| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C Virus Infection |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
|
| 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 |
Phase 2a
Part 1
The primary objective of Part 1 is to characterize the pharmacokinetics of a single fixed dose of PEG-rIL-29 administered subcutaneously (SC) as a single agent at 4 different dose levels in treatment-naive subjects with chronic hepatitis C virus (HCV) infection.
Part 2
The primary objective in Part 2 is to evaluate the safety and tolerability of repeat dosing for up to 48 weeks with 4 dose levels of PEG-rIL-29 administered SC as a fixed dose in combination with ribavirin.
Phase 2b
The primary objective of Phase 2b is to evaluate the efficacy and safety through Week 12 of up to 4 dose levels, selected from Phase 2a, of PEG-rIL-29 administered SC as a fixed dose in combination with ribavirin, compared to peginterferon alfa-2a administered SC in combination with ribavirin, in treatment-naive subjects with chronic HCV infection |
|
| E.2.2 | Secondary objectives of the trial |
| Phase 2a Part 1: 1. Evaluate the safety and tolerability of a single dose of PEG-rIL-29 compared to a single fixed dose of peginterferon alfa-2a. 2. Evaluate the changes in serum HCV RNA levels over time following a single fixed dose of PEGrIL- 29 compared to a single fixed dose of peginterferon alfa-2a. Part 2: 1. Characterize the pharmacokinetics of repeat doses of PEG-rIL-29 administered as a fixed dose in combination with ribavirin. 2. Evaluate the efficacy of repeat dosing with PEG-rIL-29 administered as a fixed dose in combination with ribavirin compared to peginterferon alfa-2a in combination with ribavirin. Phase 2b: 1. Compare the safety and tolerability of PEG-rIL-29, (up to 48 weeks) in combination with ribavirin, to peginterferon alfa-2a in combination with ribavirin. 2. Compare the efficacy of PEG-rIL-29, (up to 48 weeks) as a fixed dose over a range of dose levels in combination with ribavirin, to peginterferon alfa-2a administered with ribavirin. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females between the ages of 18 and 70 years, inclusive, at the time of signing informed consent
2. No prior therapy for chronic HCV, other than up to 2 weeks of single-agent therapy with a direct-acting antiviral agent, including but not limited to, a protease or polymerase inhibitor
3. Genotype 1, 2, 3, or 4 HCV RNA. Mixed genotype HCV infection is not allowed
4. HCV RNA ≥100,000 IU/mL
5. ALT and AST ≤5.0 × ULN
6. Documented absence of cirrhosis, with the exception of approximately 10 subjects per treatment group in Phase 2b. For subjects without cirrhosis, absence of cirrhosis must be documented as follows: genotype 1 and 4 subjects must have a documented liver biopsy performed ≤2 years before study randomization. Genotype 2 and 3 subjects must have either a documented liver biopsy performed ≤2 years before study randomization or a FibroTest performed during the screening period. Subjects without cirrhosis must have a documented liver biopsy with an Ishak score ≤4 or Metavir fibrosis score
≤3 (genotypes 1, 2, 3 or 4), or a FibroTest ≤0.72 (genotypes 2 or 3). Subjects with cirrhosis must have a documented liver biopsy with an Ishak fibrosis score of ≥5 or a Metavir fibrosis score of 4. Subjects with cirrhosis must not have decompensated liver disease.
7. No prior history of hepatocellular carcinoma at any time, nor evidence of hepatocellular carcinoma documented by abdominal imaging (e.g., ultrasound), within 12 months of study randomization; imaging may be performed during screening period. 8. Alpha-fetoprotein <100 ng/mL
9. ECG with no clinically significant abnormalities at the time of screening as deemed by the investigator
10. Platelet count ≥90,000/mm3; ANC ≥1500/mm3; hemoglobin (Hgb) ≥12 g/dL (males) or ≥11 g/dL (females)
11. Partial thromboplastin time (PTT) ≤1.5 × ULN; fibrinogen ≥ lower limit of normal (LLN)
12. Creatinine clearance ≥50 mL/min calculated according to the Cockcroft-Gault equation
13. Thyroid-stimulating hormone (TSH) and/or T4 within 0.8 to 1.2 times the normal limit, or adequately controlled thyroid function as assessed by the investigator
14. Documented baseline retinal exam performed ≤1 year of study randomization. For subjects with diabetes, hypertension, or other risk factors for retinal disease per assessment of the investigator, the exam should be performed by an ophthalmologist; may be performed during screening period
15. Able to comprehend the investigational nature of this study and sign an institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form
16. If female and of child-bearing potential, has a negative serum pregnancy
test at screening and a negative serum or urine pregnancy test within 24
hours before initial study drug treatment. For the purpose of this study, a
female subject should be considered of childbearing potential unless she is
documented as surgically sterile (i.e., by hysterectomy, bilateral oophorectomy, or medically documented ovarian failure), postmenopausal for at least 2 years, or if postmenopausal for ≤2 years, has folliclestimulating hormone (FSH) >35 mIU/mL
17. If male, or female of child-bearing potential must agree to utilize 2 separate forms of contraception, one of which must be an effective barrier method (or be nonheterosexually active or have a vasectomized partner with documented
azospermia) from the time of signing informed consent until 6 months after the
last dose of ribavirin. Medically accepted contraception methods include
intrauterine device; barrier methods, such as diaphragm, condom, cap or sponge,
used with a spermicide; or hormonal contraception. Female subjects who use
hormonal contraceptive must have used the same method for at least 3 months
before utilizing it as one of their 2 forms of contraception.
18. BMI between 18 and 39 kg/m2 at time of signing informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Mixed genotype HCV infection
2. Current or prior history of decompensated liver disease, including any of the following: current or prior history of encephalopathy of any grade, current or prior history of variceal bleeding, current or prior history of ascites, total serum bilirubin >1. 5 mg/dL (unless due to Gilbert’s disease), albumin <LLN, or INR >1.2
3. Currently lactating or breast-feeding
4. Has a female partner who is pregnant
5. Received any investigational drug, including a direct-acting antiviral agent, within 60 days prior to receiving study drug
6. Current or known history of cancer (except adequately treated in situ carcinoma of the cervix, or basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment
7. Current systemic use of immunosuppressive medications, including corticosteroids
8. Current use of heparin or coumadin
9. Positive test for hepatitis B surface antigen, human immunodeficiency virus (HIV)-1, or HIV2 antibody at screening
10. Active substance abuse, such as alcohol, or inhaled or injected drugs, within 6 months before signing informed consent. Subjects who are receiving methadone or other substitutive product under medical supervision are eligible. Use of marijuana for medical purposes is allowed.
11. Received blood products within 30 days prior to study randomization
12. Use of hematologic growth factors within 90 days prior to study randomization
13. Prior or current history of cardiomyopathy, ischemic cardiac disease, or cerebrovascular disease. Patients with a history of angioplasty, stent placement, or other revascularization procedures are excluded.
14. Prior or current history of clinically significant hemoglobinopathy or hemolytic anemia 15. Prior history of clinically significant liver disease other than chronic hepatitis C infection
16. Prior or current history of interstitial lung disease or sarcoidosis
17. History of organ transplant; prior corneal transplant is permitted
18. History of immunologically mediated disease (including, but not limited to, rheumatoid arthritis, inflammatory bowel disease, moderate to severe psoriasis [mild psoriasis is allowed], sarcoidosis, and systemic lupus erythematosus)
19. History of moderate, severe, or uncontrolled psychiatric disease; mild depression controlled at time of study entry is allowed
20. Active seizure disorder. Subjects with a seizure history on anti-seizure medication and with no seizure during the year prior to signing informed consent are allowed
21. Any other known contraindication to peginterferon alfa-2a or ribavirin therapy
22. Systemic antibiotics, antifungals, or antivirals for treatment of active infection within 14 days of enrollment
23. Currently on dialysis, including hemodialysis or peritoneal dialysis
24. Has, in the opinion of the investigator, any physical exam findings, laboratory abnormalities, or other medical, social, or psychosocial factors that may negatively impact compliance or subject’s safety by participation in this study; this should include conditions which may affect hematologic parameters, for example, prior or current history of porphyria cutanea tarda and/or hemophilia. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2a: Part 1 Primary endpoint:
• Serum levels of PEG-rIL-29
Phase 2a: Part 2 Primary endpoint:
• Overall incidence of dose reductions of PEG-rIL-29 and DLTs
Phase 2b Primary endpoints:
• Efficacy − Proportion of subjects with undetectable HCV RNA at Week 12 (i.e., complete early virologic response [cEVR])
● Safety − Incidence and severity of adverse events through Week 12 |
|
| 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 | 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 | 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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 | 2 |
| 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 | 2 |
| 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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