Randomized, Open-Label, Study to Evaluate the Safety and Efficacy of Sofosbuvir Tablet Plus Ribavirin Tablet (Part A) Versus Single Dose (2 Tablets) of EHCV Containing Sofosbuvir, Ribavirin, and Natural Anti-hemolytic (B) in Egyptian Adults With Chronic Genotype 4 HCV Infection
Randomized, Open-Label, Study to Evaluate the Safety and Efficacy of Sofosbuvir Tablet Plus Ribavirin Tablet (Part A) Versus Single Dose (2 Tablets) of EHCV Containing Sofosbuvir, Ribavirin, and Natural Anti-hemolytic (B) in Egyptian Adults With Chronic Genotype 4 HCV Infection
Two Groups of Genotype 4 HCV Patients will participate through open-label randomized Study
 comparing Sofosbuvir tablet Plus Ribavirin tablet (Part A) versus single Dose (2 tablets) of
 EHCV containing Sofosbuvir, Ribavirin, and Natural anti-hemolytic (B) evaluating the safety
 and efficacy for both arms.

 Sponsor: Wadi El Nil Hospital

 Study Centers Planned: Approximately 2 sites in Egypt
Study Design:

 Part A

 Randomized, open-label study in treatment naïve and treatment experienced adults with chronic
 genotype 4 HCV infection.

 Treatment-naïve is defined as having never received treatment for HCV with any interferon
 (IFN), RBV, or other approved or experimental HCV specific direct acting antivirals.

 Treatment-experienced is defined as:

 1. IFN Intolerant

 2. Non-response

 3. Relapse/Breakthrough

 It is planned that 40 + 40 subjects will be enrolled in the study such that an approximate
 even number of treatment naïve and treatment experienced subjects will be enrolled across the
 2 treatment arms:

 Arm 1 Sofosbuvir 400 mg once daily +RBV (1000 mg/day) for 12-24 weeks

 Arm 2 Single Dose (2 tablets) once daily each tablet containing SOF 200 mg, RBV 500 mg, and
 Natural anti-hemolytic (AH) at 200 mg for 12-24 weeks Treatment assignments will be
 stratified according to prior treatment experience and the presence or absence of cirrhosis.

 Cohorts:

 Cohort is a single-arm, open-label, non-randomized design in subjects who completed treatment
 in Part A of the study with SOF+RBV for 12-24 weeks or in Part B of the study with single
 dose EHCV (2 Tablet) containing SOF/RBV/AH FDC for 12-24 weeks.

 Diagnosis and Main Eligibility Criteria: HCV RNA > 104 IU/mL or HCV RNA > LLOQ and did not
 achieve SVR 12 after completing prior treatment in this study with chronic genotype 4 HCV
 infection. Treatment-naïve or treatment experienced adults, male and
 non-pregnant/non-lactating female subjects, ages 18 years or older. See Section 1 and 1.2 of
 the protocol for detailed Inclusion and Exclusion criteria.

 Study Procedures/

 Frequency: Study visits for all subjects will occur at screening, Baseline/Day 1.
 On-treatment visits will occur as follows:

 • Part A, Arm 1 and 2 - at the end of Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 All
 subjects will complete a 4-Week Post-treatment visit regardless of treatment duration.
 Subjects with HCV RNA < LLOQ will continue to 12 Week and 24 Week Post treatment visits
 unless confirmed viral relapse occurs at which time subjects will be early terminated from
 the study.

 Screening assessments include safety laboratory tests (chemistry, hematology, coagulation,
 and urinalysis), 12 lead ECG, HCV RNA, serology (HBV, and HIV), hemoglobin A1c, urine drug
 screen, liver imaging, serum B-hCG (for all female subjects of child-bearing potential),
 physical examination (with height and bodyweight), vital signs, medical history, concomitant
 medications, and adverse events. In addition, subjects being screened for Part A and Part B
 (Cohort 1) will have HCV genotyping and IL28B genotyping performed.

 On-treatment assessments include safety laboratory tests (chemistry, hematology, and
 coagulation), HCV RNA, urine pregnancy tests (for all female subjects of child-bearing
 potential), physical examination, vital signs, concomitant medications, and adverse events.

 Post-treatment assessments include HCV RNA, urine pregnancy tests (for all female subjects of
 child-bearing potential), vital signs, concomitant medications, and adverse events.

 Samples will be collected at Baseline/Day 1 and every visit Plasma samples will be collected
 during treatment visits for pharmacokinetic (PK) analysis of study drug (Part A only).
 Untested samples will be archived for up to 10 years.

 Test Product, Dose, and Mode of Administration: SOF is manufactured as a 400 mg tablet for
 oral administration. Subjects will take 1 tablet for a total dose of 400 mg orally once daily
 in the morning with RBV (1000 mg) splitted on 2 doses daily 600 mg on morning and 400 mg on
 evening and with food for 12-24 weeks.

 The fixed dose EHCV combinations in Single Dose (2 tablets) once daily each tablet containing
 SOF 200 mg, RBV 500 mg, and Natural anti-hemolytic (AH) at 200 mg. Subjects will take 2
 tablet with food for 12-24 weeks.

 Reference Therapy, Dose, and Mode of Administration: None

 Criteria for Evaluation:

 Safety: Adverse events will be collected from baseline through the 4 Week Post-Treatment
 Visit and AEs related to study procedures, will be collected from when subjects sign the
 consent form. Clinical laboratory tests will be performed during treatment through the 12
 Week Post-Treatment Visit.

 Efficacy: Efficacy will be evaluated using scheduled assessments of HCV RNA performed using
 COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System.

 PK Part A only. A single PK blood sample will be collected at all study visits while on
 Treatment.

 Statistical Methods: The primary efficacy endpoint is SVR12 (ie, HCV RNA < LLOQ 12 weeks
 post-treatment) in all subjects who are randomized and treated. No statistical hypothesis
 testing will be performed. For each of the two treatment groups, a 2-sided 95% confidence
 interval using the exact binomial distribution will be constructed.

 Part A: With a sample size of 40 subjects in each arm, a two sided 95% exact confidence
 interval will extend at most 29% in length.

 Part B: With a sample size of 40 subjects in each treatment group in Cohort 1, a 2-sided 95%
 exact confidence interval will extend at most 32% in length.

 Secondary efficacy endpoints include the proportion of subjects with SVR4 and SVR24.

 All continuous endpoints will be summarized using an 8 number summary (n, mean, standard
 deviation, and median, Q1, Q3, minimum, maximum) by treatment duration. All categorical
 endpoints will be summarized by number and percentage of subjects who meet the endpoint
 definition.

 Safety endpoints will be analyzed by the number and percent of subjects with events or
 abnormalities for categorical values or using an 8 number summary (n, mean, standard
 deviation, median, Q1, Q3, minimum, maximum) for continuous data by treatment group.

 Data from Part B will be analyzed separately from Part A and may be reported separately.

 This study will be conducted in accordance with the guidelines of Good Clinical Practices
 (GCPs) including archiving of essential documents.
Inclusion Criteria

 Inclusion Criteria for Part A

 Subjects must meet all of the following inclusion criteria to be eligible for participation
 in this study.

 1. Willing and able to provide written informed consent.

 2. Male or female, age ≥ 18 years.

 3. HCV RNA ≥ 104 IU/mL at screening.

 4. Confirmed chronic HCV infection as documented by either:

 a. a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping
 test at least 6 months prior to the Baseline/Day 1 visit, or

 5. HCV genotype 4 at screening as determined by the Central Laboratory. Any
 non-definitive results will exclude the subject from study participation.

 6. The subject's medical records must be sufficient to categorize prior treatment history
 as one of the following:

 i) IFN-intolerant: subject had documented intolerance to IFN during prior IFN therapy
 of up to 12 weeks duration ii) Non-response: subject did not achieve undetectable HCV
 RNA levels on treatment iii) Relapse/Breakthrough: subject achieved undetectable HCV
 RNA levels during treatment or within 4 weeks after treatment and later showed
 detectable HCV RNA

 An Absence of cirrhosis is defined as any one of the following:

 -  Liver biopsy within 2 years of Screening showing absence of cirrhosis

 -  Fibroscan with a result of ≤ 12.5 kPa within 6 months of Baseline/Day1

 -  FibroTest score of ≤ 0.48 AND APRI of ≤ 1 performed during Screening In the
 absence of a definitive diagnosis of the presence or absence of cirrhosis by the
 above criteria, a liver biopsy is required. Liver biopsy results supersede the
 results obtained by Fibroscan or Fibro Test.

 7. Body mass index (BMI) ≥ 18 kg/m2.

 8. Screening ECG without clinically significant abnormalities.

 9. Subjects must have the following laboratory parameters at screening:

 -  ALT ≤ 10 x the upper limit of normal (ULN)

 -  AST ≤ 10 x ULN

 -  Hemoglobin ≥ 12 g/dL for male, ≥ 11 g/dL for female subjects

 -  Platelets > 50,000 cells/mm3

 -  INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an
 anticoagulant regimen affecting INR

 -  Albumin ≥ 3 g/dL

 -  Direct bilirubin ≤ 1.5 x ULN

 -  HbA1c ≤ 10%

 -  Creatinine clearance (CLcr) ≥ 60 mL/min, as calculated by the Cockcroft-Gault
 equation

 10. Subject has not been treated with any investigational drug or device within 30 days of
 the screening visit.

 11. A female subject is eligible to enter the study if it is confirmed that she is:

 1. Not pregnant or nursing

 2. Of non-childbearing potential (ie, women who have had a hysterectomy, both
 ovaries removed or medically documented ovarian failure, or are postmenopausal
 women > 50 years of age with cessation [for 12 months] of previously occurring
 menses), or

 3. Of childbearing potential (ie, women who have not had a hysterectomy, both
 ovaries removed, or no medically documented ovarian failure). Women ≤ 50 years of
 age with amenorrhea will be considered to be of childbearing potential. These
 women must have a negative serum pregnancy test at screening and a negative urine
 pregnancy test on the Baseline/Day 1 visit prior to randomization. They must also
 agree to one of the following from 3 weeks prior to Baseline/Day 1 until 6 months
 after last dose of RBV:

 -  Complete abstinence from intercourse. Periodic abstinence from intercourse
 (eg, calendar, ovulation, symptothermal, post-ovulation methods) is not
 permitted.

 Or

 -  Consistent and correct use of 1 of the following methods of birth control listed
 below in addition to a male partner who correctly uses a condom from the date of
 screening until 6 months after the last dose of RBV. Women of childbearing
 potential must not rely on hormone-containing contraceptives as a form of birth
 control during the study. Female subjects using a hormone-containing
 contraceptive prior to screening may continue their contraceptive regimen in
 addition to the study specified methods of birth control.

 -  Intrauterine device (IUD) with a failure rate of < 1% per year

 -  Female barrier method: cervical cap or diaphragm with spermicidal agent

 -  Tubal sterilization

 -  Vasectomy in male partner

 12. All male study participants must agree to consistently and correctly use a condom,
 while their female partner agrees to use either 1 of the non-hormonal methods of birth
 control listed above or a hormone-containing contraceptive listed below, from the date
 of screening until 7 months after their last dose of RBV:

 -  Implants of levonorgestrel

 -  Injectable progesterone

 -  Oral contraceptives (either combined or progesterone only)

 -  Contraceptive vaginal ring

 -  Transdermal contraceptive patch

 13. Male subjects must agree to refrain from sperm donation for at least 7 months after
 the last dose of RBV.

 14. Subject must be of generally good health as determined by the Investigator.

 15. Subject must be able to comply with the dosing instructions for study drug
 administration and able to complete the study schedule of assessments.

 Inclusion Criteria for Part B

 Subjects must meet all of the following inclusion criteria to be eligible for participation
 in this study.

 1. Willing and able to provide written informed consent.

 2. Male or female, age ≥ 18 years.

 3. HCV genotype 4 at screening as determined by the Central Laboratory. Any
 non-definitive results will exclude the subject from study participation. Historical
 result from prior participation in this study is acceptable, if applicable.

 4. Cohort 1 only: HCV RNA ≥ 104 IU/mL at screening.

 5. Chronic HCV infection (≥ 6 months) documented by medical history.

 6. Cohort 1 only: HCV treatment naïve, defined as no prior exposure to any IFN, RBV, or
 other approved or experimental HCV specific direct acting antiviral agent

 7. BMI ≥ 18 kg/m2

 Absence of cirrhosis is defined as any one of the following:

 1. Liver biopsy within 2 years of Screening showing absence of cirrhosis

 2. Fibroscan with a result of ≤ 12.5 kPa within 6 months of Baseline/Day1 C- Fibro
 Test score of ≤ 0.48 AND APRI of ≤ 1 performed during Screening

 In the absence of a definitive diagnosis of the presence or absence of cirrhosis by
 the above criteria, a liver biopsy is required. Liver biopsy results supersede the
 results obtained by Fibroscan or Fibro Test.

 8. Screening ECG without clinically significant abnormalities.

 9. Subjects must have the following laboratory parameters at screening:

 -  ALT ≤ 10 x the upper limit of normal (ULN)

 -  AST ≤ 10 x ULN

 -  Hemoglobin ≥ 12 g/dL for male, ≥ 11 g/dL for female subjects

 -  Platelets > 50,000 cells/mm3

 -  INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an
 anticoagulant regimen affecting INR

 -  Albumin ≥ 3 g/dL

 -  Direct bilirubin ≤ 1.5 x ULN

 -  HbA1c ≤ 10%

 -  Creatinine clearance (CLcr) ≥ 60 mL/min, as calculated by the Cockcroft-Gault
 equation

 Subjects who received prior treatment in this study and who currently do not fulfill
 all of the above requirements may be enrolled in Part B Cohort 2 at the request of the
 Investigator and with the approval of the Medical Monitor or Study Director.

 10. Subject has not been treated with any investigational drug or device within 28 days of
 the Baseline/Day 1 visit.

 11. A female subject is eligible to enter the study if it is confirmed that she is:

 D Not pregnant or nursing e Of non-childbearing potential (ie, women who have had a
 hysterectomy, both ovaries removed or medically documented ovarian failure, or are
 postmenopausal women > 50 years of age with cessation [for 12 months] of previously
 occurring menses), or

 F Of childbearing potential (ie, women who have not had a hysterectomy, both ovaries
 removed, or no medically documented ovarian failure). Women ≤ 50 years of age with
 amenorrhea will be considered to be of childbearing potential. These women must have a
 negative serum pregnancy test at screening and a negative urine pregnancy test on the
 Baseline/Day 1 visit prior to randomization. They must also agree to one of the
 following from 3 weeks prior to Baseline/Day 1 until 30 days after the last dose of
 LDV/SOF or 6 months after last dose of RBV:

 • Complete abstinence from intercourse. Periodic abstinence from intercourse (eg,
 calendar, ovulation, symptothermal, post-ovulation methods) is not permitted.

 Or

 -  Consistent and correct use of 1 of the following methods of birth control listed
 below in addition to a male partner who correctly uses a condom from the date of
 screening until 30 days after the last dose of LDV/SOF or 6 months after the last
 dose of RBV.

 -  Intrauterine device (IUD) with a failure rate of < 1% per year

 -  Female barrier method: cervical cap or diaphragm with spermicidal agent

 -  Tubal sterilization

 -  Vasectomy in male partner

 -  Implants of levonorgestrel

 -  Injectable progesterone

 -  Oral contraceptives (either combined or progesterone only)

 -  Contraceptive vaginal ring

 -  Transdermal contraceptive patch

 12. All male study participants must agree to consistently and correctly use a condom from
 Baseline until 90 days after their last dose of LDV/SOF or 7 months after their last
 dose of RBV. If their female partner is of childbearing potential (as defined above),
 she must use 1 of the methods of birth control listed above from the date of screening
 until 90 days after their last dose of LDV/SOF or 7 months after their last dose of
 RBV.

 13. Male subjects must agree to refrain from sperm donation for at least 7 months after
 the last dose of RBV or 90 days after their last dose of LDV/SOF, as applicable.

 14. Subject must be of generally good health as determined by the Investigator.

 15. Subject must be able to comply with the dosing instructions for study drug
 administration and able to complete the study schedule of assessments.

 Exclusion Criteria

 Exclusion Criteria for Part A

 Subjects who meet any of the following exclusion criteria are not to be enrolled in this
 study.

 1. for treatment naïve subjects only: Prior exposure to IFN, RBV, or other approved or
 experimental direct-acting antiviral targeting the HCV.

 2. for treatment-experienced subjects: prior exposure to a NS5a inhibitor, NS5b
 nucleotide inhibitor, or NS5b non-nucleotide inhibitor targeting the HCV

 3. Pregnant or nursing female or male with pregnant female partner.

 4. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease, α1
 antitrypsin deficiency, cholangitis).

 5. Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).

 6. Contraindication to RBV therapy e.g., history of clinically significant
 hemoglobinopathy (sickle cell disease, thalassemia).

 7. History of malignancy diagnosed or treated within 5 years (recent localized treatment
 of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma
 in situ is allowed if appropriately treated prior to screening); subjects under
 evaluation for malignancy are not eligible.

 8. Chronic use of systemically administered immunosuppressive agents (eg, prednisone
 equivalent > 10 mg/day).

 9. Clinically-relevant drug or alcohol abuse within 12 months of screening. A positive
 drug screen will exclude subjects unless it can be explained by a prescribed
 medication; the diagnosis and prescription should be approved by the investigator.

 10. History of solid organ transplantation.

 11. Current or prior history of clinical hepatic decompensation (eg, ascites, variceal
 hemorrhage, hepatic encephalopathy, hepatorenal syndrome and hepatopulmonary
 syndrome).

 12. History of clinically-significant illness or any other major medical disorder that may
 interfere with subject treatment, assessment or compliance with the protocol.

 13. History of a gastrointestinal disorder (or post-operative condition) that could
 interfere with the absorption of the study drug.

 14. History of significant pulmonary disease, significant cardiac disease or porphyria.

 15. Excessive alcohol ingestion, defined as 3 glasses/day (1 glass is equivalent to 284 mL
 beer, 125 mL wine, or 25 mL distilled spirits) for females and 4 glasses/day for
 males.

 16. History of difficulty with blood collection and/or poor venous access for the purposes
 of phlebotomy.

 17. Donation or loss of more than 400 mL blood within 2 months prior to Baseline/Day 1.

 18. Known hypersensitivity to RBV, the study investigational medicinal product, the
 metabolites, or formulation excipients.

 Exclusion Criteria for Part B

 Subjects who meet any of the following exclusion criteria are not to be enrolled in this
 study.

 1. For treatment naïve subjects only (Cohort 1): Prior exposure to IFN, RBV, or other
 approved or experimental direct-acting antiviral targeting the HCV.

 2. Current or prior history of any of the following:

 A Clinical hepatic decompensation (ie, ascites, encephalopathy or variceal hemorrhage)
 B Clinically-significant illness (other than HCV) or any other major medical disorder
 that may interfere with subject treatment, assessment or compliance with the protocol,
 or, current evaluation for a potentially clinically significant illness (other than
 HCV) C Gastrointestinal disorder or post-operative condition that could interfere with
 the absorption of the study drug D Solid organ transplantation E Significant pulmonary
 disease, significant cardiac disease or porphyria F Psychiatric hospitalization,
 suicide attempt, and/or a period of disability as a result of their psychiatric
 illness within the last 5 years Subjects with psychiatric illness (without the prior
 mentioned conditions) that is well-controlled on a stable treatment regimen for at
 least 6 months prior to Baseline/Day 1 or that has not required medication in the last
 12 months may be enrolled.

 G Any malignancy within the 5 years prior to screening, with the exception of specific
 cancers that are cured by surgical resection (basal cell skin cancer, etc.), or
 current evaluation for possible malignancy H Difficulty with blood collection and/or
 poor venous access for the purposes of phlebotomy I Significant drug allergy (such as
 anaphylaxis or hepatotoxicity)

 3. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease, α1
 antitrypsin deficiency, cholangitis)

 4. Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)

 5. Use of any prohibited concomitant medications

 6. Contraindication to RBV therapy, including significant history of clinically
 significant hemoglobinopathy (eg, sickle cell disease, thalassemia)

 7. In the judgment of the investigatory, any clinically-relevant drug or alcohol abuse
 within 12 months of screening that may interfere with subject treatment, assessment of
 compliance with the protocol

 8. Pregnant or nursing females or male with pregnant female partner

 9. Known hypersensitivity to RBV, SOF, or formulation excipients