länssjukhuset i Kalmar), Värnamo 
(Värnamo Hospital). 
• 
Planned for platinum doublet regimen.  
• 
Prior to start of NACT pregnancy should be ruled out by menstrual history or in 
unclear cases by a urine hCG test.  
• 
Women of childbearing potential should use a safe birth control method 
(combined hormonal contraception, progesterone only hormonal contraception, 
intra uterine device, bilateral tubal occlusion, vasectomized partner, sexual 
abstinence, male or female condom, diaphragm with spermicide). 

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• 
WHO Performance Status 0-1 
• 
Weight 50-150 kg 
• 
CA-125-level ≥250 kIE/L at diagnosis 
Exclusion criteria: 
• 
Concomitant treatment with heparins, low molecular weight heparins, warfarin or 
non-vitamin K antagonist oral anticoagulants. Platelet inhibitors are allowed. 
• 
Treatment with heparins, low molecular weight heparins or non-vitamin K 
antagonist oral anticoagulants within the last year. 
• 
Known or suspected allergies against any product included in the study 
• 
Ongoing pregnancy, independent of gestational age.  Breastfeeding or planned 
pregnancy  
• 
EOC disclosed at Cesarean section  
• 
Abdominal surgery or other major surgery within the last year 
• 
Mental inability, reluctance or language difficulties that result in difficulty 
understanding the meaning of study participation 
• 
Treatment or disease which, according to the investigator, can affect treatment 
or study results 
• 
Known brain metastasis 
• 
Participation or recent participation (within the last 30 days) in a clinical study 
with an investigational product  
• 
Ongoing treatment of thromboembolic disease. 
• 
Thromboembolic disease within the last year.  
• 
Hypersensitivity to the active substance (tinzaparin) or any of the excipients. 
• 
Serious hemorrhage or conditions predisposing to serious hemorrhage. Serious 
hemorrhage is defined as fulfilling any one of these three criteria: 
a) occurs in a critical area or organ (e.g. intracranial, intraspinal, intraocular, 
retroperitoneal, intra-articular or pericardial, intra-uterine or intramuscular with 
compartment syndrome), 
b) causes a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or 
c) leads to transfusion of two or more units of whole blood or red blood cells. 
• 
Severe coagulation disorder. 
• 
Acute gastro duodenal ulcer. 
• 
Septic endocarditis. 
• 
Previous heparin-induced thrombocytopenia. 
• 
WHO Performance Status >1. 
• 
Platinum single regimen  
• 
E-GFR <30ml/min (analyzed no more than 14 days before start of treatment with 
investigational product) 
• 
Platelets <100 x10^9/L (analyzed no more than 14 days before start of treatment 
with investigational product) 
• 
Treatment for other known malignancy within the last year (except basal cell 
carcinoma) 
Investigational product(s), dosage, administration:  
Innohep® (tinzaparin), 4500 IU/8000 IU daily, subcutaneous injection 
Study endpoints: 
  Primary endpoint: 
Level of CA-125 measured before cycles one-four of chemotherapy and preoperatively.   
  Secondary endpoints: 
Levels of hemoglobin, platelets, leucocytes, C-reactive protein (CRP), albumin, 
interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) before every cycle of 
chemotherapy, preoperatively and three weeks after the last cycle of chemotherapy. 

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CA-125 measured before cycles five-seven of chemotherapy and three weeks after the 
last cycle of chemotherapy  
The compliance to tinzaparin injections and occurrence of adverse events related to 
tinzaparin will be determined. 
Objectively confirmed VTE. Death due to VTE.  
  Exploratory endpoints: 
Tissue Factor (TF), D-dimer, soluble P-selectin, thrombin-antithrombin complex and 
thrombin generation potential will be measured before every cycle of chemotherapy, 
preoperatively, and three weeks after the last cycle of chemotherapy.  
A panel of 92 inflammation-associated proteins will be measured at baseline, at visit 5 
and at visit 8 or 9.  
Study period: 
Q1 2022-Q4 2024 
 
2 Background and rationale 
Ovarian cancer (OC) is the gynecological malignancy with the highest mortality rate. In 
Sweden approximately 700 women are annually diagnosed with OC and in 2018, 568 
women died due to OC (1,2). The vast majority of OCs is epithelial OC (EOC). EOC is a 
heterogeneous disease with different characteristics in carcinogenesis, risk factors, 
morphology, response to treatment and prognosis. The majority of EOCs is assumed to 
originate from the fallopian tubes. Although it may be unclear where the cancer started, tubal, 
ovarian and primary peritoneal cancers have histopathological similarities, and are treated 
similarly (3-5). From a clinical perspective these three cancers are considered as one entity 
and are referred to as EOC in this study. To ensure the organ-specific diagnosis a 
histopathology examination of the ovaries and the fallopian tubes is required. Prior to surgery 
the diagnosis is therefore not organ-specific, but tentative and is most often based on a core 
needle biopsy, where the histopathology indicates the genital organs as origin of the cancer. 
Until the organ-specific diagnosis of the cancer has been determined, the cancer is usually 
denominated as abdominal cancer.  
International guidelines on treatment of advanced stage EOC recommend primary debulking 
surgery (PDS) followed by adjuvant chemotherapy when it is considered possible to achieve 
surgical radicality with no macroscopically residual tumor at conclusion of the surgery. 
However, if this goal is considered not achievable it is recommended to start treatment with 
NACT followed by delayed primary debulking surgery (DPDS). The choice of primary 
treatment of advanced stage EOC is dependent on the assessment of the patient and the 
primary investigation. No unanimous criteria have been suggested to select between the two 
primary treatment modalities (PDS and NACT). Several clinical, laboratory and imaging 
factors may influence the decision. When a multidisciplinary team conference deems PDS 
impossible, based on the primary investigations, the patient is offered NACT (6). 
Tinzaparin, a low-molecular weight heparin (LMWH), is an anti-thrombotic drug used in the 
treatment and prevention of thromboembolism. Tinzaparin acts by activating antithrombin 
and inactivating factor Xa (7). Moreover, tinzaparin exhibits anti-inflammatory effects 
indicating immune system modulating properties (8). In addition to its ability to inhibit 
thrombin and factor Xa, tinzaparin is effective at releasing endothelial tissue factor pathway 

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inhibitor, the natural inhibitor of both procoagulant and non-coagulant effects of TF. TF acts 
normally as a cellular receptor for factor VIIa and initiates the coagulation pathway. TF is 
present on the surface of many tumor cell types and is believed to be responsible for tumor 
cell procoagulant activity. Animal studies and in vitro studies on human ovarian cancer and 
breast cancer cells as well as umbilical vein endothelial cells have indicated an anti-
metastatic potential of tinzaparin (9). Various mechanisms have been suggested for the anti-
metastatic effect, including inhibiting the tissue factor pathway, upregulating E-Cadherin and 
downregulating von Willebrand-factor. This affects the metastatic process by inhibiting local 
invasion, the migration of tumor cells, and the promotion of tumor angiogenesis, which are all 
crucial to the metastatic growth and considered to be hallmarks of cancer (10-17).  
EOC most commonly metastasize within the peritoneal cavity and ascites is often found at 
the time of diagnosis. Malignant cells undergo an epithelial to mesenchymal transition and 
spread with the ascites. This transition includes changes in cadherin expression and up-
regulation of proteolytic pathways. When attaching to peritoneal surfaces the cancer cells 
return to the epithelial state (18). VEGF is produced by the tumor cells and promotes 
angiogenesis in the primary tumor as well as in the metastases. Furthermore, VEGF also 
increases vascular permeability which results in increased ascites production (19)  
In colon cancer patients, the use of tinzaparin 4500 IU daily for 30 days postoperatively 
reduced the levels of VEGF to the preoperative level in the first preoperative month whereas 
it remained elevated in patients who received lower dose of tinzaparin and/or shorter 
duration of treatment (20).  
Therapeutic doses of tinzaparin have been shown to antagonize cisplatin resistance in an 
EOC cell line by inhibiting expression of genes that mediate cisplatin resistance (21). The 
standard treatment for primary EOC includes platinum-based chemotherapy in combinations 
with paclitaxel. Thus, treatment with tinzaparin may potentially be assumed to counteract the 
effect of cisplatin resistance in EOC.  
Previous studies have suggested various biomarkers as prognostic factors in EOC. The 
serum level of CRP, an inflammatory biomarker, is a prognostic factor for overall survival, 
progression free survival and postoperative residual tumor mass (22,23). High levels of IL-6, 
also an inflammatory biomarker, predicts reduced overall survival and progression free 
survival (23). Thrombocytosis and anemia are associated with advanced stage EOC, 
reduced disease-free survival and overall survival (24-27). Low levels of albumin predict of 
suboptimal debulking as well as of death within six months (28,29). Low levels of hemoglobin 
and albumin and high levels of platelets and CRP may be indicators of an activated systemic 
inflammatory response indicating more advanced or maybe generalized malignancy. Other 
inflammatory markers, such as other interleukins and tumor necrosis factors may also be of 
interest to analyze.  
CA-125, a glycoprotein produced by mesodermally derived tissues, has been found useful as 
a biomarker of EOC. Higher levels of CA-125 may indicate greater tumor burden and more 
advanced disease. Studies have also found CA-125 to be of value for predicting suboptimal 
debulking (30). However, there are contradicting results regarding pre-treatment CA-125 as a 
predictor for overall survival (31,32). In women with advanced EOC receiving NACT as 
primary treatment the reduction in CA-125-level has been recognized as a predictor for 
overall survival as well as optimal cytoreduction when undergoing DPDS (33,34). A decrease 

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in CA-125 level of more than 50% after the first course of chemotherapy is indicative for 
better prognosis (35,36)  
We have previously shown that the pre-treatment levels of platelets, CRP, albumin and CA-
125 in peripheral venous blood were independent predictors of survival in FIGO stage III-IV 
EOC. Women with low levels of serum albumin or high levels of platelets, CRP or CA-125 
had significantly shorter survival than women with normal levels of these biomarkers (37).  
In order to evaluate the effect of tinzaparin on these biomarkers in advanced stage EOC we 
selected patients receiving NACT. Patients undergoing PDS are treated with 
thromboprophylactic LMWH postoperatively for four weeks and consequently it will not be 
possible to determine the effect of tinzaparin on the biomarkers. Thus, by selecting only 
patients for NACT the differences in biomarker levels in patients receiving tinzaparin in 
addition to NACT in comparison to patients receiving NACT only might indicate anti-
neoplastic properties of tinzaparin. 
Tinzaparin will have effects on the coagulation system, which is well-known. It promotes the 
inhibiting effect of Antithrombin III on the activated coagulation factors, mainly factor Xa. 
However, it is unknown if anti-neoplastic effects are correlated to remaining activation of 
platelets and coagulation. To evaluate the potential association between the biomarkers and 
coagulation, D-dimer, soluble P-selectin, thrombin-antithrombin complex and thrombin 
generation potential will be used.  
The clinical effect of tinzaparin on neoplastic growth in EOC is poorly investigated. EOC 
patients have a higher incidence of venous thromboembolism (VTE) than other cancers (34). 
The risk of VTE is 20-27% within one year after diagnosing ovarian cancer (38,39) Despite 
this high incidence the guidelines for treatment of EOC still do not include recommendations 
on long term antithrombotic prophylaxis. Thus, the long-term effect of tinzaparin on EOC has 
yet to be elucidated. This pilot study will contribute with knowledge on how tinzaparin affects 
biomarkers associated with survival and other prognostic factors in patients with EOC. 
3 Benefit-risk evaluation  
Given that tinzaparin har antitumoral effects, women in the treatment group are expected to 
have more marked changes in CA125 levels than the control group. This might indicate 
better response to NACT and a greater chance of achieving macroscopic radicality upon 
delayed primary debulking surgery. Tinzaparin is a commonly used, well tolerated, 
anticoagulant, both for treatment of manifest VTE and as prevention of VTE. Women with 
EOC have an increased risk of VTE compared to healthy women and compared to patients 
suffering from other cancers. Thus, receiving treatment with tinzaparin may be expected to 
decrease the risk of VTE, with health benefits for the subjects themselves as well as health 
economic benefits 
Tinzaparin given in thrombosis-prophylactic dosage have few known side effects, they 
include hematomas and other reactions at the injection site and, rarely, allergic reactions. 
Anemia and heparin-induced thrombocytopenia have occurred. Subjects included in this 
study will have blood samples analyzed every three weeks during the course of the study, 
thus will any anemia or thrombocytopenia be found.  

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Bleeding events have been reported during treatment with tinzaparin, mainly when high 
doses of tinzaparin were given. Simultaneous use of drugs that affects the coagulation 
increases the risk of bleeding events; in this study women with ongoing anticoagulant 
treatment will be excluded. Treatment with platelet inhibitors will be allowed. 
Since this is a pilot study and since the selected end point variables should not be affected 
by any placebo-effect this study is not blinded.  
This study entails small risks, of mainly minor bleeding events. However, the potential 
benefits concerning antineoplastic effect and risk reduction of thromboembolic events during 
chemotherapy exceed the risk for minor bleeding adverse events. 
3.1 Benefit-risk evaluation with respect to the ongoing Covid-19 pandemic 
This study will not generate any extra health care visits as screening, inclusion, 
randomization and collection of blood samples will be performed during a visit when the 
subject will attend as part of the clinical routine. Therefore, this study is not to be expected to 
increase the subjects’ risk to be infected by Covid-19. The follow up one week after end of 
treatment will be implemented as a phone call to further decrease the risk of infection. 
In case a subject has been infected by Covid-19 the following chemotherapy will be 
postponed until the subject has recovered from the infection. In case a subject has to cancel 
a visit due to Covid-19-infection she will be contacted by phone to assess any adverse 
events and the blood samples will be collected as soon as possible after she has recovered 
from the infection/is no longer considered contagious. Treatment with investigational product 
will continue during the infection. As Covid-19 is associated with increased risk of VTE, 
treatment with the investigational product might be beneficial for the subject.  
The study related procedures (screening, inclusion, randomization, collection of blood 
samples, follow up of adverse events) are not expected to pose notable extra workload on 
health care staff and resources as they will be performed during regular health care visits.  
The median age of patients diagnosed with EOC is 69 years and few patients are below 40 
years of age, thus a majority of the subjects will be vaccinated against Covid-19 at study 
start.Sponsor will evaluate the virus infection rate and the pandemic situation when all 
approvals are in place. If the risk-benefit ratio is considered positive, the study will start. 
Sponsor will continuously evaluate the Covid-19 situation during the study and if the risk-
benefit ratio develops in a negative direction the study will temporary be paused by the 
sponsor. 
 
4 Study objectives 
4.1 Primary objective 
The primary objective of the study is to evaluate the effects of tinzaparin on changes in levels 
of CA-125 in EOC patients who receive NACT. 

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4.2 Secondary objective(s) 
The secondary objective of the study is to explore the impact of tinzaparin on the dynamic of 
a spectrum of immunological and coagulation factors in EOC patients who receive NACT. 
Besides, the compliance of tinzaparin injections and adverse events caused by tinzaparin will 
be described. Thromboembolic events will be registered. 
4.3 Primary endpoint (variable) 
Primary variable: Level of CA-125 measured before cycles one-four of chemotherapy and 
preoperatively before DPDS.  
4.4 Secondary endpoints (variables)  
Secondary variables:  
Levels of hemoglobin, platelets, leucocytes, CRP, albumin, IL-6 and VEGF before every 
cycle of chemotherapy, preoperatively before DPDS and three weeks after the last cycle of 
chemotherapy. 
CA-125 measured before cycles five-seven of chemotherapy and three weeks after the last 
cycle of chemotherapy  
The compliance to tinzaparin injections and occurrence of adverse events related to 
tinzaparin will be evaluated. 
Objectively confirmed VTE, i.e. pulmonary embolism, lower-limb deep vein thrombosis or 
upper extremity deep vein thrombosis. Death due to VTE.  
4.5 Exploratory endpoints (variables) 
Exploratory variables: 
TF, D-dimer, soluble P-selectin, thrombin-antithrombin complex and thrombin generation 
potential will be measured before every cycle of chemotherapy, preoperatively and three 
weeks after the last cycle of chemotherapy.  
A panel of 92 inflammation-associated proteins will be measured at baseline, at visit 5 and at 
visit 8 or 9. Blood samples from all visits will be stored in biobanks for possible additional 
analyzes of the inflammatory panel from the remaining visits.  
5 Study design and procedures 
5.1 Overall study design  
This is an open randomized controlled clinical pilot trial (Phase II). The study includes women 
with stage III-IV EOC selected for NACT and without signs of thromboembolic disease or 
ongoing treatment of thromboembolic disease. The women will be allocated 1:1 to treatment 
with tinzaparin 4500 IU/8000 IU (dose depending on woman’s weight) subcutaneously once 
daily or no tinzaparin. The treatment group starts tinzaparin when the primary treatment 
(chemotherapy) starts. The control group will not receive tinzaparin or other low molecular 
weight heparin preparations. The NACT consists of carboplatin and paclitaxel, given 

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according to the standard regimen with cycle repeats every 21 days. Pre-treatment and 
before every cycle of chemotherapy venous blood samples will be taken for measuring the 
biomarkers hemoglobin, platelets, leucocytes, CRP, albumin, CA-125, Tissue Factor, D-
dimer, soluble P-selectin, thrombin-antithrombin complex and thrombin generation potential. 
Furthermore, a panel of 92 inflammation-associated proteins will be analyzed by a by a high-
sensitivity Proximity Extension Assay at baseline, visit 5 and visit 8 or 9. After three cycles of 
NACT, the patient will be evaluated clinically and with imaging diagnostics in order to 
determine whether the patient should undergo DPDS. In our setting, > 80% of patients 
receiving NACT for EOC undergo delayed primary debulking surgery. After DPDS, all 
patients will be treated with tinzaparin for 28 days according to clinical practice concerning 
postoperative thromboembolic prophylaxis and thereafter continue the chemotherapy for 
additional two-three courses. The participants who were allocated to tinzaparin during the 
NACT will continue the tinzaparin after ending the postoperative thromboembolic 
prophylactic tinzaparin treatment for additional 2-3 courses. The biomarkers will be 
measured preoperatively and four weeks postoperatively after DPDS and then before each 
course of chemotherapy given during the primary treatment. The women who do not undergo 
surgery will remain included in the study for the following three cycles of chemotherapy. 
Thus, the total study period constitutes 22-29 weeks. 
5.2 Procedures and flow chart 
See Appendix 1 flowchart and Appendix 2 study design 
5.3 Biological sampling procedures 
5.3.1 Handling, storage, and destruction of biological samples 
Blood samples will be taken before every cycle of chemotherapy, preoperatively and three 
weeks after the last cycle of chemotherapy. Analyzes will be undertaken at accredited 
laboratories at sites, at research laboratories at Linköping University Hospital and at Olink 
Laboratories in Uppsala. For methods se section 8.1.2. Routine blood samples will be 
analyzed continuously, and the remaining blood samples will be stored in local biobanks at 
sites until transport to laboratories in Linköping and Uppsala.  
5.3.2 Total volume of blood per subject  
The total volume of blood taken from each subject during the study is maximum 100 ml. 
5.4 Biobank 
All samples taken in this study are included in each regional biobank and are then handed 
out to Biobank Östergötland (registreringsnummer 1) The samples are handled according to 
the current biobank laws and regulations. The samples are coded/pseudonymized to protect 
the subject´s identification. All samples and the identification/code list are stored securely 
and separately to prevent unauthorized persons from having access to them. 
5.5 End of Study 
The study ends when the last subject has completed the last follow-up. The study may be 
prematurely terminated if it appears that the treatment involved a large number of serious 
adverse events (SAE) or if recruitment of subjects cannot be met within reasonable time 
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immediately inform the subjects about this and ensure appropriate treatment and follow-up. 
The regulatory authority should be informed as soon as possible, but no later than within 15 
days. Decisions on premature termination are taken by the sponsor. 
6 Subject selection  
6.1 Inclusion criteria 
To be included in the study, subjects must meet the following criteria: 
• 
The subject has given written consent to participate in the study.  
• 
Age 18 and above 
• 
Epithelial ovarian, fallopian tube or peritoneal cancer, or abdominal cancer where a 
biopsy indicates an origin from the ovary, fallopian tube or peritoneum. 
• 
Histology diagnosis of either high grade serous carcinoma, endometroid carcinoma or 
clear cell carcinoma. 
• 
FIGO stage III-IV disease. 
• 
Selected for NACT with platinum double regimen at a multidisciplinary conference at 
Department of Oncology at Linköping University Hospital 
• 
Receive treatment at either of the University Hospital in Linköping, or the hospitals in 
Jönköping (Ryhov Hospital), Eksjö (Höglandssjukhuset Eksjö), Västervik (Västervik 
sjukhus), Kalmar (Länssjukhuset i Kalmar), Värnamo (Värnamo sjukhus). 
• 
Planned for platinum doublet regimen.  
• 
Prior to start of NACT pregnancy should be ruled out by menstrual history or in 
unclear cases by a urine hCG test.  
• 
Women of childbearing potential should use a safe birth control method (combined 
hormonal contraception, progesterone only hormonal contraception, intra uterine 
device, bilateral tubal occlusion, vasectomized partner, sexual abstinence, male or 
female condom, diaphragm with spermicide). 
• 
WHO Performance Status 0-1 
• 
Weight 50-150 kg 
• 
CA-125-level ≥250 kIE/L at diagnosis 
6.2 Exclusion criteria 
Subjects must not be included in the study if any of the following criteria are met: 
• 
Concomitant treatment with heparins, low molecular weight heparins, warfarin or non-
vitamin K antagonist oral anticoagulants. Platelet inhibitors are allowed. 
• 
Treatment with heparins, low molecular weight heparins or non-vitamin K antagonist 
oral anticoagulants within the last year. 
• 
Known or suspected allergies against any product included in the study 
• 
Ongoing pregnancy, independent of gestational age.  Breastfeeding or planned 
pregnancy  
• 
EOC disclosed at Cesarean section  
• 
Abdominal surgery or other major surgery within the last year 
• 
Mental inability, reluctance or language difficulties that result in difficulty 
understanding the meaning of study participation 

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• 
Treatment or disease which, according to the investigator, can affect treatment or 
study results 
• 
Known brain metastasis  
• 
Participation or recent participation (within the last 30 days) in a clinical study with an 
investigational product  
• 
Ongoing treatment of thromboembolic disease. 
• 
Thromboembolic disease within the last year.  
• 
Hypersensitivity to the active substance (tinzaparin) or any of the excipients. 
• 
Serious hemorrhage or conditions predisposing to serious hemorrhage. Serious 
hemorrhage is defined as fulfilling any one of these three criteria: 
a) occurs in a critical area or organ (e.g. intracranial, intraspinal, intraocular, 
retroperitoneal, intra-articular or pericardial, intra-uterine or intramuscular with 
compartment syndrome), 
b) causes a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or 
c) leads to transfusion of two or more units of whole blood or red blood cells. 
• 
Severe coagulation disorder. 
• 
Acute gastro duodenal ulcer. 
• 
Septic endocarditis. 
• 
Previous heparin-induced thrombocytopenia. 
• 
WHO Performance Status >1. 
• 
Platinum single regimen  
• 
E-GFR <30ml/min (analyzed no more than 14 days before start of treatment with 
investigational product) 
• 
Platelets <100 x10^9/L (analyzed no more than 14 days before start of treatment with 
investigational product) 
• 
Treatment for other known malignancy within the last year (except basal cell 
carcinoma)  
6.3 Screening 
Prescreening will be done during a multidisciplinary conference at Department of Oncology 
at Linköping University Hospital. Subject eligibility (that subjects fulfill all inclusion criteria and 
do not meet any exclusion criteria) is established at an inclusion visit at each hospital (site) 
where the subject will receive treatment. 
6.4 Withdrawal criteria 
• 
The study subject may choose to discontinue the study at any time 
• 
The principal investigator can terminate a subject’s participation (due to, e.g., non-
tolerable adverse events/adverse reactions, pregnancy, etc.). 
• 
A concerned Competent Authority can terminate the study. 
• 
Discontinuation of treatment with curative intention or start of second line-treatment. 
The criteria below will result in discontinuation of treatment with investigational product, but 
the subjects will remain in the intention-to-treat-analyses.  
• 
Other disease that precludes continuation in the study 
• 
VTE occurring during the study. 

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• 
Bleeding events resulting in surgical or medical intervention or where discontinuation 
of treatment with tinzaparin is recommended. 
• 
Significant anemia caused by bleeding. 
• 
Heparin-induced thrombocytopenia.  
• 
Insufficient compliance (>20% missed injections) at visit 5 
The criteria below will not result in discontinuation of treatment with investigational product.  
• 
Change from platinum doublet regimen to platinum single regimen. 
A platelet count below 50 x10^9/L will result in a pause in treatment with the investigational 
product, treatment will restart when the platelet count is equal to or above 50 x10^9/L. If a 
platelet count below 50 x10^9/L is discovered, it will be measured daily until the platelet 
count is equal to or above 50 x10^9/L. 
Subjects can discontinue their participation in the study at any time without any consequence 
to her continued treatment. The investigator/sponsor can at any time terminate the study for 
a subject due to, e.g., unacceptable adverse events/adverse reactions or because the 
subject does not follow procedures in the study protocol. If the subject discontinues the 
study, follow-up of this subject will be performed according to the clinic’s routine. 
Data for subjects who prematurely discontinue the study will be included and analyzed if they 
have followed protocol (missed less than 20% of injections) until visit 5. Another subject will 
be included to achieve the desired number of included subjects according to the sample size 
calculation if a subject discontinues the study before visit 5.  
7 Study treatments 
7.1 Description of investigational product(s) 
The investigational product will be Innohep® (tinzaparin) solution for injection with either a 
dosage of 4500 IU once daily for patients weighing below 90 kg or dosage of 8000 IU for 
patients weighing more than 90 kg. The manufacturer is Leo Pharma AB and there are no 
replaceable solutions available. As comparative treatment no tinzaparin is used. 
The investigational product will be prescribed by an investigator at each site.  
7.2 Dose and administration 
Tinzaparin will be given in a weight-customized dose. Subjects weighing below 90 kg will be 
given 4500 IU once daily and subjects weighing 90 kg and above will be given 8000 IU once 
daily. Tinzaparin will be administered subcutaneously by the subject herself after instructions 
by a nurse or a doctor. The subjects will also receive a written instruction produced by the 
manufacturer. The chosen dose is the standard dose for thromboembolic prophylaxis where 
the wanted effects should occur at the same time as few side effects are expected. 
Tinzaparin shall be injected at the same time (± 2 hours) every day, in the evening, for 21-28 
weeks. 

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7.3  Packaging, labeling, and handling of investigational products(s) 
The investigational product will be prescribed by an investigator at each site. The prescription 
will include information about billing address to a study account, the subject will have no cost 
for the investigational product. The investigational product is stored in room temperature and 
no temperature monitoring is needed.  
As the investigational product will be prescribed and the subjects will retrieve it from a 
pharmacy of their choice there will be no specific labeling.  
7.4 Drug accountability and treatment compliance 
The investigational product will be administered by the subject after instructions by a doctor 
or nurse. At the visits, the subject will be asked if she has taken all injections, if there are any 
difficulties or side effects from taking them and she will be offered additional instructions if 
needed.  
Missed doses should be taken when discovered if discovered during the same day. Missed 
doses discovered the next day should not be taken and the next dose should be taken at the 
same time as it would otherwise have been taken.  
>20 % missed doses is considered as insufficient compliance.  
The subjects will record the injections and any discovered side effects in a study-specific 
diary. 
7.5 Randomization 
Subjects will randomly be assigned into two groups – Group A -receiving tinzaparin 
(intervention group) and Group B –control group - without tinzaparin. A list of random 
numbers will be created using a web-based allocator for simple randomization. The allocated 
method will be written on a paper placed in a sealed envelope. The envelopes are 
consecutively numbered according to the randomization list from 1 to 40. When the inclusion 
and exclusion criteria have been checked by the investigator, and the person has signed 
informed consent, the investigator contacts the coordinating nurse at the department of 
oncology at the University Hospital in Linköping by telephone. The coordinating nurse opens 
the randomization envelope (in consecutive number order) and report the allocation to the 
investigator; in addition, the paper with the allocation is sent to the investigator by fax and the 
coordination nurse register the allocation and number written on the envelope in the patient 
file. The investigators will not have access to the outcome of allocation of participants at 
other sites. 
The number of the envelope constitutes the identification number of the participant in the 
trial. 
The randomization will take place at least one workday before start of neoadjuvant 
chemotherapy and treatment with the investigational product. 
Additionally, in order to replace withdrawals a list of 10 random numbers from 1 to 10 with 
equal number of interventions and controls will be created. The envelopes will be numbered 
from 41 to 50 and opened consecutively in order to replace a withdrawal.   

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7.6 Blinding 
The study is not blinded for subjects and investigators. The laboratories will be blinded. Code 
breaking N/A. 
7.7 Concomitant medications 
7.7.1 Background treatment 
All subjects will receive chemotherapy of the platinum double regimen including carboplatin 
(dose calculated by Calvert formula) and paclitaxel (175 mg/m²) every three weeks. To abate 
side effects of the chemotherapy subjects will receive corticosteroids, antiemetics and 
prophylaxis against allergic reactions according to local routine. After clinical evaluation 
postoperatively some subjects will be given bevacizumab (7,5 mg/kg) in addition to 
carboplatin and paclitaxel for the remaining treatment with chemotherapy starting 4-6 weeks 
after surgery. These medications should be reported in the Case Report Form (CRF). The 
effect of the investigational product might be enhanced by other drugs affecting the 
coagulation system. None of the background medications has a direct effect on the 
coagulation system. Corticosteroids as well as the chemotherapy imply an increased risk of 
bleeding events and thrombocytopenia. All subjects will be monitored regularly with blood 
samples, thus will any anemia or thrombocytopenia be discovered. 
7.7.2 Other concomitant medications 
Medications that are considered necessary for the safety and well-being of the subject can 
be given at the discretion of the investigator, unless otherwise specified as an exclusion 
criterion. These medications should be reported in the CRF. 
7.8 Destruction 
Residual investigational products will be returned to a pharmacy by the subjects.  
7.9 Treatment after study end 
After the study end the subjects will receive no further investigational treatment and will be 
followed-up according to clinical routine.  
8 Methods for measurement of endpoints for clinical efficacy and 
safety 
8.1 Methods for measurement of endpoints for clinical efficacy 
8.1.1 Primary endpoint (variable) 
CA-125 is a tumor marker used to assess the likelihood of an ovarian mass being a 
malignancy and during treatment it is used to evaluate the patient´s response to the 
treatment. As CA-125 is used as clinical routine it will be analyzed continuously during the 
study at all study sites. For subjects outside Region Östergötland CA-125 will also be 
analyzed continuously or after study end at Linköping University Hospital using Cobas e602, 
electrochemical luminescence immunoassay, in order to have all samples analyzed with the 
same method.  

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8.1.2 Secondary endpoints (variables) 
All laboratories at sites are accredited by SWEDAC. 
Biomarker 
Analyzed 
Method 
Laboratory 
Hemoglobin 
Continuously 
(part of clinical 
routine) 
Photometry 
Local laboratory at site 
Leucocytes 
Continuously 
(part of clinical 
routine) 
Flow cytometry 
Local laboratory at site 
Platelets 
Continuously 
(part of clinical 
routine) 
Impedance and fluorescence 
cytometry or impedance method 
(RBC/PLT canal) 
Local laboratory at site 
Albumin 
Continuously 
(part of clinical 
routine) 
Turbidimetric analysis or colorimetry, 
endpoint 
Local laboratory at site 
CRP 
Continuously 
(part of clinical 
routine) 
Immunoturbidimetric analysis or 
turbidimetric fixed point measurement 
Local laboratory at site 
IL-6 
Continuously or 
after study end 
Chemical luminescence  
Central laboratory, Linköping 
University Hospital 
VEGF 
After study end 
ELISA 
Research laboratory, 
Linköping University Hospital 
Tissue Factor 
After study end 
ELISA 
Research laboratory, 
Linköping University Hospital 
D-dimer 
Continuously or 
after study end 
Latex-enhanced turbidimetry 
Central laboratory, Linköping 
University Hospital 
Soluble P-selectin 
After study end 
ELISA 
Research laboratory, 
Linköping University Hospital 
Thrombin-
antithrombin 
complex 
After study end 
ELISA 
Research laboratory, 
Linköping University Hospital 
Thrombin 
generation 
potential 
After study end 
Photometry 
Research laboratory, 
Linköping University Hospital 
Panel of 92 
inflammation 
associated 
proteins 
After study end 
Proximity Extension Assay 
technology 
Olink laboratory, Uppsala 
8.2 Methods for measurement of endpoints (variables) for clinical safety 
Anemia and heparin-induced thrombocytopenia are known but very rare side effects of 
tinzaparin. Subjects in this study will have hemoglobin and platelets measured every three 
weeks and therefore any anemia or thrombocytopenia will be discovered.  
Urine hCG will be taken before every cycle of chemotherapy in women of childbearing 
potential.  
9 Handling of Adverse Events 
All AE’s and SAE’s will be reported in both arms from the visit when the investigational 
product is given for the first time until one week after last injection.  

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AE and SAE are followed up until they are fully evaluated or no longer considered clinically 
significant by the principal investigator. 
9.1 Definitions 
9.1.1  Adverse Event (AE) 
Adverse Event (AE): Any untoward medical occurrence in a clinical investigation subject 
administered a medicinal product and, which does not necessarily have a causal relationship 
with the treatment, can be an unfavorable and unintended sign symptom or disease 
temporally associated with the use of the medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. 
9.1.2 Adverse Reaction (AR) 
All noxious and unintended reactions to the medicinal product related to any dose should be 
considered an adverse reaction (AR). The phrase “reaction” to a medicinal product means 
that the causal relationship between the medical product and an adverse event is at least a 
reasonable possibility, that is the relationship cannot be ruled out. 
9.1.3 Serious Adverse Event (SAE) 
Serious adverse event (SAE): Any untoward medical occurrence that at any dose: 
• 
results in death 
• 
is life-threatening. 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability or incapacity 
• 
results in a congenital anomaly/malformation 
Medical and scientific assessment will be made to determine if an event is “serious” and 
whether it would prompt reporting in other situations, for example important medical events 
that may not be directly life-threatening or result in death or hospitalization but may 
compromise the study subject or may require intervention to prevent one of the other results 
set forth in the definitions above. These should also normally be considered as SAEs. 
9.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
SUSAR: A reaction/event that is unexpected, serious, and suspected to be caused by the 
treatment, i.e. adverse events that are not included in the SPC. 
9.2 Assessment of Adverse Events 
9.2.1 Assessment of causal relationship  
Those AEs which are suspected of having a relationship to the investigational product will be 
followed up until the subject has recovered or is well taken care of and on their way to good 
recovery. 
All AE will be categorized either as likely related, possibly related, or not related, in 
accordance with the definitions below: 
Likely related: Clinical event, including abnormal results from laboratory analyses, occurring 
within a reasonable time after administration of the intervention/investigational product. It is 
unlikely that the event can be attributed to underlying disease or other medications but is 

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most likely caused by the investigational product and its emergence is reasonable in 
relationship with use of the investigational product. 
Possibly related: Clinical event, including abnormal results from laboratory analyses, 
occurring within a reasonable time after administration of the intervention/investigational 
product. The event could be explained by the investigational product and its emergence is 
reasonable in relationship with use of the investigational product, but there is insufficient 
information to determine the relationship. The event could be explained by an underlying 
disease or other medications. 
Not related: Clinical event, including abnormal results from laboratory analyses, that is not 
reasonably related to the use of the intervention/investigational product. The event is unlikely 
related to the intervention/investigational product and can be explained by other medications 
or underlying disease. 
9.2.2 Assessment of intensity 
Each adverse event shall be classified by an investigator as mild, moderate or severe.  
Mild: The adverse event is relatively tolerable and transient in nature but does not affect the 
subject’s normal life. 
Moderate: The adverse event causes deterioration of function but does not affect health. 
The event can be sufficiently unpleasant and interferes with normal activities but does not 
completely obstruct them. 
Severe: The adverse event causes deterioration of function or work ability or poses a health 
risk to the subject. 
9.2.3 Assessment of seriousness 
The investigator is responsible for assessing the seriousness (serious or non-serious). If the 
incident is considered serious, this should be reported as a serious adverse event (SAE) by 
the investigator to the sponsor.  
9.3 Reporting and registration of Adverse Events 
At each study visit, adverse events (AE) are registered, starting from start of treatment with 
the investigational product, up to and including 1 week after the subject has ended their 
treatment with the investigational product. All AE that occur during the study and which are 
observed by the investigator/study nurse or reported by the subject will be registered in the 
CRF regardless of whether they are related to the investigational product or not. Assessment 
of causal relationship, severity, and whether the AE is considered to be an SAE or not will be 
done by the investigator directly in the CRF. At minimum, for each AE/SAE, a description of 
the event is recorded (diagnosis/symptom if diagnosis is missing), start and stop dates, 
causal relationship, severity, if the AE is considered to be an SAE or not, measures and 
outcome. 
The signs and symptoms below are common or very common side effects of the 
chemotherapy and therefore will not be reported as AE.  
• 
Leucopenia 
• 
Neutropenia 

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• 
Infections (aside from infections at injection site) 
• 
Peripheral neuropathy 
• 
Paresthesias 
• 
Sensory disturbances 
• 
Dysgeusia 
• 
Visual disturbances 
• 
Ototoxicity 
• 
Headache 
• 
Dysarthria 
• 
Syncope 
• 
Somnolence 
• 
Cardiovascular disease 
• 
Tachycardia 
• 
Bradycardia 
• 
Hypertension 
• 
Hypotension 
• 
Interstitial lung disease 
• 
Bronchospasm 
• 
Dyspnea 
• 
Rhinitis 
• 
Cough 
• 
Abdominal pain 
• 
Vomiting 
• 
Nausea 
• 
Diarrhea 
• 
Obstipation 
• 
Anorexia 
• 
Dehydration 
• 
Stomatitis 
• 
Mucositis 
• 
Arthralgia 
• 
Myalgia 
• 
Alopecia 
• 
Exfoliative dermatitis 
• 
Palmar-plantar erytrodysesthesia 
• 
Asthenia 
• 
Lethargy 
• 
Pyrexia 
• 
Common postoperative symptoms that are not related to tinzaparin 
Innohep® (tinzaparin) is a commonly used anticoagulant with well-known side effects. Side 
effects are anemia, bleeding, hematomas and bruises, the latter mostly as local reactions at 
injection sites. The following signs and symptoms can be related to both the investigational 
product and to the chemotherapy and will therefore be considered AE´s: 
• 
Anemia 

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• 
Hematoma 
• 
Epistaxis 
• 
Hemoptysis 
• 
Other bleeding events 
• 
Local reactions at injection site 
Signs and symptoms not listed in any of the above sections will be considered AE´s.  
 
9.3.1 Reporting of Adverse Events (AE) 
All AE shall be registered in the CRF within 1 week as above.  
9.3.2 Reporting of Serious Adverse Events (SAE) 
Serious adverse events (SAE) are reported to the sponsor by sending a special SAE form 
within 24 hours of the investigator being informed of the SAE to sponsor Preben Kjølhede by 
email to preben.kjolhede@liu.se and by SMS sent to 070-5688201 informing there is an 
email regarding a SAE. 
Any SAE and AE that is likely related to the investigational product will also be reported to 
LEO Pharma by the sponsor.  
Follow-up information describing the outcome and handling of the SAE is reported as soon 
as this information is available. The original should be kept in the Investigator Site File. 
Based on knowledge of the disease in question and expected clinical course, some events 
that are otherwise serious are not considered as SAEs in this study.  
The following is a list of SAEs that shall not be reported as SAEs: 
• Expected events based on the knowledge of the disease in question and expected clinical 
course. 
• If a study subject is hospitalized with a documented cancer-related problem, this will not be 
reported as an SAE.  
9.3.3 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSAR) 
Any SUSAR that is fatal or life-threatening will be recorded and reported to the medical 
products agency (MPA) within seven days on a CIOMS form and with assistance of the MPA 
also reported into the EudraVigilance Clinical Trials Module. Sponsor will report SUSARs 
separately to the Ethical review authority. Relevant follow-up information will subsequently be 
communicated within an additional eight days. All other SUSARs that are not fatal or life-
threatening will be reported no later than 15 days after the sponsor learning of them.  
Information about SUSAR occurring during the study is compiled by the sponsor and sent out 
to the principal investigator at all participating centers.  
9.4 Follow-up of Adverse Events 
Subjects affected by adverse events will be followed-up until the AE/SAE is 
resolved/stable/persistent. In case of unacceptable adverse events the subject will be 
withdrawn from the study and followed up according to clinical routine.   

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9.5 Annual Safety Report (Development Safety Update Report, DSUR) 
As long as the study is in process, the sponsor will submit an annual safety report to the 
Swedish Medical Products Agency. It defines for which time period the report applies and a 
list of all SAE that have occurred as well as possibly SUSARs. A summary assessment of 
the safety situation for the subjects and a benefit/risk evaluation for the study should also be 
described. 
9.6 Procedures in case of emergencies, overdose or pregnancy 
Since curative treatment of FIGO stage III and IV EOC is not compatible with fertility sparing 
surgery, pregnancy occurring during the study is highly unlikely.  
Tinzaparin is used in pregnancy when the pregnant women have high risk of VTE or manifest 
VTE with low risk for the fetus. The chemotherapy given to the women included in this study 
has known teratogenous effects and all women of fertile age are advised on using effective 
contraceptives.  
If a subject becomes pregnant during the study, treatment with tinzaparin will be stopped. 
She will be followed up until birth and any congenital malformations will be reported as SAE. 
9.7 Reference Safety Information 
As reference safety information the SPC for Innohep® (Tinzaparin, LeoPharma) is used.  
10 Statistics 
10.1 Analysis population 
The study will include 20 women who are analyzed per protocol which means they have not 
missed more than 20 % of the injections and 20 women in the control-group. The analyses 
will be conducted according to both intention to treat principles and to per protocol.  
10.2 Statistical analyses 
10.2.1 Statistical methods 
Descriptive statistics for continuous data will be given as appropriate measures of central 
tendency (mean and/or median) and dispersion will be provided as standard deviation, range 
or interquartile range. Categorical nominal or ordinal data will be presented as number and 
frequency in percent. Univariate comparison of continuous data between groups will be 
conducted with analysis of variance (ANOVA), t-test or non-parametric tests (Mann-Whitney 
U-test), as appropriate. Categorical data will be compared using Pearson’s chi-squared test 
or Fisher’s exact test, as appropriate.  
In order to evaluate the changes in the levels of the biomarkers over time between the 
treatment arm and the control arm both the primary and the secondary objectives will be 
analyzed using repeated measures ANOVA models. Continuous variables that are not 
normally distributed will be transformed using Cox and Box’s method in order to achieve the 
most appropriate transformation of data to a normal distribution.  

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Outcome of statistical tests will be presented as p-value. Two-sided test for statistical 
significance will be used and a p<0.05 will be considered statistically significant. 
Subgroup analysis will be done for the group of BRCA mutated patients. Although the study 
is not powered after BRCA mutated participants, the result of such comparison may add 
interesting scientific knowledge and potentially be hypothesis generating for future studies.  
10.2.2 Drop-outs 
Repeated measures ANOVA requires measurements on all occasions of measuring. 
Consequently, missing values must be replaced. We assume that data are missing 
completely at random (MCAR) and we will use the multiple imputation procedure in SPSS. 
The number of imputed data sets will depend on the number of missing values but will not be 
less than ten.  
10.3 Adjustment of significance and confidence interval  
Not relevant for this pilot study.   
10.4 Sample size calculations 
This is a pilot study with an exploratory purpose. Sample size estimation is based on the 
primary outcome CA-125. A reduction in CA-125 between two cycles of chemotherapy of 
>50% has been shown to be a strong prognostics factor for survival. A lower response rate in 
CA-125 has been associated with an unfavorable outcome and a higher risk for suboptimal 
DPDS. In clinical practice this information is used in the evaluation to determine whether a 
patient receiving NACT shall be recommended DPDS. 
No information is available about the size of effect of tinzaparin on CA-125 levels. In order to 
be clinically significant we assume that tinzaparin must reduce the response rate on CA-125 
level after NACT additionally with at least 25%. 
The response of the chemotherapy in patients who receive NACT is evaluated at a 
multidisciplinary team conference between the third and fourth cycle of chemotherapy. Thus 
at that time (after cycle 3) information on the clinical blood samples, including CA-125 is 
available. Provided that the mean level of CA-125 was 2000 at baseline and the standard 
deviation was 25% of the mean on all occasions of measurement and the mean level of CA-
125 decreases at least 50% in the control arm and additional 25% (due to the effect of 
tinzaparin) in the treatment arm the calculated estimated sample size of the study is 16 in 
each arm in order to obtain a statistical significance between groups with 80% power at a 5% 
significance level for two-sided testing.  
To compensate for the proportion of women that does not undergo DPDS (approximately 
20%) each group should consist of 20 women. 
A simple sensitivity analysis concerning different requests to the additional effect of 
tinzaparin on CA-125 after NACT is presented in the table below. Three various scenarios of 
reduction in CA-125 levels are depicted. Based on empirical and clinical considerations we 
find it most likely that the variation in CA-125 will follow scenario B  
 
 

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Table1. Sensitivity analysis with three different scenarios A, B, and C.  
 
Scenario with 
reduction in 
CA-125 at 
each cycle 
Baseline 
(before cycle 1) Before cycle 2 Before cycle 3 Before cycle 4 
 
CA-125 level 
Control group 
50% 
2000 
1000 
500 
250 
Standard deviation 
500 
250 
125 
62.5 
A) Intervention group 50% + 
additional 25% 
on each 
occasion 
2000 
750 
(1000 - 25%) 
282  
(50% of 750 -
25%) 
106  
(50% of 282- 
25%) 
B) Intervention group 25% reduction 
in relation to 
the control 
group 
2000 
750 
(=75% of 1000) 
375 
(=75% of 500) 
187.5 
(=75% of 250) 
C) Intervention group 20% reduction 
in relation to 
the control 
group 
2000 
800 
(=80% of 1000) 
400 
(=80% of 500) 
200 
(=80% of 250) 
A Sample size per 
group  
11 
3 
B Sample size per 
group  
16 
16 
C Sample size per 
group  
25 
25 
Power 80%; two-sided p<0.05. 
10.5 Interim analysis (if relevant) 
No interim analysis is planned since this is a pilot study. Study termination will be considered 
in case of very severe adverse events and SUSAR’s or if change in standard treatment of 
EOC makes this trial redundant or uninteresting.  
11 Quality Control and Quality Assurance 
11.1 Quality Assurance and Sponsor oversight 
Sponsor will work as principal investigator in the study and hence be well aware of any 
possible problems that might arise in the study. Sponsor is responsible for making a risk 
assessment for the study as a whole as well as to take actions to mitigate the identified risks. 
Monitoring will be one way of mitigating the risks. Monitoring will be performed by Forum 
Östergötland according to the monitoring plan. Sponsor will read all monitoring reports and 
take necessary actions. All key personnel involved in the study will receive or have received 
GCP training. 

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11.2 Monitoring 
An independent quality control (monitoring) of the study will be carried out by qualified 
personnel from Forum Östergötland, the established support structure for clinical studies at 
Linköping University Hospital. Monitoring at each site will be carried out before start 
(initiation), after the first 1-3 subjects have started their participation, at least one time during 
the study, and after completion of the trial. The study will be monitored according to the study 
monitoring plan and the monitor will assess integrity of source documents, regulatory 
compliance and review potential adverse events.  
The investigators are obligated to give direct access to medical records and other source 
data for monitors, inspectors from the MPA and any possible evaluators from the ethical 
review authority.  
Monitoring will ensure that the subject’s rights, safety, and well-being are met as well as data 
in the CRF are complete, correct, and consistent with the source data. It will also check that 
the study is carried out according to the protocol and that data is collected, documented, and 
reported according to ICH-GCP and applicable ethical and regulatory requirements.  
11.3 Source data 
The investigator must keep source documents for each subject in the study. A document 
describing what has been classified as source data at each site should be included in the 
Investigator Site File (ISF). The investigator must ensure that all source documents are 
accessible for monitoring and other quality control activities. 
11.4 Deviations or serious breaches 
Serious breaches and deviations from the study protocol, GCP and other regulations that 
significantly and directly affects, or with high likelihood could affect, the subjects or the 
scientific value of the study, shall be immediately reported within 7 days (from knowledge) to 
the Swedish Medical Products Agency. It is the sponsor’s responsibility to judge the 
consequences of deviations that have occurred, and thus also to decide whether the 
Swedish Medical Products Agency should be informed. 
Minor deviations that do not affect subjects’ integrity or safety, nor significantly affect the 
study’s scientific value, will be documented in the study documentation of the principal 
investigator and the sponsor. 
11.5 Audits and inspections  
Authorized representatives for the sponsor and Competent Authorities (CA) may carry out 
audits or inspections at the study site, including source data verification. The investigator 
must ensure that all source documents are available for audits and inspections. The purpose 
of an audit or inspection is to systematically and independently review all study-related 
activities and documents, to determine whether these activities were performed, registered, 
analyzed and reported correctly according to the protocol, Good Clinical Practice (GCP) and 
applicable regulations. 

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12 Ethics 
12.1 Compliance to the protocol, GCP and regulations 
The study will be performed in compliance with the study protocol, the Declaration of 
Helsinki, ICH-GCP (Good Clinical Practice) guidelines and current national and international 
regulations governing this clinical trial. This is to ensure the safety and integrity of the study 
subjects as well as the quality of the data collected. 
12.2 Ethical review of the study 
The final study protocol should be approved by both the Swedish Ethical Review Authority 
(Etikprövningsmyndigheten, EPM) and the Swedish Medical Products Agency before the trial 
can be conducted. The final version of the informed consent form and other information 
provided to subjects, must be approved or given a written positive opinion by EPM. EPM and 
the Swedish Medical Products Agency must be informed of any changes in the study 
protocol in accordance with current requirements.  
12.3 Procedure for obtaining informed consent 
The investigators at each site shall ensure that the subject is given full and adequate oral 
and written information about the study, its purpose, any risks and benefits as well as 
inclusion- and exclusion criteria. Subjects should also be informed that they are free to 
discontinue their participation in the study at any time without having to provide a reason. 
Subjects should be given the opportunity to ask questions and be allowed time to consider 
the provided information. If the person chooses to participate, both the subject and the 
investigator shall sign the informed consent form. A copy of the subject information as well as 
the informed consent form shall be provided to the subject. The subject’s signed and dated 
informed consent must be obtained before performing any study-specific activity in the study. 
Each subject who participated in the study will be identified by a subject number on a subject 
identification list. The subject agrees that monitors, auditors, and inspectors may have 
access to their medical records and other source data. If new information is added to the 
study, the subject has the right to reconsider whether he/she will continue their participation. 
12.4 Data protection 
If any part of the data is handled by any other organization, inside or outside the EU, 
appropriate agreements and/or other documentation will be established, to ensure that the 
data processing is performed in accordance with the provisions of the General Data 
Protection Regulation (GDPR) and other relevant legislation, before any data transfer takes 
place. 
The content of the informed consent form complies with relevant integrity and data protection 
legislation. In the subject information and the informed consent form, the subject will be given 
complete information about how collection, use and publication of their study data will take 
place. The subject information and the informed consent form will explain how study data are 
stored to maintain confidentiality in accordance with national data legislation. All information 
processed by the sponsor will be pseudonymized and identified with Study ID. The 
identification list will be kept on paper and stored in a safety box at Department of Oncology, 
Linköping University Hospital. The CRFs will be pseudonymized and stored in a safety box.  

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The informed consent form will also explain that for verification of the data, authorized 
representatives of the sponsor, as well as relevant authority, may require access to parts of 
medical records or study records that are relevant to the study, including the subject’s 
medical history. 
12.5 Insurances 
Study subjects will be covered by the Swedish Pharmaceutical Insurance (Swe: 
Läkemedelsförsäkringen) in addition to the Patient insurance (Swe: Patientförsäkringen) 
12.6 Publication of results 
The study will be registered in ClinicalTrials.gov’s Protocol Registration and Results System. 
Reports from the trial will be prepared in scientific manuscripts with the intention of being 
published in peer reviewed medical journals. Authorship will comply with the 
recommendations of the International Committee of Journal Medical Editors.  
13 Substantial changes to the study 
Substantial changes to the signed study protocol are only possible through approved 
protocol amendments and by agreement from all responsible persons. Information on non-
substantial changes should be clearly noted in the amended protocol. 
In the event that substantial changes to the protocol (e.g., changing of the main objective, 
primary or secondary variables, method to measure the primary variable, changing of the 
investigational product or dosage) will be made during the course of the study, approval from 
the Swedish Ethical Review Authority (Etikprövningsmyndigheten, EPM) as well as the 
Swedish Medical Products Agency (Läkemedelsverket) shall be obtained before any 
changes are implemented. A change that concerns a new site, new investigator or a new 
study patient information sheet shall only be approved by EPM.  
Non-substantial changes will be recorded and later entered in documentation that is 
submitted, for example in any subsequent notifications of a substantial change or in 
connection with End of Trial reporting. 
The investigator must not make any deviation from or change of the protocol, except which 
necessary to eliminate an immediate risk to the study subjects, or where the changes only 
include logistical or administrative aspects of the study (e.g., change of telephone number).  
14 Collection, handling, and archiving data 
Subjects who participate in the study are coded with a specific study identification number. 
All subjects are registered in a subject identification list (subject enrolment and identification 
list) that connects the subject’s name and personal number with a study identification 
number. 
Source data will be collected from medical records, CRF´s, diaries and laboratory results. All 
data will be registered, managed, and stored in a manner that enables correct reporting, 
interpretation, and verification. The complete Trial Master File, as well as source documents, 

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will be archived for at least 10 years after the study is completed. Source data in the medical 
records system is stored and archived in accordance with the respective hospital regulations. 
14.1 Case Report Form  
A paper Case Report Form (CRF) is used for data collection. The investigator must ensure 
that data is registered and any corrections in the CRF are made as stated in the study 
protocol and in accordance with the instructions. The investigator must ensure that the 
registered data is correct, complete, and that reporting takes place according to the timelines 
that have been predefined and agreed. The principal investigator at each site signs the 
completed CRF. A copy of the completed CRF will be archived at the study site. 
If an examination/test is not performed and data does not exist, ND (Not done) or NK (Not 
known) is marked. If the question is irrelevant NA (Not applicable) is written. Corrections in 
the paper CRF are done by striking out the incorrect information and adding the correct 
information next to the incorrect information, signing, and dating the correction. 
15 Notification of study completion, reporting, and publication 
After the study is finished The Swedish Medical Products Agency shall be informed of the 
study’s completion at latest 90 days after study end, through submission of a ”Declaration of 
End of Trial Notification” form. 
Within one year after the study is completed, the results shall be analyzed, a clinical study 
report with individual data shall be prepared, and the study results shall also be reported in 
the EudraCT database. 
If the study is prematurely terminated the MPA and EPM shall be notified as soon as 
possible but no later than within 15 days. 
16 References 
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