| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The genotype 1 Chronic Hepatitis C Infection |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10057212 |
| E.1.2 | Term | Hepatitis viral infections |
|
| 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 efficacy of five weekly followed by up to 17 monthly doses of GI-5005 in combination with pegylated interferon and ribavirin in subjects with chronic genotype 1 hepatitis C infection as measured by EVR at week 12. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of GI-5005 in various clinical scenarios:
Arm 1:
- combination therapy: GI-5005 and SOC (Standard of Care) therapy;
- GI-5005 12 week monotherapy run-in phase
Arm 2:
- GI-5005 monotherapy salvage of SOC intolerant subjects;
- GI-5005/SOC combination salvage of SOC non-EVR subjects
2. To evaluate the immunogenicity of GI-5005
3. To evaluate the safety and tolerability of 5 weekly followed by up to 17 monthly doses of GI-5005 for up to a total of 18 months as monotherapy (salvage therapy within the active comparator group) or in combination with PegIFN/ribavirin.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Chronic hepatitis C infection with genotype 1 based on serum positivity for HCV RNA or a positive test for serum anti-HCV antibody for at least 6 months;
2. Two HCV RNA values of ≥1000 IU/mL within the screen period;
3. One of the following response criteria based on response to prior combination therapy with pegylated or non-pegylated interferon plus ribavirin:
• Poor responders - a subset of non-responders who achieved > 1 log10 but < 2 log10 reduction in HCV RNA after a minimum of 12 weeks of prior interferon based therapy.
• Partial responders – a subset of non-responders who achieve at least a 2 log10 reduction in HCV RNA by 12 weeks, but do not achieve an end of treatment response (ETR defined as HCV RNA negativity by PCR assay at the end of a minimum of 6 months of therapy).
• Patients who are treatment naïve and have refused IFN therapy for reasons other than contraindication.
4. Liver biopsy within 3 years of the screening visit, documenting extent of liver disease consistent with chronic hepatitis C with evidence of inflammation and/or fibrosis. Liver biopsy within 1 year for subjects consenting to paired biopsy testing;
5. If female of childbearing potential, negative pregnancy test;
6. Age ≥ 18 years;
7. Negative scratch test (immediate hypersensitivity, IgE mediated) to S. cerevisiae.
|
|
| E.4 | Principal exclusion criteria |
1. History of decompensated liver disease, including but not restricted to, portal hypertension as manifested by a known history of gastroesophageal varices, variceal bleeding, ascites or encephalopathy, histopathologic or clinical evidence of cirrhosis, hepatocellular carcinoma, or renal impairment consistent with hepatorenal syndrome;
2. History of significant non-HCV chronic liver disease, i.e. alcoholic hepatitis, autoimmune hepatitis;
3. Liver function:
• ALT or AST > 5 times the upper limit of normal (ULN).
• Alpha-fetoprotein level > 50 ng/mL (Alpha-fetoprotein level from ULN to 50 ng/mL must have a normal ultrasound during screening for inclusion).
• Total bilirubin > 1.8 mg/dL (except for elevations secondary to Gilbert syndrome).
• INR ≥1.4.
4. Null response to prior IFN plus ribavirin therapy, defined as patients that have received at least 12 weeks of interferon-based treatment with < 1 log10 reduction in viral load;
5. Subjects treated with more than 1 complete hepatitis C regimen (subjects with a history of 1 complete prior regimen and a second incomplete prior regimen may be eligible upon discussion with and approval of the medical monitor);
6. Subjects that required a dose reduction of >25% of the planned exposure of IFN or >50% of their planned ribavirin exposure during their previous interferon/ribavirin treatment;
7. Subjects that required growth factors during their previous interferon/ribavirin treatment;
8. Subjects that received small molecule inhibitor therapy combined with an interferon based regimen. (subjects that received small molecule inhibitor monotherapy can be included);
9. Treatment for HCV infection within 28 days before screening;
10. Chronic hepatitis B infection or positive hepatitis B surface antigen (HBsAg) at screening;
11. Body weight >275 pounds;
12. History of other significant chronic diseases including:
• Poorly controlled diabetes
• clinically significant or symptomatic cardiovascular or cerebrovascular disease
• autoimmune disease
• autoimmune conditions associated with chronic HCV: Symptomatic cryoglobulinemia, Glomerulonephritis, Sjogren’s syndrome, Thyroid disease (subjects with stable thyroid disease may be eligible upon discussion with and approval of the medical monitor), Porphyria cutanea tarda
• active major psychiatric disease (includes history of major depression, psychosis, suicidal ideation or attempts, or in-patient hospitalization for psychiatric management).
• renal disease (serum creatinine >1.5 ULN).
• evidence of significant hematologic abnormalities: CD4+ cell count <200/uL,
Neutrophil count < 1.5 x 103/uL, WBC < 4000/uL, Platelets <150,000/uL, Hemoglobin <12.0 g/dL (males), <11g/dL (females)
13. Known history of HIV infection or positive HIV antibody test at screening;
14. History of cancer within the last 5 years with the exception of localized basal or squamous cell carcinoma or Stage 1A cervical cancer;
15. History of Crohn’s disease or ulcerative colitis;
16. History of major organ transplantation;
17. Concurrent and chronic therapy with immunosuppressive drugs including systemic corticosteroids. Short courses of steroids for exacerbation of normally well-controlled asthma or other conditions may be permitted after consultation with the Medical Monitor;
18. Concurrent therapy with herbal supplements taken specifically for the treatment of HCV is prohibited (i.e. milk thistle). Twenty eight day wash-out of HCV related herbals is required prior to Day 1;
19. Participation in any experimental treatment protocol or therapy within 28 days before screening;
20. Alcohol and/or IV drug abuse within the past year;
21. Positive urine drug test at screen visit (medicinal use of opiates or other controlled substances may be approved on a case by case basis by the medical monitor in consultation with the principal investigator); and
22. Contraindication for IFN and/or ribavirin therapy.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Proportion of subjects in arm 1 and 2B who achieve and maintain an early virologic response (EVR) defined as ≥ 2 log10 reduction in HCV RNA by Week 12.
- Immunology endpoints: by ELISpot assay, lymphocyte proliferation assay, Cytokine mRNA detection and other exploratory immunology assays and in situ immune testing on biopsy specimens to measure the quantity and nature of cellular immune infiltrates;
- Evaluation of frequency and severity of adverse events, frequency of serious adverse events, and laboratory assessments (chemistry, hematology, urinalysis) for GI-5005 monotherapy as well as in combination with PegIFN/Ribavirin. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 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 | Information not present in EudraCT |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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