| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047457 |
| E.1.2 | Term | Viral hepatitis C |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the safety and the tolerability of single oral doses of AT-777 in healthy male and female subjects
• To evaluate the safety and tolerability of AT-777 in combination with AT-527 in HCV-infected subjects
• To evaluate the single oral dose PK of AT-777 in healthy male and female subjects
• To evaluate multiple oral dose PK of AT-777 and AT-527 when used in combination in HCV-infected subjects
• To evaluate the antiviral activity of the combination of AT-777 and AT-527 as measured by the proportion of HCV-infected subjects who achieve HCV RNA < LLOQ and TND after 2 weeks of treatment
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of the combination of AT-777 and AT-527 as measured by the proportion of HCV-infected subjects who achieve SVR12 (HCV RNA < LLOQ at 12 weeks after end of treatment (EOT)) with 8 weeks of treatment
• To determine the proportion of HCV-infected subjects who achieve HCV RNA < LLOQ by study visit
• To evaluate the proportion of HCV-infected subjects with virologic failure, on-treatment or post-treatment
• To evaluate the effect of baseline resistance-associated variants (RAVs) on SVR12 and emergence of RAVs in HCV-infected subjects with virologic failure
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Read and signed the written informed consent form (ICF) after the nature of the study has been fully explained.
2. Body mass index (BMI) of 18.0-35.0 kg/m2, inclusive.
3. QTcF interval ≤ 450 ms for males and ≤ 460 ms for females at Screening, Day -1 (Part A) and Day 1 (prior to dosing). Note: The mean of the triplicate should be used to assess the QTcF.
4. Male subjects and female subjects of childbearing potential must agree to use protocol specified methods of contraception as described in Section 5.10.
5. Females must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day -1 (Part A) or Day 1 (prior to dosing; Part B).
6. Male subjects must agree not to donate sperm from the first dose through 90 days after the last dose of study drug(s).
7. Subjects must not consume grapefruit or grapefruit juice within 7 days of the first dose of study drug(s) and must agree not to do so through the end of the dosing period.
8. Subject is, in the opinion of the investigator, willing and able to comply with the study drug regimen and all other study requirements.
Part A specific (must also meet the following):
9. Male or female healthy subjects between 18 and 55 years of age, inclusive (or the legal age of consent per local regulations).
10. Subjects must not have smoked or used nicotine-containing products within 6 months prior to Day -1 and agree not to do so for the duration of the study.
Parts B specific (must also meet the following):
11. Male or female subjects between 18 and 65 years of age, inclusive (or the legal age of consent per local regulations)
12. Subjects may be treatment-naïve or treatment-experienced (except for prior NS5A inhibitor recipients, exclusion 17), classified as one of the following:
• Treatment-naïve: Never exposed to approved or experimental HCV DAA(s) or interferon with or without ribavirin
• Treatment-experienced: Prior treatment failure to approved or experimental HCV DAA(s) and/or interferon with or without ribavirin; prior treatment must have been completed or discontinued more than three months prior to Screening for the present study
13. Subjects must have HCV genotype 1, 2 or 3 at Screening.
14. Documented medical history compatible with chronic hepatitis C, including any one of the following:
• anti-HCV antibody or HCV RNA positive at least once prior to Screening, OR
• HCV infection likely acquired from exposures more than 6 months prior to Screening
15. HCV RNA ≥ 10,000 IU/mL at Screening. |
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| E.4 | Principal exclusion criteria |
1. Female subject is pregnant or breastfeeding.
2. Co-infected with hepatitis B virus (HBV, HBsAg positive) and/or human immunodeficiency virus (HIV).
3. Donated more than 500 mL of blood or had significant blood loss within 60 days prior to Screening.
4. Abuse of alcohol and/or drugs that could interfere with adherence to study requirements as judged by the investigator.
5. Concomitant use of any known major inhibitor or inducer of cytochrome P450 (CYP) 3A4.
6. Concomitant use of any known major inhibitor or inducer of P-glycoprotein (P-gp; e.g. rifampin, St. John’s wort) or breast cancer resistance protein (BCRP). A washout period of at least 5 half-lives of the drug must be observed prior to study drug dosing, if the of the study.
7. Concomitant use of herbal or natural supplements (e.g. echinacea, milk thistle). A washout period of at least 7 days must be observed prior to study drug dosing, if the investigator feels that they can be safely discontinued or substituted for the duration of the study.
8. Concomitant use of acid blockers (e.g., proton-pump inhibitors). A washout period of at least 5 half-lives must be observed prior to study drug dosing, if the investigator feels that the drug can be safely discontinued or substituted for the duration of the study. Antacids (stomach acid neutralizers such as calcium carbonate or aluminum hydroxide-based products) will be allowed during the study, except ±4 h of dosing.
9. Use of other investigational drugs within 30 days of dosing, or plans to enroll in another clinical trial of an investigational agent while participating in the present study.
10. Subject with intestinal malabsorption (e.g., structural defects, digestive failure or enzyme deficiencies with the exception of lactose intolerance).
11. Subject with known allergy to the study medication(s) or any of their components.
12. Clinically significant abnormal ECG at Screening, Day -1 (Part A) or Day 1 (prior to dosing), as determined by the investigator.
13. Any clinically significant medical condition that, in the opinion of the investigator, would jeopardize the safety of the subject or potentially impact subject compliance or the efficacy/safety/PK observations in the study.
Part A specific (following also excluded):
14. Concomitant use of prescription medications, or systemic over-the-counter medications. A washout period of at least 5 half-lives must be observed prior to study drug dosing, if the investigator feels that the medication can be safely discontinued for the duration of the study.
15. Abnormal laboratory values at Screening or Day -1 that are considered to be clinically significant by the investigator(s). Note: Subjects with ALT, AST, total bilirubin or alkaline phosphatase outside the normal range at Screening or Day -1 will be excluded.
16. Positive screen for HCV antibody.
Parts B specific (following also excluded):
17. Prior exposure to any HCV NS5A inhibitor.
18. Prior evidence of cirrhosis, defined by any one of the following:
i. Liver biopsy showing cirrhosis
ii. Transient elastography (FibroScan®) with a result of > 12.5 kPa
Absence of cirrhosis may be confirmed by one of the above methods, if available within 1 year of Screening. Otherwise, transient elastography assessment may be done during Screening.
19. History or signs of decompensated liver disease: ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, or other clinical signs of portal hypertension or hepatic insufficiency.
20. History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC.
21. Active clinically significant diseases including:
• Primary or secondary causes of liver disease other than hepatitis C (e.g., hemochromatosis, alpha-1 antitrypsin deficiency, Wilson’s Disease, cholangitis).
• Malignant disease or suspicion or history of malignant disease within previous 5 years (except for adequately treated basal or baso-squamous cell carcinoma).
• Insulin-treated diabetes mellitus or hemoglobin A1c > 7.0%.
22. Requires frequent or prolonged use of systemic corticosteroids or other immunosuppressive drugs (e.g., for organ transplantation or autoimmune conditions). Topical or inhaled corticosteroids are permitted.
23. Any of the following laboratory parameters at Screening:
• ALT or AST > 5 x upper limit of normal (ULN)
• Total bilirubin > 1.5 x ULN, unless the subject has known Gilbert’s syndrome
• Albumin < 3.5 g/dL
• International Normalized Ratio (INR) ≥ 1.7
• Hemoglobin < 10 g/dL for females or < 12 g/dL for males
• Total white blood cell (WBC) count or absolute neutrophil count < lower limit of normal (LLN)
• Platelet count < 120 x 109/L
• Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 as estimated by the Modification of Diet in Renal Disease (MDRD) formula |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
safety assessment:
Adverse events (AEs), physical examination, vital signs, 12-lead electrocardiogram (ECG) and standard safety laboratory tests
efficacy assessment:
Plasma HCV RNA quantified using a validated commercial assay. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At different timepoints during the study as specified in the protocol |
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| E.5.2 | Secondary end point(s) |
| Plasma concentrations and derived parameters of AT-777, AT-527 and/or their metabolite/s, as applicable |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At different timepoints during the study as specified in the protocol |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Sequential, single ascending doses |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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