| 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 tolerability of AT-527 in combination with daclatasvir
•To evaluate the efficacy of the combination of AT-527 and daclatasvir as measured by the proportion of subjects who achieve SVR12 (HCV RNA < lower limit of quantitation (LLOQ) at 12 weeks after end of treatment (EOT)) with 8 or 12 weeks of treatment
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| E.2.2 | Secondary objectives of the trial |
•To determine the proportion of subjects who achieve HCV RNA < LLOQ by study visit
•To evaluate the proportion of subjects with virologic failure, on-treatment or post- treatment
•To evaluate the effect of baseline resistance-associated substitutions (RASs) on SVR12 and emergence of RASs in subjects with virologic failure
•To characterize the steady-state pharmacokinetics (PK) of the study drugs
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent.
2. Male or female subjects between 18 and 65 years of age, inclusive (or the legal age of consent per local regulations).
3. Body mass index (BMI) of 18-35 kg/m2, inclusive.
4. QTcF interval ≤ 450 ms for males and ≤ 460 ms for females at Screening. Note: The mean of the triplicate should be used to assess the QTcF.
5. Male subjects and female subjects of childbearing potential must agree to use protocol specified methods of contraception as described in Section 5.10.
6. Females must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Day 1 prior to dosing.
7. Male subjects must agree not to donate sperm from the first dose through 90 days after the last dose of study drugs.
8. Subjects must not consume grapefruit or grapefruit juice within 7 days of reporting to the clinic on Day 1 and must agree not to do so through the end of the treatment period.
9. Subjects may be treatment-naïve or treatment-experienced (except for prior NS5A inhibitor recipients, exclusion 4), 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
10. Subjects must have HCV genotype 1 documented at Screening.
11. 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
12. HCV RNA bigger or equal to 10,000 IU/mL at Screening.
13. Subject is, in the opinion of the investigator, willing and able to comply with the study drug regimen and all other study requirements
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| E.4 | Principal exclusion criteria |
1.Female subject is pregnant or breastfeeding.
2.Co-infected with hepatitis B virus and/or human HIV.
3.Abuse of alcohol and/or illicit drug use that could interfere with adherence to study requirements as judged by the investigator. A positive screen for drug(s) of abuse will exclude subjects unless it can be explained by a prescribed medication and approved by the investigator.
4.Prior exposure to any HCV NS5A inhibitor.
5.Concomitant use of any known major inhibitor or inducer of cytochrome P450 (CYP) 3A4. A washout period of at least 5 half-lives of the CYP 3A4 drug 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.
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 investigator feels that the drug can be safely discontinued or substituted for the duration of the study.
7.Concomitant use of herbal or natural supplements 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. 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 will be allowed during the study, except ±4 h of dosing.
9.Concomitant use of any other medication that is contraindicated for use with daclatasvir according to its prescribing information. 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.
10.Requires frequent or prolonged use of systemic corticosteroids or other immunosuppressive drugs
Topical or inhaled corticosteroids are permitted.
11.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.
12.Subject with intestinal malabsorption (e.g., structural defects, digestive failure or enzyme deficiencies with the exception of lactose intolerance).
13.Subject with known allergy to the study medication(s) or any of their components.
14.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.
15.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.
16.History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC.
17.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%.
•Poorly controlled asthma, with more than one urgent-care visit for acute asthma attack in previous 12 months, or asthma requiring systemic corticosteroid maintenance therapy.
•Any other clinically significant medical condition that, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results. This includes any other conditions which are contraindicated in the daclatasvir prescribing information.
18.Clinically significant abnormal ECG at Screening, as determined by the investigator.
19.Confirmed resting blood pressure > 160/95 mmHg at Screening, either untreated or on hypertension treatment. Note: Continuation of anti- hypertensive medications is allowed.
20.Any of the following laboratory parameters at Screening:
•ALT or AST > 7 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 < 4,000/mm3 or absolute neutrophil count
< 2,500/mm3
•Platelet count < 120 x 109/L
•Estimated glomerular filtration rate (GFR) < 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:
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 PK parameters of study drugs (and their metabolites, 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| There is a single treatment, with arms that differ only by treatment duration based on response |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 |
| Mauritius |
| Moldova, Republic of |
| Ukraine |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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