Dose-Ranging Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Pegylated Interferon Lambda (BMS-914143) Monotherapy in Interferon-Naive Patients with Chronic Hepatitis B Virus Infection who are HBeAg-positive

1) Signed Written Informed Consent
Freely given informed consent must be obtained from subjects prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the study.
2) Target Population
- History of CHB infection defined as HBsAg positive at screening and on at least one other occasion for a least or more then 24 weeks prior to screening;
- Detectable HBeAg and no detectable HBeAb at screening and at least once for at least or more then 4 weeks prior to screening;
- Serum ALT 1.3 to < 10 x ULN at screening and on at least 1 other occasion within 24 weeks prior to screening, based on ULN where lab is performed with no value in the intervening period falling outside required range;
- HBV DNA by PCR at least or more then 105 copies/mL (17,200 IU/mL) at screening and presence of detectable HBV DNA at least once at least or more then 4 weeks prior to screening;
- No prior IFN therapy;
- Prior HBV nucleos(t)ide therapy allowed but not within 30 days prior to screening;
- 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;
- Documented baseline retinal exam performed within maximum 1 year of study randomization; any subjects with diabetes, hypertension, or other risk factors for retinal disease per assessment of the investigator can be included with a documented normal eye exam by a licensed ocular specialist;
- Pre-treatment liver biopsy performed within maximum 2 years prior to study randomization to characterize preexisting liver status. Patients with compensated cirrhosis will be allowed to participate but will be capped at 10%; patients with cirrhosis must not have decompensated liver disease.;3)Age and Reproductive Status
- Men or women, 18 - 70 years of age;
- Contraception Requirements: Women of childbearing potential (WOCBP, see Section 3.3.3 of the protocol for definition) and sexually active men with female partners who are WOCBP, must use 2 separate forms of contraception from screening throughout the duration of the study. One (1) form of contraception must be effective barrier method (eg, condom, diaphragm, cervical cap). Exceptions to this criteria are:
i)WOCBP who have vasectomized male partners for at least 6 months before enrollment
ii)Sexually active men who are vasectomized for at least 6 months before enrollment
- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product;
- Women must not be breastfeeding;
- Requirements for male subjects:
- Male subjects (unless vasectomized) with female partners who are WOCBP must agree to inform their females partners of the protocol-specified contraception requirements and pregnancy testing recommendations during treatment and post-treatment (ie, 2 forms of contraception and weekly pregnancy testing while the subjects is enrolled in the study), and agree to adhere to these recommendations; ;REVISED PROTOCOL 3 (Amendment 4 dd. 23 May 2011):
2)Target Population
a)History of CHB infection defined as HBsAg positive at screening and with other marker of HBV infection (eg, HBV DNA, HBeAg, HBV genotype) on at least one other occasion more then 24 weeks prior to screening;
c) Serum ALT > 47 U/L and < 10 x ULN at screening and on at least 1 other occasion within 24 weeks prior to screening, the latter based on ULN of the local lab where test was performed;
g) Thyroid-stimulating hormone (TSH) and/or free T4 within 0.8 to 1.2 times the normal limit, or adequately controlled thyroid function as assessed by the investigator;
h) Documented baseline retinal which includes a dilated examination of the retina, performed within 1 year prior to study randomization by a licensed ocular specialist; for any subjects with diabetes, hypertension, or other risk factors for retinal disease; for all other subjects, a dilated retinal exam performed within 1 year of study randomization documenting a normal eye exam per assessment of the investigator or a licensed ocular specialist;;3)Age and Reproductive Status:
b) Contraception Requirements: Women of childbearing potential (WOCBP, see Section 3.3.3 for definition) and sexually active men with female partners who are WOCBP, must use 2 separate forms of contraception from screening throughout the duration of the study and for up to 24 weeks after last dose of study drug in such a manner that the risk of pregnancy is minimized. One (1) form of contraception must be effective barrier method (eg, condom, diaphragm, cervical cap). Exceptions to this criteria are:
i) WOCBP who have vasectomized male partners for at least 6 months before enrollment
ii) Sexually active men who are vasectomized for at least 6 months before enrollment
e)Requirements for male subjects:
i)Male subjects (unless vasectomized) with female partners who are WOCBP must agree to inform their females partners of the protocol-specified contraception requirements and pregnancy testing recommendations during reatment and post-treatment (ie, 2 forms of contraception and pregnancy testing at least monthly while the subjects is enrolled in the study), and agree to adhere to these recommendations; ;REVISED PROTOCOL 4 (Amendment 5):
incl criteria regarding liverbiopsy changed into:
Subjects with compensated cirrhosis or no cirrhosis are allowed to participate. However, cirrhosis will be capped at 10%. Methods of evaluating for presence/absence of cirrhosis can include the following: a documented liver biopsy < 2 years prior to study randomization or Fibrotest (Bio predictive) performed at screening. Subjects with Fibrotest results equivalent to a METAVIR score of F0-F3 (<0,74) indicate that the subject is eligible. Subjects with a METAVIR scrore of F4 (>0,75), will be eligible if the 10% cap has not been met. For indeterminate FibroTest results, subjects will be required to undergo a liver biopsy to determine eligibility.;REVISED PROTOCOL 5 (Amendment 6):
3)Age and Reproductive Status:
See section 3.3.3 in the protocol for the definition of WOCBP
a) Men and women, ages 18 years of age and above
b) Women of childbearing potential (WOCBP must use two 2 separate highly effective methods of birth control (from list below) throughout the duration of the on-treatment study period and for up to 24 weeks after the last dose of study drug to minimize the risk of pregnancy.
WOCBP must follow instructions for birth control for the entire duration of the study including a minimum of 24 weeks after dosing has been completed.
Acceptable methods of highly effective birth control include:
* condom with spermicide
* diaphram and spermicide
* cervical cap and spermicide
* sponge and spermicide
* Vasectomized male partner for a minimum of 6 months
As noted above, these methods generally require a spermicide except in countries where it may not be available. The use of intrauterine devices (IUDs) shall be at the discretion of the investigator if it is permitted by local regulations. Hormonal contraceptives may be used in this study bu cannot be considered one of the two forms of effective birth control required because a drug interaction study verifying the effectiveness of hormone based contraceptives have not been conducted with Lambda.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.;e) Sexually active men must use two (2) seperate highly effective methods of birth control if their partners are WOCBP. Ment that are sexually actie with WOCBP must follow instructions for birth control for the entire duration of the study and a minimum of 24 weeks after the last dose of study drugs.
Requirements for male subjects:
i)Male subjects with female partners who are WOCBP must agree to inform their female partners of the protocol-specified contraception requirement and pregnancy testing recommendations during treatment and post-treatment (ie, 2 forms of contraception and monthly pregnancy testing while the subjects is enrolled in the study) and 24 weeks post dosing.
ii) Male subjects must confirm that their female sexual partners are not pregnant at the time of screening.
iii) Acceptable methods of contraception for males are:
(a) Condom plus spermicide (this method generally requires a spermicide except in countries where it may not be available).
(b) Vasectomy for at least 6 months and with a history of confirmed azoospermia.
Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug.

1) Target Disease Exceptions
a) Co-infection with HIV, HCV or hepatitis D virus (HDV);
b) Evidence of a medical condition contributing to chronic liver disease other than HBV (such as but not limited to: hematochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, biliary disesase, hepatic steatosis, and toxin exposure).;2) Medical History and Concurrent Diseases
a) Current evidence of or history of variceal bleeding, hepatic encephalopathy, or ascites requiring diuretics or paracentesis or evidence of any of these findings on physical examination performed at screening;
b) Current evidence of or history of pancreatitis;
c) History of bone marrow or organ transplant or therapy with an immunomodulatory agent, cytotoxic agent, or systemic corticosteroids within 2 months of screening;
d) 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 screening;
e) History of hepatocellular carcinoma (HCC) or for patients without a known history, evidence of HCC as documented by abdominal imaging (eg, ultrasound), within 18 months of study randomization;
f) Patients with a screening QTcF > 450 msec (males) or > 470 msec (females), based on the average of 3 or more ECGs (ECGs obtained 5 minutes apart while subject is resting in a supine position).
g) Patients with other clinically significant ECG abnormalities (indicative of dysarrhythmia, myocardial ischemia or other serious cardiovascular disorder) at the time of screening in the opinion of the investigator;
h) Active substance abuse, such as alcohol, or inhaled or injected drugs, as defined by Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 1) within 6 months prior to screening. Subjects who are receiving methadone or other substitutive product under medical supervision are eligible. Use of marijuana for medical purpose is allowed;
i) Prior or current history of cardiomyopathy or significant ischemic cardiac or cerebrovascular disease, including history of angina, myocardial infarction, interventional procedure for coronary artery disease (including angioplasty, stent procedure, or cardiac bypass surgery);
j) Prior or current history of clinically significant hemoglobinopathy or hemolytic anemia;
k) Prior or current history of interstitial lung disease or sarcoidosis;
l) History of immunologically mediated disease (including, but not limited to, rheumatoid arthritis, inflammatory bowel disease, moderate to severe psoriasis [mild psoriasis is allowed], and systemic lupus erythematosus);
m) History of moderate, severe, or uncontrolled psychiatric disease; mild depression controlled at time of screening is allowed;
n) Active seizure disorder as defined by either untreated seizure disorder or continued seizure activity within the past year prior to screening despite treatment with anti-seizure medication;
o) 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 such as prior or current history of porphyria cutanea tarda and/or hemophilia.;3) Physical and Laboratory Test Findings
a) Hemoglobin < 12.0 g/dL (males) or < 11.0 g/dL (females);
b) Platelet count < 90,000/mm3;
c) Confirmed creatinine clearance (CrCl) (as estimated by Cockcroft and Gault) less or equal to 50 mL/min;
d) Total serum bilirubin > 2.5 mg/dL (> 42.75 *mol/L) (unless due to Gilbert*s disease);
e) INR > 1.2;
f) Serum albumin < LLN;
g) Alpha Fetoprotein equal or more then 100 ng/mL;
h) PTT > 1.5 x ULN; fibrinogen < LLN.;4) Allergies and Adverse Drug Reaction
a)History of hypersensitivity to drugs with a similar biochemical structure to pegIFNlambda or pegIFNAlpha (eg, other interferons);
b) Any other known contraindication to pegIFNalpha.;5) Prohibited Treatments and/or Therapies
a) Received any investigational drug within 60 days prior to study randomization;
b) Current use of heparin or coumadin;
c) Received blood products within 30 days prior to study randomization;
d) Use of hematologic growth factors within 90 days prior to study randomization;
e) Systemic antibiotics, antifungals, or antivirals for treatment of active infection within 14 days of study randomization.;6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated;
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.;REVISED PROTOCOL 3 (Amendment 4 dd. 23 May 2011):
2) Medical History and Concurrent Diseases
m) History of severe or uncontrolled psychiatric disease; mild or moderate depression controlled at time of screening is allowed;
3) Physical and Laboratory Test Findings
f) Serum albumin less or equal to 3.5 g/dl;
h) PTT > 1.5 x ULN.
5) Prohibited Treatments and/or Therapies
a) Received any investigational drug within 30 days prior to study randomization;
d) Use of hematologic growth factors within 30 days prior to study randomization;