Non Inferiority Trial of Locally Manufactured 'Hepa-B' Vaccine in Bangladesh.
Non Inferiority Trial of Locally Manufactured 'Hepa-B' Vaccine in Bangladesh.
Hepatitis B is a common and serious infectious disease of the liver, affecting millions of
 people throughout the world. Persistent Hepatitis B virus infections may cause development of
 chronic hepatic insufficiency, cirrhosis and hepatocellular carcinoma. Adding to that,
 Hepatitis B Virus carriers can transmit the disease for many years. It is transmitted through
 blood or other body fluids infected with the Hepatitis B virus. It is a major cause of
 morbidity and mortality in countries like Bangladesh. Immunization with Hepatitis B vaccine
 has been proved effective to prevent HBV infection. But the vaccines, which are recommended
 till now, are expensive. Locally manufactured Hepatitis B vaccine will be safe, cost
 effective and affordable for all.

 The test vaccine will induce similar seroprotection rates to hepatitis B one month
 post-vaccination and at 7 months, one month after the third dose of vaccine compared to
 reference vaccine. This will be done by comparing the percentages of participants with ≥10
 mIU/ml anti-HBs by vaccinated with either Hepa B or Engerix B vaccine. The non-inferiority
 margin will be 10%.
Research Protocol Title: A randomized observer-blinded non inferiority trial to evaluate the
 immunogenicity and safety of locally manufactured Hepatitis B Vaccine 'Hepa B' in Bangladeshi
 healthy adults.

 Background (brief):

 1. Burden: Hepatitis B is a serious and common infectious disease of the liver, affecting
 millions of people throughout the world1. The severe pathological consequences of
 persistent Hepatitis B virus (HBV) infections include the development of chronic hepatic
 insufficiency, cirrhosis and hepatocellular carcinoma (HCC) 1. More than 2000 million
 people alive today have been infected with HBV at some time in their lives. 1 Of these,
 about 350 million remain infected chronically and become carriers of the virus. 1 Three
 quarters of the world's population live in areas where there are high levels of
 infection 1. Every year there are over 4 million acute clinical cases of HBV and about
 25% of carriers, 1 million people a year, die from chronic active hepatitis, cirrhosis
 or primary liver cancer 1. HBV prevalence in Bangladesh is 2.3 to 9.7 percent with an
 approximate carrier pool of 10 million. These include healthy adult population 4.4 to
 9.7%, healthy children 3%, school girls 2.3%, a rural community 6.4%, and slum
 communities 3.8%.2,3 About 25-30% population of Bangladesh do not test positive for
 HBsAg rather test positive for another marker of HBV that is with anti HBc4. Thus about
 50 million Bangladeshi people are infected with HBV and transmission of their blood and
 body fluids may transmit HBV to healthy uninfected person4.

 2. Knowledge gap: The prevention of chronic HBV infection has become a high priority in the
 global community. Immunization with hepatitis B vaccine is the most effective means of
 preventing HBV infection and its consequence. Vaccine against hepatitis B was introduced
 in the early 1980s. Recombinant vaccines became available in the mid 1980s.1 Bangladesh
 introduced Hepatitis B vaccine in the EPI, immunization schedule in a small scale from
 2003 but nationwide it was available from 20095 .The HBV prevalence in Bangladesh is 2.3
 to 9.7 percent with an approximate carrier pool of 10 million. These include healthy
 adult population 4.4 to 9.7%, healthy children 3%, school girls 2.3%, a rural community
 6.4%, and slum communities 3.8%2,3 . WHO recommended to vaccinate all children and
 adolescents younger than 18 years-old living in low or intermediate endemicity and also
 in these settings to vaccinate people in high-risk groups who may acquire the
 infection6. Currently there is no locally manufactured Hepatitis B vaccine available in
 Bangladesh. The results of this study will provide information regarding the
 immunogenicity and safety of the locally manufactured Hepatitis B vaccine 'Hepa B' as a
 test vaccine using 'Engerix B' as a comparator vaccine in a non inferiority study
 design.

 3. Relevance: The study of this locally manufactured Hepatitis B vaccine, 'Hepa B' among
 adults will be able to give us information regarding the safety and immunogenicity of
 the vaccine and compare this locally produced Hepatitis B vaccine 'Hepa B' with 'Engerix
 B' vaccine. Hepa B has undergone technology transfer from BioBridge company in Pune,
 India. Incepta and BioBridge entered into an agreement for transfer of technology for
 manufacture of locally produced 'Hepa- B' in Bangladesh. The regulatory requirements as
 well as licensure of the vaccine will be initiated in Bangladesh. Currently there are no
 locally manufactured Bulk of Hepatitis B available in Bangladesh. Once these clinical
 trials will be completed, Incepta will apply for licensure of Hepa B to the Bangladesh
 DGDA. This will significantly reduce the cost of vaccine and ensure availability to the
 people of Bangladesh. Currently the imported vaccine "Engerix B 1 ml" is sold at a price
 of 608 taka where as Incepta can sell the product at 500 taka. So, in each unit price
 difference is 108 taka. As each individual needs 3 doses, so it will be 324 taka saved
 for each subject. Thus the vaccine cost could be significantly reduced and save a large
 amount of foreign currency of Bangladesh Government.

 Hypothesis (if any): Locally produced intramuscular non-infectious recombinant DNA
 vaccine Hepa-B is non inferior in terms of immunogenicity and safety among adults in
 Bangladesh as compared to Engerix-B.

 Objectives:

 Primary Objective

 • To evaluate and compare the immunogenicity and safety of locally produced Hepatitis B
 vaccine 'Hepa-B' with Engerix-B among healthy adults in Bangladesh.

 Methods:

 This will be a randomized observer-blinded and comparative study on a total of 158
 healthy adult participants. Hepa B (Test group) and Engerix B (Comparator Group)
 controlled non inferiority study in healthy adult (20-45 years of age). 79 participants
 will receive Hepa B 1.0 ml and another 79 participants will receive Engerix B 1.0 ml
 Outcome measures/variables: To evaluate and compare the immunogenicity and safety of
 locally produced Hepa B with Engerix B.

 Primary Objective:

 • To evaluate and compare the immunogenicity and safety of locally produced Hepatitis B
 vaccine 'Hepa B' with 'Engerix B' in healthy adults in Bangladesh.

 Primary end points:

 1. The test vaccine will induce similar seroprotection rates to hepatitis B one month
 post vaccination and at 7 months, one month after the third dose of vaccine
 compared to comparator vaccine. This will be done by comparing the percentage of
 participants with ≥10 mIU/ml anti HBs after vaccination with either Hepa B or
 Engerix B vaccine. The non inferiority margin will be 10%.

 2. Number of immediate reactions reported within 30 minutes after vaccination

 3. Number of solicited adverse events (prelisted in the participant's memory aid)
 occurring up to 4 days following vaccination.

 4. Number of unsolicited AEs up to 30 days after each dose of vaccination.

 5. Occurrence of serious adverse events (SAEs) throughout the trial.

 Secondary end points:

 1. The Ratio of the GMTs of test and comparator vaccines in different time points.
Inclusion Criteria:

 1. Considered healthy as per medical judgment of the investigator

 2. Age: 20 to 45 years

 3. Sex: Male, Female and Transgender

 4. For married women, a negative urine pregnancy test (Rapid Diagnostic Test) during
 screening and prior to first, second and third dose of vaccination.Moreover, medical
 history will be taken thoroughly by study physician from the woman of childbearing age
 to completely exclude the probability of pregnancy.The women who are married and
 living with a partner must agree to use a reliable contraceptive method to prevent
 pregnancy until final follow-up following vaccination. However abstinence is also
 acceptable.

 Exclusion Criteria:

 1. Prior history of hepatitis B infection

 2. Vaccination with any hepatitis B vaccine

 3. Recent febrile illness (within 2 weeks)

 4. Known or suspected hypersensitivity to any component of Hepatitis B vaccine (e.g.,
 aluminium, yeast).

 5. History of received hepatitis B immune globulin (HBIG), serum immune globulin, or any
 other blood-derived product.

 6. Known or suspected impairment of immunologic function or recent use of
 immunomodulatory medications (e.g., systemic corticosteroids) more than 14 days with
 in last 6 months. Does not include topical and inhaled steroids.

 7. Receipt of investigational drugs or other investigational vaccines within 3 months
 prior to first injection with the study vaccine.

 8. Pregnant women, nursing mothers, and women planning to become pregnant within the
 study period.

 9. HBsAg reactive, anti-HBs antibody (≥10mlU/ml), anti-HBc (total) reactive, and abnormal
 liver function test [serum alanine aminotransferase (ALT) level], serum creatinine and
 CBC (As mentioned in Appendix IV).