| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hepatitis C virus infection |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019751 |
| E.1.2 | Term | Hepatitis C virus |
| E.1.2 | System Organ Class | 100000004848 |
|
| 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 |
• Safety and tolerability
• Plasma and urine pharmacokinetics (PK)
• The effect of food on the PK of IDX21437
• Antiviral activity
|
|
| E.2.2 | Secondary objectives of the trial |
|
| 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. Male or female subjects between 18 and 65 years of age, inclusive (or the legal age of consent per local regulations).
3. Minimum body weight of 50 kg and body mass index (BMI) of 18-32 kg/m2 (Group A) or 18-35 kg/m2 (Groups B-E), inclusive.
4. All subjects of childbearing potential must have agreed to use a double-method of birth control (one of which must be a barrier) from Screening through at least 90 days after the last dose of the study drug.
Non-childbearing potential is defined as:
• Females: postmenopausal, defined as amenorrheic for at least 2 years and serum follicle stimulating hormone (FSH) level consistent with postmenopausal status at Screening, or a self-reported hysterectomy, bilateral oophorectomy or bilateral tubal ligation at least 6 months prior to Screening.
• Males: a self-reported vasectomy at least 6 months prior to Screening.
5. Females must have a negative serum beta-human chorionic gonadotropin (β-HCG) at Screening and a negative pregnancy test (urine or β-HCG) at Day -1.
6. Male subjects must have agreed not to donate sperm from the first dose through 90 days after the last dose of study drug.
7. Subject must not have consumed grapefruit or grapefruit juice within 7 days of reporting to the clinic on Day -1, and agrees not to do so through the end of the study.
8. Subject is, in the opinion of the investigator, willing and able to comply with the study drug regimen and all other study requirements.
Group A Specific (must also meet the following)
9. Subject must not have smoked or used nicotine-containing products within 6 months prior to Day -1 and agrees not to do so for the duration of the study.
Groups B, C, D and E Specific (must also meet the following)
10. Subjects in Group B may have received prior treatment with interferon (IFN) and ribavirin for hepatitis C infection but not treatment with any direct-acting antivirals (DAA). Subjects in Groups C, D and E must be HCV treatment-naïve (i.e., no prior exposure to any antiviral treatment for hepatitis C infection).
11. Documented clinical history compatible with chronic hepatitis C, including any one of the following:
• anti- HCV antibody positive at least 6 months prior to Screening or dosing, OR
• HCV genotype results at least 6 months prior to Screening or dosing, OR
• HCV RNA present in plasma by a sensitive and specific assay at least 6 months prior to Screening or dosing, OR
• Histologic evidence of chronic hepatitis C infection
12. HCV Genotype 1, 2, 3, 4, 5 or 6 by HCV genotyping performed at Screening (genotype dependent on the group/cohort enrolling). Note: For a specific genotype, mixed subtypes are acceptable but mixed genotypes are not.
13. Plasma HCV RNA ≥ 5.0 log10 IU/mL at Screening.
Group E Specific (must also meet the following)
14. Subjects must be Child-Pugh Class A.
|
|
| 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 60 days prior to dosing.
4.Abuse of alcohol and/or drugs that could interfere with adherence to study requirements as judged by the investigator.
5.Positive screen result for drugs of abuse or alcohol at Screening or on Day –1.
6.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.
7.Concomitant use of herbal or dietary supplements. A washout period of at least 7 days must be observed prior to study drug dosing.
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.Concomitant use of the following medications: amlodipine, aripiprazole, atorvastatin, carvedilol, diazepam, diltiazem, fluoxetine, isradipine, perphenazine, procainamide, simvastatin, thioridazine or verapamil. A washout period of at least 5 half-lives must be observed prior to initiating study drug dosing, if the investigator feels that the drug can be safely discontinued or substituted for the duration of the study.
10.Use of other investigational drugs within 60 days of dosing, or plans to enroll in another clinical trial of an investigational agent while participating in the present study.
11.Subject with intestinal malabsorption (e.g., structural defects, digestive failure or enzyme deficiencies with the exception of lactose intolerance).
12.Subject with known allergy to the study medication or any of its components.
13.Cardiac disease, family history of congenital heart disease, family history of prolonged QT, or family history of sudden death of unknown etiology.
14.One or more of the following abnormalities:
•First degree, or greater, heart block.
•QTcF interval ≥ 430 ms for males or ≥ 450 ms for females, at Screening, Day -1 and Day 1 (prior to the first dose).
•Clinically significant abnormal ECG at Screening or Day -1, as determined by the investigator.
15.At Screening or Day -1: an estimated glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 as estimated by the Modification of Diet in Renal Disease (MDRD) formula.
16.Hemoglobin (Hgb) < 13.0 g/dL for males, < 12.0 g/dL for females.
17.Any 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.
Group A Specific (following also excluded)
18.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.
19.Abnormal laboratory values at Screening or Day -1 that are considered to be clinically significant by the investigator(s).
20.Positive screen for HCV antibody.
Groups B, C and D Specific (following also excluded)
21.Clinical (in the opinion of the investigator) or laboratory evidence of cirrhosis (e.g., Metavir 4 or Ishak 6).
Groups B, C, D and E Specific (following also excluded)
22.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.
23.History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC.
24.Active clinically significant diseases including:
•Primary or secondary causes of liver disease (other than hepatitis C).
•Malignant disease or suspicion or history of malignant disease within previous 5 years (except for adequately treated basal cell carcinoma).
•Poorly controlled diabetes mellitus as evidenced by hemoglobin A1c ≥ 8.5% at Screening.
25.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.
26.Abnormal values at Screening or Day -1:
•ALT or AST > 5 x upper limit of normal (ULN)
•platelet count < 120 x 109/L
•Any other laboratory abnormality that is considered to be clinically significant by the investigator(s) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
plasma PK samples
urine PK samples |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| see protocol Tables 7-4, 7-5 & 7-6 |
|
| E.5.2 | Secondary end point(s) |
PK endpoints=plasma and urine concentrations of IDX21437 and metabolites
Safety endpoints=adverse events and laboratory abnormalities
Antiviral activity endpoints=change in HCV RNA viral load |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
see Tables 7-1 through 7-6.
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
| tolerability, food effect, anti-viral activity |
|
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 19 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 |
|
| 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
|
|
| 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 | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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