| CTRI Number |
CTRI/2011/09/002001 [Registered on: 12/09/2011] Trial Registered Prospectively |
| Last Modified On: |
28/03/2013 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group, Placebo Controlled Trial |
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Public Title of Study
|
Comparative study in childrens with chronic Hepatitis B virus infection who are HBeAg positive. |
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Scientific Title of Study
|
A Comparative Study of the Antiviral Efficacy and Safety of Entecavir (ETV) versus Placebo in Pediatric Subjects with Chronic Hepatitis B Virus (HBV) Infection who are HBeAg-Positive |
| Trial Acronym |
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Secondary IDs if Any
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| Secondary ID |
Identifier |
| AI463-189 |
Protocol Number |
| NCT01079806 |
ClinicalTrials.gov |
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Details of Principal Investigator or overall Trial Coordinator (multi-center study)
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| Name |
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| Designation |
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| Affiliation |
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| Address |
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| Phone |
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| Fax |
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| Email |
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Details of Contact Person
Scientific Query
Modification(s)
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| Name |
Dr Rahul Bargaje |
| Designation |
Disease Area Head (Virology), GDMA |
| Affiliation |
Bristol Myers Squibb India Pvt. Ltd. |
| Address |
Bristol Myers Squibb India Pvt. Ltd., 6th floor, Towers 1 & 2, The Indiabulls Finance Centre,S.B. Marg, Elphinstone (W),Mumbai
Mumbai
MAHARASHTRA
400 013
India |
| Phone |
912266534210 |
| Fax |
|
| Email |
rahul.bargaje@bms.com |
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Details of Contact Person
Public Query
Modification(s)
|
| Name |
Subashri Shivkumar |
| Designation |
Hub Unit Director |
| Affiliation |
Bristol Myers Squibb India Pvt. Ltd. |
| Address |
Bristol Myers Squibb India Pvt. Ltd.,
6th floor, Towers 1 & 2,
The Indiabulls Finance Centre,
S.B. Marg, Elphinstone (W),
Mumbai
Mumbai
MAHARASHTRA
400 013
India |
| Phone |
912266534245 |
| Fax |
|
| Email |
subashri.shivkumar@bms.com |
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Source of Monetary or Material Support
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| The pharmaceutical company sponsoring this study is Bristol-Myers Squibb |
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Primary Sponsor
Modification(s)
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| Name |
The pharmaceutical company sponsoring this study is BristolMyers Squibb |
| Address |
Bristol Myers Squibb India Pvt. Ltd.,
6th floor, Towers 1 & 2,
The Indiabulls Finance Centre,
S.B. Marg, Elphinstone (W),
Mumbai - 4000013 |
| Type of Sponsor |
Pharmaceutical industry-Global |
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Details of Secondary Sponsor
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Countries of Recruitment
Modification(s)
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Argentina
Brazil
Canada
Democratic People's Republic of Korea
Germany
Greece
India
Poland
Romania
Russian Federation
Taiwan
United States of America
Belgium
Israel
United Kingdom |
Sites of Study
Modification(s)
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| No of Sites = 2 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr B D Goswami |
Institute of digestive & Liver Disease, Dispur Hospital Ltd. |
Ground Floor,Ganeshguri, Guwhati-781006
Kokrajhar
ASSAM |
0361-2221962
bhabadev@rediffmail.com |
| Dr Sethu Babu |
Sai Vani Hoapital |
Sai Vani Hoapital,First Floor Opp. Indira Park, Hyderabad
Hyderabad
ANDHRA PRADESH |
91-40-27634462
sethu9@rediffmail.com |
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Details of Ethics Committee
Modification(s)
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| No of Ethics Committees= 4 |
| Name of Committee |
Approval Status |
| Institutional Ethics Committee of VGM Hospital |
Approved |
| The Ethics Committee of Dispur Hospital |
Approved |
| The Ethics Committee of Nagarjuna Hospital |
Approved |
| Virtuous Independent Ethics Committee |
Approved |
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Regulatory Clearance Status from DCGI
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Health Condition / Problems Studied
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| Health Type |
Condition |
| Patients |
Pediatric Subjects ( 12 to 18 yrs ) with Chronic Hepatitis B Virus (HBV) Infection who are HBeAg-Positive, |
|
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Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
entecavir (BMS-200475) 0.5 mg tablets or Oral Solution |
Entecavir : Tablets or Oral Solution, Oral, 0.015 mg/kg up to 0.5 mg, once daily, 96-144 weeks, depending on response
Placebo : Tablets or Oral Solution, Oral, 0 mg, once daily, 48-96 weeks, depending on response
i.e. Treatment arm ( Intervention ) Will receive Entecavir Tablet or Entecavir Solution
|
| Comparator Agent |
Matching Placebo |
Matching Placebo : Tablets or Oral Solution, Oral, 0 mg, once daily, 48-96 weeks, depending on response. Placebo arm : Entecavir Tablet or solution is compared with matchin placebo as tablet or oral form
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Inclusion Criteria
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| Age From |
12.00 Year(s) |
| Age To |
17.00 Year(s) |
| Gender |
Both |
| Details |
Inclusion Criteria
1) Signed Written Informed Consent
a) Freely given informed consent must be obtained prior to clinical trial
participation, including informed consent for any screening procedures conducted
to establish subject eligibility for the trial. Minor’s parents or legally acceptable
representatives must give fully informed written consent. Assent should be
obtained when the minor is judged to be of an age of reason (see Appendix 1);
2) Target Population
a) History of CHB infection defined as HBsAg-positive at the Screening visit and on
at least one other occasion ≥ 24 weeks prior to screening;
b) Detectable HBeAg AND no detectable anti-HBe antibodies at screening and at
least once ≥ 4 weeks prior to screening;
c) Serum ALT 1.5 to < 10 x ULN at screening and at least on one other occasion
within 8 to 24 weeks prior to screening;
d) HBV DNA by PCR ≥ 105 copies/mL at screening and evidence of the presence of
HBV DNA at least once ≥ 4 weeks prior to screening;
3) Age and Sex
a) Male and females, 2 to <18 years of age.
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 6 weeks after
the last dose of investigational product in such a manner that the risk of pregnancy
is minimized.
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined
as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
> 35 mIU/mL
Women who are using oral contraceptives, other hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing
abstinence or where their partner is sterile (eg, vasectomy) should be considered
to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) at screening AND within
72 hours prior to the start of investigational product. |
|
| ExclusionCriteria |
| Details |
Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 6 weeks after the last dose of
investigational product
b) WOCBP using a prohibited contraceptive method. At this time there are no
known contraindicated contraceptives to entecavir
c) Women who are pregnant or breastfeeding
d) Women with a positive pregnancy test on enrollment or prior to investigational
product administration
e) Sexually active fertile men not using effective birth control if their partners are
WOCBP
Target Disease Exceptions
a) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV)
or hepatitis D virus (HDV)
b) Other forms of acute and chronic conditions which may cause increased ALT as
determined by the investigators (eg, acute viral illness, Wilson Disease, other
metabolic disorders, autoimmune hepatitis, alcoholic liver disease)
c) Liver transplant recipients
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 these on physical
examination performed for this study;
b) Current evidence of, or history of pancreatitis
c) Received bone marrow or organ transplant or therapy with an
immunomodulatory, cytotoxic, or systemic corticosteroid therapies within
2 months of enrollment
d)Evidence of current pre-malignant lesions and malignancies including HCC(to
be excluded by screening and evaluation practices standard in the country of
enrollment)
e)Other serious medical conditions that might preclude completion of this study
4) Physical and Laboratory Test Findings
a) Hemoglobin 10.0 g/dL
b) Platelet count 70,000/mm3
c) Inadequate renal function with estimated glomerular filtration rate of
50 mL/min/1.73m2 d) Total serum bilirubin 2.5 mg/dL ( 42.75 ¦Ìmol/L)
e) INR 1.5
f) Serum albumin 3.0 g/dL ( 30 g/L)
g) Alpha Fetoprotein ¡Ý 50 ng/mL
5) Allergies and Adverse Drug Reactions
a) Known allergy to nucleoside analogues
6) Prohibited Treatments and/or Therapies
a) ¡Ý 12 weeks of prior therapy with any nucleoside or nucleotide antiviral agent with
activity against hepatitis B virus (including but not limited to adefovir, tenofovir
famciclovir, clevudine, lamivudine, telbivudine, or emtricitabine)
b) Therapy with interferon alpha, thymosin alpha or any nucleos[t]ide antiviral agent
with activity against hepatitis B virus within 24 weeks of screening
c) Any prior therapy with ETV;
d) Any use of illegal drugs OR use of alcoholic beverages which in the investigator¡¯s
opinion is sufficient to prevent adequate compliance with study procedures or
increase the risk pancreatitis or hepatotoxicty;
e) Concomitant medications which may cause immunosuppression, nephrotoxicity
or hepatotoxicity or affect renal excretion or hepatic metabolism are not
permitted
f) Concomitant use of Traditional Chinese Medicines or other herbal products
purported to have antiviral activity or intended for use in improving/protecting
liver function
g) During the treatment phase of the study, a subject may not be coenrolled in
another clinical trial where an investigational drug is administered
7) Other Exclusion Criteria
a) Unable to tolerate oral medication;
b) Children that are currently breastfeeding, or those who were breastfed while their
mother received LVD; maternal LVD treatment during pregnancy
c) Prisoners or subjects who are involuntarily incarcerated
d) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.
A liver biopsy prior to the start of study medication is optional. If a biopsy has been
performed prior to randomization, then histological results will be collected; likewise,
results from any subsequent on-study biopsies will be collected.
Subjects may be rescreened twice (for a total of three screens) if it can be reasonably
expected that study criteria will be met. However, beyond this, subjects should be
reevaluated only after consultation with the study team.
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Method of Generating Random Sequence
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Computer generated randomization |
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Method of Concealment
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Centralized |
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Blinding/Masking
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Participant Blinded |
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Primary Outcome
|
| Outcome |
TimePoints |
To compare the proportion of subjects in each treatment group who achieve a
combination of HBV DNA suppression and HBeAg seroconversion (undetectable
HBeAg AND detectable anti-HBe antibodies) at Week 48. |
To compare the proportion of subjects in each treatment group who achieve a
combination of HBV DNA suppression and HBeAg seroconversion (undetectable
HBeAg AND detectable anti-HBe antibodies) at Week 48. |
|
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Secondary Outcome
|
| Outcome |
TimePoints |
Assess the serologic response rates (defined as HBsAg loss and/or seroconversion;
and HBeAg loss and/or seroconversion) including durability of response off
treatment;
• Assess the virological response rates;
• Assess the biochemical response rates;
• Assess ETV resistance rates;
• Evaluate the long-term safety of ETV use in pediatric patients. |
Week 48 |
|
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Target Sample Size
|
Total Sample Size="180"
Sample Size from India="10"
Final Enrollment numbers achieved (Total)= ""
Final Enrollment numbers achieved (India)="" |
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Phase of Trial
|
Phase 3 |
Date of First Enrollment (India)
Modification(s)
|
24/04/2012 |
| Date of Study Completion (India) |
Date Missing |
| Date of First Enrollment (Global) |
07/07/2010 |
| Date of Study Completion (Global) |
Date Missing |
|
Estimated Duration of Trial
|
Years="5"
Months="0"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Completed |
| Recruitment Status of Trial (India) |
Completed |
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Publication Details
|
NA |
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Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
|
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Brief Summary
|
The aim of this study is to provide data to guide the clinical use of ETV in children and
adolescents with chronic hepatitis B (CHB); the only available data on ETV use in
children < 18 years of age come from the dose finding study which is summarized to
support the dose selection for this study.
Despite the availability of several treatments for adults suffering from CHB, treatment
options for pediatric patients remain limited. In the United States of America, three drugs
have been approved for the treatment of CHB in children (interferon- ¦Á and lamivudine
from age 2 to < 18; and adefovir from age ¡Ý 12 to < 18);11,12,13 and in Europe no drug has
been approved. Each of the currently approved therapies for treating CHB in children in
the United States has significant limitations. Interferon- ¦Á is associated with many side
effects including significant short term growth retardation; 3,11 LVD is associated with
high rates of antiviral resistance (19% after 1 year and 64% after 3 years); 12,14 and ADV
has a limited indication (for children 12 to < 18) as it was no better than placebo
virologically or serologically in children < 12 years old. 13 Partly as a result of these
limitations of the currently approved therapies, placebo is still considered a viable
treatment option in the pediatric population. Additional support for the role of placebo in
managing children with CHB is also the fact that progression to liver failure, liver
cirrhosis or hepatocellular carcinoma as a result of CHB is rare before age 18. |