Clinical Trial Details (PDF Generation Date :- Thu, 14 Jul 2016 00:46:45 GMT)
CTRI Number CTRI/2011/08/001957 [Registered on: 19/08/2011] - Trial Registered Prospectively
Last Modified On 06/11/2012
Post Graduate Thesis No
Type of Trial Interventional
Type of Study Vaccine
Preventive
Study Design Randomized, Parallel Group, Active Controlled Trial
Public Title of Study A STUDY TO EVALUATE THE IMMUNOGENICITY AND SAFETY OF BBILs TYPHOID Vi
CAPSULAR POLYSACCHARIDE-TETANUS TOXOID PROTEIN CONJUGATE VACCINE VS REFERENCE VACCINE IN HEALTHY SUBJECTS.
Scientific Title of Study
A PHASE III, RANDOMIZED, MULTICENTERIC, CONTROLLED STUDY TO EVALUATE THE IMMUNOGENICITY AND SAFETY OF BBILs TYPHOID Vi CAPSULAR
POLYSACCHARIDE-TETANUS TOXOID PROTEIN CONJUGATE VACCINE VS REFERENCE VACCINE IN HEALTHY SUBJECTS.
Secondary IDs if Any Secondary ID Identifier
BBIL/CTP/04/2010 Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Details of Principal Investigator
Name Dr Anit Singh
Designation Asst. Medical Director
Affiliation Bharat Biotech International Ltd
Address Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal
Hyderabad, Andhra Pradesh Hyderabad ANDHRA PRADESH 500 078 India Phone 04023480567 Fax 04023480560 Email [email protected] Details Contact Person (Scientific Query)
Details Contact Person (Scientific Query)
Name Dr Anit Singh
Designation Asst. Medical Director
Affiliation Bharat Biotech International Ltd
Address Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal
Hyderabad, Andhra Pradesh Hyderabad ANDHRA PRADESH 500 078 India Phone 04023480567 Fax 04023480560 Email [email protected] Details Contact Person (Public Query)
Details Contact Person (Public Query)
Name Dr Anit Singh
Designation Asst. Medical Director
Affiliation Bharat Biotech International Ltd
Address Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal
Hyderabad, Andhra Pradesh Hyderabad
ANDHRA PRADESH 500 078 India Phone 04023480567 Fax 04023480560 Email [email protected] Source of Monetary or Material Support
Source of Monetary or Material Support
> Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal Hyderabad, Andhra
Pradesh
Primary Sponsor Primary Sponsor Details
Name Bharat Biotech International Ltd
Address Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal
Hyderabad, Andhra Pradesh
Type of Sponsor Pharmaceutical industry-Indian
Details of Secondary Sponsor Name Address NIL NIL Countries of Recruitment List of Countries India
Sites of Study Name of Principal
Investigator
Name of Site Site Address Phone/Fax/Email
Dr Monjori Mitra Institute of Child Health Institute of Child, Health11Dr.Biresh Guha Street Kolkata WEST BENGAL 09831075734 monjori.mitra@medclins earch.com
Dr P Venugopal King George Hospital Department of pediatrics, KGH , Vishakapatnam Visakhapatnam ANDHRA PRADESH 9848027203 venugopal_kgh@yahoo .com
DrBSudhaka Priya Children Hospital Dept of pediatrics Priya Children Hospital New P&T Colony,Patamata Krishna ANDHRA PRADESH 9885066297 [email protected] m
Dr Mukesh Gupta soumya Child Clinic soumya Child Clinic, Near Laxmi mandir Cinima, Tonk road Jaipur RAJASTHAN 09460553950 drmukeshgupta.pediatri [email protected] Dr J Bhuvaneshwar Rao
Sri Srinivasa Children Hospital
Sri Srinivasa Children Hospital, Pediatrics Chiluku Durgaya Street Nakala Road Krishna ANDHRA PRADESH 9849084660 [email protected] Details of Ethics Committee
Name of Committee Approval Status Date of Approval Is Independent Ethics
Committee?
Central Ethics Committee
Approved 20/06/2011 Yes
Institute of Child Health Approved 03/08/2011 No Institute of Preventive
medicine
Institutional ethics committee ,Mahavir medical Research center Approved 29/08/2011 No Institutional Ethics Committee, King George Hospital Approved 09/04/2011 No
KLE University Approved 22/09/2011 No
Sanjeevini ethics committee Approved 28/05/2011 Yes Vishakapatnam Central Ethics Committee Approved 20/06/2011 Yes Regulatory Clearance Status from DCGI
Status Date
Approved/Obtained 09/08/2011
Health Condition / Problems Studied
Health Type Condition
Healthy Human Volunteers To prevent Typhoid
Intervention / Comparator Agent
Type Name Details
Comparator Agent TYPBAR Typhoid Vi capsular
polysaccharide vaccine (TYPBAR) administered as one dose of 0.5 ml in all age Reference groups by intramuscular route.
Intervention TYPHOID TT Vaccine Typhoid Vi capsular
polysaccharide-TT protein conjugate vaccine manufactured by Bharat Biotech international Limited, Hyderabad.
Administered as one dose of 0.5 ml in all age Test groups by intramuscular route.
Inclusion Criteria Inclusion Criteria
Age From 6.00 Month(s)
Age To 45.00 Year(s)
Gender Both
Details 1. Provide voluntary written and signed informed consent from
volunteer or if minor from parent/legal guardian.
2. Healthy subjects in two cohorts aged 6 to 24 months, and 2 - 45 years.
3. Are not participating in or plan to participate in another research during the next three months & be available throughout study period. 4. Family does not plan to move during the study period, and housed not further that 50 Km away from the study site.
Exclusion Criteria Exclusion Criteria
Details Fever of any origin or infections more than 3 days within one month
prior
to screening or on the day of screening
2) Any confirmed or suspected immunosuppressive condition. 3) Any treatment with immunosuppressive or immunostimulant therapy
4) Use of any marketed or investigational or herbal medicine or non-registered drug or vaccine for typhoid.
5) Life threatening or serious cardiac (NYHA grade 3&4), respiratory, gastrointestinal, hepatic, renal, endocrine and systemic disorders.
6) Have been vaccinated against typhoid fever or had exposure to typhoid fever within the last three years.
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
An Open list of random numbers
Blinding/Masking Open Label
Primary Outcome Outcome Timepoints
The comparative assessment of the
immunogenicity of the test vaccine (conjugate typhoid vaccine) versus the comparator (polysaccharide typhoid vaccine) by estimation of:
1. 4 fold Seroconversion rates in each treatment arm at 6 weeks post vaccination.
2. 4 fold Seroconversion rate in Cohort-1(2 years) from base line to 6 weeks post vaccination.
3. Extent of rise of anti Vi IgG antibody from baseline values to 6 weeks post vaccination
The comparative assessment of the
immunogenicity of the test vaccine (conjugate typhoid vaccine) versus the comparator (polysaccharide typhoid vaccine) by estimation of:
1. 4 fold Seroconversion rates in each treatment arm at 6 weeks post vaccination.
2. 4 fold Seroconversion rate in Cohort-1(2 years) from base line to 6 weeks post vaccination.
3. Extent of rise of anti Vi IgG antibody from baseline values to 6 weeks post vaccination
Secondary Outcome Outcome Timepoints
1. Comparative assessment of safety and tolerability of the vaccine in all subjects up to 3 months post vaccination.
2. Based on the Geometric Mean Titers of the primary objectives 1& 2 the superiority of test over reference vaccine will be determined
3 months
Target Sample Size Total Sample Size=981
Sample Size from India=981
Phase of Trial Phase 3
Date of First Enrollment (India) 12/09/2011 Date of First Enrollment (Global) No Date Specified Estimated Duration of Trial Years=1 Months=0 Days=0 Recruitment Status of Trial (Global) Not Applicable Recruitment Status of Trial (India) Completed Publication Details
Cohort
Age group
Vaccine Groups
Total
TEST
REFERENCE
1
?6 months to ?2 years
327
327
2
>2 years to ?45 years
327
327
654
Total
981
The null hypothesis for the study assumes that the mean seroconversion rate (i.e a 4 fold rise of anti- Vi IgG antibody titer from baseline ) in the test group ( ?T ) and the control group (?C) are equal i.e ?T = ?C and the alternate hypothesis is that they are not equal i.e ?T ? ?C.
The proposed sample size has been calculated on the basis of information from previous studies where the conjugate vaccine has demonstrated a seroconversion rate of about 80%. Therefore assuming an effect size in seroconversion rates as 10%, ? of 0.05 and 80% power and equal allocation rates in both arms, the number of evaluable subjects required per group would be 294.
If we assume a 10% drop out rate- evaluable subjects per group would be required i.e a total of 327. The sample size has been calculated using the Statistical software version 6. In the group <2 years we propose to recruit 327. Total sample size proposed for the study would be 981.
Cohort-1: 327 (subjects aged ?6months to ?2 years Open Labeled, single arm).
Cohort-2: 654 (subjects aged >2 years to ?45 years- Double Blinded, two arms with equal allocation ratio).
Note-1: The comparator vaccine is a polysaccharide vaccine which has T-cell independent nature of immune response and is not effective below 2 years and hence not approved for use in this age group. Also we examine other vaccines which could be used as comparator vaccine in below 2 years age group. The other vaccines which could be given in the control arm of this group would be different in the various stratified age range based on the Expanded Program on Immunization (EPI)/Indian Academy of Pediatrics (IAP) vaccine schedule leading to complexity of the study design and also statistical analysis. Considering all these issues this group (Cohort-1) would be single arm, an open labeled study.
Note-2: The number of the subjects in Cohort-2 enrolled would be more (~400 subjects) in <15 years age group and less (~254 subjects) in >15 years because the common age group of getting typhoid fever is 2-15 years.
RANDOMIZATION The Subjects will be randomly assigned to test vaccine or Reference vaccine group as per the codes generated by the computer program.
A copy of computer generated randomization list of subject numbers will be maintained by study member located at the center. The blinding key or decoding list of randomization will be provided to statistician at the time of statistical analysis by Asian Clinical Trials, Hyderabad.
Services such as generation of randomization list, labeling of vials, blinding and generation of decoding list or envelops will be provided by the Asian Clinical Trials, Hyderabad.
OBJECTIVE To evaluate the Safety and Immunogenicity of Typhoid Vi capsular polysaccharide-TT protein conjugate vaccine Vs Reference vaccine
in healthy subjects.
PRIMARY END POINTS The comparative assessment of the immunogenicity of the test vaccine (conjugate typhoid vaccine) versus the comparator
(polysaccharide typhoid vaccine) by estimation of:
1. 4 fold Seroconversion rates in each treatment arm at 6 weeks post vaccination.
2. 4 fold Seroconversion rate in Cohort-1(<2 years) from base line to 6 weeks post vaccination. 3. Extent of rise of anti Vi IgG antibody from baseline values to 6 weeks post vaccination.
SECONDARY END POINT
1. Comparative assessment of safety and tolerability of the vaccine in all subjects up to 3 months post vaccination.
2. Based on the Geometric Mean Titers of the primary objectives 1& 2 the superiority of test over reference vaccine will be determined.
RATIONALE Typhoid fever is a very common and serious disease in developing countries like India. Salmonella typhi, the bacteria responsible to
typhoid fever has become resistant to various antibiotics with raising concern.
Methods to control typhoid fever, such as sanitary water and food supply alone with effective sewage treatment are not likely to be available in these countries in near future.
The use of effective and safe vaccine especially in children could lessen the incidence of disease in endemic areas. The currently licensed vaccines have various limitations 1) Most of these vaccines have a efficacy of only 70 %, 2) Orally administered attenuated Ty21a requires at least three doses and has a low rate of efficacy in area with a high incidence of typhoid fever and its efficacy has not been demonstrated in children. 3) Parenterally administered vaccines are an age dependent serum antibody response and reinjection did not elicit a booster response (T-cell independent).
To overcome the above limitations Vi polysaccharide has been conjugated with tetanus toxoid protein, this conjugation technique has been developed by Bharat Biotech. The new vaccine has a higher immunogenicity response and is T-cell dependent. All previous typhoid conjugate vaccines clinical studies have shown that the efficacy and immunogenicity of Typhoid conjugate vaccine are higher than Vi polysaccharide vaccine alone8, 9, 10.
This vaccine has already undergone the safety, immunogenicity and dose ranging studies in children 2 to 17 years in Phase II. The results suggest that the vaccine was absolutely safe, potent to produce an immune response to protect against Typhoid. The vaccine is efficacious to induce antibody titers required to protect for Typhoid disease and also superior to already registered commercially available Vi Capsular Polysaccharide vaccine. The single dose of 25?g/0.5mL Typhoid-TT conjugate vaccine showed adequate immune response, when compared to two doses of 25?g/ 0.5mL and two doses of 15?g/0.5mL dose of vaccine response and there is no significant difference between the groups.
Hence the current study is to be undertaken to demonstrate the Immunogenicity and Safety of the new conjugate vaccine in
the dosage of 25 ?g/0.5mL as single dose to diverse healthy population of age ?6 months to ?2 yrs, and ? 2yrs to ? 45 yrs.
DATA ANALYSIS Data analysis will be performed by Indian Statistical Institute, Hyderabad / Medclin Research Kolkata. The data from various trial centers
would be collected by representatives of Bharat Biotech after reviewing it at the site.
The pre-vaccination geometric mean antibody (anti Vi anti IgG) titer at baseline will be compared with the 6 weeks post vaccination titers for detecting any statistically significant differences. The level of significance for the GMT analysis in both the arm will be considered as p<0.05 and the 95% CI for GMT.
The mean of pre as well as post immunization antibody levels will be compared between two groups by Kruskal Wallis test. Repeated measure antibody levels in each group will be compared with the respective mean pre-immunization antibody levels by Friedman’s ANOVA test.
The mean seroconversion rate in each group will be calculated and between group comparisons will be done using Chi Square test or Fisher’s exact test. The 95% CI will also be computed and values of p<0.05 will be considered statistically significant.
The safety data will be described as the percentage of subjects presenting with each of the local and systemic reactions and comparisons will be made between the two groups using chi-square test or Fisher’s exact tests. The 95% CI will also be computed and values of p<0.05 will be considered statistically significant.