A Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335, Odalasvir, and Simeprevir
Condition: Chronic Hepatitis C
MeSH terms: Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic
Intervention: AL-335; Odalasvir (ODV); Simeprevir (SMV)
Intervention description: AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).; ODV capsules will be administered in a dose range of 25 to 50 mg.; SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).
Intervention MeSH terms: Simeprevir; Odalasvir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 161.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the safety and tolerability of AL-335 in combination
      with odalasvir (ODV) with or without simeprevir (SMV) in participants with genotype (GT)1 or
      GT2 or GT3 chronic hepatitis C (CHC) infection.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Participant has provided written consent

          2. In the Investigator's opinion, the participant is able to understand and comply with
             protocol requirements, instructions, and protocol stated restrictions and is likely to
             complete the study as planned

          3. Male or female, 18-70 years of age

          4. Body mass index (BMI) 18-35 kilogram per meter square (kg/m^2), inclusive

          5. A woman of childbearing potential must have a negative serum (beta-human chorionic
             gonadotropin) pregnancy test at screening

          6. Female participants must either:

               -  not be of childbearing potential defined as: i. Postmenopausal for at least 12
                  months (that is [i.e.], 2 years of amenorrhea without an alternative medical
                  cause) and a serum follicle stimulating hormone (FSH) level in the postmenopausal
                  range (per reference laboratory), OR ii. Surgically sterile (example [e.g.],
                  underwent total hysterectomy, bilateral oophorectomy, or bilateral tubal
                  ligation/bilateral tubal clips without reversal operation), or otherwise
                  incapable of becoming pregnant, OR

               -  be of childbearing potential AND

               -  not heterosexually active (e.g., abstinent or homosexual) from screening until 6
                  months after study drug administration (or longer, if dictated by local
                  regulations), OR

               -  if heterosexually active

                    -  have a vasectomized partner (confirmed sterile per verbal account of the
                       participant), OR

                    -  using an acceptable method of birth control from screening and agree to
                       continue to use the same method of contraception throughout the study and
                       for 6 months after study drug administration (or longer, if dictated by
                       local regulations). Oral hormone based contraceptives are not allowed from
                       14 days before the planned study drug administration until 6 months after
                       the last dose of treatment due to the potential for drug-drug interactions
                       which might undermine their efficacy. An intrauterine device (IUD), being
                       either hormonal (i.e., Intra-Uterine System [IUS*]) or non-hormonal, is
                       considered highly effective and reliable; therefore participants using an
                       IUD/IUS are not required to use additional contraceptive methods (no
                       double-barrier method is required). Other non-oral hormone-based
                       contraception methods (e.g., injectable, implants, transdermal system,
                       vaginal ring) may be continued, but as the interaction of the study drug
                       with hormone-based contraception is unknown, these methods are not
                       considered to be reliable and therefore participants should use a
                       double-barrier method (e.g., male condom+either diaphragm or cervical cap
                       with or without spermicide).

                         -  An IUS does not rely on systemic plasma concentrations and is therefore
                            not expected to be impacted by a potential drug-drug interaction (DDI)

             Note 1: Sexual abstinence is considered a highly effective method only if defined as
             refraining from heterosexual intercourse during the entire period of risk associated
             with the study drug. The reliability of sexual abstinence needs to be evaluated in
             relation to the duration of the study and the preferred and usual lifestyle of the
             participant.

             Note 2: A male and female condom should not be used together due to risk of breakage
             or damage caused by latex friction

          7. A post-menopausal female who is receiving hormone replacement therapy and is willing
             to discontinue hormone therapy 30 days before study drug dosing and agrees to remain
             off hormone replacement therapy for the duration of the study may be eligible for
             study participation.

               -  Male participants must either:

               -  be surgically sterile (had a vasectomy), or otherwise incapable of fathering a
                  child, OR

               -  not be heterosexually active (e.g., abstinent or homosexual) from enrollment (Day
                  1) in the study until at least 6 months after study drug administration, OR

               -  if heterosexually active:

                    -  have a partner who is postmenopausal (2 years amenorrhea), surgically
                       sterile (e.g., has had a total hysterectomy, bilateral oophorectomy, or
                       bilateral tubal ligation/bilateral tubal clips without reversal operation),
                       or otherwise incapable of becoming pregnant OR

                    -  be practicing an acceptable method of birth control from enrollment in the
                       study (Day 1) and agree to continue to use the same method of contraception
                       throughout the study and for at least 6 months after study drug
                       administration (or longer, if dictated by local regulations). An acceptable
                       method of birth control for male participants is a double-barrier method
                       (e.g., male condom+either diaphragm or cervical cap with or without
                       spermicide).

             Note: Male participants with a female partner who uses hormonal contraceptives (oral,
             injectable, implants) or a hormonal (IUS) or non-hormonal IUD and male participants
             who are vasectomized or otherwise incapable of fathering a child are not required to
             use additional contraceptive methods.

             Note 1: Sexual abstinence is considered a highly effective method only if defined as
             refraining from heterosexual intercourse during the entire period of risk associated
             with the study drug. The reliability of sexual abstinence needs to be evaluated in
             relation to the duration of the study and the preferred and usual lifestyle of the
             participant.

             Note 2: A male and female condom should not be used together due to risk of breakage
             or damage caused by latex friction.

             NOTE: Contraceptive use by men and women should be consistent with local regulations
             regarding the use of contraceptive methods for participants participating in clinical
             studies if these are stricter than what is proposed in these inclusion criteria

          8. Participants must agree to refrain from sperm/egg donation from start of dosing
             through 6 months after the completion of study drug administration

          9. Genotype (GT) 1a or 1b or GT2 or 3 chronic hepatitis C (CHC), depending on cohort,
             with positive Hepatitis C virus (HCV) antibody and a positive HCV ribonucleic acid
             (RNA) at screening including documentation of CHC infection for at least 6 months.
             Genotype testing must occur at a screening visit. NOTE: GT1 patients are eligible for
             inclusion even if they cannot be successfully subtyped unless a specific subtype is
             required for a cohort

         10. Screening HCV RNA viral load greater than or equal to (>=) 50,000 International Units
             per milliliter (IU/mL), except for participants with compensated cirrhosis (Child Pugh
             Class A) who may have HCV RNA viral load >=10^4 IU/mL

         11. No prior treatment for CHC (defined as no prior exposure to any approved or
             investigational drug including direct-acting antivirals, and interferon-based
             treatments)

         12. Fibroscan, collected within 6 months of baseline visit, with liver stiffness score
             less than or equal to (<=) 12.5 kilo Pascal (kPa) to be eligible (except for
             participants with cirrhosis, see below).

               -  participants with compensated cirrhosis must meet the Child-Pugh Class A
                  definition (see Appendix G) and at least one of the following criteria: i. Liver
                  biopsy result indicating the presence of cirrhosis (e.g., Metavir F4; Ishak >5)
                  or ii. Fibroscan evaluation with a liver stiffness score >12.5 kPa

         13. Participant is otherwise in good health as deemed by the investigator, based on the
             findings of a medical evaluation including medical history, physical examination,
             laboratory tests and electrocardiogram (ECG)

         14. Willing to avoid prolonged sun exposure and use of tanning devices while taking
             Simeprevir (SMV) and through 4 weeks of follow up. Participant should also be advised
             to use a broad-spectrum sunscreen and lip balm of at least sun protection factor >30
             to help protect against potential sunburn

        Exclusion Criteria:

          1. Pregnant, planning on becoming pregnant (during treatment and up to 6 months after the
             end of treatment [EOT]), or breast-feeding female participant, or male participant
             whose female partner is pregnant or planning on becoming pregnant (during treatment
             and up to 6 months after the EOT)

          2. Other than CHC with or without compensated cirrhosis, clinically significant
             cardiovascular, respiratory, renal, gastrointestinal, hematologic, neurologic, thyroid
             or any other medical illness or psychiatric disorder, as determined by the
             Investigator and/or Sponsor's Medical Monitor

          3. History or other clinical evidence of significant or unstable cardiac disease (e.g.,
             angina, congestive heart failure, myocardial infarction, diastolic dysfunction,
             significant arrhythmia, coronary heart disease, and/or clinically significant ECG
             abnormalities), moderate to severe valvular disease or uncontrolled hypertension at
             screening

          4. Screening echocardiogram ejection fraction <55 percentage (%) or any other
             echocardiographic finding suggestive of clinically relevant cardiomyopathy

          5. Creatinine clearance of <60 mL/min (Cockcroft-Gault)

          6. Positive test for Hepatitis A virus immunoglobulin (HAV) Immunoglobulin M (IgM),
             Hepatitis B surface antigen (HBsAg), or Human Immunodeficiency Virus (HIV) Ab

          7. Abnormal screening laboratory results that are considered clinically significant by
             the investigator

          8. History of clinical hepatic decompensation, e.g., variceal bleeding, spontaneous
             bacterial peritonitis, ascites, hepatic encephalopathy or active jaundice (within last
             year)

          9. Any condition that, in the opinion of the investigator, would compromise the study's
             objectives or the well-being of the participant or prevent the participant from
             meeting the study requirements

         10. Participation in an investigational drug trial or having received an investigational
             vaccine within 30 days or 5 half lives (whichever is longer) prior to study medication

         11. Clinically significant abnormal screening ECG findings (e.g., PR >200 msec, QRS
             interval >120 millisecond (msec) or corrected QT interval (QTc) >450 msec for male
             participants and >470 msec for female participants), based on an average of triplicate
             ECGs. Any evidence of heart block or bundle branch block is also exclusionary

         12. History or family history of abnormal ECG intervals, for example prolonged QT syndrome
             (torsade de pointes) or sudden cardiac death

         13. The participant has a positive prestudy drug screen, including methadone unless the
             drug is prescribed by the participant's physician. The list of drugs that should be
             screened for includes amphetamines, barbiturates, cocaine, opiates, phencyclidine
             (PCP), and benzodiazepines

         14. Laboratory abnormalities including:

               -  Hematocrit <0.34

               -  White blood cell counts <3,500/millimeter (mm)^3 (<1,000/mm^3 for participants
                  with compensated cirrhosis)

               -  Absolute neutrophil count <1,000/mm^3 (<750/mm^3 for participants with
                  compensated cirrhosis)

               -  Platelets <=120,000/mm^3 (platelets ≤90,000/mm^3 for participants with
                  compensated cirrhosis)

               -  Glycosylated hemoglobin (HbA1C) >55 mmol/mol

               -  Prothrombin time >=1.5 * upper limit of normal (ULN)

               -  Albumin <=32 gram per liter (g/L), bilirubin >=1.5 milligram per deciliter
                  (mg/dL) at screening (participants with documented Gilbert's disease allowed)

               -  Serum ALT concentration >=5* ULN

               -  CK >1.5* ULN A single repeat laboratory evaluation under appropriate conditions
                  (e.g., fasted, no antecedent exercise) is allowed for eligibility determination

         15. Any condition possibly affecting drug absorption (e.g., gastrectomy or other
             significant gastrointestinal tract surgery, such as gastroenterostomy, small bowel
             resection, or active enterostomy)

         16. Clinically significant blood loss or elective blood donation of significant volume
             (i.e., >500 mL) within 60 days of first dose of study drug; >1 unit of plasma within 7
             days of first dose of study drug

         17. Evidence of clinically relevant active infection that would interfere with study
             conduct or its interpretation

         18. History of regular alcohol intake >10 standard drinks per week of alcohol for females
             and >15 standard drinks per week for males (one unit is defined as 10 g alcohol)
             within 3 months of the screening visit

         19. The use of prohibited medications, including prescription, over the counter (OTC)
             medications, herbal medications, inducers or inhibitors of Cytochrome P450 (CYP450)
             enzymes or drug transporters (including P-gp) within 14 days prior to the first dose
             of study medication is excluded, unless previously approved by the Sponsor's Medical
             Monitor. NOTE: Chronic medication use is permitted so long as they are medically
             necessary, deemed acceptable by the Principal Investigator and Medical Monitor, and
             not Prohibited Medications (see Section 5.12)

         20. Hypersensitivity to the active substances (including sulfa allergy) or to any of the
             excipients of AL-335, Odalasvir (ODV) or SMV

         21. Evidence on recent (within 6 months) liver ultrasound of hepatic mass or lesion
             concerning for malignancy (participants with cirrhosis only)