| 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 |
| Subjects with chronic hepatitis B virus infection (CHB). |
|
| 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 | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052329 |
| E.1.2 | Term | Hepatitis B e antigen positive |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| 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 safety and tolerability of pegIFNλ as measured by the
frequency of SAEs and discontinuations due to AEs;
• To assess the HBeAg seroconversion rate at 24 weeks (Week 72) off
treatment. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate antiviral activity, as determined by the proportion of subjects who achieve an HBV DNA < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan HBV Test for use with the High Pure System (HPS) assay;
• To evaluate mean change from baseline in HBV DNA over time;
• To assess biochemical response rates;
• To evaluate the relationship between changes in serum HBV DNA and
pegIFNλ PK parameters;
• To evaluate HBeAg loss and seroconversion;
• To evaluate quantitative HBeAg levels over time;
• To characterize the PK of pegIFNλ administered as a fixed dose
• To evaluate for the presence of or change in titer of anti-drug
antibodies in treated subjects over time |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics Blood Sample Amendment Number 01 - Site Specific
(version 1.0, dated 05-Aug-2010)
The objective of this Amendment is to permit the collection and storage
of blood samples for use in future exploratory pharmacogenetic
research. Bristol-Myers Squibb will use DNA obtained from the blood
sample and health information collected from the main clinical trial,
AI452005 to study the association between genetic variation and drug
response. Bristol-Myers Squibb may also use the DNA to study the
causes and further progression of Hepatitis B infection. Samples from
this study may also be used in conjunction with pharmacogenetic
research results from other clinical studies to accomplish this objective.
Amendment Number 11 replaces Amendments 07 and 08 - Part B Sub Study (site specific) - Lambda/Entecavir Combination Therapy (version
1.0, 24-May-2013)
Primary Objectives: To evaluate the safety and tolerability of
Lambda/ETV regimen as measured by the frequency of SAEs and
discontinuations due to AEs
Secondary Objectives:
1) To assess the HBeAg seroconversion rate at 24 weeks off treatment
(Week 84)
2) To evaluate the antiviral activity of this Lambda/ETV regimen, as
determined by the proportion of subjects who achieve an HBV DNA < 50
IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan
HBV Test for use with the High Pure System (HPS) assay
3) To evaluate mean change from baseline in HBV DNA over time in
subjects treated with Lambda/ETV
4) To assess biochemical response rates in subjects treated with
Lambda/ETV.
5) To evaluate HBeAg loss and seroconversion in subjects treated with
Lambda/ETV regimen.
6) To evaluate quantitative HBeAg levels over time in subjects treated
with Lambda/ETV regimen
7) To characterize the PK of Lambda/ETV regimen
8) To evaluate the relationship between changes in serum HBV DNA and
PK parameters for the Lambda/ETV regimen
9) To characterize the rate of resistance to ETV during treatment with
the Lambda/ETV regimen through Week 84 (descriptive) |
|
| E.3 | Principal inclusion criteria |
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
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 ≥ 24 weeks prior to screening;
b) Detectable HBeAg and no detectable HBeAb at screening and at least once ≥ 4 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;
d) HBV DNA by PCR ≥ 105 copies/mL (17,200 IU/mL) at screening and presence of detectable HBV DNA at least once ≥ 4 weeks prior to screening;
e) No prior IFN therapy;
f) Prior HBV nucleos(t)ide therapy allowed but not within 30 days prior to screening;
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 ≤ 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 ≤ 1 year of study randomization documenting a normal eye exam per assessment of the investigator or a licensed ocular specialist;
i) Subjects with compensated cirrhosis or no cirrhosis are allowed to participate. However, cirrhotics 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 (≤ .74) indicate that the subject is eligible. Subjects with a METAVIR score of F4 (≥ .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.
3. Age and Reproductive Status
See Section 3.3.3 for the definition of WOCBP
a) Men and women, ages 18 years of age and above
b) Women of childbearing potential (WOCBP) must use method(s) of contraception based in Table 3.3.1-1 on page 31 of the study protocol. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required.
The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo 5 half lives.
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.
d) Women must not be breastfeeding
e) Male subjects must confirm that their female sexual partners are not pregnant at the time of screening.
Acceptable methods of contraception are outlined in Table 3.3.1-1
For Part B, all inclusion/exclusion criteria remain the same as outlined in
the main study, with the exception of inclusion criteria 2(f), and
additionally:
• Subjects must be HBV nucleos(t)ide-naive
• Able to tolerate oral medication |
|
| E.4 | Principal exclusion criteria |
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 diseasedisesase, 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 severe, or uncontrolled psychiatric disease; mild or
moderate 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) ≤ 50 mL/min;
d) Total serum bilirubin > 2.5 mg/dL (> 42.75 μmol/L) (unless due to
Gilbert's disease);
e) INR > 1.2;
f) Serum albumin ≤ 3.5 g/dl;
g) Alpha Fetoprotein ≥ 100 ng/mL;
h) PTT > 1.5 x ULN.
4) Allergies and Adverse Drug Reaction
a) History of hypersensitivity to drugs with a similar biochemical structure to pegIFNλ or pegIFNα (eg, other interferons);
b) Any other known contraindication to pegIFNα.
5) Prohibited Treatments and/or Therapies
a) Received any investigational drug within 30 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 30 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints are to measure:
• Number and percent of subjects with serious adverse events (SAEs) and discontinuations due to adverse events;
• Proportion of subjects who achieve HBeAg seroconversion at Week 24 post-dosing (ie, Week 72).
During the study, safety assessments are performed weekly during the first month of treatment and every 4 - 8 weeks during study treatment, and every 4 - 12 weeks during post-treatment follow-up.
For Part B Endpoints, please refer to the Part B sub-study Amendment
Number 11 section 8.2. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) 24 weeks post-dosing (Week 72)
2) Week 24 and 24 weeks post-dosing (Week 72)
|
|
| E.5.2 | Secondary end point(s) |
1) Proportion of subjects who achieve an HBV DNA < 50 IU/mL
(approximately 300 copies/mL) at Weeks 24, 48, 72, 96, 120, 144, 168
and 192 using the Roche COBAS® TaqMan - HPS assay; Mean change
from baseline in log10 HBV DNA levels over time;
2) Proportion of subjects with ALT normalization (≤ 1 x ULN) at Weeks
24, 48, 72, 96, 120, 144, 168 and 192;
3) HBeAg loss at Weeks 24, 48, 72, 96, 120, 144, 168 and 192;
4) HBeAg seroconversion at Weeks 24, 48, 96, 120, 144, 168 and 192;
5) Mean change from baseline in log10 quantitative HBeAg levels over
time;
6) Number and percent of subjects with adverse events (AEs) or
laboratory abnormalities;
7) Pharmacokinetic parameters of pegIFNλ will be derived from serum
concentration versus time data.
− The following PK endpoints will be assessed for the sub-study with
intensive PK collection:
* Cmax: Maximum observed concentration;
* Tmax: Time of maximum observed concentration;
* C0: Trough serum concentration pre-dose;
* Cmin: serum concentration 168 hours post observed dose (C0 will be
used as an estimate of Cmin if sample is not collected);
* AUC(TAU): Area under the concentration-time curve in 1 dosing
interval from time 0 to 168 hours post observed dose;
* AI Accumulation index: ratio of AUC(TAU) at steady-state to AUC(TAU)
after the first dose (only conducted if data warrant);
− For other subjects with only trough PK collection, the following PK
parameters will be assessed:
* C0: Trough serum concentration pre-dose
For Part B Endpoints, please refer to the Part B sub-study Amendment
Number 11 section 8.2. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Weeks 24, 48, 72, 96, 120, 144, 168, 192
2) Weeks 24, 48, 72, 96, 120, 144, 168, 192
3) HBeAg loss: Weeks 24, 48, 72, 96, 120, 144, 168, 192;
4) HbeAg seroconversion: Weeks 24, 48, 72, 96, 120, 144, 168, 192
5) Duration of trial
6) Duration of trial
7) Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK),
16, 24, 40, 48 |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Beck Depression Inventory II; Fatigue Severity Scale; Interferon antibodies; Immunogenicity assessment |
|
| 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.8.2.4 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Australia |
| Canada |
| France |
| Germany |
| Hong Kong |
| Italy |
| Korea, Republic of |
| Netherlands |
| Singapore |
| Taiwan |
| United States |
|
| 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
|
| The end of the study is defined as the date of the last visit for the last subject to complete the study. The last visit is defined as the last post-treatment follow-up subject visit. |
|
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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