Hepatitis C
Conditions
Brief summary
This randomized, double-blind, placebo-controlled, 3-part study will assess the safety, tolerability, pharmacokinetics (PK), and antiviral activity (Part 3 only) of orally administered AL-611 in healthy volunteers (HV; Parts 1-2) and subjects with CHC (Part 3). Part 1: HV will receive 1 of 5 single ascending doses (SAD) of AL-611 Part 2: Eight HV from Cohort 3 in Part 1 are planned to receive a second single dose of AL-611 or placebo (as per their randomized assignment in Part 1) in a fed state after a washout period Part 3: Subjects with CHC infection will receive 1 of 3 planned multiple ascending doses (MAD)
Interventions
DRUGPlacebo
Placebo to Match AL-611
DRUGAL-611
AL-611 tablets
Sponsors
Alios Biopharma Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject has provided written consent. * In the investigator's opinion, the subject is able to understand and comply with protocol requirements, instructions, and protocol stated restrictions and is likely to complete the study as planned. * Except in compensated cirrhosis (cirrhosis cohorts only) and diagnosis of HCV (Part 3 only), subject is in good health as deemed by the investigator, based on the findings of a medical evaluation including medical history, physical examination, laboratory tests, and ECG. * Male or female, 18-60 years of age for HV and 18-70 years of age for subjects with CHC. * Body mass index (BMI) 18-30 kg/m2, inclusive, for HV and 18-35 kg/m\^2, inclusive, for subjects with CHC. The minimum weight is 50 kg in both populations. * A female subject is eligible to participate in this study if she is of non-childbearing potential (defined as females with a documented tubal ligation, bilateral oophorectomy, or hysterectomy) or postmenopausal (defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females). * If male, subject is surgically sterile or practicing specific forms of birth control until 6 months after the end of the study. Male subjects must agree to refrain from sperm donation from start of dosing through 6 months after the completion of study drug administration. * Subject agrees to refrain from blood donation from screening until 56 days after the last study visit. * For HV, estimated glomerular filtration rate (eGFR) in the normal range as determined by modification of diet in renal disease (MDRD) formula. For CHC (Part 3) eGFR\>60ml/min/1.73m\^2 as determined by MDRD (alternative calculations (eg, Cockroft-Gault) may be permissible, if approved by the Sponsor). Additional inclusion criteria for subjects with CHC infection (Part 3): * Subjects must have GT1 or GT3 CHC (or GT1-6 for Part 3 optional cohorts) infection identified at screening. * Documentation of HCV infection for greater than 6 months before randomization as defined by either documented HCV serology demonstrating the presence of anti-HCV antibodies at least 6 months before randomization or documented presence of HCV RNA at least 6 months before randomization. * Screening HCV RNA viral load ≥50,000 IU/mL (except for subjects with compensated cirrhosis, who may have HCV RNA viral load ≥10\^4 IU/mL) using Ampliprep COBAS® Taqman® HCV Test 2.0 * Cirrhotic subjects in Part 3 must have compensated cirrhosis AND meet the Child-Pugh Class A definition AND have a screening Fibroscan with a liver stiffness score\>12.5 kPa.
Exclusion criteria
1. History or other clinical evidence of significant or unstable cardiac disease (eg, angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia (eg, long QT syndrome, torsades de pointes), coronary heart disease), moderate to severe valvular disease or poorly controlled hypertension at screening. 2. Family history of prolonged QT syndrome (eg, torsade de pointes) or sudden cardiac death. 3. Clinically significant abnormal screening ECG findings (eg, PR \>220 msec, QRS interval \>120 msec or corrected QT interval (QTcF) \>450 msec for male subjects and \>470 msec for female subjects). 4. Participation in either an investigational drug trial or an investigational vaccine trial within 30 days or 5 half lives (whichever is longer) prior to starting study medication. 5. Clinically significant blood loss or elective blood donation of significant volume (ie, \>500 mL) within 60 days prior to screening; \>1 unit of plasma within 7 days prior to screening. 6. Unwilling to abstain from alcohol for 48 hours prior to the start of dosing through the study completion visit. 7. History of regular alcohol intake \>14 units per week of alcohol for females and \>21 units per week for males (one unit is defined as 10 g alcohol) within 3 months of randomization 8. The subject has a positive alcohol test at screening or on Day -2. 9. Hypersensitivity to the active substance or to any of the excipients of AL-611 10. Abnormal (using local normal range) heart rate, respiratory rate, temperature or blood pressure (BP) values (evaluated in a semi-recumbent or recumbent position after 5 minutes of rest). One repeat measurement after an additional \ 5 minutes of rest is permitted. In addition, a repeat measurement performed on a separate day is also permitted. 11. Clinically significant cardiovascular, respiratory, renal, gastrointestinal, hepatic, hematologic, neurologic, oncologic (except adequately treated basal cell carcinoma and cervical intraepithelial neoplasia \[CIN\] I or II), autoimmune, or any other medical illness or psychiatric disorder, as determined by the Investigator. CHC with/without compensated cirrhosis acceptable for cohorts enrolling CHC subjects with/without compensated cirrhosis, respectively, but non-HCV related hepatic disease is exclusionary. 12. Positive test for hepatitis A virus (HAV) IgM, hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV) antibody. For HV HCV is exclusionary. 13. Evidence of active infection (topical fungal infections which are considered not clinically significant are permitted). CHC is inclusionary for Part 3 only. 14. History of regular use of tobacco (ie, ≥10 cigarettes per day or equivalent for alternative nicotine products (eg, e cigarettes)) within 3 months of randomization. 15. The subject has a positive drug screen during screening or on Day -2. For CHC, prescribed medications with a stable dose for at least 21 days may be considered by the Investigator and Sponsor Medical Monitor; cannabis is permitted. 16. From 14 days (or 5 half-lives, whichever is longer) prior to admission to the Phase 1 Unit until randomization, use of any medications, including prescription, over the counter, and herbal medications, is exclusionary. The only exceptions are acetaminophen, ibuprofen, hormone replacement therapy, and thyroid hormone replacement therapy. 17. Abnormal screening laboratory results that are considered clinically significant by the investigator or as specified in the protocol. Additional
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence and severity of Treatment emergent Adverse events | Up to 21 days |
| Physical examination findings | Up to 21 days |
| Incidence and severity of vital sign abnormalities | Up to 21 days |
| Incidence and severity of 12 lead electrocardiagram abnormalities | Up to 21 days |
| Incidence and severity of clinical laboratory abnormalities | Up to 21 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| tmax of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| C24h of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| Clast of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| tlast of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| t1/2 of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| CL/F of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| Vz/F of AL-611 following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 following single dose administration |
| Cmax of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| AUClast of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| Cmax of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration | Day 1 to Day 21 | PK parameters of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration |
| tmax of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration | Day 1 to Day 21 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration |
| Cmin of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration | Day 1 to Day 21 | PK parameters of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration |
| t1/2 of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration | Day 1 to Day 21 | PK parameters of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration |
| AUClast of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration | Day 1 to Day 21 | PK parameters of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration |
| AUC0_tau of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration | Day 1 to Day 21 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration |
| AUC0-inf of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration | Day 1 to Day 8 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following single dose administration |
| C0_h of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration | Day 1 to Day 21 | PK parameter of AL-611 and ALS-022358 (and other metabolites if applicable) following repeat dose administration |
| Concentrations in urine of AL-611 and ALS 022358 (and other metabolites if applicable) after a single oral dose | Day 1 to Day 8 | Concentrations in urine of AL-611 and ALS 022358 (and other metabolites if applicable) after a single oral dose in HV in fasted conditions |
| HCV RNA viral load in subjects with CHC | Screening to Day 21 | HCV RNA viral load (over time, maximum decrease from baseline, and change from baseline over time) in subjects with CHC, defined by GT and host characteristic (eg, presence/absence of compensated cirrhosis) |
| Sequence analysis of HCV | Day 1 to Day 21 | — |
Countries
Belgium
Outcome results
None listed