Intensive Dose Tinzaparin in Hospitalized COVID19 Patients
Conditions: Covid19, Hospitalization
Sponsor: University Hospital of Patras

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PROTOCOL SYNOPSIS  
OBSERVATIONAL RETROSPECTIVE STUDY 
Title: 
INTensive dosE tinzapaRin in hospitAlized Covid-19 paTients 
Short Title 
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Protocol Date:  
14 June 2021  
 
 
 
 

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PROTOCOL SYNOPSIS 
Study Title 
INTensive dosE tinzapaRin in hospitAlized Covid-19 paTients 
Study Rationale 
Introduction  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A prothrombotic state, attributable to a cytokine storm induced by severe acute 
respiratory syndrome coronavirus 2 (SARS-Cov-2) and leading to activation of 
the coagulation cascade, is a recognized feature of Coronavirus disease 2019 
(COVID-19) infection. This can manifest in venous thromboembolism (VTE), 
arterial thrombosis events (ATE) and disseminated intravenous coagulation 
(DIC) and coagulopathy is reflective of more severe disease and adverse 
prognosis [1]. A significant number of patients with COVID-19 require single or 
multiple organ support on the Intensive Care Unit (ICU), estimated to be between 
12 and 17% of patients [2,3,4,5]. with the reported mortality in these cohorts 
between 25 and 40% [2, 6]. 
International guidelines recommend that hospitalized patients with COVID-19 
should receive pharmacological prophylaxis against VTE, in the absence of 
contraindications [7,8,9]. With respect to how VTE prophylaxis is achieved, Low 
Molecular Weight Heparins (LMWH), in addition to their well-known 
anticoagulant properties, appear to have additional antiviral and anti-
inflammatory effects that may be potentially beneficial in hospitalized COVID-19 
patients. [10,11]. 
Though international and national guidelines states that all hospitalized patients 
with COVID-19 should receive pharmacologic thromboprophylaxis, the rising 
incidence of thrombotic complications in COVID-19 patients has led a lot of 
hospitals to adopt the strategy of increasing the dose of anticoagulation for 
prophylaxis to ‘intermediate’ or “therapeutic” doses using a risk-adapted strategy 
with increased doses administration based on factors associated with increased 
risk; clinicians weigh the benefits and risks of therapeutic anticoagulation in 
terms of thrombosis and major bleeding risk for individual patients. 
Additionally, LMWHs have different physiochemical characteristics as a result of 
the diverse methods of their manufacturing. The variations in molecular 
composition and pharmacological properties of LMWHs are reflected in 
differences in their clinical efficacy and safety. Each LMWH should, therefore, be 
considered as a unique substance. Tinzaparin is the only LMWH known that is 
prepared by enzymatic hydrolysis with heparinase  [12,13,14,15]. Due to its 
preparation method, tinzaparin has distinct properties than other LMWHs 
including and not limited to: higher Anti-IIa activity and Anti-Xa/Anti-IIa activity 
ratio, higher release of Tissue Factor Pathway Inhibitor (TFPI), less dependence 
from renal function for its clearance and more complete neutralization from its 
antidote, if needed. Due to the key role of increased Thrombin generation (IIa) 
and Tissue factor (TF) pathway activation in COVID-19-associated thrombosis 
[16], special properties of tinzaparin in Anti-IIa activity and TFPI production and 
release from endothelial cells, as well as significant effects of TFPI in various 
vascular, inflammatory, cardiovascular, hematological and oncological disorders 
[17,18,19,20,21], tinzaparin could have an expanded role beyond its well-known 
anticoagulant function. 
The purpose of this study is to evaluate the overall clinical effectiveness and 
safety of ‘intermediate’ or “therapeutic” doses anticoagulation with tinzaparin 
administered for thromboprophylaxis in COVID-19 patients with moderate 
disease severity during hospitalization in Greek hospitals. 

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Study Objectives 
 
Primary Objectives 
 
 
 
 
 
Secondary 
Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
Study Endpoints 
 
 
The primary objective of this study is to evaluate the current management 
approach with “intermediate” or “therapeutic” doses of tinzaparin for 
thromboprophylaxis in hospitalized patients, non on ICU organ support, with 
confirmed COVID-19.  
 
Evaluate incidence of thrombotic events  
 
Evaluate incidence of bleeding events  
 
The secondary objective is to  
 Examine the course of illness of COVID-19 via measure of clinical 
improvement and/or survival, assessed at pre-specified time points post 
admission 
Patients demographic & somatometric data, medical history (thrombosis & 
bleedings related history, co-morbidities, chronic use of medications, results of 
laboratory tests etc.), clinical parameters, anticoagulant prophylaxis dose & 
duration, efficacy (thrombosis events), safety (bleedings), imaging and laboratory 
tests results and information about other supportive treatment will be recorded; 
more than one outcomes could be recorded. 
Based on analysis of collected data, we’ll examine correlations between 
thromboprophylaxis approach, patients’ profiles and clinical outcomes. 
 
Primary Endpoints 
 
Incidence of thrombotic events (total & per type e.g. PE, DVT, 
symptomatic, incidental, proximal, distant etc.) 
 
Incidence of bleeding events (total & per type e.g. Major, CRNMB and 
minor) 
Secondary Endpoint 
 
World Health Organization (WHO) progression scale  (range from 0 
(healthy) to 10 (death); values below or equal to 5 correspond to the 
absence of any oxygen supply beside nasal or facial mask) 
 
Length of hospital stay (days) 
Study Design 
 
This is a retrospective phase IV, observational, non-interventional cohort study 
that aims to collect data regarding thromboprophylaxis management in high 
thrombotic risk hospitalized, non on ICU, patients with COVID-19 pneumonia. 
Specifically, we will collect retrospectively data for patients received  
thromboprophylaxis with tinzaparin, according to current clinical practice, during 
hospitalization, for one year before the study initiation date, to evaluate safety 
and efficacy of thromboprophylaxis and to examine possible associations of 

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patients’ profiles with thrombotic and bleeding events and the course of illness in 
this cohort of patients. 
We will collect data retrospectively in paper CRFs, recorded from the treating 
physicians. 
Additionally, we will assess the association of a panel of laboratory and clinical  
parameters representing an inﬂammatory and hemostatic state with VTE and 
bleeding events and clinical outcomes. 
Institutional Review Board will approve the study. 
 
Basic/common markers/parameters 
 D-Dimmers 
 C-reactive protein (CRP) 
 hemoglobin 
 platelets count 
 ferritin 
 fibrinogen 
 SpO2 in FiO2 21% 
 
In all cases, laboratory and clinical parameters will be collected at 3 time points: 
at admission/baseline, after one week and at discharge. 
 
  
Subject Population 
Key criteria for 
Inclusion and 
Exclusion 
 
Inclusion Criteria 
1. Patients admitted to hospital with COVID-19, PCR+ SARS-CoV-2 
infection (from any specimen) administered thromboprophylaxis with 
tinzaparin in intermediate or therapeutic dose 
2. Age ≥ 18 years  
3. Signed informed consent 
 
Exclusion Criteria 
1. Patients admitted to ICU with COVID-19, PCR+ SARS-CoV-2 infection 
(from any specimen) 
2. Age < 18 years  
3. Pregnancy 
4. Current diagnosis or suspicion of pulmonary thromboembolism or deep 
vein thrombosis 
5. Progression to death was imminent and inevitable within 24 hours from 
the admission, irrespective of the provision of treatments 
6. Not signed informed consent 
 
 
 
 

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Study Phases 
              Screening 
 
 
 
 
Data collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical analysis 
& report 
 
 
 
 
(1) Screening: screening patient files for eligibility, obtaining consent,  
If eligible 
 All the data will be gathered from medical records by chart review of the 
individual patients in a retrospective fashion. There will no direct patient 
interaction in the study.  
 
 
Demographic data collection (Gender, Date of birth, Weight, Height, etc.) 
 
Medical history & pathologic features (Thrombosis & bleedings related 
history, risk factors, recent surgery, co-morbidities, chronic use of 
medications, results of laboratory tests, clinical parameters etc.) 
 
Anti-coagulant administration data 
 
Thrombotic & bleeding events during course of hospitalization 
 
Other adverse events related to anticoagulation 
 
Clinical improvement and/or survival during hospitalization 
 
Timepoints of evaluation 
Data of Covid-19 pneumonia patients retrospectively enrolled in the study will be 
evaluated on a regular basis following the Baseline Visit;  
Visit 1 – Baseline, at admission;  
Visit 2 - will be after 1 week ± 2 days  
Visit 3 - will be by at discharge from hospital 
 
Statistical analysis  
Statistical and Analytic Plan 
Descriptional statistical analysis will be performed for all study data along with 
epidemiology methods. Categorical data will be analyzed using the chi-square 
and Fisher exact test. Continuous variables will be reported as mean and 
standard deviations (SD) and will be analyzed using the t-test analysis. An 
unadjusted odds ratio (OR) will be calculated using a Cochran-Mantel-Haenszel 
test. To determine the impact of potential effect modifiers a logistic regression 
model will be used to calculate the adjusted odds ratio. For more complex 
correlations (i.e. inferential statistics) we will use, among other methods, chi-
square or Fisher exact tests, ANOVA, Mann-Whitney U tests and t-tests, 
according to the data properties and in order to evaluate the relationships 
between different patient and disease characteristics with the primary and 
secondary study outcomes, such as: 
 Number of patients enrolled 
 Co-morbidities 
 Thrombosis risk factors 
 Laboratory parameters 
 Clinical parameters 
 Type and duration of thromboprophylaxis therapy 
 Therapy outcomes 
 Thromboprophylaxis related complications 
and to present them, accordingly.  

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Due to the fact that this is an observational study the results of all correlations 
will be carefully discussed and will be used only to assess hypotheses.  
Finally and depending on the collected data multivariate analysis may be 
performed in order to reveal confounding factors. 
 
Clinical Study Report (CSR) 
Analyzed parameters will be presented with standards statistical measures 
(mean values, median values, ranges, quartiles, percentages etc.) and the 
results will be presented accordingly into tables and informative plots. 
A p-value of less than 0.05 will be considered statistically significant and all 
values will be reported with a 95% confidence interval (CI). 
 
Study Registration 
Study will be registered in  
NIH, U.S. National Library of Medicine, Clinical Trials database of privately and 
publicly funded clinical studies, https://clinicaltrials.gov/ct2/home 
 
 
Efficacy Evaluations 
 
Symptomatic/Suspected 
vein 
thromboembolism, 
including 
pulmonary embolism and deep vein thrombosis  
Confirmation of symptomatic PE requires symptoms of PE and one of the 
following findings 
1. A (new) intraluminal filling defect in (sub) segmental or more 
proximal branches on spiral CT scan or on MRI scan; 
2. A (new) intraluminal filling defect or an extension of an existing 
defect or a new sudden cut-off of vessels on the pulmonary 
angiogram; 
3. An inconclusive lung scan accompanied by documentation of 
(new) DVT in the lower extremities e.g., by compression 
ultrasound or venography. 
Confirmation of symptomatic DVT requires symptoms of DVT and: 
1. A (new) non-compressible venous segment on ultrasonography 
Incidental PE with one of the following: 
2. A (new) intra-luminal filling defect on CT scan, MRI scan, or 
pulmonary angiogram; 
3. An inconclusive lung scan accompanied by documentation of 
(new) DVT in the lower extremities e.g., by compression 
ultrasound or venography. 
Fatal PE is: 
1. PE based on objective diagnostic testing or autopsy or 

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2. Death not attributed to a documented cause and for which 
DVT/PE cannot be ruled out 
Incidental DVT with the following finding: 
Confirmation of incidental DVT requires inconclusive or no- symptoms of DVT and: 
1. A (new) non-compressible venous segment on ultrasonography 
 
Safety Evaluations 
(with regards to 
anticoagulation ) 
 
Major, Clinically Relevant Non-Major Bleeding (CRNMB), and minor 
bleeding  
Major bleeding will be defined as overt bleeding associated with: a fall in 
hemoglobin of 2 g/dL or more, or leading to a transfusion, or bleeding that occurs 
in a critical site or contributing to death. 
 
 
Bleeding in a critical area or organ such as: 
 
 Retroperitoneal 
 Intracranial 
 Intraocular 
 Intraspinal 
 Intra-articular 
 Pericardial 
 Intramuscular with compartment syndrome 
 
 
A clinically overt bleeding event 
 that is associated with a fall in hemoglobin of 2.0 g/dL (>1.24 mMol/L) or 
more, or 
 leading to a transfusion of ≥ 2 units of packed red blood cells or whole 
blood 
 
 
Bleeding contributing to death 
 
o 
Other clinically relevant non-major bleedings (CRNMB) will be 
defined as overt bleeding not meeting the criteria for major bleeding but 
associated with medical intervention, unscheduled contact (visit or 
telephone call) with a physician, (temporary) cessation of study 
treatment, or associated with discomfort for the patient such as pain, or 
impairment of activities of daily life. 
  
o 
All other bleeding events will be classified as minor 
 
 
 
 

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 
World Health Organization (WHO) progression scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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