A Phase II, Randomized, Double Blind, Placebo-Controlled Clinical Trial to Investigate the Anti-oxidant Activity of Heptex in Patients With Apparent Risk Factors of Nonalcoholic Steatohepatitis (NASH)
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Sponsor: Natural Wellness Egypt

 
 
 
 
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CLINICAL STUDY PROTOCOL 
A Phase II, Randomized, Double Blind, Placebo-Controlled Clinical 
Trial to Investigate the Anti-oxidant Activity of Heptex in Patients 
with Apparent Risk Factors of  Nonalcoholic Steatohepatitis (NASH) 
 
 
 
STUDY NUMBER: NW_PHYLLANTEX_17052018 
 
STUDY NAME: PHYLLANTEX 
 
 
 
 
Version 
Number: 
Final V1.1 
Date: 
30-Dec-2019 
 
 
All information included in this protocol is confidential and is the exclusive property of Natural Wellness Egypt. This 
information must not be disclosed to any unauthorized party without the prior written consent of Natural Wellness 
Egypt. The use of included confidential information is only permitted to those who received the protocol for the 
agreed upon purpose. 

 
 
 
 
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NAMES AND ADDRESSES OF 
SPONSOR 
Name: Natural Wellness Egypt Scientific Office  
Address: 21 Nagati Serag St. From Ibrahim El Rafey 
Nasr City, Cairo, Egypt 
Tel:(+202) 22720135 
Fax:(+202) 22739899 
 
 
SPONSOR’S REPRESENTATIVE 
Name: Dr. Reem Alaa/ Clinical Research Associate 
Address: 21 Nagati Serag St. From Ibrahim El Rafey 
Nasr City, Cairo, Egypt 
Mobile: (+2) 01202728990 
Telephone: (+202) 22720135 
Email: research.associate2@mynaturalwellness.com 
 
 
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 Operations Manager 
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 
PROTOCOL SYNOPSIS 
Title 
A Phase II, Randomized, Double Blind, Placebo-Controlled Clinical Trial to 
Investigate the Anti-oxidant Activity of Heptex in Patients with Apparent Risk 
Factors of Nonalcoholic Steatohepatitis (NASH) 
Study Number 
NW_PHYLLANTEX_17052018 
Study Sponsor 
Natural Wellness Egypt 
Product Name 
Heptex 
Study Drug 
Dukung Anak 200 mg + Milk Thistle 100 mg 
Dukung Anak is a Powdered Extract from Aerial Parts of Phyllanthus niruri, 
Milk Thistle is a Powdered Extract from Fruits of Silybum marianum. 
Indication 
Anti-oxidant (Liver support) 
Trial Location(s) 
 
Tropical Medicine Department, Faculty of Medicine, Ain Shams 
University, Abbasiya, Cairo, Egypt. 
 
Tropical Medicine Department, Faculty of Medicine, Helwan University, 
Helwan, Egypt. 
 
National 
Hepatology 
and 
Tropical 
Medicine 
Research 
Institute 
(NHTMRI), Fom Al Khalig Sq, El-Sayeda Zainab, Giza, Egypt. 
Principal Investigator 
Name: Prof. Dr. Mohamed Kamal Shaker  
Affiliate Address: Tropical Medicine Department, Faculty of Medicine, Ain 
Shams University, Abbasiya, Cairo, Egypt. 
Mobile: (+2) 01001888364 

 
 
 
 
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Name: Prof. Dr. Mohamed El-Kassass 
Affiliate Address: Tropical Medicine Department, Faculty of Medicine, Helwan 
University, Helwan, Egypt. 
Mobile: (+2) 01114455552 
Name: Dr. Mohamed Hassany Barbary 
Affiliate Address: National Hepatology and Tropical Medicine Research 
Institute (NHTMRI), Fom Al Khalig Sq, El-Sayeda Zainab, Giza, Egypt. 
Mobile: (+2) 01128500015 
Sponsor’s Medical Expert 
Name: Dr. Tarek Nassar 
Address: 21 Nagati Serag St. From Ibrahim El Refaey,  
Nasr City, Cairo, Egypt 
Mobile: (+2) 01004616605 
Telephone: (+202) 22720135 
Email:tarek.nassar@mynaturalwellness.com 
Central Laboratory 
Al-Mokhtabar 
Main branch address is: 64 Gamaet EI Dewal EI Arabya, Mohandessin, Giza, 
Egypt. 
Medical and/or technical 
department(s) for 
Fibroscan and Ultrasound  
For FibroScan: 
 
Tropical Medicine Department, Ain Shams University Specialized 
Hospital, Khalifa El-Maamon st, Abbasiya sq., Cairo, Egypt. 
 
Tropical Medicine Department at NHTMRI, Fom Al Khalig Sq, El-Sayeda 
Zainab, Giza, Egypt. 
 
Air Force Specialized Hospital, New Cairo, Cairo, Egypt. 
 

 
 
 
 
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For Ultrasound: 
 
Tropical Medicine Department, Ain Shams Hospital, Khalifa El-Maamon 
st, Abbasiya sq., Cairo, Egypt. 
 
Tropical Medicine Department at NHTMRI, Fom Al Khalig Sq, El-Sayeda 
Zainab, Giza, Egypt. 
 
Air Force Specialized Hospital, New Cairo, Cairo, Egypt. 
Study Objective(s) 
 
Primary Objectives: 
 
To explore the anti-oxidant activity of Heptex as assessed by improvement 
in serum aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) levels in patients with apparent risk factors of NASH. 
Secondary Objectives: 
 
To explore the optimum dose that is safe in patients with apparent risk 
factors of NASH giving the most significant effect among two different 
doses of Heptex. 
 
To explore the hepatoprotective effect of Heptex as assessed by the change 
in Fibrosis score. 
 
To explore the hepatoprotective effect of Heptex as assessed by the 
occurrence of hepatic complications. 
Exploratory Objectives: 
 
To explore the lipid-lowering effect of Heptex as assessed by the change in 
lipid profile. 
Study Design 
This is a phase II, randomized, double blind placebo-controlled, three-arm, 
parallel-group, interventional clinical trial evaluating anti-oxidant activity of 
Heptex; a herbal medicinal product of Aerial Parts of Phyllanthus niruri 
(Dukung Anak) and Fruits of Silybum marianum (Milk Thistle) in patients with 
apparent risk factors of NASH. 

 
 
 
 
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Study duration: 12 weeks of recruitment and 36 weeks of treatment. This period 
will include 2 washout periods (at Week 13 & Week 25)1. 
Sample Size: 47 subjects per arm, 141 in total. 
Participants in trial will be patients between 18 and 65 years consenting to 
participate in this study, who have elevated liver enzymes34, controlled 
attenuation parameter (CAP)-confirmed hepatic steatosis, and Fib score of F1 
and F2 assessed by the FibroScan liver stiffness measurement.  
FibroScan will be done for all patients at screening visit and those with F1 and 
F2 will be considered for inclusion in the study. FibroScan will be repeated for 
all patients after 6 months and at the end of treatment duration and results will 
be compared. 
Screening of patients will be continued for about 12 weeks. Eligible patients 
will be randomized in a 1:1:1 allocation ratio, into one of the three treatment 
groups, to receive either placebo or one of the two doses of Heptex.  
Randomization will be done using interactive response technology. 
Main Selection Criteria 
Inclusion Criteria: 
1) Male or female aged between 18 and 65 years. 
2) Both male and female patients who have childbearing potential must 
agree to practice an acceptable method of birth control during the study 
and for at least 6 months after the cessation of treatment; such 
contraceptive methods must include at least one barrier method. 
3) Controlled Attenuation Parameter (CAP)-confirmed hepatic steatosis. 
                                                          
1 According to ICH M3 R2 (ICH Harmonised Tripartite Guideline. 2009. Guidance on nonclinical safety 
studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. Dated 11 June 
2009, Accessed at: http://www.ich.org/). Despite the long-term tolerability of the marketed product, the 
conducted repeated dose studies will be related to the proposed duration of the clinical trial by adding suitable 
washout periods throughout the clinical study duration. 

 
 
 
 
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4) Patients with elevated liver enzymes (alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST)) 34. 
5) Liver fibrosis stage F1-F2 as diagnosed by the FibroScan liver stiffness 
measurement of 5-10 kPa.  
6) Liver condition according the following criteria; 
o 
Serum albumin > 3 g/dl 
o 
INR < 2 
o 
No ascites on ultrasound 
o 
No documented or suspected hepatic encephalopathy  
7) Willing to stop any other liver support and hepatoprotective 
medications throughout study duration. 
8) Able and willing to provide written informed consent. 
9) Able and willing to complete all study visits and procedures, including 
compliance with the requirements and restrictions listed in the consent 
form.   
Exclusion Criteria: 
1) Pregnant or lactating women. 
2) Patients with BMI > 40 Kg/m2 or BMI < 18.5 Kg/m2. 
3) Serum creatinine > 1.5 x ULN OR creatinine clearance (GFR) < 60 
mL/minute. 
4) Platelet count < 75,000/mm3. 
5) Uncontrolled diabetes mellitus as evident by HbA1c ≥ 8.5%. 
6) Patients who are currently receiving Thiazolidinediones. 
7) Patients with ischemic heart disease (IHD). 
8) History of parenteral nutrition. 
9) History of liver transplant. 

 
 
 
 
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10) Viral hepatitis, drug-induced liver injury, metabolic liver disease or 
auto-immune liver disease. 
11) Liver cancer or serum alpha-fetoprotein (AFP) >100ng/ml. Patients 
with an AFP between 50 and 100ng/ml may be included as long as a 
liver ultrasound within 3 months of screening, or at screening, shows 
no evidence of potential hepatocellular cancer.  
12) Use of drugs known to induce steatosis (valproate, amiodarone or 
prednisone) or to affect body weight and carbohydrate metabolism. 
13) Use of drugs known to alter liver enzymes. 
14) Allergy or allergic history to any of the drug components. 
15) History of alcohol abuse as assessed by the investigator within the past 
2 years, or an alcohol use pattern that may interfere with the patient’s 
study compliance. Patients must have abstained from alcohol for at 
least 6 months prior to study start.  
16) Patients with history of clinically-significant illness or any other major 
medical disorder that may interfere with subject treatment, assessment, 
or compliance with the protocol. 
17) Receipt of an investigational drug within 6 months prior to screening, 
or active enrolment in another investigational medication or device 
trial. 
18) Patients with any chronic illness or prior treatment which in the 
opinion of the investigator should preclude participation in the trial. 
19) Inability to understand and cooperate with the investigators or to give 
valid consent. 
Total expected number of 
patients: 
141 patients (47 patients per arm) 
Expected number of sites: 
3 Sites 

 
 
 
 
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Investigational product; 
(dosing and mode of 
administration) 
Heptex Capsule (size 1) consisted of the following; 
Dukung Anak is a Powdered Extract 200 mg (from Aerial Parts of Phyllanthus 
niruri), 
Milk Thistle is a Powdered Extract 100 mg (from Fruits of Silybum marianum). 
Mode of administration: 
Each patient will take 2 capsules size 1 of the study medication (either Placebo 
or Heptex) orally (PO) three times daily (TID) on empty stomach (15 min before 
meals or 1 hour after meals) with plenty of water (240 ml water, or full glass of 
water). The Placebo and Heptex capsules will be identical in physical 
appearance and mode of administration. 
Control Arm 1: 
Placebo (Rice bran) in 2 capsules size 1, administered PO TID on empty 
stomach with plenty of water. 
Experimental Arm 2: 
The contents of one capsule of Heptex is equally distributed and inserted into 2 
capsules size 1, administered PO TID on empty stomach with plenty of water. 
Experimental Arm 3: 
The contents of two capsules of Heptex is equally distributed and inserted into 2 
capsules size 1, administered PO TID on empty stomach with plenty of water. 
Assessment Schedule 
This phase II study will last for 36 weeks in addition to screening period, and it 
will include 2 washout periods (at Week 13 & Week 25). A total of 6 visits will 
be performed as shown in the table below; 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Washout 
period 
(Week 13) 
Visit 5 
Washout 
period 
(Week 25) 
Visit 6 
Screening 
(12 weeks) 
Baseline 
Follow up 
Follow up 
Follow up 
Follow up 
(EOS) 
Week 0 
Week 8 
Week 12 
Week 24 
Week 36 
Data to be collected 
Screening visit: 

 
 
 
 
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During screening visit, data on informed consent process, inclusion and 
exclusion criteria, demographics, medical and surgical history, concomitant 
medications, physical examination, vital signs, FibroScan liver stiffness 
measurement (KPa), abdominal ultrasound, controlled attenuation parameter 
(CAP), lab tests (serum pregnancy test for females, PCR; HCV RNA, HAV IgM 
antibody test, HBsAg test, alpha fetoprotein, CBC, sodium, potassium, serum 
fibrinogen, albumin, bilirubin, prothrombin time, PTT, INR, ALT, AST, kidney 
function tests, lipid profile, and HbA1c) will be collected. Then Fib-4 score will 
be calculated. 
Baseline (week 0):  
At baseline visit, data on concomitant medications, physical examination and 
vital signs will be collected. Then occurrence of adverse events and serious 
adverse events including hepatic complications will be collected. Data on the 
dispensed drug will be recorded. 
Week 8 and week 12:  
At week 8 and week 12, data on concomitant medications, physical 
examination, vital signs, controlled attenuation parameter (CAP), lab tests 
(serum pregnancy test for females, CBC, serum fibrinogen, albumin, bilirubin, 
prothrombin time, PTT, INR, ALT and AST) will be collected. Then Fib-4 
score will be calculated and occurrence of adverse events and serious adverse 
events including hepatic complications will be collected. The drug 
accountability for the dispensed drug will be recorded. 
Week 24: 
At week 24, data on concomitant medications, physical examination, vital signs, 
FibroScan liver stiffness measurement (KPa), controlled attenuation parameter 
(CAP), lab tests (serum pregnancy test for females, CBC, sodium, potassium, 
serum fibrinogen, albumin, bilirubin, prothrombin time, PTT, INR, ALT, AST, 
kidney function tests, lipid profile and HbA1c) will be collected. Then Fib-4 

 
 
 
 
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score will be calculated and occurrence of adverse events and serious adverse 
events including hepatic complications will be collected. The drug 
accountability for the dispensed drug will be recorded. 
Week 36: 
At week 36, data on concomitant medications, physical examination, vital signs, 
FibroScan liver stiffness measurement (KPa), controlled attenuation parameter 
(CAP), lab tests (serum pregnancy test for females, CBC, sodium, potassium, 
serum Fibrinogen, albumin, bilirubin, prothrombin time, PTT, INR, ALT, AST, 
kidney function tests, lipid profile and HbA1c) will be collected. Then Fib-4 
score will be calculated and occurrence of adverse events and serious adverse 
events including hepatic complications will be collected. Study completion form 
will be filled. 
Criteria For Evaluation 
During interim analysis (at 6 months of treatment) and final analysis at the end 
of treatment, the following endpoints will be evaluated: 
Primary Endpoints: 
 
Compare the mean relative change in ALT & AST levels between the 
experimental arms and the control arm. 
 
Compare proportions of patients with normal ALT & AST at end of 
treatment between the experimental arms and the control arm. The cut-off 
values of ALT were 0-43 IU/L and of AST were 0-40 IU/L2. 
Secondary Endpoints: 
 
Comparing the mean change in Fib-4 score between the experimental arms 
and the control arm. 
 
Comparing the frequency and percentage of patients experiencing hepatic 
                                                          
2 Uslusoy H, Nak S, Gülten M, Bıyıklı Z. Non-alcoholic steatohepatitis with normal aminotransferase values. 
World Journal of Gastroenterology. 2009;15(15):1863. 

 
 
 
 
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complications between the experimental arms and control arm. 
Exploratory Endpoints: 
 
Compare the mean relative change in lipid profile levels between the 
experimental arms and the control arm. 
Statistical methodologies 
Statistical Power and Sample Size Justification3 
Reference to Sanyal AJ, et al. there was a decrease in Alanine aminotransferase 
level among placebo arm of -20 (U/liter) among the placebo arm while for the 
active arm, a double of this improvement will be of clinical value. 
Accordingly, with an alpha error of 5% using one-sided 95% CI of Mann–
Whitney U test, a sample power of 80% and an effect size between placebo and 
lowest active dose of 0.63, a sample of 43 patients for each arm will be 
required plus an expected drop-out rate of 10% during 9 months’ study 
duration. Thus, a sample of 47 patients per each treatment arm will be 
appropriate and the total same of the 3 arms will be 141 patients. 
Randomization method: 
The arms randomization will be performed using Interactive web response 
system (IWRS). 
Statistical methodologies: 
The statistical analysis of this study will consist of reporting the individual data 
listings, providing descriptive statistics for parameters of interest, and statistical 
testing of the primary and secondary variables.  
The final statistical analyses will be performed when the patients on Heptex and 
placebo complete 9 months of treatment.  
Detailed analysis methods will be provided in the statistical analysis plan. 
                                                          
3 Gpower 3.1 

 
 
 
 
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Descriptive analysis: 
Percent (%) distribution for all categorical variables and mean with (SD) and 
median (Minimum: Maximum) for continuous variables according their 
distribution. 
Primary analysis: 
The main objectives of this phase II study is to explore the anti-oxidant activity 
of Heptex as assessed by improvement in serum aspartate aminotransferase 
(AST) and alanine aminotransferase (ALT) levels by measuring: 
 
The mean relative change in ALT & AST levels between the experimental 
arms and the control arm from baseline till end of treatment using T-test 
(Mann-Whitney test in case of non-parametric data). This analysis will be 
a comparative analysis and will be done on eligible population of patients 
without protocol violation and who have at least one treatment dose and an 
evaluable primary endpoint (AST and ALT). 
 
Number of patients with normal ALT & AST at end of treatment between 
the experimental arms and the control arm. The cut-off values of ALT 
were 0-43 IU/L and of AST were 0-40 IU/L4 using chi square (Fischer test 
for non-parametric data). This analysis will be comparative analysis and 
will be conducted on the eligible population of patients without protocol 
deviation, who have at least one treatment dose and an evaluable primary 
endpoint (ALT and AST). 
Secondary Analysis: 
 
The mean change in Fib-4 score between the experimental arms and the 
control arm from baseline till end of treatment using T-test (Mann-
Whitney test in case of non-parametric data). This analysis will be a 
                                                          
4 Uslusoy H, Nak S, Gülten M, Bıyıklı Z. Non-alcoholic steatohepatitis with normal aminotransferase values. 
World Journal of Gastroenterology. 2009;15(15):1863. 

 
 
 
 
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comparative analysis and will be done on eligible population of patients 
without protocol violation and who have at least one treatment dose and an 
evaluable primary endpoint (AST and ALT). 
 
Number of patients experiencing hepatic complications between the 
experimental arms and control arm at the end of the treatment using chi-
square (Fischer for non-parametric data). This analysis will be a 
comparative analysis and will be done on eligible population of patients 
without protocol violation and who have at least one treatment dose and an 
evaluable primary endpoint (AST and ALT). 
Exploratory Analysis: 
 
The mean relative change in lipid profile levels between the experimental 
arms and the control arm from baseline till end of treatment using T-test 
(Mann-Whitney test in case of non-parametric data). This analysis will be 
a comparative analysis and will be done on eligible population of patients 
without protocol violation and who have at least one treatment dose and an 
evaluable primary endpoint (AST and ALT). 
All tests will be performed on the 5% level of significance. 
Procedure for accounting for missing, unused, and spurious data will be 
explained in the statistical analysis plan. 
Any deviation(s) from the original statistical plan will be described in the final 
report). 
Interim analysis: 
Interim analysis will be performed when all patients complete 6 months of 
treatment. If a statistically significant difference is observed between placebo 
and active arm(s), the study will be terminated for the benefit of patients who 

 
 
 
 
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were randomly assigned to placebo arm and to rapidly disseminate evidence 
supporting a treatment benefit to the broader community5.  
Estimate Duration of the 
Study   
 
Protocol Planned Date: October 2018 
 
First Patient In (FPI): December 2018 
 
Last Patient In (LPI): March 2019 
 
Last Patient Out (LPO): December 2019 
 
Estimated enrollment duration: 3 Months 
 
Estimate treatment duration: 9 Months 
 
Database lock planned date: January 2020 
 
Estimated Report date: February 2020 
 
 
                                                          
5 Zannad F, et al. Development of Therapeutics for Heart Failure. When to Stop a Clinical Trial Early for 
Benefit: Lessons Learned and Future Approaches. Circulation: Heart Failure. 2012; 5: 294-302. doi: 
0.1161/CIRCHEARTFAILURE.111.965707 

 
 
 
 
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2 
ASSESMENT SCHEDULE 
Data to be collected 
Study Schedule* 
V1 
screening 
V2 
Week 0 
V3 
Week 8 
V4 
Week 12 
V5 
Week 24 
V6 
Week 36 
Informed consent 
X 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical/ Surgical history 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Fibroscan liver stiffness measurement 
X 
 
 
 
X 
X 
Fib-4 
X  
 
X 
X 
X  
X 
Abdominal Ultrasound 
X 
 
 
 
 
 
Controlled Attenuation Parameter (CAP) 
X 
 
X 
X 
X 
X 
Serum pregnancy test for females 
X 
 
X 
X 
X 
X 
PCR 
X 
 
 
 
 
 
Alpha fetoprotein  
X 
 
 
 
 
 
HCV RNA 
X 
 
 
 
 
 
HAV IgM 
X 
 
 
 
 
 
HBsAg 
X 
 
 
 
 
 
CBC 
X 
 
X 
X 
X 
X 
Sodium 
X 
 
 
 
X 
X 
Potassium 
X 
 
 
 
X 
X 
Serum Fibrinogen 
X 
 
X 
X 
X 
X 
Liver Profile tests 
- Albumin, bilirubin, 
- PT, PTT, INR,  
- ALT and AST 
X 
 
X 
X 
X 
X 
Kidney function tests 
X 
 
 
 
X 
X 
Lipid Profile 
X 
 
 
 
X 
X 
HbA1c 
X 
 
 
 
X 
X 
Study drug dispensed 
 
X 
X 
X 
X 
 
Drug Accountability 
 
 
X 
X 
X 
X 
Adverse Events 
Serious Adverse Events  
Hepatic complications 
 
X 
X 
X 
X 
X 
Study Completion Form 
 
 
 
 
 
X 
* Washout periods at week 13 and week 25. 

 
 
 
 
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3 
GRAPHICAL STUDY DESIGN 
 
 
 
 
 
 
 
 

 
 
 
 
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4 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Events 
AESI 
Adverse Event of Special Interest 
AFP 
Alpha-Fetoprotien 
ALT 
Alanine Transaminase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Transaminase 
BMI 
Body Mass Index 
CAP 
Controlled Attenuation Parameter 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
DBP 
Diastolic Blood Pressure 
DVP 
Data Validation Plan 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EIU 
Exposure In-Utero  
ESC 
European Society of Cardiology 
ESH 
European Society of Hypertension 
FPI 
First Patient In 
g/dl 
gram per deciliter 
GFR 
Glomerular Filtration Rate 
HbA1c 
Glycated hemoglobin 
HAV 
Hepatitis A Virus 
HCV 
Hepatitis C Virus 
HDPE 
High-density polyethylene 
ICH 
International Conference on Harmonisation 
ID 
Identification number 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IHD 
Ischemic Heart Disease 
IND 
Investigational New Drug 

 
 
 
 
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Abbreviation 
Definition 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board  
IWRS 
Interactive Web Response System 
kPa 
Kilopascal 
LPI 
Last Patient In 
LPO 
Last Patient Out 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/dl 
milligram per diciliter 
mm3 
cubic millimeter 
mmHg 
Millimeter of mercury 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NASH 
Non-Alcoholic Steato-Hepatitis 
ng/ml 
Nanogram per milliliter 
PCR 
Polymerase Chain Reaction 
PO 
Orally 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QC 
Quality Control 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDV 
Source Data Verification  
SOP 
Standard Operating Procedure 
SVR 
Sustained Viral Response 
TID 
Three Times per day 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 
 

 
 
 
 
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5 
TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ................................................................................................................. 3 
2 
ASSESMENT SCHEDULE ........................................................................................................... 16 
3 
GRAPHICAL STUDY DESIGN ..................................................................................................... 17 
4 
LIST OF ABBREVIATIONS .......................................................................................................... 18 
5 
TABLE OF CONTENTS ................................................................................................................ 20 
6 
MEDICAL BACKGROUND& RATIONALE .................................................................................. 24 
6.1 
Medical Background ................................................................................................................. 24 
6.2 
Rationale .................................................................................................................................. 26 
7 
STUDY OBJECTIVES................................................................................................................... 28 
7.1 
Primary ..................................................................................................................................... 28 
7.2 
Secondary ................................................................................................................................. 28 
8 
STUDY DESIGN ............................................................................................................................ 29 
8.1 
Description of the study design................................................................................................ 29 
8.2 
Duration of study participation ................................................................................................ 29 
8.3 
Estimated study dates .............................................................................................................. 30 
8.4 
Data to be collected at different study intervals ..................................................................... 30 
9 
SELECTION OF PATIENTS ......................................................................................................... 32 
9.1 
Sample size ............................................................................................................................... 32 
9.2 
Inclusion criteria ....................................................................................................................... 32 
9.3 
Exclusion criteria ...................................................................................................................... 32 
10 
TREATMENT OF TRIAL PARTICIPANTS ................................................................................... 34 
10.1 
Randomization ......................................................................................................................... 34 
10.2 
Investigational product ............................................................................................................ 34 
10.3 
Labelling and packaging ........................................................................................................... 34 
10.4 
Mode of administration: .......................................................................................................... 35 
10.5 
Accountability of Study Treatment: ......................................................................................... 35 

 
 
 
 
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11 
CONCOMITANT MEDICATIONS ................................................................................................. 36 
12 
SOURCE DATA ............................................................................................................................ 37 
13 
CLINICAL DATA MANAGEMENT ............................................................................................... 38 
13.1 
Data Management system ....................................................................................................... 38 
13.2 
Data Entry ................................................................................................................................. 38 
13.3 
Data Validation and Discrepancies Management By CRO ....................................................... 38 
13.4 
Clinical data Coding .................................................................................................................. 38 
14 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 39 
14.1 
Quality Control ......................................................................................................................... 39 
14.1.1 
In process quality control of biometrics ........................................................................... 39 
14.1.2 
Monitoring and site data quality control ......................................................................... 39 
14.2 
Quality Assurance ..................................................................................................................... 39 
15 
PHARMACOVIGILANCE .............................................................................................................. 40 
15.1 
Adverse Events Monitoring ...................................................................................................... 40 
15.2 
Reporting Period ...................................................................................................................... 41 
15.3 
Definitions ................................................................................................................................ 41 
15.4 
Adverse Event of Special Interest ............................................................................................. 42 
15.5 
Serious Adverse Events ............................................................................................................ 42 
15.6 
Adverse Reaction (Adverse Drug Reaction) ............................................................................. 42 
15.7 
Suspected Adverse Reaction .................................................................................................... 43 
15.8 
Unexpected Adverse Drug Reaction ........................................................................................ 43 
15.9 
Abnormal Test Findings ............................................................................................................ 44 
15.10 Hospitalization .......................................................................................................................... 44 
15.11 Severity Assessment ................................................................................................................. 45 
15.12 Causality Assessment ............................................................................................................... 46 
15.13 Exposure During Pregnancy ..................................................................................................... 47 
15.14 Withdrawal Due to Adverse Events ......................................................................................... 48 
15.15 Eliciting Adverse Event Information ......................................................................................... 49 
15.16 Procedures for Recording Adverse Events ............................................................................... 49 

 
 
 
 
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15.17 Reporting Requirements .......................................................................................................... 49 
15.18 Instructions for Reporting Serious Adverse Events for Study Team ........................................ 50 
15.19 Sponsor Reporting Requirements to Regulatory Authorities .................................................. 52 
15.20 Breaking Randomization Code ................................................................................................. 52 
16 
STATISTICAL CONSIDERATIONS ............................................................................................. 53 
16.1 
Sample Size Calculation ............................................................................................................ 53 
16.2 
Analysis populations ................................................................................................................. 53 
16.3 
Study Endpoints ....................................................................................................................... 53 
16.3.1 
Primary Efficacy Endpoint: ............................................................................................... 53 
16.3.2 
Secondary Efficacy Endpoints: ......................................................................................... 53 
16.3.3 
Exploratory Endpoint: ...................................................................................................... 54 
16.4 
Statistical Analyses ................................................................................................................... 54 
16.4.1 
Descriptive analysis: ......................................................................................................... 54 
16.4.2 
Primary analysis: .............................................................................................................. 54 
16.4.3 
Secondary analysis: .......................................................................................................... 55 
16.4.4 
Exploratory analysis: ........................................................................................................ 55 
16.4.5 
Interim analysis: ............................................................................................................... 55 
16.5 
Randomization ......................................................................................................................... 56 
17 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 57 
17.1 
Ethical principles: ..................................................................................................................... 57 
17.2 
Laws and regulations: ............................................................................................................... 57 
17.3 
Informed consent: .................................................................................................................... 57 
17.4 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) .................................... 58 
18 
DISCONTINUATION/ WITHDRAWAL OF PARTICIPANTS FROM STUDY ............................... 59 
19 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A 
SITE ............................................................................................................................................... 60 
20 
RESPONSIBILITIES OF INVESTIGATORS AND SPONSORS .................................................. 61 
20.1 
Responsibilities of the Investigators ........................................................................................ 61 
20.2 
Responsibilities of Sponsor ...................................................................................................... 62 

 
 
 
 
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21 
CONFIDENTIALITY AND DATA PROTECTION ......................................................................... 63 
21.1 
Confidentiality .......................................................................................................................... 63 
21.2 
Data protection ........................................................................................................................ 63 
22 
PUBLICATIONS ............................................................................................................................ 64 
23 
REFERENCES .............................................................................................................................. 65 
 

 
 
 
 
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6 
MEDICAL BACKGROUND& RATIONALE 
6.1 
MEDICAL BACKGROUND 
Nonalcoholic fatty liver disease (NAFLD) is a chronic condition in which excessive fat is 
accumulated in the liver without alcohol causing it [1]. 
There are two types of NAFLD; simple fatty liver and nonalcoholic steatohepatitis 
(NASH). The difference between these two is that NASH includes inflammation and 
liver cell damage along with fat accumulation in the liver [2]. NASH is the advanced 
form of NAFLD, which can progress to fibrosis, cirrhosis and then hepatocellular 
carcinoma [3 - 5]. 
Although the mechanisms involved in the occurrence and progression of fatty liver is 
unclear, many studies have proposed the pathogenesis of NAFLD. The “multiple parallel 
hits” hypothesis was mainstreamed. In 1998, Day et al. proposed that “the first hit”, 
either high-fat diet or diabetes-induced steatosis, will sensitize the liver to other risk 
factors related to oxidative stress (OS) and induce severe lipid peroxidation “the second 
hit” [6]. 
Afterwards, NASH was found to be closely associated with insulin resistance (IR), 
obesity and type 2 diabetes [7, 8], along with (OS) that was presumed to contribute to 
hepatic injury in patients with the disease [8, 9]. Hence, therapy targeting IR and OS 
could be beneficial in patients with NASH. 
Many studies have been conducted to investigate the efficacy of antioxidants such as 
vitamin E in normalizing liver enzymes (alanine aminotransferase “ALT” & aspartate 
aminotransferase “AST”) in patients with NASH [10 - 14]. 
Hasegawa T et al. reported a decrease in serum ALT level in NASH patients during the 
1‐ year α‐ tocopherol treatment along with improvement in the histological findings, 
such as steatosis, inflammation and fibrosis, while α‐ tocopherol had no effect on serum 
ALT in patients with NAFL [10]. 

 
 
 
 
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In 2003, Harrison SA et al. conducted a prospective, double-blind, randomized, placebo-
controlled trial where all NASH patients were randomized to receive either vitamins E 
and C or placebo daily for 6 months. Despite there was no improvement seen in 
necroinflammatory activity or ALT, the combination was found to be effective in 
improving fibrosis scores (specifically for patients with diabetes). For AST, no 
differences were noted between groups or within groups [11]. 
Another double-blind, randomized, placebo-controlled trial that was conducted in 2004 
found that ursodeoxycholic acid (UDCA) in combination with vitamin E twice daily 
significantly improved serum ALT & AST levels and liver histology of patients with 
NASH. It was also found that patients received the combination had less steatosis and a 
lower activity index at the end of the 2 years of treatment [12]. 
For a very long time, Silybum marianum, commonly known as milk thistle, is used in the 
treatment of liver diseases [15, 16]. The lipophilic extract from plant seeds is the active 
form of milk thistle, this composed of a complex mixture of isomer flavonolignans [15]. 
Many studies (in vitro and in vivo) have shown the beneficial value of silymarin when it 
comes to its effects in liver diseases, whether acting as antioxidant, anti-inflammatory, 
and anti-fibrotic [17 - 21]. 
A meta-analysis was previously conducted to assess the therapeutic effect of silymarin in 
the treatment of patients with NAFLD. It included eight randomized clinical trials 
(RCTs) with a total of 587 patients. It showed that patients receiving silymarin (whether 
monotherapy or in combination) had significantly lower AST and ALT levels than those 
in control patients (p = 0.0002 & p = 0.1 respectively) [22]. 
A randomized, placebo-controlled trial that was conducted in Iran evaluated the efficacy 
of silymarin in the treatment of NASH. Eighty patients were assigned to either receive 
placebo or silymarin (with 210 mg/ day) orally for 8 weeks. It showed that patients 
receiving silymarin had significantly lower AST & ALT levels than patients receiving 
placebo (p = 0.38 & p = 0.026 respectively) [23]. 

 
 
 
 
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Another RCT was conducted in Iran to assess the effect of silymarin in patients with 
NASH. It included 100 patients that were randomized either to receive placebo (Group 
A) or 280 mg of silymarin (Group B). Treatment was continued for 24 weeks, and 
patients were evaluated every 4 weeks. When compared to baseline, a significant 
reduction was reported in both ALT & AST levels in patients receiving silymarin (p = 
0.001 & p = 0.006 respectively). On the contrary, no significant reduction was observed 
in patients receiving placebo (p = 0.237 & p = 0.343 respectively) [24]. 
In the same trial, a significantly higher percentage of patients with normal ALT & AST 
levels was observed in the silymarin-receiving group when compared to the placebo-
receiving group (p = 0.001 & p = 0.0001 respectively) [24]. 
Phyllanthus niruri is also a widely used herb in traditional medicine. Many studies 
showed that Phyllanthus species could protect the liver from damages caused by OS and 
lipid peroxidation by antagonizing the first and preventing the second [25 - 27]. 
Many laboratory studies investigated its potential antioxidant, antimicrobial, anti-
inflammatory, and hepatoprotective properties in liver diseases [28 - 32]. 
However, one pilot study was conducted in Malaysia to examine the safety and efficacy 
of Phyllanthus niruri in patients with NASH (randomized, double-blind, parallel-group, 
placebo-controlled trial with a total of 52 NASH patients who were randomized (1:1) to 
receive Phyllanthus niruri (n = 25) or placebo (n = 27) three times daily for 48 weeks) 
[33]. 
Although ALT & AST levels were decreased in patients on Phyllanthus niruri, there 
were no significant differences in ALT (p > 0.95) & AST (p = 0.39) levels between the 
two groups. Thus, this study was unable to demonstrate the clinical benefits of 
Phyllanthus niruri in patients with NASH. This study was limited by the small sample 
size that might contributed to the differences in baseline characteristics between the two 
groups [33]. 
This information along with the very promising preclinical data encouraged us to 
conduct further research (on a larger scale) to investigate both safety and efficacy of 
Phyllanthus niruri combined with Silybum marianum in patients suffering from NASH. 
6.2 
RATIONALE 
Data about the efficacy of a combination of Phyllanthus niruri (Dukung Anak) and 

 
 
 
 
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Silybum marianum (Milk Thistle) in patients with NASH are still lacking. Therefore, this 
study was designed to evaluate both on a larger clinical scale. 
 
 
 
 
 
 
 

 
 
 
 
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7 
STUDY OBJECTIVES 
7.1 
PRIMARY 
 To explore the anti-oxidant activity of Heptex as assessed by improvement in 
serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
levels in patients with apparent risk factors of NASH. 
7.2 
SECONDARY 
 To explore the optimum dose that is safe in patients with apparent risk factors 
of NASH giving the most significant effect among two different doses of 
Heptex. 
 To explore the hepatoprotective effect of Heptex as assessed by the change in 
Fibrosis score. 
 To explore the hepatoprotective effect of Heptex as assessed by the 
occurrence of hepatic complications. 
 

 
 
 
 
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8 
STUDY DESIGN 
8.1 
DESCRIPTION OF THE STUDY DESIGN 
This is a phase II, randomized, double blind placebo-controlled, three-arm, parallel-
group, interventional clinical trial evaluating anti-oxidant activity of Heptex; a herbal 
medicinal product of Aerial Parts of Phyllanthus niruri (Dukung Anak) and Fruits of 
Silybum marianum (Milk Thistle). 
Study duration: 12 weeks of recruitment and 36 weeks of treatment. This period will 
include 2 washout periods (at Week 13 & Week 25). 
Sample Size: 47 subjects per arm, 141 in total. 
Participants in trial will be patients between 18 and 65 years consenting to participate in 
this study, who have elevated liver enzymes [34], controlled attenuation parameter (CAP)-
confirmed hepatic steatosis, and Fib score of F1 and F2 assessed by the FibroScan liver 
stiffness measurement.  
FibroScan will be done for all patients at screening visit and those with F1 and F2 will be 
considered for inclusion in the study. FibroScan will be repeated for all patients after 6 
months and at the end of treatment duration and results will be compared. 
Screening of patients will be continued for about 12 weeks. Eligible patients will be 
randomized in a 1:1:1 allocation ratio, into one of the three treatment groups, to receive 
either placebo or one of the two doses of Heptex.  Randomization will be done using 
interactive response technology. 
 
8.2 
DURATION OF STUDY PARTICIPATION 
This phase II study will last for 36 weeks in addition to a screening period, and it will 
include 2 washout periods (at Week 13 & Week 25). A total of 6 visits will be performed as 
shown in the table below; 

 
 
 
 
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Visit 1 
Visit 2 
Visit 3 
Visit 4 
Washout 
period 
(Week 13) 
Visit 5 
Washout 
period 
(Week 25) 
Visit 6 
Screening 
(12 weeks) 
Baseline 
Follow up Follow up 
Follow up 
Follow up 
(EOS) 
Week 0 
Week 8 
Week 12 
Week 24 
Week 36 
 
8.3 
ESTIMATED STUDY DATES 
 Protocol Planned Date: October 2018 
 First Patient In (FPI): December 2018 
 Last Patient In (LPI): March 2019 
 Last Patient Out (LPO): December 2019 
 Estimated enrollment duration: 3 Months 
 Estimate treatment duration: 9 Months 
 Database lock planned date: January 2020 
 Estimated Report date: February 2020 
8.4 
DATA TO BE COLLECTED AT DIFFERENT STUDY INTERVALS 
Screening visit: 
During screening visit, data on informed consent process, inclusion and exclusion 
criteria, demographics, medical and surgical history, concomitant medications, physical 
examination, vital signs, FibroScan liver stiffness measurement (KPa), abdominal 
ultrasound, controlled attenuation parameter (CAP), lab tests (serum pregnancy test for 
females, PCR; HCV RNA, HAV IgM antibody test, HBsAg test, alpha fetoprotein, CBC, 
sodium, potassium, serum fibrinogen, albumin, bilirubin, prothrombin time, PTT, INR, 
ALT, AST, kidney function tests, lipid profile, and HbA1c) will be collected. Then Fib-4 
score will be calculated. 
Baseline (week 0): 
At baseline visit, data on concomitant medications, physical examination and vital signs 
will be collected. Then occurrence of adverse events and serious adverse events 

 
 
 
 
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including hepatic complications will be collected. Data on the dispensed drug will be 
recorded. 
 
Week 8 and week 12: 
At week 8 and week 12, data on concomitant medications, physical examination, vital 
signs, controlled attenuation parameter (CAP), lab tests (serum pregnancy test for females, 
CBC, serum fibrinogen, albumin, bilirubin, prothrombin time, PTT, INR, ALT and AST) 
will be collected. Then Fib-4 score will be calculated and occurrence of adverse events 
and serious adverse events including hepatic complications will be collected. The drug 
accountability for the dispensed drug will be recorded. 
Week 24: 
At week 24, data on concomitant medications, physical examination, vital signs, 
FibroScan liver stiffness measurement (KPa), controlled attenuation parameter (CAP), lab 
tests (serum pregnancy test for females, CBC, sodium, potassium, serum fibrinogen, 
albumin, bilirubin, prothrombin time, PTT, INR, ALT, AST, kidney function tests, lipid 
profile and HbA1c) will be collected. Then Fib-4 score will be calculated and occurrence 
of adverse events and serious adverse events including hepatic complications will be 
collected. The drug accountability for the dispensed drug will be recorded. 
Week 36: 
At week 36, data on concomitant medications, physical examination, vital signs, 
FibroScan liver stiffness measurement (KPa), controlled attenuation parameter (CAP), lab 
tests (serum pregnancy test for females, CBC, sodium, potassium, serum Fibrinogen, 
albumin, bilirubin, prothrombin time, PTT, INR, ALT, AST, kidney function tests, lipid 
profile and HbA1c) will be collected. Then Fib-4 score will be calculated and occurrence 
of adverse events and serious adverse events including hepatic complications will be 
collected. Study completion form will be filled. 

 
 
 
 
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9 
SELECTION OF PATIENTS 
9.1 
SAMPLE SIZE 
It is planned to recruit 141 patients (47 patients per arm), in 2 centers in Egypt. 
9.2 
INCLUSION CRITERIA 
1) Male or female aged between 18 and 65 years. 
2) Both male and female patients who have childbearing potential must agree to 
practice an acceptable method of birth control during the study and for at least 
6 months after the cessation of treatment; such contraceptive methods must 
include at least one barrier method. 
3) Controlled Attenuated Parameter (CAP)-confirmed hepatic steatosis. 
4) Patients with elevated Liver enzymes (ALT and/or AST) [34]. 
5) Liver fibrosis stage F1-F2 as diagnosed by the FibroScan liver stiffness 
measurement of 5-10 kPa.  
6) liver condition according the following criteria; 
o Serum albumin > 3 g/dl 
o INR < 2 
o No ascites on ultrasound 
o No documented or suspected hepatic encephalopathy  
7) Willing to stop any other liver support and hepatoprotective medications 
throughout study duration. 
8) Able and willing to provide written informed consent. 
9) Able and willing to complete all study visits and procedures, including 
compliance with the requirements and restrictions listed in the consent form.   
9.3 
EXCLUSION CRITERIA 
1) Pregnant or lactating women. 
2) Patients with BMI > 40 Kg/m2 or BMI < 18.5 Kg/m2. 

 
 
 
 
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3) Serum creatinine > 1.5 x ULN OR creatinine clearance (GFR) < 60 
mL/minute. 
4) Platelet count < 75,000/mm3. 
5) Uncontrolled diabetes mellitus as evident by HbA1c ≥ 8.5%. 
6) Patients who are currently receiving Thiazolidinediones. 
7) Patients with ischemic heart disease (IHD). 
8) History of parenteral nutrition. 
9) History of liver transplant. 
10) Viral hepatitis, drug-induced liver injury, metabolic liver disease or auto-
immune liver disease. 
11) Liver cancer or serum alpha-fetoprotein (AFP) >100ng/ml. Patients with an 
AFP between 50 and 100ng/ml may be included as long as a liver ultrasound 
within 3 months of screening, or at screening, shows no evidence of potential 
hepatocellular cancer.  
12) Use of drugs known to induce steatosis (valproate, amiodarone or prednisone) 
or to affect body weight and carbohydrate metabolism. 
13) Use of drugs known to alter liver enzymes. 
14) Allergy or allergic history to any of the drug components. 
15) History of alcohol abuse as assessed by the investigator within the past 2 years, 
or an alcohol use pattern that may interfere with the patient’s study 
compliance. Patients must have abstained from alcohol for at least 6 months 
prior to study start.  
16) Patients with history of clinically-significant illness or any other major medical 
disorder that may interfere with subject treatment, assessment, or compliance 
with the protocol. 
17) Receipt of an investigational drug within 6 months prior to screening, or active 
enrolment in another investigational medication or device trial. 
18) Patients with any chronic illness or prior treatment which in the opinion of the 
investigator should preclude participation in the trial. 
19) Inability to understand and cooperate with the investigators or to give valid 
consent. 
 

 
 
 
 
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10 
TREATMENT OF TRIAL PARTICIPANTS 
10.1 
RANDOMIZATION 
Before randomization, fulfillment of the inclusion/exclusion criteria should be assured 
and the signed informed consent obtained. After that, eligible patients will be 
randomized in a 1:1:1 allocation ratio, into one of the three treatment groups, to 
receive either placebo or one of the two doses of Heptex.  Randomization will be done 
using interactive response technology. 
Control Arm 1: 
Placebo (Rice bran) in 2 capsules size 1, administered PO TID on empty stomach with 
plenty of water. 
Experimental Arm 2: 
The contents of one capsule of Heptex is equally distributed and inserted into 2 
capsules size 1, administered PO TID on empty stomach with plenty of water. 
Experimental Arm 3: 
The contents of two capsules of Heptex is equally distributed and inserted into 2 
capsules size 1, administered PO TID on empty stomach with plenty of water. 
10.2 
INVESTIGATIONAL PRODUCT 
Heptex Capsule (Size 1) consists of the following; 
Dukung Anak is a Powdered Extract 200 mg (from Aerial Parts of Phyllanthus niruri), 
Milk Thistle is a Powdered Extract 100 mg (from Fruits of Silybum marianum). 
Sponsor will provide the study treatment for the patients during the whole treatment 
duration according to regulation of Local Health Authorities involved in the product 
supply. Clinical Supplies will be pre-prepared for a sufficient number of patients 
entering double-blind treatment. 
10.3 
LABELLING AND PACKAGING 
Investigational products will be packed in HDPE (High-density polyethylene) white 
bottles. Bottles will be packed in white carton boxes. A label will identify the patient’s 
initials, patient stratification, randomization number, site number, visit date, visit 
number, batch number, no. of capsules, sponsor’s name, dosage form, expiry date, 

 
 
 
 
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storage instructions and instructions to keep out of the reach of children in addition to 
a statement that this medication is for clinical trial use only. Investigational products 
will be stored at ambient temperature (not to exceed 30°c). During each study visit 
(from visit 2 to visit 6), each patient will receive a number of bottles containing the 
amount of medications sufficient for 8 or 12 weeks (according to visit interval). 
10.4 
MODE OF ADMINISTRATION: 
Each patient will take 2 capsules size 1 of the study medication (either Placebo or 
Heptex) orally (PO) three times daily (TID) on empty stomach (15 min before meals or 
1 hour after meals) with plenty of water (240 ml water, or full glass of water) for 9 
months. The Placebo and Heptex capsules will be identical in physical appearance and 
mode of administration. 
10.5 
ACCOUNTABILITY OF STUDY TREATMENT: 
The investigator or officially delegated pharmacist will be responsible for recording the 
receipt, administration and return of all drug supplies, and for ensuring the supervision 
of the storage and allocation of these supplies.  
It is essential that the patients are able to accurately account for all supplies issued to 
them (i.e. Patient Event Log records of study drug taken should match drug supplies 
returned).  
The investigator may withdraw any patient from the study if missing drug supplies 
cannot be satisfactorily accounted for, or if drug accountability records are consistently 
inaccurate, e.g. a patient may be discontinued if he has been cautioned to account 
correctly for medication issued and on a subsequent visit has failed to record two or 
more doses taken.  
Any quality issue noticed with the receipt or use of an Investigational Product 
(deficient IP in condition, appearance, pertaining documentation, labeling, expiry date, 
etc.) should be promptly notified to the Sponsor, who will initiate a complaint 
procedure. 
Under no circumstances will the Investigator supply Investigational Product to a third 
party, allows the Investigational Product to be used other than as directed by this 
Clinical Trial Protocol, or dispose of Investigational Product in any other manners. 

 
 
 
 
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11 
CONCOMITANT MEDICATIONS 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except other liver support, 
hepatoprotective medications and any medications prohibited as per the eligibility criteria. If these 
are required, the participant will be withdrawn. Any medication, other than the study 
medication taken during the study will be recorded in the CRF. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the subject is receiving during participation in the study must 
be recorded in the electronic case report form. The investigator should review all 
concomitant medications for any potential interactions. During the Post-Treatment Period, 
all medications will be collected. 

 
 
 
 
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12 
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, 
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. 
 
 

 
 
 
 
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13 
CLINICAL DATA MANAGEMENT 
13.1 
DATA MANAGEMENT SYSTEM 
Data will be collected and managed using Electronic Data Capture (EDC) technology. 
The system to be used is “OpenClinica, version 3.14”. 
13.2 
DATA ENTRY 
Data entry and updates will be performed by authorized site staff (the investigator or 
offially delegated personnel). All personnel to be involved in the data entry will have the 
proper levels of access, grants and privileges. 
Data entry screens development, validation rules programming and maintenance of study 
database will be the responsibility of  DATACLin CRO. 
13.3 
DATA VALIDATION AND DISCREPANCIES MANAGEMENT BY 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 valifdation 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 
through the EDC system. 
13.4 
CLINICAL DATA CODING 
DATACLin CRO will be reposnible 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. 
 

 
 
 
 
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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
QUALITY CONTROL 
 
14.1.1 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.  
14.1.2 Monitoring and site data quality control 
Study monitors will perform ongoing source data verification to confirm that 
criticalprotocol data entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
100 % Source Data Verification (SDV) will be performed only for Critical 
Variables. 
If specific issues are identified in a certain site, the percentage of Quality Control 
in the concerned siteand/or in all sites must be appropriately increased and 
corrective actions must be set up. 
14.2 
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. 
 
 
 

 
 
 
 
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15 
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. 
15.1 
ADVERSE EVENTS MONITORING 
All AEs regardless of seriousness or relationship to Investigational Product (IP), 
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.  
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 IP, 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 IP. 

 
 
 
 
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15.2 
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 procedures and/or receiving IP, 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. 
15.3 
DEFINITIONS 
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 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 
 
Exposure During Pregnancy 
 
Drug Quality Defect That Has Impact On The Patient Safety 

 
 
 
 
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15.4 
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. 
15.5 
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. 
15.6 
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 Investigational 
Product related to any dose. 

 
 
 
 
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15.7 
SUSPECTED ADVERSE REACTION 
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. 
15.8 
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 Investigational 
Product. "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 Investigational Product 
under investigation. 

 
 
 
 
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15.9 
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 
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. 
15.10 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: 

 
 
 
 
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 
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. 
 
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. 
15.11 SEVERITY ASSESSMENT 
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. 

 
 
 
 
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15.12 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 the investigational 
product caused or contributed to an adverse event. If the investigator's causality 
assessment is "unknown but not related to investigational product", 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. 
WHO-UMC Causality Categories 
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 

 
 
 
 
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Causality 
Term 
Assessment Criteria 
Conditional/U
nclassified 
 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 
15.13 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). 
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 Investigational Products, 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.  

 
 
 
 
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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. 
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).  
15.14 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. 

 
 
 
 
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15.15 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?" 
15.16 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. 
15.17 REPORTING REQUIREMENTS 
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 Investigational Product, 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. 
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 

 
 
 
 
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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. 
Reporting of Non-Serious Adverse Event 
All Non-Serious Adverse Events will be reported on the adverse event page(s) of the 
CRF and reported WITHIN 180 CALENDAR DAYS to the local regulatory authority. 
15.18 INSTRUCTIONS FOR REPORTING SERIOUS ADVERSE EVENTS 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 

 
 
 
 
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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 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 
Dr. 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 
Dr. Reem Alaa 
Title 
Clinical Research Associate 
Mobile 
(+2) 01202728990 
E-mail 
research.associate2@mynaturalwellness.
com  
Tel 
(+202) 22720135 
Fax 
(+202) 2275 2709 

 
 
 
 
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15.19 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 timeframes for reporting specified above. 
15.20 BREAKING RANDOMIZATION CODE 
In case of an Adverse Event, the code must be broken only in exceptional circumstances 
when knowledge of the Investigational Product is essential for treating the patient. If 
possible, a contact should be initiated with the Monitoring Team before breaking the 
code. 
If the blind is broken, the Investigator will document the date, time of day and reason for 
code breaking in the CRF. 

 
 
 
 
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16 
STATISTICAL CONSIDERATIONS 
16.1 SAMPLE SIZE CALCULATION6 
Reference to Sanyal AJ, et al. There was a decrease in Alanine aminotransferase level 
among placebo arm of -20 (U/liter) among the placebo arm while for the active arm, a 
double of this improvement will be of clinical value. Accordingly, with an alpha error 
of 5% using one-sided 95% CI of Mann–Whitney U test, a sample power of 80% and 
an effect size between placebo and lowest active dose of 0.63, a sample of 43 patients 
for each arm will be required plus an expected drop-out rate of 10% during 9 months’ 
study duration. Thus, a sample of 47 patients per each treatment arm will be 
appropriate and the total same of the 3 arms will be 141 patients. 
16.2 ANALYSIS POPULATIONS 
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 dose assessment (ALT & AST) attending any 
post treatment visit and efficacy variables will be analyzed using the last-observation-
carried-forward convention (LOCF).  
16.3 STUDY ENDPOINTS 
During interim analysis (at 6 months of treatment) and final analysis at the end of 
treatment, the following endpoints will be evaluated: 
16.3.1 Primary Efficacy Endpoint: 
 
- Compare the mean relative change in ALT & AST levels between the experimental 
arms and the control arm. 
- Compare proportions of patients with normal ALT & AST at end of treatment between 
the experimental arms and the control arm. The cut-off values of ALT were 0-43 IU/L 
and of AST were 0-40 IU/L7. 
16.3.2 Secondary Efficacy Endpoints: 
 
- Comparing the mean change in Fib-4 score between the experimental arms and the 
control arm. 
- Comparing the frequency and percentage of patients experiencing hepatic complications 
                                                          
6 Gpower 3.1 
7 Uslusoy H, Nak S, Gülten M, Bıyıklı Z. Non-alcoholic steatohepatitis with normal aminotransferase values. 
World Journal of Gastroenterology. 2009;15(15):1863. 

 
 
 
 
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between the experimental arms and control arm. 
16.3.3 Exploratory Endpoint: 
- Compare the mean relative change in lipid profile levels between the experimental arms 
and the control arm. 
16.4 
STATISTICAL ANALYSES 
The statistical analysis of this study will consist of reporting of individual data 
listings, providing descriptive statistics for parameters of interest, and statistical 
testing of the primary and secondary variables.  
The final statistical analyses will be performed when the patients on Heptex and 
placebo complete 9 months of treatment.  
Detailed analysis methods will be provided in the statistical analysis plan. 
16.4.1 Descriptive analysis: 
- Percent (%) distribution for all categorical variables and mean with (SD) and median 
(Minimum: Maximum) for continuous variables according their distribution. 
16.4.2 Primary analysis: 
- The main objectives of this phase II study is to explore the anti-oxidant activity of 
Heptex as assessed by improvement in serum aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) levels by measuring: 
- The mean relative change in ALT & AST levels between the experimental arms and the 
control arm from baseline till end of treatment using T-test (Mann-Whitney test in case 
of non-parametric data). This analysis will be a comparative analysis and will be done 
on eligible population of patients without protocol violation and who have at least one 
treatment dose and an evaluable primary endpoint (AST and ALT). 
- Number of patients with normal ALT & AST at end of treatment between the 
experimental arms and the control arm. The cut-off values of ALT were 0-43 IU/L and 
of AST were 0-40 IU/L8 using chi square (Fischer test for non-parametric data). This 
analysis will be comparative analysis and will be conducted on the eligible population 
of patients without protocol deviation, who have at least one treatment dose and an 
evaluable primary endpoint (ALT and AST). 
All tests will be performed on the 5% level of significance. 
                                                          
8 Uslusoy H, Nak S, Gülten M, Bıyıklı Z. Non-alcoholic steatohepatitis with normal aminotransferase values. 
World Journal of Gastroenterology. 2009;15(15):1863. 

 
 
 
 
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Procedure for accounting for missing, unused, and spurious data will be explained in 
the statistical analysis plan. 
Any deviation(s) from the original statistical plan will be described in the final report). 
16.4.3 Secondary analysis: 
- The mean change in Fib-4 score between the experimental arms and the control arm 
from baseline till end of treatment using T-test (Mann-Whitney test in case of non-
parametric data). This analysis will be a comparative analysis and will be done on 
eligible population of patients without protocol violation and who have at least one 
treatment dose and an evaluable primary endpoint (AST and ALT). 
- Number of patients experiencing hepatic complications between the experimental arms 
and control arm at the end of the treatment using chi-square (Fischer for non-
parametric data. This analysis will be a comparative analysis and will be done on 
eligible population of patients without protocol violation and who have at least one 
treatment dose and an evaluable primary endpoint (AST and ALT). 
16.4.4 Exploratory analysis: 
- The mean relative change in lipid profile levels between the experimental arms and the 
control arm from baseline till end of treatment using T-test (Mann-Whitney test in case 
of non-parametric data). This analysis will be a comparative analysis and will be done 
on eligible population of patients without protocol violation and who have at least one 
treatment dose and an evaluable primary endpoint (AST and ALT). 
16.4.5 Interim analysis: 
- Interim analysis will be performed when all patients complete 6 months of treatment. If 
a statistically significant difference is observed between placebo and active arm(s), the 
study will be terminated for the benefit of patients who were randomly assigned to 
placebo arm and to rapidly disseminate evidence supporting a treatment benefit to the 
broader community9.
                                                          
9Zannad F, et al. Development of Therapeutics for Heart Failure. When to Stop a Clinical Trial Early for Benefit: Lessons 
Learned and Future Approaches. Circulation: Heart Failure. 2012; 5: 294-302. doi: 
10.1161/CIRCHEARTFAILURE.111.965707 

 
 
 
 
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16.5 
RANDOMIZATION 
During screening visit, each patient will be allocated to a Patient Identifier (Patient 
ID) number. This will be a 4-digit number where the first digit identifies the study site 
and the last 3 digits (sequential numbers within the site) will identify the patient at a 
given study center. The subject ID will be retained throughout the study and will be 
used to uniquely identify each patient. Even patient who are not eligible to participate 
in the study will be assigned a patient ID and will be recorded in the screening log. 
For patients eligible to receive double-blind treatment, a randomization number will 
be allocated at baseline visit (Visit 2/ Week 0) at the time of randomization. This 
randomization number will be used to identify and dispense the drug kits allocated to 
each subject. 
Note that the subject identifier number (Subject ID) which uniquely identifies the 
subject is different from the randomization number (uniquely identifies a drug kit). It 
is the investigator’s responsibility to ensure that each subject receives the study 
medication allocated to him.  
Randomization of patients to one of the 3 treatment arms will be done through 
“Interactive response system”.  
The double-blind supplies will be provided to the investigator along with individually 
sealed envelopes containing the randomization (assigned drug) for each patient. This 
allows the investigator to break the treatment code for an individual patient in the 
event of an emergency. These sealed randomization envelopes must be kept in a 
secure place for inspection by Sponsor and/or its designated representative from time 
to time during the course of study and will be collected by the Clinical Research 
Associate at the end of the study. Even if a pharmacy is used to store and/or dispense 
the medication, the sealed copy of the randomization will remain with the investigator.  
 
 

 
 
 
 
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17 
ETHICAL AND REGULATORY STANDARDS 
17.1 
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. 
17.2 
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. 
17.3 
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. 

 
 
 
 
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17.4 
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. 
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). 
 

 
 
 
 
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18 
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. 
 

 
 
 
 
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19 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE 
CLOSE-OUT OF A SITE 
The sponsor may discontinue the study or close-out a site in some cases e.g.; 
- 
If the information on the product leads to doubt as to the benefit/risk ratio; 
- 
If the Investigator has received from the Sponsor all Investigational Product, means and 
information necessary to perform the Clinical Trial and has not included any patient after 
a reasonable period of time mutually agreed upon; 
- 
If results of interim analysis show a statistically significant difference between placebo 
and active arms (in favor of active arm), the study will be terminated for the benefit of 
patients who were randomly assigned to placebo arm and to rapidly disseminate evidence 
supporting a treatment benefit to the broader community; 
- 
If the aim of the Clinical Trial has become outdated or is no longer of interest; 
- 
In the event of breach by the Investigator of a fundamental obligation under this 
agreement, including but not limited to breach of the Clinical Trial Protocol, breach of 
the applicable laws and regulations or breach of the ICH guidelines for Good Clinical 
Practice. 
In any case, the Sponsor will inform the appropriate Ethics Committee(s) (IRB/IEC) and Health 
Authorities. In addition, investigators should be notified by written notice. 
 

 
 
 
 
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20 
RESPONSIBILITIES OF INVESTIGATORS AND SPONSORS 
20.1 
RESPONSIBILITIES OF THE 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 electronic 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 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. 
 

 
 
 
 
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20.2 
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. 
 

 
 
 
 
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21 
CONFIDENTIALITY AND DATA PROTECTION 
21.1 
CONFIDENTIALITY 
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. 
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. 
21.2 
DATA PROTECTION 
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. 

 
 
 
 
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22 
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 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. 
   
 
 

 
 
 
 
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23 
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