A Prospective, Single- Center, Phase IV, Interventional, Single Arm Trial for the Evaluation of Subcutaneous Recombinant Hirudin 15 mg (RB Variant) in Prophylaxis of Deep Vein Thrombosis (DVT) Post Major Orthopedic Operations
Phase: PHASE4
Conditions: Prophylaxis of Deep Vein Thrombosis
Sponsor: MinaPharm Pharmaceuticals

Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1.0 amendment 1 
Page 1 of 28 
Confidential 
 
 
 
 
 
 
 
 
 
 
Title Page 
 
 
 
 
 
 
A Prospective, Single- Center, Phase IV Interventional, Single Arm Trial for the 
Evaluation of subcutaneous recombinant  Hirudin 15 mg (RB variant) in 
prophylaxis of Deep Vein Thrombosis (DVT) post major orthopedic operations 
 
 
 
 
 
 
 
 
 
Principle Investigator: Prof. Ayman Soliman 
Sub Investigator: Dr. Abdallah Hammad 
Study Site: Alexandria University 
Protocol Name: THRIVE-DVT 
 
Protocol Number: Sub-Thromb-001 
 
Version:1.0, amendment 1 
 
Date: 25th of January, 2022 
 
 
 
 
CONFIDENTIALITY STATEMENT 
 
 
This study was performed in compliance with Good Clinical Practice (GCP), including the archiving of essential documents. This report has been 
prepared in accordance with ICH Harmonized Tripartite Guideline on the Structure and Content of Clinical Study Reports, dated November 1995. 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Minapharm 
Pharmaceuticals (or any of its affiliated companies). The use of such confidential information must be restricted to the recipients for the agreed 
purpose and must be disclosed, published or otherwise communicated to any unauthorized persons, for any reasons, in any form whatsoever without 
the prior written consent of  Minapharm Pharmaceuticals  (or the concerned affiliate company); “Affiliate Company” means any corporation, 
partnership or other entity which at the date of communication or afterwards with Minapharm Pharmaceuticals 

Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1.0 amendment 1 
Page 2 of 28 
Confidential 
 
 
 
1.   Synopsis 
 
 
 
 
Title 
Description 
Study Title 
Prospective, Single- Center, Interventional, Single Arm Trial for 
the Evaluation of subcutaneous recombinant Hirudin 15 mg (RB 
variant) in prophylaxis of Deep Vein Thrombosis (DVT) post 
major orthopedic operations 
Study number 
Sub-Thromb-001 
Study Phase 
Phase IV 
Study Design 
Prospective, Single arm, single-center 
Study population 
Patients undergoing major orthopedic operations 
Study procedures 
Drug: r-Hirudin 
Other Name: Thrombexx 
100 Patients will be treated with r-Hirudin (Thrombexx) for a 
total of 15 days beginning with 15 mg BID s.c starting 6 hours 
after surgery or upon adequate hemostasis and continued until 
end of study. 
Clinical & laboratory 
investigations 
For Events of Deep Vein Thrombosis (DVT) within 15 days 
post-op.) 
All of the patients underwent Routine bilateral compression 
Doppler. 
For Clinical PE (Pulmonary Embolism) Events from Day of 
surgery and During Hospitalization period or end of study 
Clinical PE events PE (Pulmonary Embolism) events were 
confirmed by spiral CT. 
For follow up: 
APTT should be done before the first dose then after 4 & 8 
hours of the first dose, then on days  1,8,15 post operatively. 
Study duration 
Enrolment period: 
3 months duration 
Follow-up duration: 
Follow-up per patient will be for a period of 15 days 
Eligibility Criteria 
Inclusion Criteria: 
 
18 years of age or older 
 
Body Weight >60 kg 
 
Patients undergoing major orthopedic operations 

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Confidential 
Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
 
Patients ready to sign informed consent form (ICF) 
 
Patients should discontinue any agents that affect 
haemostasis prior to the study medication use unless 
strictly indicated. These agents include medications such 
as: anticoagulants, thrombolytics, non-steroidal anti- 
inflammatory agents (including Ketorolac 
tromethamine), preparations containing aspirin, systemic 
salicylates, ticlopidine, dextran 40, clopidogrel, other 
anti-platelet agents including glycoprotein IIb/IIIa 
antagonists or systemic glucocorticoids. 
Exclusion Criteria: 
 
Significant bleeding injury such as solid organ laceration 
or intracranial bleed at discretion of attending physician 
 
Hypersensitivity to Hirudin or prior documented Allergy 
to its components 
 
Pregnant or breast feeding 
 
Hemorrhagic stroke in preceding 3 months 
 
abnormal baseline coagulation characterized by an INR 
>1.4, obtained at the discretion of the treating clinician 
 
Required therapeutic anticoagulation for atrial 
fibrillation, prior VTE, or mechanical heart valve 
 
Patients with a history of coagulation disorder 
 
Treatment with concomitant anti-platelet agent other 
than aspirin 326 mg or more daily (Platelet count< 100 
X109 /dl) 
 
Active bleeding 
 
Subjects with a life expectancy less than 1 month 
Study objective 
 
The primary objective of this study is to evaluate the 
efficacy of r-Hirudin RB variant 15 mg in DVT 
prophylaxis post major orthopedic operations 
 
The secondary objective of this study is to evaluate the 
safety of r-Hirudin RB variant 15 mg in DVT 
prophylaxis post major orthopedic operations in terms of 
serious bleeding. 
Study endpoint 
Primary endpoint: 
 Primary end points included new onset symptomatic 
thrombosis requiring medical or surgical intervention 
or death due to thrombosis defined as fatal PE, 
ischemic stroke, mesenteric thrombosis, or 
myocardial infarction. 
Secondary endpoint: 
 
The Secondary end point of major bleeding is defined as 
clinically evident hemorrhage associated with a 

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Confidential 
Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
hemoglobin decrease ≥ 2 g/dL that leads to a transfusion 
of ≥2 units of whole blood or packed red cells outside of 
the perioperative period (time from the start of the 
surgery or procedure and up to 12 hours after), or 
hemorrhage that is intracranial, retroperitoneal, or into a 
prosthetic joint. 
 
Recording serious adverse events (SAE)/ adverse events 
(AE) during the study duration. 
Study medication 
Thrombexx ; 
Because thrombin plays a central role in thrombogenesis, the 
goal of most treatment regimens is to block thrombin generation 
or inhibit its activity. 
1-  r-Hirudin binds directly with thrombin to its active & 
fibrinogen binding site. 
2-  r-hirudin does not require access to heparin binding site 
& can thus neutralize clot bound thrombin. Hence, down 
regulating thrombin generation & potentially enhancing 
early revascularization. 
Direct thrombin inhibitors were developed to overcome the 
inability of the heparin/ antithrombin complex to inactivate 
bound thrombin. In contrast to heparin and low-molecular- 
weight heparin, which catalyze the inactivation of thrombin and 
activated factor X (factor Xa) by antithrombin, direct thrombin 
inhibitors bind to thrombin and block its interaction with its 
substrates. 
II- They do not bind to plasma proteins; direct thrombin 
inhibitors produce a more predictable anticoagulant response 
than heparin. 
III- Unlike heparin, direct thrombin inhibitors do not interact 
with platelet factor 4 or high-molecular-weight multimers of von 
Willebrand factor. Consequently, the activity of direct thrombin 
inhibitors in the vicinity of a platelet-rich thrombus is not 
compromised. 
IV- Finally, thrombin bound to fibrin or fibrin degradation 
products is susceptible to inactivation by direct thrombin 
inhibitors. Because the active site of thrombin is not involved in 
the interaction of the enzyme with fibrin, it remains accessible 
to active site-directed thrombin inhibitors. Consequently, these 
agents inactivate fibrin-bound thrombin without displacing the 
enzyme from fibrin. In contrast, bivalent thrombin inhibitors, 
such as Hirudin and bivalirudin, displace bound thrombin during 
the inhibition reaction by competing with fibrin for access to 
exosite 1 on thrombin. 

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Confidential 
Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
Dose: 
In DVT Prophylaxis: 15 mg twice daily, subcutaneous for 15 
days 
In case of renal insufficiency, the dose is titrated because r- 
Hirudin is excreted renally. 
According to Creatinine clearance: 
•Creatinine clearance › 31-60 ml/min (5 mg s.c twice daily) 
•Creatinine clearance ‹ 31 ml/min (1.7 mg s.c twice daily) 
Sample size 
100 patients 
Statistical analysis 
- Descriptive analysis: 
All statistical tests used a significance level of P=0.05, two 
tailed tests are performed for all analyses used statistical testing. 
Descriptive analysis for quantitative data will include count, 
mean with 95% CI, standard deviation, median, minimum and 
maximum. For qualitative categorical variables; frequency and 
percentage and 95% confidence interval will be applied. 
Stopping rules 
DVT 
PE 
Major bleeding 
Allergy 
APTT value increases by 2-2.5 folds 
According to investigator evaluation 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
 
 
 
Table of Contents 
 
Title Page ..........................................................................................................................................1 
 
1. 
Synopsis ....................................................................................................................................2 
 
Table of Contents ..............................................................................................................................6 
 
2. 
LIST OF ABBREVIATIONS...................................................................................................9 
 
3. 
SIGNATURE(S) PAGE..........................................................................................................10 
 
4. 
INTRODUCTION ..................................................................................................................11 
 
4.1. 
Background ..................................................................................................................... 11 
 
4.2. 
Correlative studies:.......................................................................................................... 11 
 
4.3. 
Study Rationale ............................................................................................................... 12 
 
5. 
STUDY OBJECTIVES...........................................................................................................12 
 
5.1. 
Primary Objectives .......................................................................................................... 12 
 
5.2. 
Secondary objectives ....................................................................................................... 12 
 
6. 
TRIAL DESIGN .....................................................................................................................12 
 
6.1. 
The pre-operative Phase .................................................................................................. 12 
 
6.2. 
The operative Phase ........................................................................................................ 13 
 
6.3. 
The Follow-up Phase....................................................................................................... 13 
 
7. 
FLOW CHARTS: ...................................................................................................................13 
 
7.1. 
STUDY FLOW CHARTS: ............................................................................................. 13 
 
7.2. 
STUDY PHASES............................................................................................................ 14 
 
8. 
STUDY OUTCOME MEASURES ........................................................................................15 
 
8.1. 
Primary Endpoints ........................................................................................................... 15 
 
8.2. 
Secondary Endpoints ....................................................................................................... 16 
 
9. 
STUDY POPULATION .........................................................................................................16 
 
9.1. 
Recruitment strategy: ...................................................................................................... 16 
 
9.2. 
Inclusion Criteria............................................................................................................. 16 
 
9.3. 
Exclusion Criteria............................................................................................................ 16 
 
10. 
STUDY PROCEDURE: ......................................................................................................17 
 
10.1. 
Selection of the study population: ............................................................................... 17 
 
10.2. 
Case Report Form ........................................................................................................ 17 
 
11. 
SOURCE DATA..................................................................................................................17 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
12. 
TREATMENT OF TRIAL PARTICIPANTS .....................................................................18 
 
12.1. 
Description of Study Medication(s) ............................................................................ 18 
 
12.2. 
Concomitant Medication (if applicable) ...................................................................... 19 
 
13. 
DATA COLLECTION ........................................................................................................19 
 
15.1. 
DATA MANAGEMENT ............................................................................................ 20 
 
15.2. 
AMENDMENT TO THE PROTOCOL ...................................................................... 20 
 
15.2.1. 
Protocol Deviations .............................................................................................. 20 
 
15.2.2. 
Onsite Audits........................................................................................................ 20 
 
15.2.3. 
Study Monitoring ................................................................................................. 21 
 
15.3. 
PREMATURE DISCONTINUATION OF STUDY................................................... 22 
 
16. 
SAFETY REPORTING AND DEFINITIONS ...................................................................22 
 
16.1. 
Adverse Events Monitoring ......................................................................................... 22 
 
16.2. 
Reporting Period .......................................................................................................... 23 
 
16.3. 
Adverse Event (AE): ................................................................................................... 23 
 
16.4. 
Serious Adverse Events ............................................................................................... 24 
 
16.4.1. 
Instructions for Reporting Serious Adverse Events ............................................. 24 
 
17. 
STATISTICAL METHODOLOGY ....................................................................................24 
 
17.1. 
Determination of Sample Size ..................................................................................... 24 
 
17.2. 
Analysis Variables: ...................................................................................................... 25 
 
17.2.1. 
Primary analysis variables:................................................................................... 25 
 
17.2.2. 
Secondary analysis variables:............................................................................... 25 
 
17.2.3. 
Statistical Method:................................................................................................ 25 
 
17.2.4. 
Interim Analysis ................................................................................................... 25 
 
18. 
ETHICS................................................................................................................................25 
 
18.1. 
INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITIUTIONAL REVIEW 
BOARD (IRB)............................................................................................................................ 25 
 
18.2. 
Ethical principles: ........................................................................................................ 26 
 
18.3. 
Laws and regulations: .................................................................................................. 26 
 
18.4. 
PATIENT INFORMATION AND CONSENT .......................................................... 26 
 
18.5. 
DISCONTINUATION OF THE STUDY ................................................................... 27 
 
18.5.1. 
PREMATURE DISCONTINUATION OF STUDY ........................................... 27 
 
18.6. 
PUBLICATION OF STUDY PROTOCOL AND RESULTS .................................... 27 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
18.7. 
STUDY DOCUMENTATION, RECORD KEEPING AND RETENTION OF 
DOCUMENTS ........................................................................................................................... 27 
 
18.8. 
CONFIDENTIALITY OF STUDY DOCUMENTS AND PATIENT RECORDS .... 28 
 
18.9. 
AUDITS AND INSPECTIONS .................................................................................. 28 
 
19. 
References ............................................................................................................................28 

Page 9 of 28 
Confidential 
Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
 
 
 
 
 
 
 
 
2.   LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
APTT 
Activated Partial Thromboplastin Time 
AE 
Adverse Event 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
CRF 
Case Report Form DM
 
Data 
Management 
DNA 
Deoxyribonucleic acid 
DTI 
Direct Thrombin Inhibitor 
DVT 
Deep Vein Thrombosis 
GCP 
Good Clinical Practices 
IRB/IEC 
Institutional Review Board/Independent Ethics 
Committee 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
PE 
Pulmonary Embolism 
RB 
Recombinant 
Bacteria 
S.A.E. 
Serious 
Adverse 
Event 
VTE 
Venous Thromboembolism 

Page 10 of 28 
Confidential 
Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
3.   SIGNATURE(S) PAGE 
 
Study Title: Prospective, single Center, Interventional, Open label Trial for the Evaluation of 
subcutaneous recombinant Hirudin 15 mg (RB variant) in prophylaxis of Deep Vein Thrombosis 
(DVT) post major orthopedic operations 
 
Contact details of the person authorized to sign the protocol and amendments 
 
 
Name of Medical Manager: Dr. Doris Ezzat 
 
Address: El-Bardissi Street, 2T Takseem Asmaa Fahmy Street, Heliopolis, Cairo – Egypt 
 
Mobile: (202) 01223794130 
 
Telephone: (202) 24143170 
 
Fax: (202) 24143179 
 
E-mail: dezzat@minapharm.com 
 
Website: www.minapharm.com 
 
 
 
Contact details of the investigator(s) for the trial 
 
 
Name of Principle Investigator: Dr. Ayman Soliman 
Title: Professor of Orthopedics, Alexandria University Address: 
Mobile: +201111056406 
E-mail: ssssoliman@gmail.com   
 
 
I have read this report and confirm that to the best of my knowledge it accurately describes he 
conduct and results of the study. 
 
Medical Manager Signature: 
Principal Investigator Signature: 
 
 
 
 
 
Date of Signature:                                            Date of Signature: 

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Confidential 
Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
4.   INTRODUCTION 
 
4.1. 
Background 
Hirudin is the most potent naturally-occurring direct thrombin inhibitor (DTI), and the first 
parenteral anticoagulant used on humans.1 
 
Originally derived from the medicinal leech (Hirudo medicinalis), it consists of a 65 amino acids 
polypeptide chain, forming non-covalent, equimolar, non-reversible 1:1 complexes with α 
thrombin.1 When hirudin-bound, thrombin-catalyzed reactions and fibrinogen clotting are 
blocked, and coagulation is subsequently inhibited.2 Hirudin was previously produced in limited 
amounts, however, recombinant DNA technology allowed its mass production.3 These 
recombinant forms bind bivalent to thrombin with pharmacokinetic and anticoagulant profile 
similar to that of the native form.4 
 
Recombinant Hirudin is a direct inhibitor of thrombin. It binds in 1:1 ratio with thrombin thus 
blocking the coagulation cascade and the formation of thrombi.5 
 
Unlike heparins, the action of Hirudin is totally independent from any coagulation cofactor that 
may interfere or alter its action. 5 
 
Thrombexx is useful in the prevention of thromboembolic complications in at risk patients 
thrombexx (15 mg) is administered by subcutaneous injection 5-15 minutes before orthopedic or 
general surgery (after induction of regional block anasthesia) then 15 mg twice daily for 9-12 
days and in bedridden patients until patient is fully ambulant (maximum 12 days) 5 
 
According to the FDA Therapeutic Equivalence Evaluation, 30th Edition, the biosimilar of 
recombinant hirudin, Desirudin is FDA approved, therefore, the same applies to recombinant 
hirudin in Egypt. 
 
4.2. Correlative studies: 
1-   Study of Prevention of Thromboembolic with Use of Recombinant Hirudin, Results of a 
Double-Blind, Multicenter Trial Comparing the Efficacy of Desirudin (Revasc) with That 
of Unfractionated Heparin in Patients Having a Total Hip Replacement6 which showed that 
desirudin to be more effective than heparin in the prevention of deep vein thrombosis, 
without any increase in the requirements for transfusion or the risk of hemorrhage. The 
prevalences of over-all and proximal deep-vein thrombosis in the 174 patients who had 
been managed with desirudin and were included in the per-protocol analysis were 7 and 3 
per cent (thirteen and six patients), respectively.6 
2-  Multicenter Trial of Desirudin for the Prophylaxis of Thrombosis: An Alternative to 
Heparin-Based Anticoagulation (DESIR-ABLE) shows that no patients experienced 
primary endpoints which is major bleeding and no new onset of symptomatic thrombosis 
requiring medical or surgical intervention or death.7 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
4.3. 
Study Rationale 
The purpose of this study is to conduct several investigations required to evaluate the 
efficacy and safety of subcutaneous Thrombexx ampoules in the prophylaxis of Deep 
Vein Thrombosis (DVT) post major orthopedic operations 
 
5.   STUDY OBJECTIVES 
 
5.1. 
Primary Objectives 
 To evaluate the efficacy of Subcutaneous Thrombexx® ampoules (r-Hirudin RB variant 
15 mg) in DVT prophylaxis post major orthopedic operations 
 
5.2. 
Secondary objectives 
 
 
 To evaluate the safety of Subcutaneous Thrombexx® ampoules (r-Hirudin RB variant 15 
mg) in DVT prophylaxis post major orthopedic operations in terms of serious bleeding. 
 Predictive factors; baseline characteristics, Thrombexx® dose, duration and concomitant 
medications. 
 Study population demographics and characteristics. 
 
 
 
6.   TRIAL DESIGN 
 
A Prospective, Single- Center, Phase IV Interventional, Single Arm conducted in Egypt to 
assess the efficacy and safety of patients undergoing major orthopedic operations such as 
Total knee & hip Arthroplasty with complete data and who had 2 weeks’ follow-up. 
 
This study will be conducted through main phases, preoperative phase which will be as a 
screening visit, operative phase which is the surgery will be done and a total of 3 follow- 
up visits which is the postoperative phase. 
 
1- Pre-operative phase 
 
2- Operative phase 
 
3- Post operative phase (follow-up) 
 
Detailed descriptions of the study design are as follows: 
 
6.1. 
The pre-operative Phase 
 
 
During this phase, patients will be screened for fulfillment of the inclusion and exclusion. 
Patient’s demography, history of diseases will be collected, laboratory investigations such as 
Hemoglobin count, Platelets count, APTT, INR, SGPT, SGOT, Serum albumin, serum 
Bilirubin, serum creatinine and random blood glucose and pregnancy test for females in 
childbearing period. 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
APTT should be done before IMP administration, in addition to the patient’s data of 
Thrombexx® administration regimen decided by the treating investigator according to the 
standard clinical practice or as prescribed in the usual manner in accordance with the terms of 
the local marketing authorization with regards to dose, population and indication (and within 
the approved label). 
Medical history and Medication history should also be collected. 
 
Main complaint of the patient during routine physical examination should be recorded 
 
 
6.2. 
The operative Phase 
 
 
During this phase, patient’s registries for the type of surgery done, Type of anesthesia, patient 
position and type of prosthesis, & blood transfusion during surgery should be recorded. And 
IMP dispensing 6 hours after surgery or upon adequate hemostasis will be done. APTT will 
be done 4 & 8 hours after the first dose 
 
6.3. 
The Follow-up Phase 
 
During this phase, which is approximately 15 days, PE which is confirmed by spiral CT chest, 
any new DVT appears also to be confirmed by Doppler ultrasound, Bleeding assessment, 
APTT will be done on days 1, 8 & 15, concomitant medications, Hospital stay and any 
adverse event data will all be recorded 
 
7.   FLOW CHARTS: 
 
7.1. 
STUDY FLOW CHARTS: 
 
Activity 
Pre- 
operative 
phase  
(Screening) 
Operative 
phase 
(Day 0) 
Follow-
up 
1 (Day 
1) 
Follow-
up 
2 (Day 
8) 
Follow-up 
3/ End of 
Study (Day 
15) 
ICF Signature 
☓ 
Inclusion/Exclusion 
Criteria 
☓ 
Demographic Data 
☓ 
Medical History 
☓ 
Vital signs 
☓ 
Concomitant 
Medication 
☓ 
Physical Examination 
☓ 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
Laboratory investigation 
☓ 
 
☓ 
☓ 
☓ 
Type of surgery 
 
☓ 
 
 
 
Assessment of 
bleeding 
 
☓ 
☓ 
☓ 
 
IMP Administration 
 
☓ 
☓ 
☓ 
☓ 
Assessment of DVT 
 
 
☓ 
☓ 
☓ 
Assessment of PE 
 
 
☓ 
☓ 
☓ 
Assessment of therapeutic 
response 
 
 
 
 
☓ 
APTT 
☓ 
☓ 
☓ 
☓ 
☓ 
Adverse Event 
 
☓ 
☓ 
☓ 
☓ 
Study completion 
 
 
 
 
☓ 
 
 
7.2. 
STUDY PHASES 
The study consists of 3 phases: 
 
Visit 1: Preoperative phase (screening) 
 
  Patient Screening (Check eligibility) 
  Signed ICF 
  Gathering Patient Information as Demographic, Vital Signs, BMI, Physical Examination, 
Medical History, Concomitant medications 
  Laboratory Investigations (Hb, PLt count, APTT, INR, SGPT, SGOT, Serum Albumin, 
Serum Bilirubin, serum creatinine, Creatinine clearance, Random blood sugar) 
  Patients main complaint (Knee, Hip) 
 
Operative phase (Day 0) 
 
Patient Data to be collected: 
 
  Type , Date of surgery 
  Type of anaesthesia 
  Patient position 
  Type of prosthesis 
  Blood transfusion 
 
Start of IMP administration. 
 
APTT 4 & 8 hours after IMP administration 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
Visit 2: Post operative phase (Follow-up 1(Day 1) 
 
  Assessment of bleeding 
  Type of blood transfusions 
  Assessment of DVT 
  Routine bilateral compression Doppler (confirmation for DVT) 
  Assessment of PE 
  Spiral CT (confirming PE) 
  IMP administration 
  Laboratory investigations (Hb%, Platelets count) 
  APTT 
Assessment will be done in the hospital, as post-operative period before discharge from hospital. 
 
 
Visit 3: Follow-up 2 (Day 8) 
 
  Assessment of bleeding 
  Type of blood transfusions 
  Assessment of DVT 
  Routine bilateral compression Doppler (confirmation for DVT) 
  Assessment of PE 
  Spiral CT (confirming PE) 
  IMP administration 
  Laboratory investigations (Hb%, Platelets count) 
  APTT 
Assessment in day 8 will be done from outpatient clinic in most patients. 
 
Visit 4: Follow-up 3/ End of Study (Day 15) 
 
  Assessment of bleeding 
  Type of blood transfusions 
  Assessment of DVT 
  Laboratory Investigations 
  Routine bilateral compression Doppler (confirmation for DVT) 
  Assessment of PE 
  Spiral CT (confirming PE) 
  APTT 
  End of Study 
Assessment in day 15 will be done from outpatient clinic. 
 
 
 
8.   STUDY OUTCOME MEASURES 
 
8.1. 
Primary Endpoints 
 Primary end points included new onset symptomatic thrombosis requiring medical 
or surgical intervention or death due to thrombosis defined as fatal PE, ischemic 

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Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
stroke, mesenteric thrombosis, or myocardial infarction. 
 The number of clinical PE events will be measured by spiral CT 
 Mean changes in APTT where it will be done before first dose, 4 & 8 hours after 
first dose then on days  1,8,15 post operatively 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
8.2. 
Secondary Endpoints 
 Major Bleeding: was defined as clinically evident hemorrhage associated with a 
hemoglobin decrease ≥ 2 g/dL that leads to a transfusion of ≥2 units of whole blood 
or packed red cells outside of the perioperative period (time from the start of the 
surgery or procedure and up to 12 hours after), or hemorrhage that is intracranial, 
retroperitoneal, or into a prosthetic joint. 
 Number of any reported (AE) or (SAE) during the study duration. 
 
 
9.   STUDY POPULATION 
 
This is a prospective study, it is important to have a well-defined study population in place prior 
to the start of the study. Study populations should be defined using specific inclusion and 
exclusion criteria, which will be used to evaluate a potential subject’s ability to participate in the 
study. 
 
9.1. 
Recruitment strategy: 
It is essential that the recruitment process take into account factors that will optimize the type and number 
of participants enrolled in the study while minimizing time and expense. Failure to meet target accrual 
goals can affect the “power” of a study, making it less successful in providing quality results. 
 
Recruitment plan will be through explaining to patients the clinical trial objective in Alexandria 
University hospital; referral also will be used to increase the flow rate of recruitment. 
 
9.2. 
Inclusion Criteria 
 Patients aged 18 years of age or older 
 
Body Weight >60 kg 
 
Patients undergoing major orthopedic operations Total knee & hip Arthroplasty 
 
Patients ready to sign (ICF) 
 Patients should discontinue any agents that affect haemostasis prior to the study 
medication use unless strictly indicated. These agents include medications such as: 
anticoagulants, thrombolytics, non-steroidal anti-inflammatory agents (including 
Ketorolac tromethamine), preparations containing aspirin, systemic salicylates, 
ticlopidine, dextran 40, clopidogrel, other anti platelet agents including glycoprotein 
IIb/IIIa antagonists or systemic glucocorticoids. 
 
9.3. 
Exclusion Criteria 
 Significant bleeding injury such as solid organ laceration or intracranial bleed at 
discretion of attending physician 
 Hypersensitivity to Hirudin or prior documented allergy to its components 
 Pregnant or breast feeding females 
 Hemorrhagic stroke in preceding 3 months 
 Abnormal baseline coagulation characterized by an INR >1.4, obtained at the 
discretion of the treating clinician 
 
 

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Sponsor: Minapharm Pharmaceuticals 
Protocol Number: Sub-Thromb-001 
Version: 1 amendment 1 
 
 
 
 Required therapeutic anticoagulation for atrial fibrillation, prior VTE, or mechanical 
heart valve 
 Treatment with concomitant anti-platelet agent other than aspirin 326 mg or more 
daily 
 Subjects with a life expectancy less than 1 month 
 
 
 
10. STUDY PROCEDURE: 
 
10.1. Selection of the study population: 
Subjects will be selected according to inclusion and exclusion criteria, willing to sign informed 
consent and able to complete the study. 
 
Subject's informed consent had to be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
 
Prior to obtaining informed consent, information should had been given in a language and at a 
level of complexity understandable to the subject in both oral and written form by the investigator 
or designee. Each subject should have the opportunity to discuss the trial and its alternatives with 
the investigator. the written Informed Consent Form should have been signed and personally 
dated by the subject, or his legal representative, and by the person who conducted the informed 
consent discussion (investigator or designee). The subject or his legal representative must had 
received a copy of the signed and dated Informed Consent Form. As part of the consent process, 
each subject must have consented to direct access to his medical records for trial-related 
monitoring, auditing, IRB/IEC review and regulatory inspection. 
 
10.2. Case Report Form 
After the protocol approval, the site will be trained on the protocol and the data collection system 
by template of Case Report Form (CRF) with the appropriate documentations. 
 
The data collection will take place through the previously mentioned phases within three months 
from the first patient entered till the last patient data collected with the optimum tracking and 
quality control for the patients’ records and registries to ensure the validity of the collected data. 
 
11. SOURCE DATA 
 
Source documents are original documents and records from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 

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previous and concurrent medication may be summarized into the CRF), clinical and office charts, 
laboratory and pharmacy records…etc, ... 
All documents will be stored safely in a secured room. In all study-specific documents, other than 
the signed informed consent, the patient will be referred to by the patient initials and patient 
number i.e. patient ID. 
 
12. TREATMENT OF TRIAL PARTICIPANTS 
 
12.1. Description of Study Medication(s) 
Because thrombin plays a central role in thrombogenesis, the goal of most treatment regimens 
is to block thrombin generation or inhibit its activity. 
 
1- r-Hirudin binds directly with thrombin to its active & fibrinogen binding site. 
 
2- r-hirudin does not require access to heparin binding site & can thus neutralize clot bound 
thrombin. Hence, down regulating thrombin generation & potentially enhancing early 
revascularization. 
 
Direct thrombin inhibitors were developed to overcome the inability of the heparin/ 
antithrombin complex to inactivate bound thrombin. In contrast to heparin and low- 
molecular-weight heparin, which catalyze the inactivation of thrombin and activated factor X 
(factor Xa) by antithrombin, direct thrombin inhibitors bind to thrombin and block its 
interaction with its substrates. 
 
II- They do not bind to plasma proteins, direct thrombin inhibitors produce a more predictable 
anticoagulant response than heparin. 
 
III- Unlike heparin, direct thrombin inhibitors do not interact with platelet factor 4 or high- 
molecular-weight multimers of von Willebrand factor. Consequently, the activity of direct 
thrombin inhibitors in the vicinity of a platelet-rich thrombus is not compromised. 
 
IV- Finally, thrombin bound to fibrin or fibrin degradation products is susceptible to 
inactivation by direct thrombin inhibitors. Because the active site of thrombin is not involved 
in the interaction of the enzyme with fibrin, it remains accessible to active site-directed 
thrombin inhibitors. Consequently, these agents inactivate fibrin-bound thrombin without 
displacing the enzyme from fibrin. In contrast, bivalent thrombin inhibitors, such as Hirudin 
and bivalirudin, displace bound thrombin during the inhibition reaction by competing with 
fibrin for access to exosite 1 on thrombin. 
 
Dose of Thrombexx®: 
 
In DVT Prophylaxis: 15 mg twice daily, subcutaneous for 15 days 
In case of renal insufficiency, the dose is titrated because r-Hirudin is excreted renally. 
According to Creatinine clearance: 
 
 Creatinine clearance › 31-60 ml/min (5 mg s.c twice daily) 

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 Creatinine clearance ‹ 31 ml/min (1.7 mg s.c twice daily) 
In case of patients who will receive spinal anesthesia; Thrombexx will be given 8-10 hours before 
puncture/catheter and 2-4 hours after puncture/catheter manipulation or removal, as per European 
Guidelines.  
 
12.2.    Concomitant Medication (if applicable) 
 
Throughout the study Investigators might prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in the exclusion criteria. 
If these were required, the participant will be withdrawn. 
Any medication, other than the study medication had taken during the study will be recorded in the 
CRF. 
 
 
13. DATA COLLECTION 
 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data reliable to the study for each study 
participant. 
 
Subjects who are screened but choose not to continue in the study or those that are found to be 
ineligible for the study will be considered “screen failures”. The reason for the failure will be 
recorded on the source document and in the CRF. 
 
The Clinical Research Associate (CRA) will verify the paper CRF documentation for each 
subject against the source documents at the study center. Instances of missing or un- 
interpretable data will be brought to the attention for resolution. A copy of the source document 
and CRF will be placed in the Investigator’s study file and the original CRF will be kept by 
Minapharm at the end of the study. The CRF will be the sole property of the Minapharm. 
 
Data reported in the paper CRF derived from source documents should be consistent with 
source documents or the discrepancy should be explained. Only the investigator/designee and 
clinical research coordinator are authorized to make entries on the paper CRF. 
 
The investigators will be responsible to ensure the accuracy, completeness and timelines of the 
data reported. 
 
All source documents and reports must be reviewed by the designated clinical team and data 
entry staff, who will ensure that they are accurate and complete. Clinical assessments data must 
be entered into source data. Adverse events must be graded, assessed for severity and causality, 
and reviewed by the site investigator or designee. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. During the study, the investigator must maintain complete and accurate 
documentation for the study. All relevant clinical data from source documents will be entered 
into the paper CRF. 
 
After completion of the paper CRFs by the investigator, monitor will review all subject paper 
CRFs for completeness and accuracy. Requests for clarifications or correction will be sent to 
the investigator, if necessary. Statistical analysis will be carried out after all necessary 
corrections have been done and database has been locked. 

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Minapharm will serve as the statistical and data management for this study and will be 
 
 
responsible for data management, quality review, analysis, and reporting of the study data. 
 
The protocol and paper CRF are confidential documents. The paper CRFs will be supplied by 
the Minapharm. Appropriate information for the completion of paper CRF will be provided to 
all participating centers. The paper CRFs must accurately reflect data contained in subject’s 
records (i.e. source documents). In order to maintain confidentiality, the subject will be 
identified only by his/her assigned study subject number and/or initials. 
 
Clinical data will be entered into paper CRF from the source documents. The data system 
includes password protection and internal quality checks to identify data that appear 
inconsistent, incomplete, or inaccurate. 
 
Queries generated during data entry will be sent to investigator for resolution and record of the 
same would be kept. 
 
15.1.  DATA MANAGEMENT 
All data collected in this study will be entered manually by data entry team on Oracle database 
specially designed to meet the needs of clinical trials prepared by Minapharm. 
 
Edit checks will be run on the data and queries issued as needed and queries will be resolved. 
Full quality control data verification will be done and then data will be declared clean. Database 
will be locked after Minapharm medical department approval. 
 
Extraction of data for statistical analysis will be done once database lock occurs. All data 
collected in the paper CRFs will be documented in subject data listings and summarized in tables, 
as appropriate. 
 
15.2.  AMENDMENT TO THE PROTOCOL 
Modifications of the signed protocol are only possible by approved protocol amendments 
authorized by Minapharm. The protocol amendments will be approved by the IRB/IEC prior to 
implementation. The Investigator must not implement any deviation from, or change to the 
protocol, except where it is necessary to eliminate an immediate hazard to trial subject or when 
the change(s) involves only logistical or administrative aspects of the trial. 
 
15.2.1. 
Protocol Deviations 
 
The Investigator will not deviate from the protocol without prior written approval from sponsor (or 
designee), except in medical emergencies. In such cases, Minapharm must be notified as soon as 
possible. The governing IEC will be informed of all protocol deviations by the Investigator. 
 
15.2.2. 
On-site Audits 
 
Minapharm may conduct audits at the study center(s). Audits will include, but will not be limited 
to, study medication supply, presence of required documents, the informed consent process, and 
comparison of paper CRFs with source documents. The investigator agrees to participate with 
audits conducted at a reasonable time in a reasonable manner. These audits are for the purpose of 
verifying the adherence to the protocol, the completeness and exactness of the data being entered 

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in the CRF, and compliance with regulations. Subject confidentiality will be maintained during all 
 
 
audits. Regulatory authorities may also audit the investigator during or after the study. The 
investigator must contact Minapharm immediately if this occurs and must fully cooperate with the 
audits conducted at a reasonable time in a reasonable manner. 
 
15.2.3.             Study Monitoring 
 
The clinical research associate (CRA) will undertake the study monitoring/supervision. In 
accordance with applicable regulations, ICH-GCP, Minapharm monitors will contact the site prior 
to the subject enrollment to review the protocol and data collection procedures with site staff. In 
addition, the monitor will periodically contact the center, including conducting on-center 
monitoring visits at an appropriate frequency, according to the monitoring plan. 
 
During these contacts, the monitor will: 
 
1. Check the progress of the study. 
 
2. Review study data collected. 
 
3. Conduct source document verification and CRF data entry. 
 
4. Identify any issues and address their resolution. 
This will be done in order to verify that the: 
1.   Data are authentic, accurate, and complete. 
 
2.   Safety and rights of subjects are being protected. 
 
3.   Study is conducted in accordance  with  the  currently  approved  protocol  (and  any 
amendments), ICH-GCP, and all applicable regulatory requirements. 
 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues. 
 
Monitoring visits at each investigative site will be conducted by the CRAs at regular intervals. 
The first monitoring visit will be conducted immediately after the enrollment of first subject in 
the study and the subsequent monitoring visits will be conducted based on the recruitment status 
and activities at the site. The CRAs are responsible for applying the applicable monitoring plan. 
Any data clarification from Data Management (DM) will be resolved by the site. In addition, 
the CRAs will be in frequent contact through verbal and written communication with the 
investigators. It is essential that the CRAs have access to all documents (related to the study 
and the individual participants) at any time when these are requested. In return, the CRA will 
adhere to all requirements for subject confidentiality as outlined in the ICF. The investigator 
and his/her staff will be expected to cooperate with CRA, to be available during a portion of 
the monitoring visit to answer questions, and to provide any missing information. 
 
Original subject records (source documents) will be audited or reviewed during the course of 
monitoring to verify the accuracy of the source documents and accuracy of data entered from 
these source documents into the paper CRF. 

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Source data is defined as all information in original records and certified copies of original 
 
 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source documents are original documents, data, 
records and subject files. 
 
15.3.  PREMATURE DISCONTINUATION OF STUDY 
 
The sponsor may prematurely terminate the trial if any of the following situations occurs: 
 
 APTT value of the subject increased by 2-2.5 folds. 
 Comprehensive deficiency in the recorded data or protocol compliance so that the 
results of the study cannot be reliably assessed. 
 
 Occurrence of AEs necessitating termination such as major bleeding, DVT, PE, allergy 
or for any other reason according to investigator evaluation. 
 
 The IRB/IEC changes  its  opinion  regarding  the  safety/efficacy/relevance  of  the 
compound. 
 
 Regulatory authority decision. 
 
If the trial is prematurely terminated or suspended for any reason, the investigators and 
subsequently the trial subjects will be informed promptly, standard therapy and follow-up for 
subjects will be assured and, where required by the applicable regulatory requirement(s), the 
relevant regulatory authority(s) will be informed. The IRB/IEC and all trials sites will be 
informed promptly and provided with a detailed written explanation for the termination or 
suspension. As directed by Minapharm, all study materials must be collected and all CRFs 
completed to the greatest extent possible. 
 
16. 
SAFETY REPORTING AND DEFINITIONS 
 
Safety assessments will consist of monitoring and recording any adverse events reported, 
including serious adverse events and non-serious adverse events; measurement of protocol- 
specified safety laboratory assessments; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. 
 
16.1.  Adverse Events Monitoring 
All AEs regardless of seriousness or relationship to IMP, spanning from the signature of the 
informed consent form, until the end of the study as defined by the protocol for that patient, are to 
be recorded on the corresponding page(s) included in the CRF and reported as described in the 
following sections. 
 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Sponsor or its 
designated representative. 

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For all adverse events, sufficient information should be obtained by the investigator to determine 
the causality of the adverse event. The investigator is required to assess causality. For adverse 
events with a causal relationship to the investigational product, follow-up by the investigator is 
required until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, 
and Sponsor concurs with that assessment. This may imply that observations will continue 
beyond the last planned visit per protocol, and that additional investigations may be requested by 
the Monitoring Team up to as noticed by the sponsor 
 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the IMP. 
 
16.2.  Reporting Period 
For serious adverse events, the reporting period to Sponsor or its designated representative begins 
from the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, i.e. prior to undergoing any study-related procedure and/or receiving 
investigational product, through and till the end of the Follow Up Period as specified in the study 
protocol. 
 
Any serious adverse event occurring any time after the reporting period must be promptly 
reported if a causal relationship to investigational product is SUSPECTED. 
 
16.3.  Adverse Event (AE): 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage. 
 
Examples of adverse events include but are not limited to: 
 
 Abnormal test findings 
 Clinically significant symptoms and signs 
 Changes in physical examination findings 
 Hypersensitivity 
 Progression/worsening of underlying disease 
 
Additionally, they may include the signs or symptoms resulting from: 
 
 Drug overdose 
 Drug withdrawal 
 Drug abuse 
 Drug misuse 
 Drug interactions 
 Drug dependency 

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 Exposure during pregnancy 
 Drug Quality Defect that has impact on the patient safety 
 
16.4.  Serious Adverse Events 
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence at 
any dose that: 
 
 Results in death 
 life-threatening Event (Immediate Risk Of Death) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Results in congenital anomaly/birth defect 
 Important medical event 
 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life-threatening 
and/or result in death or hospitalization. However, if it is determined that the event may 
jeopardize the subject and/or may require intervention to prevent one of the other adverse event 
outcomes, the important medical event should be reported as serious 
 
16.4.1. 
Instructions for Reporting Serious Adverse Events 
In the case of occurrence of a SAE, the Investigator must immediately: 
 
1. Sending within 24 hours, preferably by e-mail the signed and dated corresponding page(s) from 
the CRF to the representative of the Monitoring Team whose name, fax number and e-mail 
address appear on the Clinical Trial Protocol and qualified person for pharmacovigilance 
 
2. ATTACH the photocopy of all examinations carried out and the dates on which these 
examinations were performed. Care should be taken to ensure that the patient's identity is 
protected and the patient's identifiers in the Clinical Trial are properly mentioned on any copy of 
source document provided to the Sponsor. For laboratory results, include the laboratory normal 
ranges; 
 
3. All further documentation should be sent to the Monitoring Team within 1 working day of 
knowledge. In addition, any effort should be made to further document each SAE that is fatal or 
life threatening within the week (7 days) following initial notification 
 
17. 
STATISTICAL METHODOLOGY 
 
17.1.  Determination of Sample Size 
Sample size: Records for 100 patients who underwent major orthopedic surgery collected from 1 
site 
 
The sample size is based on literature review for previous studies, and a sample of 168 patients 
will be sufficient to detect an incidence of 12.5% of DVT with an acceptable error of 5%, and a 

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17.2.  Analysis Variables: 
 
17.2.1. 
Primary analysis variables: 
 
 Proportion of patients experienced new onset symptomatic thrombosis 
 The number of clinical PE (Pulmonary Embolism) events will be measured by 
spiral CT 
 
17.2.2. 
Secondary analysis variables: 
 
 
Number of adverse events recorded 
 
Proportion of patients experienced major bleeding 
 
17.2.3. 
Statistical Method: 
Descriptive analysis: 
 
All statistical tests used a significance level of P=0.05, two tailed tests were performed for all 
analyses used statistical testing. 
 
Descriptive analysis for quantitative data will include count, mean with 95% CI, standard 
deviation, median, minimum and maximum. For qualitative categorical variables; frequency and 
percentage and 95% confidence interval will be applied. 
 
17.2.4. 
Interim Analysis 
Not applicable in this Prospective study 
 
 
18. 
ETHICS 
 
18.1.  INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITIUTIONAL REVIEW 
BOARD (IRB) 
 
 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee (IRB/IEC) before 
study start. A signed and dated statement that the protocol and informed consent have been 
approved by the IRB/IEC must be given to Minapharm Pharmaceuticals before study initiation. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Minapharm monitors and auditors and regulatory authorities as required 

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18.2.  Ethical principles: 
 
This Clinical Trial will be conducted in accordance with the principles laid down by the 18th 
World Medical Association (Helsinki, 1964) and all applicable amendments laid down by the 
World Medical Association and ICH guidelines for Good Clinical Practice [(E6)R1)] 
 
18.3.  Laws and regulations: 
 
This Clinical Trial will be conducted in compliance with all international laws and regulations, 
and national laws and regulations of Egypt in which the Clinical Trial is performed, as well as 
any applicable guidelines. 
 
18.4.  PATIENT INFORMATION AND CONSENT 
 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the Patient of all 
pertinent aspects of the Clinical Trial including the 
written information giving 
approval/favourable opinion by the Ethics Committee (IRB/IEC). All participants should be 
informed to the fullest extent possible about the study, in language and terms they are able to 
understand. 
 
Prior to a patient’s participation in the Clinical Trial, the written Informed Consent Form and any 
other local applicable documents in accordance with Egyptian laws and regulations, should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written Informed Consent Form will be provided to the patient. 
 
The Informed Consent Form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
 
Minapharm Pharmaceuticals will provide investigators in a separate document with a proposed 
informed consent form (ICF) that is considered appropriate for this study and complies with the 
ICH GCP guideline and regulatory requirements. Any changes to this ICF suggested by the 
investigator must be agreed to by Minapharm before submission to the IRB/IEC and a copy of the 
approved version must be provided to the Minapharm manager after IRB/IEC approval. 

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18.5.  DISCONTINUATION OF THE STUDY 
 
Minapharm reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. 
 
18.5.1. 
PREMATURE DISCONTINUATION OF STUDY 
 
Minapharm may prematurely terminate the trial if any of the following situations occurs: 
 
 APTT value for the subject increases by 2-2.5 folds 
 
 Comprehensive deficiency in the recorded data or protocol compliance so that the 
results of the study cannot be reliably assessed. 
 
 Occurrence of AEs necessitating termination. 
 
 Minapharm terminates the development plan for the compound. 
 
 The IRB/IEC changes  its  opinion  regarding  the  safety/efficacy/relevance  of  the 
compound. 
 
 Regulatory authority decision. 
 
If the trial is prematurely terminated or suspended for any reason, the investigators and 
subsequently the trial subjects will be informed promptly, standard therapy and follow-up for 
subjects will be assured and, where required by the applicable regulatory requirement(s), the 
relevant regulatory authority(s) will be informed. The IRB/IEC and all trials sites will be informed 
promptly and provided with a detailed written explanation for the termination or suspension. As 
directed by Minapharm, all study materials must be collected and all CRFs completed to the 
greatest extent possible. 
 
18.6. PUBLICATION OF STUDY PROTOCOL AND RESULTS 
 
Minapharm assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicalstudys.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
 
18.7. STUDY DOCUMENTATION, RECORD KEEPING AND RETENTION OF 
DOCUMENTS 
 
Records and documents pertaining to the conduct of this study, including CRFs, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study, or for the length of time required 
by local health authorities, whichever is longer. After that period of time, the documents may be 
destroyed. 

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No records may be disposed of without the written approval of Minapharm. A written notification 
should be provided to Minapharm prior to transferring any records to another party or moving 
them to another location. 
 
18.8. 
CONFIDENTIALITY OF STUDY DOCUMENTS AND PATIENT RECORDS 
 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Minapharm. Patient enrollment log must be kept strictly 
confidential to enable patient identification at the center. 
 
18.9. AUDITS AND INSPECTIONS 
Source data/documents must be available to inspections by Minapharm or designee or Health 
 
Authorities. 
 
 
 
 
 
19. 
References 
 
1. Greinacher A, Warkentin TE. The direct thrombin inhibitor hirudin.Thromb Haemost. 
2008;99:819–29. 
 
2. Markwardt F. Hirudin as alternative anticoagulant–a historical review.Semin Thromb Hemost. 
2002;28:405–14. 
 
3. Markwardt F. Hirudin as an inhibitor of thrombin. Methods Enzymol.1970;19:924–32. 
 
 
4. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral coagulants:antithrombotic therapy 
and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based 
Clinical Practice Guidelines. Chest. 2012;141:e24S–43S. 
 
5. Thrombexx ® [Package insert], Minapharm pharmaceuticals under license of Rhein Biotech, 
2004 
 
6. BENGT I. ERIKSSON, STEFFAN EKMAN, SIV LINDBRATT, MARKUS BAUR, DORIS BACH, CARSTEN 
TØRHOLM, PETER KÄLEBO and PHILIPPE CLOSE J Bone Joint Surg Am. 1997;79:326-33. 
 
7. Sergio D. Bergese, Harold S. Minkowitz, Paul A. Arpino, David C. Sane and Jerrold H. Levy, CLIN APPL 
THROMB HEMOST 2013 19: 418 originally published online 15 July 2012, DOI: 10.1177/1076029612452779