A Study of the Efficacy and Safety of PPI-668 (NS5A Inhibitor) Plus Sofosbuvir, With or Without Ribavirin, in Patients With Chronic Hepatitis C Genotype-4
A Study of the Efficacy and Safety of PPI-668 (NS5A Inhibitor) Plus Sofosbuvir, With or Without Ribavirin, in Patients With Chronic Hepatitis C Genotype-4
The study will assess the efficacy of PPI-668 (USAN: ravidasvir hydrochloride) in combination
 with sofosbuvir, with or without ribavirin, in the following Egyptian HCV gt-4 patient
 populations:

 1. Treatment-naïve patients, with and without cirrhosis (Group 1)

 2. Previous non-responders to interferon-based therapies, without cirrhosis (Group 2)

 3. Previous non-responders to interferon-based therapies, with cirrhosis (Group 3)
Inclusion Criteria:

 1. Males or females, ≥ 18 years & ≤ 65 years of age.

 2. HCV antibody positive, with serum HCV RNA ≥ 10,000 IU/mL, with clinical history
 compatible with chronic hepatitis C.

 3. HCV genotype-4 infection, confirmed at the central study laboratory

 4. Body mass index (BMI) between 18 and 35 kg/m2, inclusive.

 5. 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.

 6. Patients for Group 1 must be treatment-naïve - i.e., they have never received any
 antiviral treatment for their HCV infection, including interferon, pegylated
 interferon, ribavirin, or other regulatory-approved or investigational HCV antiviral
 therapies.

 7. Patients for Groups 2 and 3 must have previously failed treatment with an
 interferon-based therapy - i.e., interferon or pegylated interferon, with or without
 ribavirin, with no other previous HCV antiviral therapies.

 Patients for Group 2 must be non-cirrhotic diagnosed on screening visit by both
 Fibroscan™ liver stiffness measurement < 12.5 kPa and FIB-4 score < 3.25 if the
 results of Fibroscan and FIB-4 score are not matching; liver biopsy will be used for
 detection of cirrhosis. In case that the liver biopsy is not applicable, hepatic
 imaging or ultrasound reports could be used for determination of cirrhosis.

 Patients for Group 3 must have underlying cirrhosis diagnosed on screening visit by
 both Fibroscan liver stiffness measurement > 12.5 kPa and FIB-4 score > 3.25, if the
 results of Fibroscan and FIB-4 score are not matching liver biopsy will be used for
 detection of cirrhosis. In case that the liver biopsy is not applicable, hepatic
 imaging or ultrasound reports could be used for determination of cirrhosis.

 8. Willing and able to give informed consent

 9. Willing and able to complete all study visits and procedures, including compliance
 with the requirements and restrictions listed in the consent form.

 Exclusion Criteria:

 1. Mixed genotype or non-typable HCV genotype infection,

 2. Positive test for HBsAg or HIV antibody, or IgM antibody to HAV or HEV

 3. History of schistosomiasis or positive test for schistosoma surface antigen at Screen.

 4. 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.

 5. History of treatment with any investigational or regulatory-approved direct-acting
 antiviral (DAA) agent for HCV infection - nucleos(t)ide or non-nucleosidic HCV
 polymerase inhibitor, HCV protease inhibitor, NS5A inhibitor, or other antiviral agent
 for HCV infection other than pegylated -interferon and/or ribavirin Previous pegylated
 interferon and/or ribavirin treatment is allowed for Groups 2 and 3 but prohibited for
 group 1, as noted above in Inclusion criterion 6)

 6. Evidence of a medical condition other than HCV that is contributing to liver disease

 7. History of, or clinical signs of, hepatic decompensation or portal hypertension:

 Variceal bleeding, or documented esophageal or GI varices (at investigator discretion,
 patients suspected of having esophageal varices should be evaluated by endoscopy, and
 varices excluded) Ascites by history or on physical examination Documented or
 suspected hepatic encephalopathy

 Physical signs of portal hypertension:

 Clinically significant splenomegaly Spider angiomata History of porto-systemic shunt
 procedure(s)

 8. Uncontrolled diabetes mellitus as evidenced by HgbA1C ≥ 8.5% at Screening.

 9. Hemoglobin < 11g/dL for females and < 12 g/dL for males

 10. WBC count < 3,500/mm3 OR absolute neutrophil count (ANC) < 1800/mm

 11. Platelet count < 75,000/mm3

 12. Serum creatinine > 1.3 x ULN OR creatinine clearance (GFR) < 50 mL/minute

 13. Serum ALT or AST >10x ULN

 14. Serum albumin ≤ 3.2 g/dl

 15. Direct serum bilirubin > 2xULN

 16. INR > 1.7.

 17. History of poorly controlled asthma, with one or more hospitalizations or emergency
 room visits in the previous 6 months

 18. History of any malignancy within the last 5 years (except prostate cancer still within
 Glisson's capsule or basal cell carcinoma of the skin).

 19. 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.

 20. History of drug abuse as assessed by the investigator within the last 2 years.

 21. Pregnancy, including current lactation in female patients, male patients with partners
 who are pregnant, or female patients intending to become pregnant.

 22. Major surgery requiring overnight hospitalization within 3 months prior to Screening

 23. Participation in another clinical trial of an investigational drug or device within 6
 months prior to Screening

 24. Current use or history of use within the preceding 6 months of immunosuppressive or
 immune-modulating agents, including: azathioprine, systemic corticosteroids
 (prednisone or prednisone equivalent of more than 10mg/day for more than 10 days), or
 other immunosuppressive agents. Use of inhaled steroids for mild/moderate asthma and
 topical steroids for minor skin conditions is allowed.

 25. History of solid organ or bone marrow transplantation.

 26. History of use of medications associated with QT prolongation concurrently or within
 the 30 days prior to Screening Visit, including: macrolides, antiarrhythmic agents,
 azoles, fluoroquinolones, and tricyclic anti-depressants.

 27. correction, or a personal or family history of Torsades de Pointe.

 28. Cardiac ischemia with history of recurrent angina, clinically symptomatic cardiac
 abnormalities, or requirement for cardiac pacemaker

 29. History of a known allergy to ribavirin (RBV), or any excipient in the investigational
 product, or history of drug or other allergy that, in the opinion of the investigator,
 mitigates against study participation