A Phase IV, Multi-Centric, Prospective, Observational Study to Assess the Clinical Efficacy and Safety of Leflunomide in Egyptian Patients With Active Rheumatoid Arthritis
Conditions: Active Rheumatoid Arthritis
Sponsor: Eva Pharma

 
 
 
Study Protocol: EVA_CLEAR_11022017 
Version Number: Final V2.0/19-Jun-2017 
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CLINICAL STUDY PROTOCOL 
COMPOUND: Leflunomide 
STUDY TITLE 
A Phase IV, Multi-Centric, Prospective, Observational Study to Assess the Clinical 
Efficacy and Safety of Leflunomide in Egyptian Patients with Active Rheumatoid Arthritis 
 
STUDY CODE: EVA_CLEAR_11022017 
 
Study Name: CLEAR 
Phase: IV 
Protocol Version: Final V2.0 
Protocol Date: 19-Jun-2017 
Previous Versions (date): 19-Apr-2017  
 
 
 
 
All information included in this protocol is confidential and is the exclusive property of EVAPHARMA. This 
information must not be disclosed to any unauthorized party without the prior written consent of 
EVAPHARMA. The use of included confidential information is only permitted to those who received the 
protocol for the agreed upon purpose. 
 
 

 
 
 
Study Protocol: EVA_CLEAR_11022017 
Version Number: Final V2.0/19-Jun-2017 
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NAMES AND ADRESSESS OF 
Sponsor 
Name: EVAPHARMA 
Address: 9 El sharekat st.,El Opera , Abdeen,Cairo-Egypt 
Tel: (+202) 239 92700   
Fax: (+202) 239 92782 
Sponsor Representative 
Medical advisor/Deputy QPPV : Dr. Mina Maxy 
Address: 9 El sharekat st.,El Opera , Abdeen,Cairo-Egypt 
Mobile: (+2) 01110014883 
Email: mina.maxy@evapharma.com 
Sr.PM:Dr.Sameh Samy 
Mobile: +20106 16 33332 
Email: sameh.samy@evapharma.com 
GM :Dr. Amgad Talaat  
Email: amgad.talaat@Evapharma.com 
01223186108 
Address: 9 El sharekat st.,El Opera , Abdeen,Cairo-Egypt 
CRO (Contract Research Organization) 
CRO Name: DATACLin 
Address: 38 Gamal Salem St., Mosadak St., Dokki, Giza, 
Egypt 
Tel: (+202) 3761-7301/2 
Fax: (+202) 3345 0061 
E-mail: info@dataclin.com 
CRO Representative 
Name: Dr. Mohamad Taha/ General Manager 
Address: 38 Gamal Salem St., Mosadak St., Dokki, Giza, 
Egypt 
Mobile: (+2) 0106 705 2002 
Tel: (+202) 3761-7301/2 (Ext: 110) 
Fax: (+202) 3345 0061 
Email: mohamad.taha@dataclin.com 
CRO Monitoring Team Representative 
Name: Dr. Mina Saeed/ Clinical Project Lead 
Address: 38 Gamal Salem St., Mosadak St., Dokki, Giza, 
Egypt 
Mobile: (+2) 01022242873 
Tel: (+202) 3761-7301/2 (Ext: 111) 
Fax: (+202) 3345 0061 
Email: mina.saeed@dataclin.com 
 
 

 
 
 
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1. Table of Content 
1. Table of Content ................................................................................................ 3 
2. List of Abbreviations ......................................................................................... 7 
3. Synopsis ............................................................................................................ 9 
4. Study and Disease Information ...................................................................... 17 
4.1. Background ................................................................................................. 17 
4.2. Rationale ..................................................................................................... 17 
4.3. Incidence and Prevalence ........................................................................... 18 
5. Study Questions and Objectives ................................................................... 18 
5.1. Study Questions .......................................................................................... 18 
5.2. Primary Objectives ...................................................................................... 18 
5.3. Secondary Objectives .................................................................................. 18 
6. Study Methods ................................................................................................ 19 
6.1. Study Design ............................................................................................... 19 
6.2. Study Flowchart and Graphical Study Design .............................................. 19 
6.3. Recruitment Modalities ................................................................................ 19 
6.3.1. 
Selection of Subjects............................................................................................... 19 
6.3.1.1. 
Inclusion Criteria ............................................................................................................. 19 
6.3.1.2. 
Exclusion Criteria ........................................................................................................... 20 
6.3.2. 
Selection of Investigators ........................................................................................ 20 
6.4. Duration of Study Participation .................................................................... 20 
7. Management of Data ....................................................................................... 20 
7.1. Source Data................................................................................................. 20 
7.2. Data Collection ............................................................................................ 21 
7.2.1. 
Data Collection Schedule ........................................................................................ 21 

 
 
 
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7.2.2. 
Data Collection Process .......................................................................................... 22 
7.3. Conventions (Data Entry) ............................................................................ 23 
7.4. Data Validation and Discrepancy Management by the CRO ........................ 23 
7.5. Clinical Data Coding .................................................................................... 23 
8. Statistical Considerations .............................................................................. 23 
8.1. Determination of Sample Size ..................................................................... 23 
8.2. Randomization ............................................................................................. 24 
8.3. Analysis Population ..................................................................................... 24 
8.4. Study Endpoints .......................................................................................... 24 
8.4.1. 
Primary Endpoints ................................................................................................... 24 
8.4.2. 
Secondary Endpoints .............................................................................................. 24 
8.4.3. 
Safety Endpoints ..................................................................................................... 25 
8.5. Endpoints Variables ..................................................................................... 25 
8.5.1. 
Efficacy Variables ................................................................................................... 25 
8.5.2. 
Safety Variables ...................................................................................................... 25 
8.6. Other Covariate/Control Variables ............................................................... 25 
8.7. Statistical Analysis Methods ........................................................................ 25 
8.7.1. 
Descriptive Analysis ................................................................................................ 25 
8.7.2. 
Comparative Analysis ............................................................................................. 25 
8.7.3. 
Interim Analysis ....................................................................................................... 26 
8.8. Handling of Missing Values ......................................................................... 26 
9. Treatment ......................................................................................................... 26 
9.1. Product ........................................................................................................ 26 
9.2. Mode of Administration ................................................................................ 26 
10. 
Pharmacovigilance ...................................................................................... 27 
10.1. Definitions .................................................................................................... 27 

 
 
 
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10.1.1. 
Adverse Events ....................................................................................................... 27 
10.1.2. 
Adverse Event of Special Interest ........................................................................... 28 
10.1.3. 
Serious Adverse Events .......................................................................................... 28 
10.1.4. 
Adverse Reaction (Adverse Drug Reaction) ........................................................... 28 
10.1.5. 
Suspected Adverse Reaction .................................................................................. 28 
10.1.6. 
Unexpected Adverse Drug Reaction ....................................................................... 29 
10.1.7. 
Abnormal Test Findings .......................................................................................... 29 
10.1.8. 
Hospitalization ......................................................................................................... 30 
10.2. Adverse Events Monitoring .......................................................................... 31 
10.3. Reporting Period .......................................................................................... 31 
10.4. Severity Assessment ................................................................................... 31 
10.5. Causality Assessment ................................................................................. 32 
10.5.1. 
WHO-UMC Causality Categories ............................................................................ 32 
10.6. Exposure During Pregnancy ........................................................................ 33 
10.7. Withdrawal Due to Adverse Events ............................................................. 35 
10.8. Eliciting Adverse Event Information ............................................................. 35 
10.9. Procedures for Recording Adverse Events .................................................. 35 
10.10. Reporting Requirements ......................................................................... 35 
10.10.1. 
General Instructions ............................................................................................ 35 
10.10.2. 
Reporting of Serious Adverse Event ................................................................... 36 
10.10.3. 
Reporting of Non-Serious Adverse Event ........................................................... 36 
10.11. Instructions for Reporting SAEs for Study Team ..................................... 36 
10.12. Sponsor Reporting Requirements to Regulatory Authorities ................... 37 
10.13. Breaking Randomization Code ................................................................ 37 
11. 
Ethical and Regulatory Standards .............................................................. 38 
11.1. Ethical principles .......................................................................................... 38 

 
 
 
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11.2. Laws and Regulations ................................................................................. 38 
11.3. Data Informed Consent ................................................................................ 38 
11.4. Institutional Review Board/Independent Ethics Committee (IRB/IEC) .......... 38 
11.5. Discontinuation / Withdrawal of participants from study ............................... 39 
12. 
Quality Control and Quality Assurance ..................................................... 39 
12.1. Quality Control ............................................................................................. 39 
12.1.1. 
In Process Quality Control of Biometrics ................................................................. 39 
12.1.2. 
Monitoring and Site Data Quality Control ................................................................ 39 
12.2. Quality Assurance ....................................................................................... 40 
13. 
Responsible Parties..................................................................................... 40 
13.1. Responsibilities of Investigators ................................................................... 40 
13.2. Responsibilities of Sponsor ......................................................................... 41 
14. 
Administrative Expectations ....................................................................... 41 
14.1. Record Retention and Archiving of Study Documents ................................. 41 
14.2. Confidentiality and Protection of Study Data ................................................ 41 
14.3. Insurance ..................................................................................................... 42 
14.4. Sponsor Audits and Inspections by Regulatory Agencies ............................ 42 
14.5. Premature Discontinuation of The Study/Premature Close-out of a Site ...... 42 
14.6. Ownership and Use of Study Data ............................................................... 43 
15. 
Amendments and Updates .......................................................................... 43 
16. 
Milestones .................................................................................................... 43 
17. 
Appendices .................................................................................................. 43 
18. 
Publications ................................................................................................. 43 
19. 
References ................................................................................................... 44 
 

 
 
 
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2. List of Abbreviations 
Abbreviation 
Term 
ACR/EULAR  
The American College of Rheumatology/European League Against 
Rheumatism 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Transaminase 
ANOVA 
Analysis of Variance 
Anti-CCP 
Anti-Cyclic Citrullinated Peptide 
AST 
Aspartate Transaminase 
BMI 
Body Mass Index 
CBC 
Complete Blood Count 
CDAI 
Clinical Disease Activity Index  
Child C-class 
Child–Pugh score, Class C 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRP 
C-Reactive Protein 
DAS28 
Disease Activity Score 28 
DBP 
Diastolic Blood Pressure 
DMARDs 
Disease-Modifying Antirheumatic Drugs 
ESR 
Erythrocyte Sedimentation Rate 
FBG 
Fasting Blood Glucose 
HAQ Disability Index 
Health Assessment Questionnaire, Disability Index 
HBsAg 
Hepatitis B Surface Antigen 
HCV-Ab 
Hepatitis C Virus Antibody 
ID 
Identification number 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board  
IV 
Intravenous 
LPI 
Last Patient In 
LPO 
Last Patient Out 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
ml 
Milliliter 
NA 
Not Applicable 
QC 
Quality Control 
RA 
Rheumatoid Arthritis 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 

 
 
 
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SDAI  
Simple Disease Activity Index 
SOP 
Standard Operating Procedure 
Sr ACPA 
Serum Anti-Citrullinated Peptide Antibody 
Sr RF 
Serum Rheumatoid Factor 
Sr Cr 
Serum Creatinine 
WHO 
World Health Organization 
 
 
 

 
 
 
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3. Synopsis 
STUDY TITLE 
A Phase IV, Multi-Centric, Prospective, Observational Study to Assess 
the Clinical Efficacy and Safety of Leflunomide in Egyptian Patients 
with Active Rheumatoid Arthritis. (CLEAR) 
STUDY CODE 
EVA_CLEAR_11022017 
STUDY SPONSOR 
EVAPHARMA Egypt 
PRODUCT NAME 
Arthfree 
ACTIVE INGREDIENT 
Leflunomide 
INDICATION 
Active Rheumatoid Arthritis 
STUDY LOCATION (S) 
Egypt 
PRINCIPLE INVESTIGATOR 
Prof. Adel Mahmoud (Professor of Internal Medicine, Rheumatology 
and Immunology) 
Head of Rheumatology Department, Faculty of Medicine, Ain Shams 
University, Abbasiya, Cairo, Egypt. 
Address: 53 El Makrizy, Borg Elatebaa,Roxy, Heliopolis  
Mobile:00201005265425  
Email:dr_adel_mahmoud25@yahoo.com 
SPONSOR'S MEDICAL EXPERT 
Dr.Mina Maxy 
Address: 9 El sharekat st.,El Opera , Abdeen,Cairo-Egypt 
Mobile: (+2) 01110014883 
Email: mina.maxy@evapharma.com 
CENTRAL LABORATORY 
NA 
MEDICAL AND/OR TECHNICAL 
DEPARTMENTS 
NA 
STUDY QUESTIONS 
1. What is the clinical efficacy of Leflunomide as first line therapy and 
as add-on therapy to other DMARDs (such as Methotrexate, 
Hydroxychloroquine, and Sulfasalazine) with or without Steroids 
use in Egyptian patients with Active Rheumatoid Arthritis? 
2. What are the pattern of management and characteristics of 
Egyptian patients with Active Rheumatoid Arthritis receiving 
Leflunomide treatment? 
3. What is the clinical safety of Leflunomide as first line therapy and 

 
 
 
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as add-on therapy to other DMARDs (such as Methotrexate, 
Hydroxychloroquine, and Sulfasalazine) with or without Steroids 
use in Egyptian patients with Active Rheumatoid Arthritis? 
STUDY OBJECTIVES 
Primary Objective: 
1. Assessing the clinical efficacy of Leflunomide as first line therapy 
and as add-on therapy to other DMARDs (such as Methotrexate, 
Hydroxychloroquine, Sulfasalazine) with or without Steroids in 
Egyptian patients with Active Rheumatoid Arthritis. 
Secondary Objectives: 
1. Describing pattern of management and characteristics of Egyptian 
patients with Active Rheumatoid Arthritis receiving Leflunomide 
treatment. 
2. Identifying the safety profile of Leflunomide whether used as first 
line therapy and/or as add-on therapy to other DMARDs (such as 
Methotrexate, Hydroxychloroquine, Sulfasalazine) with or without 
Steroids in Egyptian patients with Active Rheumatoid Arthritis. 
SUMMARY OF STUDY DESIGN 
Study Design Description: 
This is a phase IV, multi-centric, prospective, observational study to 
assess the clinical efficacy and safety of Leflunomide as first line 
therapy and as add-on therapy to other DMARDs (such as 
Methotrexate, Hydroxychloroquine, Sulfasalazine) with or without 
Steroids use in Egyptian patients with Active Rheumatoid Arthritis. 
Study Duration: 
3 months for recruitment and 9 months for treatment. 
Sample Size: 
It is estimated to recruit 400 patients (around 17 patients per site). 
Patients will be between 18 and 60 years of age, with Active 
Rheumatoid Arthritis selected according to the ACR/EULAR 
classification criteria with score ≥ 6 points. 
Patients will be Leflunomide naïve or after previous Leflunomide 
administration (after at least 6 month wash out period from date of 
baseline visit). 
Patients will be with or without other DMARDs including Methotrexate, 
Sulfasalazine and/or Hydroxychloroquine with or without steroids use 
who experienced therapy resistance, inadequate response or 
intolerance. 

 
 
 
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RECRUITMENT MODALITIES 
Selection of Patients: 
Inclusion Criteria: 
Patient must meet ALL of the following criteria to be eligible for enrolment into the 
study 
1. Active Rheumatoid Arthritis patients selected according to the 
ACR/EULAR classification 2010 criteria with score ≥ 6 points. 
2. Male or female patients aged 18-60 years old. 
3. Leflunomide naïve patients or patients with previous Leflunomide 
administration (after at least 6 month wash out period from date of 
baseline visit) who will be prescribed Leflunomide at the sole 
decision of the treating physician. 
4. Patients with or without another DMARDs including Methotrexate, 
Sulfasalazine and/or Hydroxychloroquine with or without steroids 
use who experienced therapy resistance, inadequate response or 
intolerance. 
5. Patients read, understand and signed informed consent prior to 
inclusion. 
6. Patients willing to complete and literate in the language of the 
available Health Assessment Questionnaire (HAQ Disability Index) 
either alone or with minimal assistance from caregivers and/or 
trained site personnel. 
Exclusion Criteria: 
Patient meeting the following criteria is not eligible for enrolment into the study 
1. Female patients who are pregnant or lactating at the time of 
inclusion or those who are planning for pregnancy within the 
coming year from the time of inclusion to the study. 
2. Patients with contraindications to active constituent of Leflunomide. 
3. Patients with severe concurrent infection (necessitating IV 
antibiotics or hospitalization). 
4. Patients with history of non-treated hepatitis B &/or C infection. 
5. Patients with history of severe liver disease (child C class). 
6. Patients with history of severe renal insufficiency (creatinine 
clearance ≤30 ml/min.). 
Selection of Investigators: 
The study will be conducted by rheumatologists. 
In order to ensure the representativeness of investigators, the 
participating investigators will be randomly selected among an 
extended list of sites (private clinics; rheumatologist) provided by the 

 
 
 
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study sponsor. 
TOTAL EXPECTED NUMBER 
OF PATIENTS 
It is estimated to recruit around 17 patients per site (Total 400 
patients). 
EXPECTED NUMBER OF SITES 
24 sites (Private clinics) 
MEDICINAL  PRODUCT 
Arthfree (Leflunomide 20mg) 
Dose: 1 tablet once daily, should be swallowed whole with sufficient 
amounts of liquids. The extent of Leflunomide absorption is not 
affected if taken with meals. Doses higher than 20 mg/day are not 
recommended. Improvement in the rheumatoid condition usually starts 
after 4 to 6 weeks and may further improve up to 4 to 6 months. 
Loading dose: a tablet of Leflunomide 100 mg for three days. should 
be swallowed whole with sufficient amounts of liquids. The extent of 
Leflunomide absorption is not affected if taken with meals. 
Due to the long half-life in patients with rheumatoid arthritis and 
recommended dosing interval (24 hours), a loading dose is needed to 
provide steady-state concentrations more rapidly. 
Patients will be prescribed Arthfree (Leflunomide) at the sole decision 
of the treating physician. 
DATA COLLECTION SCHEDULE 
This phase IV study will last for 9 months in addition to recruitment 
period of 3 months. A total of 6 visits will be performed as shown in the 
table below; 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Baseline & 
ICF signing 
Week 6 (± 
2 weeks) 
Week 12 
(± 2 
weeks) 
Week 20 
(± 2 
weeks) 
Week 28 
(± 2 
weeks) 
Week 36 (± 
2 weeks) 
EOS 
Clinical 
Assessment 
Clinical 
Assessment 
Clinical Assessment if applicable 
Clinical 
Assessment 
Lab Data 
Lab Data 
Lab Data if applicable 
Lab Data 
 
Safety Data 
 
DATA TO BE COLLECTED (FOR 
PRIMARY AND SECONDARY 
OBJECTIVES)** 
At Baseline Visit: 
Data on Informed consent, Inclusion and exclusion criteria, 
Demographics, Smoking status, Alcohol consumption, Medical history, 
Gynecological History for female patients only, Concomitant 
medications, Laboratory tests and Poor prognostic factors will be 

 
 
 
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collected along with RA history. 
Disease assessment (CDAI) and Physical examination will be done 
and also Vital signs will be recorded. 
Patients will fill Health Assessment Questionnaire (HAQ Disability 
Index) and related data will be recorded. 
At Visit 2 (Week 6 ± 2 weeks) & Visit 3 (Week 12 ± 2 weeks) & Visit 
4 (Week 20 ± 2 weeks) & Visit 5 (Week 28 ± 2 weeks): 
Data on Concomitant medications and Laboratory tests will be 
collected. 
Disease assessment (CDAI) and Physical examination will be done 
and also Vital signs will be recorded. 
Patients will fill Health Assessment Questionnaire (HAQ Disability 
Index) and related data will be recorded. 
Data on Adverse events/Serious adverse events experienced by 
patient since the previous visit will be documented. 
At Visit 6 (Week 36 ± 2 weeks): 
Data on Concomitant medications and Laboratory tests will be 
collected. 
Disease assessment (CDAI) and Physical examination will be done 
and also Vital signs will be recorded. 
Patients will fill Health Assessment Questionnaire (HAQ Disability 
Index) and related data will be recorded. 
Data on Adverse events/Serious adverse events experienced by 
patient since the previous visit will be documented. 
Study Completion Form will be also filled. 
STUDY ENDPOINTS 
Primary Endpoints: 
- 
To assess disease severity (Remission, Low activity, 
Moderate activity and High activity) and  the mean relative 
change of in Clinical Disease Activity Index (CDAI) among 
patients with active rheumatoid arthritis treated with 
Leflunomide as first line therapy and as add-on therapy to 
other DMARDs (such as Methotrexate, Hydroxychloroquine, 
Sulfasalazine) with or without Steroids between baseline and 
week 36. 
- 
To assess the mean relative change in Health Assessment 
Questionnaire score (HAQ Disability Index) among patients 

 
 
 
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with active rheumatoid arthritis treated with Leflunomide as 
first line therapy and as add-on therapy to other DMARDs 
(such as Methotrexate, Hydroxychloroquine, Sulfasalazine) 
with or without Steroids between baseline and week 36. 
Secondary Endpoints: 
- 
To describe pattern of management and patients’ 
characteristics (including demographics, medical history, RA 
severity, RA Duration, line of therapy, daily dose, treatment 
duration, reasons for treatment adjustment and Previous 
therapies) of active RA patients receiving Leflunomide 
treatment. 
- 
To assess the frequency of AEs/SAEs among patients using 
Leflunomide as first line therapy and as add-on therapy to 
other DMARDs (such as Methotrexate, Hydroxychloroquine, 
Sulfasalazine) with or without Steroids and its relation to study 
medication. 
STATISTICAL 
CONSIDERATIONS 
 
Statistical Power and Sample Size Justification 
The primary objective of CLEAR study is to assess the 
clinical efficacy of Leflunomide as first line therapy and as 
add-on therapy to other DMARDs (such as Methotrexate, 
Hydroxychloroquine, Sulfasalazine) with or without Steroids 
as measured by the mean relative change in Clinical Disease 
Activity Index (CDAI) and Health Assessment Questionnaire 
(HAQ Disability Index) among patients with active rheumatoid 
arthritis.  
Considering an alpha error of 5% using two-sided 95% CI of 
Wilcoxon signed-rank test and a study power of 80%, a 
sample of 332 patients will be required to detect an effect 
size of 0.158 between baseline and study endpoint, plus an 
expected drop-out rate of 20% during the 9 months 
observational study duration. Thus, a sample of 398 patients 
will be appropriate that rounded to 400 patients. 
 
Randomization method 
Not applicable. 
 
Statistical methodologies: 
- 
Descriptive analysis: 
o Percent (%) distribution for all categorical variables and 

 
 
 
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mean with (SD) and median (Minimum: Maximum) for 
continuous variables according their distribution. 
- 
Comparative analysis: 
o Student t-test and One Way ANOVA to estimate the 
comparison between the treatment arms for the 
numerical variables (according to their distribution; 
non-parametric substitution tests could be used). 
o Paired t-test and repeated measure ANOVA test to 
estimate the change in numerical variables throughout 
the study visits (according to their distribution; non-
parametric substitution tests could be used). 
o Chi2 test (or Fisher’s Exact test) for unpaired and 
McNemar’s test for paired categorical variables. 
 All tests will be performed on the 5% level of significance. 
 Any deviation(s) from the original statistical plan will be 
described in the final report). 
 Procedure for accounting for missing, unused, and 
spurious data will be explained in the statistical analysis 
plan (SAP). 
 
Interim analysis 
When approximately the enrolled patients completed 50% of 
their visits (after Visit 3), an interim analysis for safety and 
efficacy will be conducted by an independent data monitoring 
committee. Serious adverse events will be monitored by the 
committee on an ongoing basis throughout the study. 
ESTIMATED DURATION 
- 
Protocol planned date: June 2017 
- 
First patient In (FPI): September 2017 
- 
Last patient In (LPI): December 2017 
- 
Last patient Out (LPO): September 2018 
- 
Estimated enrollment duration: 3 months 
- 
Estimate treatment duration: 9 months 
- 
Database lock planned date: September 2018 
- 
Estimated Report date: November 2018 

 
 
 
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Data to be collected 
**Data Collection Schedule 
Visit 1 
(Baseline) 
Visit 2 
(Week 6) 
Visit 3 
(Week 12) 
Visit 4 
(Week 20) 
Visit 5 
(Week 28) 
Visit 6 
(Week 36) 
Informed consent 
x 
 
 
 
 
 
Inclusion/ Exclusion 
x 
 
 
 
 
 
Physical Examination/ 
Vital Signs1 
x 
x 
x 
x 
x 
x 
Demographics 
x 
 
 
 
 
 
Smoking Status 
x 
 
 
 
 
 
Alcohol Consumption 
x 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
Gynecological History 
(FEMALES ONLY) 
x 
 
 
 
 
 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
RA History2 
x 
 
 
 
 
 
Disease Assessment3 
x 
x 
x 
x 
x 
x 
Laboratory Tests4 
x 
x 
x 
x 
x 
x 
Health Assessment 
Questionnaire (HAQ 
Disability Index)5 
x 
x 
x 
x 
x 
x 
Poor Prognostic 
Factors6 
x 
 
 
 
 
 
Adverse Events & 
Serious Adverse Events 
 
x 
x 
x 
x 
x 
Study Completion Form 
 
 
 
 
 
x 
1: Physical Examination/Vitals Signs: Height will be collected in V1 only.  
2: Rheumatoid Arthritis History will include RA Duration, Previous/Current therapies including duration, dose, adverse events/serious adverse 
events experienced during previous treatment and Reason for starting Leflunomide* (previous DMARDs failure, insufficient response, allergy, 
intolerance, side effects) *dose (if the patient received loading dose or not) and Previous X-RAY reports. 
3: Disease Assessment will be done by Clinical Disease Activity Index (CDAI). 
4: Laboratory Tests include CBC, ESR assessed by Westergren method (First hour), C-reactive protein (titer), AST, ALT, Sr Cr, Sr ACPA, Sr RF 
titer, FBG, HBsAg and HCV-Ab. 
5: Stanford University-Health Assessment Questionnaire (HAQ Disability Index). 
6: Poor prognostic factors: Presence of 1 or more of; Bony erosions by radiograph, High swollen joint count, Extra-articular disease (nodules, 
vasculitis, Felty’s syndrome), Functional limitation (HAQ), High disease activity as measured by composite indices (DAS28, SDAI and/or CDAI), 
High acute phase reactants (CRP and ESR) or High RF and/or anti-CCP. 
 
 
 
 

 
 
 
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4. Study and Disease Information 
4.1. Background 
Rheumatoid Arthritis (RA) is a systemic, chronic, autoimmune and inflammatory disease that 
affects joints, muscles, tendons, connective tissues and fibrous tissues1,2. RA is considered to be 
the most common autoimmune disease in adults that affects approximately 1% of the global 
population3,4. 
In The Global Burden of Disease 2010 study “GBD 2010 Study” which was conducted in 187 
countries, it was found that Disability-Adjusted Life Year (DALY “per 100000”) for RA in 1990 was 
63 which was increased in 2010 to be 705. 
Data from a systematic literature review of Medline, Embase and Global Health Library which 
reclaimed a total of 335 publications showed that in 1990, the estimated crude prevalence of RA 
in Africa based on the available studies was 0.36% (2.3 million affected individuals) which was 
thought to be increased in 2010 to 0.42% with burden of 4.3 million affected individuals6. 
During the past 30 years, the management of RA has changed drastically as few therapeutic 
agents were extant7. At the present time, numerous therapeutic agents are used in managing RA 
along with relieving signs and symptoms such as DMARDs, Glucocorticoids and NSAIDs7,8. 
In 2016, Despite the fact that The European League Against Rheumatism (EULAR) 
recommended that Methotrexate (MTX) should be part of the first line treatment strategy, 
Leflunomide or Sulfasalazine were recommended as part of the first treatment strategy in patients 
with a contraindication to Methotrexate or with early intolerance8. 
Leflunomide is one of the most used DMARDs around the world, it can be used as a 
monotherapy or in combination with other DMARDs to inhibit the production of inflammatory cells 
and accordingly to reduce inflammation9. 
In a number of studies which were conducted to investigate the efficacy and safety of 
Leflunomide n RA management, it was found that Leflunomide was equivalent to Methotrexate 
and its safety profile was acceptable compared to other DMARDs9,10,11. It was also found that 
Leflunomide was superior to Methotrexate in terms of Quality of Life measurements9,10,11. 
4.2. Rationale 
The aim of this study is to assess the clinical efficacy and safety of Leflunomide as first line 
therapy and as add-on therapy to other DMARDs (such as Methotrexate, Hydroxychloroquine, 
Sulfasalazine) with or without Steroids in Egyptian patients with Active Rheumatoid Arthritis. 

 
 
 
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4.3. Incidence and Prevalence 
RA is considered to be the most common autoimmune disease in adults that affects 
approximately 1% of the global population3,4. 
In The Global Burden of Disease 2010 study “GBD 2010 Study” which was conducted in 187 
countries, it was found that Disability-Adjusted Life Year (DALY “per 100000) for RA in 1990 was 
63 which was increased in 2010 to be 705. 
Data from a systematic literature review of Medline, Embase and Global Health Library which 
reclaimed a total of 335 publications showed that in 1990, the estimated crude prevalence of RA 
in Africa based on the available studies was 0.36% (2.3 million affected individuals) which was 
thought to be increased in 2010 to 0.42% with burden of 4.3 million affected individuals6. 
In 2004, A study was conducted to assess the prevalence of rheumatic diseases in rural Egypt 
and the results showed that in 857 individuals, The prevalence of RA in rural Egypt was 0.29% in 
the population, which was similar to other oriental rural populations but lower than Western 
populations12. 
5. Study Questions and Objectives 
5.1. Study Questions 
1. What is the clinical efficacy of Leflunomide as first line therapy and as add-on therapy to other 
DMARDs (such as Methotrexate, Hydroxychloroquine, and Sulfasalazine) with or without Steroids 
use in Egyptian patients with Active Rheumatoid Arthritis ? 
2. What are the pattern of management and characteristics of Egyptian patients with Active 
Rheumatoid Arthritis receiving Leflunomide treatment? 
3. What is the clinical safety of Leflunomide as first line therapy and as add-on therapy to other 
DMARDs (such as Methotrexate, Hydroxychloroquine, and Sulfasalazine) with or without Steroids 
use in Egyptian patients with Active Rheumatoid Arthritis? 
5.2. Primary Objectives 
1. Assessing the clinical efficacy of Leflunomide as first line therapy and as add-on therapy to other 
DMARDs (such as Methotrexate, Hydroxychloroquine, Sulfasalazine) with or without Steroids in 
Egyptian patients with Active Rheumatoid Arthritis. 
5.3. Secondary Objectives 
1. Describing pattern of management and characteristics of Egyptian patients with Active 
Rheumatoid Arthritis receiving Leflunomide treatment. 

 
 
 
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2. Identifying the safety profile of Leflunomide whether used as first line therapy and/or as add-on 
therapy to other DMARDs (such as Methotrexate, Hydroxychloroquine, Sulfasalazine) with or 
without Steroids in Egyptian patients with Active Rheumatoid Arthritis. 
6. Study Methods 
6.1. Study Design 
This is a phase IV, multi-centric, prospective, observational study to assess the clinical efficacy 
and safety of Leflunomide as first line therapy and as add-on therapy to other DMARDs (such as 
Methotrexate, Hydroxychloroquine, Sulfasalazine) with or without Steroids use in Egyptian 
patients with Active Rheumatoid Arthritis. 
6.2. Study Flowchart and Graphical Study Design 
 
6.3. Recruitment Modalities 
6.3.1. Selection of Subjects 
6.3.1.1. Inclusion Criteria 
Patient must meet ALL of the following criteria to be eligible for enrolment into the study 
1. Active Rheumatoid Arthritis patients selected according to the ACR/EULAR classification 2010 
criteria with score ≥ 6 points. 
2. Male or female patients aged 18-60 years old. 
3. Leflunomide naïve patients or patients with previous Leflunomide administration (after at least 6 
month wash out period from date of baseline visit) who will be prescribed Leflunomide at the sole 
decision of the treating physician. 

 
 
 
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4. Patients with or without another DMARDs including Methotrexate, Sulfasalazine and/or 
Hydroxychloroquine with or without steroids use who experienced therapy resistance, inadequate 
response or intolerance. 
5. Patients read, understand and signed informed consent prior to inclusion. 
6. Patients willing to complete and literate in the language of the available Health Assessment 
Questionnaire (HAQ Disability Index) either alone or with minimal assistance from caregivers 
and/or trained site personnel. 
6.3.1.2. Exclusion Criteria 
Patient meeting the following criteria is not eligible for enrolment into the study 
1. Female patients who are pregnant or lactating at the time of inclusion or those who are 
planning for pregnancy within the coming year from the time of inclusion to the study. 
2. Patients with contraindications to active constituent of Leflunomide. 
3. Patients with severe concurrent infection (necessitating IV antibiotics or hospitalization). 
4. Patients with history of non-treated hepatitis B &/or C infection. 
5. Patients with history of severe liver disease (child C class). 
6. Patients with history of severe renal insufficiency (creatinine clearance ≤30 ml/min.). 
6.3.2. Selection of Investigators 
The study will be conducted by rheumatologists. 
In order to ensure the representativeness of investigators, the participating investigators will 
be randomly selected among an extended list of sites (private clinics; rheumatologist) 
provided by the study sponsor. 
6.4. Duration of Study Participation 
3 months for recruitment and 9 months for treatment. 
7. Management of Data 
7.1. Source Data 
Source documents are original documents, data, and records from which participants’ CRF data 
are obtained. These include, but are not limited to, hospital records (from which medical history 
and previous and concurrent medication may be summarized into the CRF), clinical and office 
charts, laboratory and pharmacy records…etc. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g.: 
there is no other written or electronic record of data) 
All documents will be stored safely in confidential conditions. On all study-specific documents, 

 
 
 
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other than the signed consent, the participant will be referred to by the study participant 
number/code, not by name. 
Direct access to source documents will be granted to DATACLin CRO monitoring team as 
authorized representatives from the sponsor and to regulatory authorities to permit trial-related 
monitoring, audits and inspections. 
7.2. Data Collection 
7.2.1. Data Collection Schedule 
Data to be collected 
Data Collection Schedule 
Visit 1 
(Baseline) 
Visit 2 
(Week 6) 
Visit 3 
(Week 12) 
Visit 4 
(Week 20) 
Visit 5 
(Week 28) 
Visit 6 
(Week 36) 
Informed consent 
x 
 
 
 
 
 
Inclusion/ Exclusion 
x 
 
 
 
 
 
Physical Examination/ 
Vital Signs1 
x 
x 
x 
x 
x 
x 
Demographics 
x 
 
 
 
 
 
Smoking Status 
x 
 
 
 
 
 
Alcohol Consumption 
x 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
Gynecological History 
(FEMALES ONLY) 
x 
 
 
 
 
 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
RA History2 
x 
 
 
 
 
 
Disease Assessment3 
x 
x 
x 
x 
x 
x 
Laboratory Tests4 
x 
x 
x 
x 
x 
x 
Health Assessment 
Questionnaire (HAQ 
Disability Index)5 
x 
x 
x 
x 
x 
x 
Poor Prognostic 
Factors6 
x 
 
 
 
 
 
Adverse Events & 
Serious Adverse Events 
 
x 
x 
x 
x 
x 
Study Completion Form 
 
 
 
 
 
x 
1: Physical Examination/Vitals Signs: Height will be collected in V1 only.  
2: Rheumatoid Arthritis History will include RA Duration, Previous/Current therapies including duration, dose, adverse events/serious adverse 
events experienced during previous treatment and Reason for starting Leflunomide* (previous DMARDs failure, insufficient response, allergy, 
intolerance, side effects) *dose (if the patient received loading dose or not) and Previous X-RAY reports. 
3: Disease Assessment will be done by Clinical Disease Activity Index (CDAI). 
4: Laboratory Tests include CBC, ESR assessed by Westergren method (First hour), C-reactive protein (titer), AST, ALT, Sr Cr, Sr ACPA, Sr RF 
titer, FBG, HBsAg and HCV-Ab. 

 
 
 
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5: Stanford University-Health Assessment Questionnaire (HAQ Disability Index). 
6: Poor prognostic factors: Presence of 1 or more of; Bony erosions by radiograph, High swollen joint count, Extra-articular disease (nodules, 
vasculitis, Felty’s syndrome), Functional limitation (HAQ), High disease activity as measured by composite indices (DAS28, SDAI and/or CDAI), 
High acute phase reactants (CRP and ESR) or High RF and/or anti-CCP. 
 
7.2.2. Data Collection Process 
Data will be collected using NCR CRF according to the below manner; 
At Baseline Visit: 
Data on Informed consent, Inclusion and exclusion criteria, Demographics, Smoking status, 
Alcohol consumption, Medical history, Gynecological History for female patients only, 
Concomitant medications, Laboratory tests and Poor prognostic factors will be collected 
along with RA history. 
Disease assessment (CDAI) and Physical examination will be done and also Vital signs will 
be recorded. 
Patients will fill Health Assessment Questionnaire (HAQ Disability Index) and related data 
will be recorded. 
At Visit 2 (Week 6 ± 2 weeks) & Visit 3 (Week 12 ± 2 weeks) & Visit 4 (Week 20 ± 2 
weeks) & Visit 5 (Week 28 ± 2 weeks): 
Data on Concomitant medications and Laboratory tests will be collected. 
Disease assessment (CDAI) and Physical examination will be done and also Vital signs will 
be recorded. 
Patients will fill Health Assessment Questionnaire (HAQ Disability Index) and related data 
will be recorded. 
Data on Adverse events/Serious adverse events experienced by patient since the previous 
visit will be documented. 
At Visit 6 (Week 36 ± 2 weeks): 
Data on Concomitant medications and Laboratory tests will be collected. 
Disease assessment (CDAI) and Physical examination will be done and also Vital signs will 
be recorded. 
Patients will fill Health Assessment Questionnaire (HAQ Disability Index) and related data 
will be recorded. 

 
 
 
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Data on Adverse events/Serious adverse events experienced by patient since the previous 
visit will be documented. 
Study Completion Form will be also filled. 
Data on Adverse events/Serious adverse events experienced by patient since the previous 
visit will be documented. 
Study Completion Form will be also filled. 
7.3. Conventions (Data Entry) 
Double data entry (interactive verification):Two people independently enter the same data and 
the second entry operator resolves discrepancies between first and second entry while being 
aware of the values entered by the first entry operator. 
Data entry will be done using ClinCapture version 2.1.15.9. 
7.4. Data Validation and Discrepancy Management by the CRO 
The computerized handling of data by DATACLin CRO may generate additional queries 
automatically through pre-programmed and tested validation rules. Validation rules will be 
detailed in the Data validation Plan (DVP). 
In addition to automatic validation rules, manual/ medical review of data may generate further 
queries that will be raised on the system as well. Site staff will be responsible for resolving 
automatic and manual queries by confirming or modifying the data questioned. 
7.5. Clinical Data Coding 
DATACLin CRO will be responsible for coding of safety data using the latest available version of 
MedDRA (Medical Dictionary for Regulatory Activities). 
Collected trade names of drugs (e.g. concomitant medications) will be also coded to the relevant 
generic names. 
8. Statistical Considerations 
8.1. Determination of Sample Size 
The primary objective of CLEAR study is to assess the clinical efficacy of Leflunomide as first line 
therapy and as add-on therapy to other DMARDs (such as Methotrexate, Hydroxychloroquine, 
Sulfasalazine) with or without Steroids as measured by the mean relative change in Clinical 
Disease Activity Index (CDAI) and Health Assessment Questionnaire (HAQ Disability Index) 
among patients with active rheumatoid arthritis. 

 
 
 
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Considering an alpha error of 5% using two-sided 95% CI of Wilcoxon signed-rank test and a 
study power of 80%, a sample of 332 patients will be required to detect an effect size of 0.158 
between baseline and study endpoint, plus an expected drop-out rate of 20% during the 9 
months observational study duration. Thus, a sample of 398 patients will be appropriate that 
rounded to 400 patients. 
8.2. Randomization 
Not Applicable. 
8.3. Analysis Population 
The obtained clinical data will be analyzed on an intention-to-treat basis. Primary analysis will be 
done by intention-to-treat including all eligible enrolled patients with at least one treatment dose 
and post first assessment score (CDAI and HAQ ) attending any post treatment visit and efficacy 
variables will be analyzed using the last-observation-carried-forward convention (LOCF). 
8.4. Study Endpoints 
8.4.1. Primary Endpoints 
- 
To assess disease severity (Remission, Low Activity, Moderate Activity and High activity) and the 
mean relative change in Clinical Disease Activity Index (CDAI) among patients with active 
rheumatoid arthritis treated with Leflunomide as first line therapy and as add-on therapy to other 
DMARDs (such as Methotrexate, Hydroxychloroquine, Sulfasalazine) with or without Steroids 
between baseline and week 36. 
- 
To assess the mean relative change in Health Assessment Questionnaire Score (HAQ 
Disability Index) among patients with active rheumatoid arthritis treated with Leflunomide as first 
line therapy and as add-on therapy to other DMARDs (such as Methotrexate, Hydroxychloroquine, 
Sulfasalazine) with or without Steroids between baseline and week 36. 
8.4.2. Secondary Endpoints 
- 
Qualitative and quantitative descriptive analysis with (95% confidence intervals) for the 
below variable : 
o Demographics 
o Medical History 
o RA severity 
o RA duration 
o Line of therapy 
o Daily dose 
o Treatment duration 
o Reason for treatment adjustment 

 
 
 
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o Previous therapies 
8.4.3. Safety Endpoints 
- 
To assess the frequency of AEs/SAEs among patients using Leflunomide as first line therapy and 
as add-on therapy to other DMARDs (such as Methotrexate, Hydroxychloroquine, Sulfasalazine) 
with or without Steroids and its relation to study medication. 
8.5. Endpoints Variables 
8.5.1. Efficacy Variables 
 Clinical Disease Activity index (CDAI) in baseline and at week 36 to measure disease severity 
and relative mean change between study endpoints. 
 Health assessment questionnaire (HAQ Disability Index) in baseline  and at week 36 to 
measure relative mean change between study endpoints. 
8.5.2. Safety Variables 
 AE/SAE form to assess frequency of AEs/SAEs among patients. 
8.6. Other Covariate/Control Variables 
 
Management patterns and patients characteristics as described parameters below: 
 Demographics 
 Medical History 
 RA severity 
 RA duration 
 Line of therapy 
 Daily dose 
 Treatment duration 
 Reason for treatment adjustment 
 Previous therapies 
8.7. Statistical Analysis Methods 
8.7.1. Descriptive Analysis 
o Percent (%) distribution for all categorical variables and mean with (SD) and median 
(Minimum: Maximum) for continuous variables according their distribution. 
8.7.2. Comparative Analysis 
o Student t-test and One Way ANOVA to estimate the comparison between the treatment 

 
 
 
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arms for the numerical variables (according to their distribution; non-parametric substitution 
tests could be used). 
o Paired t-test and repeated measure ANOVA test to estimate the change in numerical 
variables throughout the study visits (according to their distribution; non-parametric 
substitution tests could be used). 
o Chi2 test (or Fisher’s Exact test) for unpaired and McNemar’s test for paired categorical 
variables. 
- 
All tests will be performed on the 5% level of significance. 
- 
Any deviation(s) from the original statistical plan will be described in the final report. 
8.7.3. Interim Analysis 
- 
When approximately the enrolled patients completed 50% of their visits (after Visit 3), an interim 
analysis for safety and efficacy will be conducted by an independent data monitoring committee. 
Serious adverse events will be monitored by the committee on an ongoing basis throughout the 
study. 
8.8. Handling of Missing Values 
- 
Procedure for accounting for missing, unused, and spurious data will be explained in the statistical 
analysis plan (SAP). 
9. Treatment 
9.1. Product 
Each Arthfree 20 mg contains: 
Active ingredient: Leflunomide 20 mg 
Inactive ingredients: Microcrystalline cellulose, Lactose monohydrate, Maize starch, Anhydrous 
colloidal silica, Polyvinylpyrrolidone, Croscarmellose sodium, Magnesium stearate. 
Each Arthfree 100 mg contains: 
Active ingredient: Leflunomide 100 mg 
Inactive ingredients: Microcrystalline cellulose, Lactose monohydrate, Maize starch, Anhydrous 
colloidal silica, Polyvinylpyrrolidone, Croscarmellose sodium, Magnesium stearate. 
Patients will be prescribed Arthfree (Leflunomide) at the sole decision of the treating physician. 
9.2. Mode of Administration 
Arthfree (Leflunomide 20mg) 

 
 
 
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Dose: 1 tablet once daily, should be swallowed whole with sufficient amounts of liquids. The 
extent of Leflunomide absorption is not affected if taken with meals. Doses higher than 20 mg/day 
are not recommended. Improvement in the rheumatoid condition usually starts after 4 to 6 weeks 
and may further improve up to 4 to 6 months. 
Loading dose: a tablet of Leflunomide 100 mg for three days. should be swallowed whole with 
sufficient amounts of liquids. The extent of Leflunomide absorption is not affected if taken with 
meals. 
Due to the long half-life in patients with rheumatoid arthritis and recommended dosing interval (24 
hours), a loading dose is needed to provide steady-state concentrations more rapidly. 
10. Pharmacovigilance 
For Safety Reference; this study will be conducted consistent with The International Conference on 
Harmonization Guideline E2A and 21 CFR Part 312 and WHO Guidelines. 
Safety assessments will consist of monitoring and recording adverse events; including serious and 
non-serious adverse events, measurement of protocol-specified safety laboratory assessments, 
measurement of Protocol-Specified Vital Signs and other Protocol-Specified Measures that are 
deemed critical to the safety evaluation of the study. 
10.1. 
Definitions 
10.1.1. Adverse Events 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
associated with the use of a product or a medical device; the event does not necessarily 
need to have a causal relationship with the treatment or usage. 
Examples of Adverse Events include but are not limited to: 
 
Abnormal lab test findings of clinical concerns 
 
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 
10.1.2. Adverse Event of Special Interest 
An Adverse Event of Special Interest (AESI) is an AE (Serious or Non-Serious) of scientific 
and medical concern specific to the Sponsor’s Product Or Program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor may be appropriate. 
Such events may require further investigation in order to characterize and understand them. 
AESIs may be added or removed during a study by Protocol Amendment. 
In this study, No Adverse Event of Special Interest will be collected. 
10.1.3. Serious Adverse Events 
A serious adverse event or serious adverse drug reaction is any untoward medical 
occurrence at any dose that: 
 
Results In Death 
 
Is Life-Threatening (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. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
10.1.4. Adverse Reaction (Adverse Drug Reaction) 
An adverse reaction means any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. This would include all noxious and unintended responses to the MP related to any 
dose. 
10.1.5. Suspected Adverse Reaction 

 
 
 
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Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the drug caused the AE. A suspected adverse reaction implies a judgment by the clinical 
investigator or study sponsor that there is a reasonable possibility that the AE has a causal 
relationship with the Investigational Product, though with a lesser degree of certainty about 
causality, compared to the use of the term “adverse reaction” (or “adverse drug reaction”) as 
defined above 
For the purposes of U.S. IND safety reporting, the meaning of ‘Reasonable Possibility’ is 
clarified in FDA’s recent changes to CFR 312 by the following examples of types of 
evidence that would suggest a causal relationship between the drug and the AE, such as: 
 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema) 
 
One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture) 
 
An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
10.1.6. Unexpected Adverse Drug Reaction 
An AE or suspected adverse reaction is considered “Unexpected” if it is not listed in the 
Approved Product Label (for regulatory-approved, commercially available products) or in the 
investigator brochure, or is not listed at the specificity or severity that has been observed in 
a serious adverse event at hand; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational plan or 
elsewhere in the available information about the MP. "Unexpected," as used in this context, 
also refers to AEs or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with the given class of drugs or may be anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular MP under investigation. 
10.1.7. Abnormal Test Findings 
Treatment-emergent laboratory test abnormalities considered to be of clinical concern 
should be recorded as AEs in the CRF 
The criteria for determining whether an abnormal objective test finding should be reported 
as an adverse event are as follows: 
1. Test result is associated with accompanying symptoms, and/or 
2. Test result requires additional diagnostic testing or medical/surgical intervention, and/or 

 
 
 
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3. Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or 
4. Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. 
Any abnormal test result that is determined to be an error does not require reporting as an 
adverse event. 
10.1.8. Hospitalization 
Adverse events reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital 
to an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical 
floor to a coronary care unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
 
Rehabilitation facilities 
 
Hospice facilities 
 
Respite care (e.g., caregiver relief) 
 
Skilled nursing facilities 
 
Nursing homes 
 
Routine emergency room admissions 
 
Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event. Examples include: 
 
Admission for treatment of a preexisting condition not associated with the development of a 
new adverse event or with a worsening of the preexisting condition (e.g., for work-up of 
persistent pre-treatment lab abnormality) 
 
Social admission (e.g., subject has no place to sleep) 
 
Administrative admission (e.g., for yearly physical exam) 
 
Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol) 
 
Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery) 
 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 

 
 
 
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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as adverse events. However, the medical condition for which the procedure 
was performed should be reported if it meets the definition of an adverse event. For 
example, an acute appendicitis that begins during the adverse event reporting period should 
be reported as the adverse event, and the resulting appendectomy should be recorded as 
treatment of the adverse event. 
10.2. 
Adverse Events Monitoring 
All AEs regardless of seriousness or relationship to Medicinal Product (MP), 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 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. 
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 MP, 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 MP, 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 MP. 
10.3. 
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 procedures and/or 
receiving MP, 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 MP is SUSPECTED. 
10.4. 
Severity Assessment 

 
 
 
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The severity of each AE and laboratory abnormality is to be assessed by the investigator 
according to following criteria 
 
Mild (Grade 1): AE or laboratory abnormality that is transient or is easily tolerated on continuation 
of study drug. 
 
Moderate (Grade 2): AE or laboratory abnormality that causes the patient discomfort and causes 
interference with the patient's usual activities. 
 
Severe (Grade 3): AE or laboratory abnormality that is incapacitating and causes considerable 
interference with the patient's usual daily activities, and/or may be life-threatening if it worsens. 
 
Life-Threatening (Grade 4): The AE or laboratory abnormality is life threatening as it exists (i.e., 
no worsening is required for the abnormality to be life-threatening). 
 
Death Related AE (Grade 5) 
Note the distinction between the severity and the seriousness of an adverse event. A severe 
event is not necessarily a serious event. For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met at 
ease one of the 6 seriousness criteria. 
10.5. 
Causality Assessment 
The investigator’s assessment of causality must be provided for all adverse events (Serious and 
Non-Serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements if 
applicable. An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that MP caused or contributed to an adverse event. If the investigator's 
causality assessment is "unknown but not related to MP", this should be clearly documented on 
study records. 
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable. 
10.5.1. WHO-UMC Causality Categories 
Causality 
Term 
Assessment Criteria 

 
 
 
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Causality 
Term 
Assessment Criteria 
Certain 
 
Event or laboratory test abnormality, with plausible time 
relationship to drug intake 
 
Cannot be explained by disease or other drugs 
 
Response to withdrawal plausible (pharmacologically, 
pathologically) 
 
Event definitive pharmacologically or phenomenologically (i.e. 
an objective and specific medical disorder or a recognized 
pharmacological phenomenon) 
 
Rechallenge satisfactory, if necessary 
Probable / 
Likely 
 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
 
Unlikely to be attributed to disease or other drugs 
 
Response to withdrawal clinically reasonable 
 
Rechallenge not required 
Possible 
 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
 
Could also be explained by disease or other drugs 
 
Information on drug withdrawal may be lacking or unclear 
Unlikely 
 
Event or laboratory test abnormality, with a time to drug intake 
that makes a relationship improbable (but not impossible) 
 
Disease or other drugs provide plausible explanations 
Conditional/Unc
lassified 
 
Event or laboratory test abnormality 
 
More data for proper assessment needed, or 
 
Additional data under examination 
Unassessable/
Unclassified 
 
Report suggesting an adverse reaction 
 
Cannot be judged because information is insufficient or 
contradictory 
 
Data cannot be supplemented or verified 
 
10.6. 
Exposure During Pregnancy 
For Investigational Products and for Marketed Products, an exposure during pregnancy (also 
referred to as Exposure In-Utero [EIU]) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been directly 
exposed to the Investigational Product(e.g., environmental exposure), or the female becomes, or 
is found to be, pregnant after discontinuing and/or being directly exposed to the Investigational 
Product (maternal exposure). 

 
 
 
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2. A male has been exposed, either due to treatment or environmental, to the Investigational 
Products prior to or around the time of conception and/or is exposed during his partner’s 
pregnancy (paternal exposure). 
If any study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the Medicinal Product, the investigator must submit this information 
to the Sponsor. 
This must be done irrespective of whether an adverse event has occurred and within 24 hours of 
awareness of the pregnancy.  
The information submitted should include the anticipated date of delivery. 
Follow-up is conducted to obtain pregnancy outcome information on all Exposure during 
pregnancy reports with an unknown outcome. The investigator will follow the pregnancy until 
completion or until pregnancy termination (i.e., induced abortion) and then notify the Sponsor of 
the outcome. The investigator will provide this information as a follow up to the initial Exposure in 
Utero Pregnant Form. The reason(s) for an induced abortion should be specified.  
An EIU report is NOT created when an ectopic pregnancy report is received since this pregnancy 
is not usually viable. Rather, a serious adverse event case is created with the event of ectopic 
pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[Including that in an aborted fetus, stillbirth or neonatal death]), the investigator should follow the 
procedures for reporting serious adverse events. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth (i.e., 
no minimum follow-up period of a presumably normal infant is required before an Exposure in 
Utero Pregnant Form can be completed).  
The “normality” of an aborted fetus can be assessed by gross visual inspection, unless pre-
abortion test findings are suggestive of a congenital anomaly. 
Additional information about pregnancy outcomes that are classified as serious adverse events 
follows: 
1. Spontaneous abortion; includes miscarriage and missed abortion. 
2. All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as serious adverse events. In addition, any infant death after 1 month that the 
investigator assesses as possibly related to the exposure during pregnancy to the investigational 
medication should be reported. 

 
 
 
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Additional information regarding the exposure during pregnancy may be requested by the 
investigator. Further follow-up of birth outcomes will be handled on a case-by-case basis (e.g. 
follow-up on preterm infants to identify developmental delays).  
10.7. 
Withdrawal Due to Adverse Events 
Withdrawal due to adverse event should be distinguished from withdrawal due to Insufficient 
Response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate Adverse Event CRF Page. 
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below. 
10.8. 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting adverse 
event information at all patient evaluation time points. 
Examples of non-directive questions include the following: 
 
"How have you felt since your last clinic visit?" 
 
"Have you had any new or changed health problems since you were last here?" 
10.9. 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse events on 
the Adverse Event CRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event Form. 
10.10. 
Reporting Requirements 
10.10.1. General Instructions 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event Form in CRF. 
After prescription of MP, all adverse events, regardless of relationship to study drug, will 
be reported.  
Each adverse event is to be assessed to determine if it meets the criteria for serious 
adverse events. If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate. 

 
 
 
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10.10.2. Reporting of Serious Adverse Event 
If a serious adverse event occurs, Sponsor or its representative is to be notified within 24 
HOURS OF AWARENESS OF THE EVENT by the investigator or delegate on behalf. In 
particular, if the serious adverse event is fatal or life-threatening, notification to Sponsor or 
its representative must be made IMMEDIATELY, irrespective of the extent of available 
adverse event information.  
This timeframe also applies to additional new information (Follow-Up) on previously 
forwarded serious adverse event reports as well as to the initial and follow-up reporting of 
Exposure during pregnancy cases. 
In the rare event that the investigator does not become aware of the occurrence of a 
serious adverse event immediately (e.g., if an outpatient study subject initially seeks 
treatment elsewhere), the investigator is to report the event within 24 hours after being 
aware of it and document the time of his/her first awareness of the adverse event. 
For all serious adverse events, the investigator is obligated to pursue and provide 
information to Sponsor or its representative in accordance with the timeframes for 
reporting specified above. In addition, an investigator may be requested by Sponsor or its 
representative to obtain specific additional follow-up information in an expedited fashion.  
In general, this information will include a description of the adverse event in sufficient 
detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, 
such as concomitant medications and illnesses must be provided. In the case of a subject 
death, a summary of available autopsy findings must be submitted as soon as possible to 
Sponsor or its representative or its designated representative. 
10.10.3. Reporting of Non-Serious Adverse Event 
All Non-Serious Adverse Events will be documented on the Adverse Event Page(s) of the 
CRF and reported properly to the local regulatory authority.  
10.11. 
Instructions for Reporting SAEs for Study Team 
In the case of occurrence of a SAE, the Investigator must immediately: 
1. 
SEND 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 
Study Protocol 
2. 
ATTACH a 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 

 
 
 
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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. 
If the CRA is Not Available, Please Contact: 
Name 
Mina Saeed 
Title 
Pharmacovigilance Manager 
Mobile 
(+2) 01022242873 
E-mail 
mina.saeed@dataclin.com 
Tel 
(+202) 3761-7301/2 
Fax 
(+202) 3345 0061 
And Sponsor’s Representative: 
Name 
Mina Maxy 
Title 
Medical advisor/Deputy QPPV 
Mobile 
(+2) 01110014883 
E-mail 
mina.maxy@evapharma.com 
Tel 
Tel: (+202) 239 92700   
Fax 
Fax: (+202) 239 92782 
 
10.12. 
Sponsor Reporting Requirements to Regulatory Authorities 
During the course of the study, the Sponsor will report All Adverse Events to the Local 
Health Authorities, in accordance with the Local Timeframes for Reporting. 
10.13. 
Breaking Randomization Code 
Not Applicable.  

 
 
 
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11. Ethical and Regulatory Standards 
11.1. 
Ethical principles 
This study will be conducted in accordance with the 18th World Medical Assembly 
(Helsinki, 1964) and all subsequent amendments and ICH guidelines for Good Clinical 
Practice (ICH-E6). Study team will ensure all necessary regulatory submissions (e.g.: 
IRB/IEC) are performed in accordance with local regulations including local data protection 
regulations. 
11.2. 
Laws and Regulations 
This Clinical Trial will be conducted in compliance with all applicable international laws and 
regulations, and national laws and regulations of Egypt in which the Clinical Trial is 
performed, as well as any applicable guidelines. 
11.3. 
Data Informed 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/favorable 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 
must 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. 
11.4. 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
The Investigator or the Sponsor must submit this Clinical Trial Protocol to the appropriate 
Ethics Committee (IRB/IEC).Written dated approval/favorable opinion signed by the 
Chairman with Ethics Committee (IRB/IEC) composition must be obtained. 
Investigational Product will not be released at the study site and the Clinical Trial will not 
start until a copy of this written and dated approval/favorable opinion has been received by 
the Sponsor. 

 
 
 
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During the Clinical Trial, any amendment or modification to the Clinical Trial Protocol 
should be submitted to the Ethics Committee (IRB/IEC). It should also be informed of any 
event likely to affect the safety of patients or the continued conduct of the Clinical Trial, in 
particular any change in safety. 
If requested, a summary of the Clinical Trial’s outcome at the end of the Clinical Trial is 
sent to the Ethics Committee (IRB/IEC). 
11.5. 
Discontinuation / Withdrawal of participants from study 
Each participant has the right to withdraw from the study at any time. In addition, the 
investigator may discontinue a participant from the study at any time if the investigator 
considers it necessary for any reason including:  
1. Ineligibility (either arising during the study or retrospective having been overlooked at 
screening) 
2. Significant protocol deviation  
3. Significant non-compliance with treatment regimen or study requirements  
4. Disease progression which requires discontinuation of the study medication or results in 
inability to continue to comply with study procedures. 
5. Consent withdrawn. 
6. Lost to follow up  
The reason for withdrawal will be recorded in the CRF. 
If the participant is withdrawn due to an adverse event, the investigator will arrange for 
follow-up visits or telephone calls until the adverse event has resolved or stabilized. 
Patients who withdraw from the study will not be replaced. 
12. Quality Control and Quality Assurance 
12.1. 
Quality Control 
12.1.1. In Process Quality Control of Biometrics 
As per DataClin CRO SOPs, quality control by an independent qualified reviewer is 
performed on all biometrics related documents developed internally. This includes study 
protocol, case report form, informed consent form and study plans. In addition to these 
documents, database QC is performed automatically (programmed edit checks) and 
manually (manual review of line listings) to ensure that data is complete and consistent. 
12.1.2. Monitoring and Site Data Quality Control 

 
 
 
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Study monitors will perform ongoing source data verification to confirm that critical protocol 
data collected into the CRFs by authorized site personnel are accurate, complete, and 
verifiable from source documents. 
100 % Source Data Verification (SDV) will be performed only for All Signed Informed 
Consents and Critical Variables which will be described in a “Critical Variables List” that 
will be ready before sites monitoring 
If specific issues are identified in a certain site, the percentage of Quality Control in the 
concerned site and/or in all sites must be appropriately increased and corrective actions 
must be set up. 
12.2. 
Quality Assurance 
All study procedures will be subject to pre-planned internal audit(s) by DataClin CRO 
quality assurance team. This covers biometrics phases, clinical operations and overall 
project management. 
13. Responsible Parties 
13.1. 
Responsibilities of Investigators 
The Investigator is responsible to strictly follow the study protocol and all applicable 
regulations and guidelines.  
Investigator’s responsibilities include recording precise and accurate data pertinent to the 
study in the CRF in addition to obtaining written informed consents from patients prior to 
inclusion in the study. 
The investigator will be responsible for taking all appropriate measures to ensure patient’s 
safety all over the study duration. 
Study documents will be appropriately retained until the end of the study. In addition the 
Investigator should comply with local regulations with regards to record retention. 
It is recommended that the Investigator retains the study documents at least five years 
after the completion or discontinuation of the study. 
The Investigator agrees to allow and help with the performance of sponsor auditors/ 
regulatory authorities’ inspectors to have direct access to study records, all necessary 
data, documents and facilities. Once the investigator is notified of an inspection, he shall 
inform the sponsor and authorize sponsor to participate in this inspection. The 
confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. The investigator will make sure that any results and information 
resulting from the inspections will be immediately communicated to sponsor. It will be the 

 
 
 
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investigator’s responsibility to take corrective actions for any issues raised during the 
audits or inspections. 
Names and responsibilities of coordinating investigator(s) and the other participating 
investigators will be documented prior to the start of the trial. All investigators will be given 
instructions on following the protocol, complying with a uniform set of standards for the 
assessment of clinical and laboratory findings, and completing the CRFs. Communication 
between investigators should be facilitated. 
13.2. 
Responsibilities of Sponsor 
The sponsor will be responsible for providing adequate resources to ensure the proper 
conduct of the study according to study protocol and all applicable laws and regulations. 
The sponsor will delegate a CRO to conduct the study. 
Sponsor/ delegated CRO is responsible for all regulatory submission(s). In addition, 
sponsor/ delegated CRO will contract insurance for all participating patients during study 
participation. 
Delegated CRO will be responsible for ongoing reporting of adverse events and serious 
adverse events to local regulatory authorities. 
14. Administrative Expectations 
14.1. 
Record Retention and Archiving of Study Documents 
The Investigator shall arrange for the retention of study documentation until the end of the 
study. In addition the Investigator will comply with specific local regulations/ 
recommendations with regards to patient record retention  
It is recommended that the Investigator retains the study documents at least five years (5) 
after the completion or discontinuation of the study, unless otherwise specified in the 
Investigator Agreement in line with additional standards and/or local laws. 
However, applicable regulatory requirements should be taken into account in the event 
that a longer period is required. 
14.2. 
Confidentiality and Protection of Study Data 
All study related material, information and unpublished documents provided to the 
investigator are the exclusive property of sponsor. 
These materials or information cannot be disclosed by any person to unauthorized 
persons without the prior formal written approval from sponsor. 

 
 
 
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The Investigator will consider all received information or resulted data as confidential and 
will take all necessary steps to ensure that there is no break of confidentiality, other than 
for information to be disclosed by law. 
Patient's personal data (name, phone number, address …etc) shall be kept confidential all 
over the study participation period and after study completion as well. 
Upon archiving or processing patients’ personal data, sponsor shall take all appropriate 
measures to prevent access to this data by any unauthorized third party. 
14.3. 
Insurance 
The Sponsor may contract Insurance according to Local Regulatory Requirements.  
14.4. 
Sponsor Audits and Inspections by Regulatory Agencies 
The Investigator agrees to allow sponsor auditors/Competent Authorities inspectors to 
have direct access to his/her study records for review, being understood that these 
personnel are bound by professional secrecy, and as such will not disclose any personal 
identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a future inspection by the authorities, he will 
inform the sponsor and authorize sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be 
respected during these inspections. 
Any result and information arising from the inspections by the competent authorities will be 
immediately communicated by the Investigator to sponsor. 
The Investigator shall take appropriate measures required by sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.5. 
Premature Discontinuation of The Study/Premature Close-out of a Site 
Sponsor can decide at any time and for any reason to prematurely stop or to interrupt the 
study; the decision will be communicated in writing to the Investigator. 
Similarly, should the Investigator decide to withdraw from the study, she/he will have to 
immediately inform sponsor in writing. 
If appropriate, according to local regulations, Ethic Committee(s) (IRB/IEC) and 
Competent Authorities should be informed. 

 
 
 
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14.6. 
Ownership and Use of Study Data 
No use of the data will be possible without the authorization of sponsor conducting the 
study. 
15. Amendments and Updates 
Any change to the protocol will be recorded in a written amendment, which will be signed by the 
Investigator.  
Amendment to the protocol may require regulatory submissions (e.g.: IRB/IEC) in accordance with 
local regulations.  
In some cases, an amendment may require a change to the written subject information/informed 
consent form.  
16. Milestones 
- 
Protocol planned date: June 2017 
- 
First patient In (FPI): September 2017 
- 
Last patient In (LPI): December 2017 
- 
Last patient Out (LPO): September 2018 
- 
Estimated enrollment duration: 3 months 
- 
Estimate treatment duration: 9 months 
- 
Database lock planned date: September 2018 
- 
Estimated Report date: November 2018 
17. Appendices 
Stanford HAQ 
20-Item Disability Scal 
2015 American 
College of Rheumatolo 
EULAR 
recommendations for  
18. Publications 
All study investigators give full authority to the sponsor for primary publication of results. No other 
publication is allowed before the primary publication. Any subsequent publications by a study 
participant must be approved by the sponsor and make reference to the study and the primary 

 
 
 
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publication. Sponsor may request that his name and/or names of one or several of its employees 
appear or do not appear in such publications. 
19. References 
                                                          
 
1 https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html  
2 http://www.who.int/chp/topics/rheumatic/en/ 
3 Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis 
and other rheumatic conditions in the United States: part I. Arthritis Rheum 2008;58:15–25. 
4 Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care 
2012;18:S295-302. 
5 Murray C, Ezzati M, Flaxman A, et al. GBD 2010: a multi-investigator collaboration for global comparative descriptive 
epidemiology. Lancet 2012;380:2055–8.) 
6 Dowman, Ben et al. "Estimating The Burden Of Rheumatoid Arthritis In Africa: A Systematic Analysis". Journal of 
Global Health 2.2 (2012) 
7  Singh, Jasvinder A. et al. "2015 American College Of Rheumatology Guideline For The Treatment Of Rheumatoid 
Arthritis". Arthritis Care & Research 68.1 (2015) 
8  Smolen, Josef S et al. "EULAR Recommendations For The Management Of Rheumatoid Arthritis With Synthetic And 
Biological Disease-Modifying Antirheumatic Drugs: 2016 Update" 
9  Jones, Peter. "Reappraisal Of The Clinical Use Of Leflunomide In Rheumatoid Arthritis And Psoriatic Arthritis". Open 
Access Rheumatology: Research and Reviews (2010) 
10  Emery, P. "A Comparison Of The Efficacy And Safety Of Leflunomide And Methotrexate For The Treatment Of 
Rheumatoid Arthritis". Rheumatology 39.6 (2000): 655-665. 
11  Fox, Robert, and Simon Helfgott. "Leflunomide In The Treatment Of Rheumatoid Arthritis And Other Autoimmune 
Disorders". APLAR Journal of Rheumatology 7.1 (2004): 71-78. 
12  (Abdel-Tawab RR, Abdel-Nasser AM, Darmawan J, et al. The prevalence of rheumatic diseases in rural egypt: 
COPCORD-Egypt: Abstract, 11th APLAR Congress, Jeju, Korea, 2004.)