A Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335, Odalasvir, and Simeprevir

• Status: Completed
• Trial end date: 2018-05-11
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Alios Biopharma Inc.
• Treatments: Odalasvir; Simeprevir

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)