| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatitis C Virus Genotype 1 |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019751 |
| E.1.2 | Term | Hepatitis C virus |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019744 |
| E.1.2 | Term | Hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 |
For Segment 1:
• Evaluate the safety and tolerability of ACH-0141625 or placebo at multiple oral dose levels, in combination with SOC therapy.
• Evaluate the Rapid Virologic Response at Week 4 (RVR4), defined as HCV RNA ≤ limit of quantification [LOQ]), for combination therapy ACH-0141625 plus SOC after 4 weeks of dosing.
For Segment 2:
• Evaluate the safety and tolerability of ACH-0141625 at multiple oral dose levels, in combination with SOC therapy, 180 μg once every week pegylated interferon alfa-2a and 1000 to 1200 mg/day ribavirin (herein referred to as SOC), after 12 weeks of dosing.
• Evaluate cEVR, defined as HCV RNA reported as undetectable at Week 12 for subjects treated with combination therapy of ACH-0141625 plus SOC after 12 weeks of dosing. |
|
| E.2.2 | Secondary objectives of the trial |
• Segment 1: cEVR, define as HCV RNA reported as undetectable at Week 12.
• Segment 2: Rapid Virologic Response at Week 4 (RVR4), defined as HCV RNA ≤ limit of detection (LOQ), for combination therapy of ACH-0141625 plus SOC after 4 weeks of dosing in subjects infected with hepatitis C virus genotype 1.
* Evaluate eRVR, defined as HCV RNA reported as undetectable at Weeks
4 and 12 for subjects treated with combination therapy of ACH-0141625
plus SOC after 12 weeks of dosing in subjects infected with hepatitis C
virus genotype 1.
* Early Virologic Response (EVR12);
* End of Treatment Response (ETR)
* Sustained Virologic Response at 12 weeks (SVR12)
* Sustained Virologic Response (SVR),
* Time to HCV RNA ≤LOQ;
* Time to undetectable
* Change from Baseline in log10 HCV RNA at Weeks 4, 12, 24, 48, 60 and 72;
* PK/PD relationship
* Segment 2: To assess the viral kinetics and pharmacodynamics of 6 genotype 1a subjects following 5 days of monotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and females aged 18 years or older
2. Chronic HCV infection, documented by one of the following:
• positive for anti-HCV antibody, HCV RNA, or an HCV genotype at least 6 months before screening, and positive for HCV RNA and anti-HCV antibody at the time of screening;
• or positive for anit-HCV antibody and HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of CHC disease, such as the presence of fibrosis).
3. HCV genotype 1 (including 1a, 1b or mixed 1a/1b); subjects with mixed genotypes (e.g. 1/2, 1/3, etc.) or other genotypes (e.g. 2, 3, 4, 5, or 6) will be excluded.
4. Females who are post-menopausal and amenorrheic must have an FSH measurement at screening with results in the post-menopausal range for the central laboratory. Females of childbearing potential or surgically sterilized females must have a negative pregnancy test at screening and baseline. Females must use a non-hormonal method of contraception and must agree not to get pregnant during the study and for six months following the discontinuation of standard of care.
5. Fertile males, defined as all males physiologically capable of conceiving offspring, may be enrolled in this study. Males in this category must agree to use a condom and his female partner must agree to use one or more methods of contraception from the date of screening until 6 months after their last dose of RBV. Males must not donate sperm while enrolled in this study and for three months following the last exposure to RBV
6. Signed and dated written informed consent form
7. Willing to participate in all study activities (including the ability to safely self-inject study drug subcutaneously) and all study requirements (including effective contraception) during study period
8. Treatment naïve subjects. |
|
| E.4 | Principal exclusion criteria |
1. Body Mass Index (BMI) > 36
2. Pregnant or nursing (lactating) females, confirmed by a positive hCG laboratory test or females contemplating pregnancy. Men whose female partners are pregnant or contemplating pregnancy.
3. Participation in any interventional clinical trial within previous 35 days.
4. History of participation in a clinical trial with a protease inhibitor or previous treatment with a protease inhibitor, where at least one dose of the protease inhibitor was consumed.
5. Use of herbal or homeopathic products, illicit drugs, CYP3A4/5 substrates, inducers or inhibitors (See Appendix 8), hormonal methods of contraception, corticosteroids, immunosuppressives, or cytotoxic agents within 28 days of first dose of study drug.
6. History of poor compliance with health and treatment regimens.
7. Have a clinically significant laboratory abnormality at screening:
• Absolute neutrophil count (ANC) <1,500 / mm2 (1.5 x 109/L)
• Platelets <90,000/mm2 (90 x 109/L)
• Hemoglobin <13 g/dL for males; <12 g/dL for females
• Serum creatinine > 1.5 x ULN or creatinine clearance < 50 mL/min; estimated by the Cockroft-Gault formula [(140-age) x weight (kg) / 72 x serum creatinine (mg/dL), if female multiply by 0.85].
• Total bilirubin > 1.2 mg/dL
• Segment 1: Serum alanine transaminase (ALT) > 2 x ULN
• Segment 2: (ALT) > 5 x ULN
• Segment 1: Serum aspartate aminotransferase (AST) > 2 x ULN
• Segment 2: (AST) > 5 x ULN
• Fasting serum glucose > 140 mg/dL and HbA1c > 7.5% (including diabetic subjects on medication) or new onset diabetes.
• Abnormal thyroid stimulating hormone (TSH) of >1.2 ULN, or unstable thyroid disease.
• Alpha fetoprotein (AFP) > 20 ng/mL unless a liver imaging study (CT or MRI) shows no clinically significant lesions within 6 months prior to the Baseline visit.
8. Known HIV-1 or HIV-2 infection/serology
9. Positive Hepatitis B Surface Antigen (HBsAg)
10. Segment 1: Subjects with any history of decompensated liver disease defined as cirrhotic subjects with a Child-Pugh score of ≥ 7. Decompensated liver disease includes the presence of ascites, variceal bleeding, hepatic encephalopathy, or other signs of progressive portal hypertension or progressive hepatic insufficiency. (based on fibroscan or liver biopsy). Segment 2: Subjects who have had a liver biopsy that shows bridging fibrosis or cirrhosis (Metavir >3, Ishak>4).
11. Nonalcoholic steatohepatitis (NASH) if ballooning degeneration or Mallory bodies are present on liver biopsy.
12. Other forms of liver disease (e.g. alcoholic, autoimmune, biliary, Wilson’s, Gilbert’s, Dubin Johnson, and Crigler Najjar syndromes).
13. Subjects who prematurely discontinued, interrupted, or dose reduced prior PegIFN-alfa and RBV therapy, due to noncompliance or safety and/or tolerability issues.
14. Encephalopathy or altered mental status of any etiology
15. History of moderate, severe or uncontrolled psychiatric disease (e.g. depression, including a history of hospitalization or prior suicidal attempt), bipolar disease, schizophrenia, or personality disorder. Subjects with a history of mild, stable depression may be considered provided that a pretreatment assessment (including a depression scale, BDI-II or HADS) of the subject’s affective status supports that the subject is clinically stable. Subjects with a score that is elevated (greater than 29 for BDI-II, 7 for HADS) will require further clinical evaluation for depression prior to inclusion into the study. The investigator must formulate and document a depression management plan prior to randomization for these subjects, and must review the subject’s affective status according to the plan at every visit.
16. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basel cell carcinoma of the skin.
17. Use of colony stimulating factor agents within 90 days prior to baseline.
18. History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures.
19. History of major organ transplantation (solid or hematopoietic) other than cornea or hair transplant.
20. History of seizure disorder
21. History of known coagulopathy including hemophilia
22. Clinically significant findings on fundoscopic or retinal examination at screening based on the investigator’s clinical judgment or by ophthalmologist/optometrist
23. History of immunologically mediated disease (e.g. rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, inflammatory bowel disease, moderate/severe psoriasis).
24. History or clinical evidence of chronic cardiac disease; ECG with clinically significant abnormality. The Long QT syndrome or QTc > 450 msec for males and > 470 msec for females at screening or Baseline.
25. Received concomitant systemic antibiotics, antifungals, or antivirals for the treatment of active |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Segment 1: Proportion of subjects with RVR4, defined as undetectable HCV RNA in plasma by Roche- COBAS® TaqMan® HCV Test, v2.0 For Use With The High Pure System (HPS) at Week 4. The assay has a dynamic range of 25 – 391 x106 IU/mL with a limit of quantification (LOQ) of 25 IU/mL and a limit of detection (LOD) of approximately 25 IU/mL.
Segment 2: Proportion of subjects with cEVR, defined as HCV RNA reported as undetectable at Week 12 for subjects treated with combination therapy of ACH-0141625 plus SOC after 12 weeks of dosing in subjects infected with hepatitis C virus genotype 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Segment 1: Week 4
Segment 2: Week 12 |
|
| E.5.2 | Secondary end point(s) |
Segment 1: The proportions of subjects with eRVR, EVR12, cEVR12, ETR, SVR12, SVR and changes in HCV RNA over the course of each study segment.
Segment 2: The proportions of subjects with RVR4, eRVR, EVR12, ETR, SVR12, SVR and changes in HCV RNA over the course of each study segment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Over the course of each study segment |
|
| 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 | Yes |
| 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 | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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