Download rajiv gandhi university of health sciences, karanataka

lRAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1.
Name of the candidate and
Address
:
Dr. Veena V
W/o. Dr. Lokesh K N
#15. G-1,1st floor, B.B.Mansion apartment
3rd shop lane,Tata silk farm,Basavanagudi
Bangalore- 560004
2.
Name of the Institution
:
Kempegowda Institute of Medical Sciences,
Banashankari 2nd stage, Bangalore-560070.
3.
Course of Study and Subject
:
M.D in Community Medicine
4.
Date of Admission to Course
:
10th May 2010
5.
Title of the Topic
:
Clinical
evaluation
of
safety
and
immunogenicity
of
an
indigenously
developed purified chick embryo cell rabies
vaccine when administered intradermally in
animal bite cases.
6.
Brief resume of the intended work
6.1
Need for the study:
Rabies is an acute, practically 100% fatal viral disease affecting both man and
animals. An estimated 20,000 human rabies deaths and 17.4 million animal bite cases
are known to occur in India every year1. Semple (sheep brain) vaccine was in use for
treating animal bite cases for more than 75 years in our country & following a
Supreme Court ruling, the Government of India, in December 2004, stopped the
production of this vaccine. Consequently, safer modern rabies vaccines viz. cell
culture and embryonated egg rabies vaccines replaced the Semple vaccine in
Government Hospitals. This caused a sudden increased demand for modern rabies
vaccines which lead to an acute shortage of these life saving medicines both in
Government & Private Sectors.
Studies in India & abroad have shown that intradermal rabies vaccination
(IDRV) is safer, immunogenic and cost effective when compared to intra muscular
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rabies vaccination3,4. Based on the ICMR feasibility study & WHO expert
consultation on rabies5, Drug Controller General of India (DCGI) in Feb & May 2006
approved the IDRV using updated Thai Red Cross (TRC) regimen (2-2-2-0-2) which
is scientific, rational & largely benefits the poor & needy who visit these government
hospitals.
Considering the rabies endemicity in the country and increased demand for
modern rabies vaccines, there is a need to indigenously develop rabies vaccine for
intradermal use, so as to stop importing of these vaccines from other countries.
Therefore, this pioneer study is undertaken to evaluate the safety and immunogenicity
of an indigenously developed purified chick embryo cell rabies vaccine by
intradermal route using updated Thai Red Cross regimen and in comparison to a
WHO approved and widely used purified chick embryo cell rabies vaccine.
6.2 Review of Literature:

The WHO sponsored national multi-centric rabies survey carried out by the
APCRI showed that India has about 17.4 million cases of animal bites & 20,000
human rabies deaths every year.1

The rabies vaccines for intra muscular use are in short supply & are costly thus
contributing to their non-availability in both government & private hospitals
across the country. Thus the IDRV can make the rabies vaccine more affordable
to the common man.2

The study conducted by Thai Red Cross Society, Thailand has established the
safety and efficacy of the IDRV using Updated TRC regimen.3

Study conducted at Philippines has shown the safety & efficacy of the PCEC
vaccine using the TRC regimen in animal bite victims.4

The WHO expert consultation on rabies5 and WHO position paper on rabies6
emphasized the need to use Updated TRC regimen in post-exposure prophylaxis
which is safe and immunogenic.
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6.3 (a) Aim:
To compare the safety and immunogenicity of an indigenously developed purified
chick embryo cell vaccine v/s WHO/GOI approved purified chick embryo cell
vaccine for intradermal route using updated Thai Red Cross regimen in animal bite
cases.
6.3 (b) Objectives:
1. To assess the safety of new indigenously produced purified chick embryo cell
vaccine when compared to WHO/GOI approved purified chick embryo cell vaccine
by intradermal route in animal bite cases.
2. To assess the immunogenicity of new indigenously produced purified chick
embryo cell vaccine when compared to WHO/GOI approved purified chick embryo
cell vaccine by intradermal route in animal bite cases.
7. Materials and Methods:
7.1
Source of Data: Animal bite victims who attend the anti rabies clinic of
Preventive Medicine Unit at KIMS Hospital and Research Centre, Bangalore.
7.2 (a) Study Place: Anti rabies clinic of KIMS Hospital and Research Centre run
by Department of Community Medicine, KIMS, Bangalore.
7.2 (b) Study Design: Randomised (1:1), active control, parallel assigned and open
label study.
7.2 (c) Study Period: One Year
7.2 (d) Study Subjects: Animal bite victims of either sex in the age group of 18-55yrs.
7.2 (e) Inclusion Criteria:

Subjects with low risk Category II and Category III exposures.

Subjects willing to give signed informed consent.

Subjects willing to give blood samples on recommended days.

Subjects available for minimum of 6 months follow-up.

Dog/Cat domesticated, available for 10 days observation, apparently healthy,
provoked bite, wound washed with soap and water and consulting for vaccination
within 48 hours of exposure.
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7.2 (f) Exclusion Criteria:

Pregnancy & lactation.

Subjects who had received any type of rabies vaccine/immunoglobulin in the past.

Subjects with very severe bite wounds.

Subjects with chronic illness or cancers.

Subjects on steroids or any other immunosuppressant or is known to be HIV
positive.

Subjects planning for surgery in the next 3 months.

Subjects on concomitant antimalarials.

Subjects with history of allergy to any ingredient of the vaccine.

Participation in another clinical trial in the past 3 months.

Past history of chronic alcoholic abuse.
7.2 (g) Sample Size: 70 animal bite cases (35 subjects in each vaccine group).
7.2 (h) Sampling: Simple Random Sampling.
7.2 (i) Methodology:
The two vaccines will be allocated randomly using computer generated 70
random numbers on a separate slip. The random number and the type of
vaccine will be printed & will be enclosed inside a sealed envelope. On the
cover of the envelope, only the random number will be printed. The patient
who fulfills the inclusion and exclusion criteria and sign informed consent will
be asked to pick an envelope randomly and whichever the vaccine printed
inside the envelope will be administered.
a) Collection of data: A standard case record proforma will be used for each subject
which contains socio demographic profile, details of exposure, wound description,
personal history, general physical examination, systemic examination, details of
treatment given and follow up for any adverse events.
b) Vaccines to be used:

Purified chick embryo cell vaccine developed by Zydus Cadila health
care Ltd will be used for the study.

Purified chick embryo cell vaccine (Rabipur) manufactured by
Novartis vaccines will be used for comparison.
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The lyophilized vaccines will be reconstituted with 1ml of diluent
provided by the manufacturer/developer and will be used within 6 hours of
reconstitution as per WHO recommendation.
c) Procedure of intradermal vaccination
Rabies vaccines will be administered intradermally using updated TRC
regimen (2-2-2-0-2). This involves injection of 0.1ml of reconstituted vaccine per ID
site on two such ID sites per visit (one on each deltoid area, an inch above the
insertion of deltoid muscle) on day 0, 3, 7, and 28. The day 0 is the day of first dose
of administration of vaccine. Subjects with category III exposure will be administered
rabies immunoglobulin (RIGs) on day “0” as per WHO guidelines.
ID Injection Technique
Using aseptic technique, freeze-dried vaccine will be reconstituted with the
diluent supplied by the manufacturer/developer. With 1ml syringe 0.2 ml (i.e. 0.1ml per
ID site  2 sites) of vaccine will be drawn after expelling the air bubbles carefully from
the syringe. Using the technique of BCG inoculation, half the volume of vaccine (i.e. an
inch above the insertion of deltoid muscle). A raised papule will appear causing a
peaud’Orange (Orange peel) appearance. Remaining half of the vaccine will be injected
into the dermis on the opposite deltoid.
d) Safety Assessment
The Adverse Events (both local & systemic) will be recorded by observing the
subjects for about 30 minutes after administration of vaccine & also subsequent to
vaccination. Adverse events will be evaluated using 4- point scale.
0
None
Absence of symptoms
1
Mild
Presence of mild symptoms
2
Moderate
Symptoms which have an effect on daily
normal activities
3
Severe
Symptoms
activities
5
which
prevent
daily
normal
e) Assessment of Immunogenicity
5ml of venous blood will be drawn with aseptic technique from the ante
cubital vein of the subjects on days 0, 14, 28, 90 & 180 (5 samples per subject). The
blood samples are allowed to stand for about 30 minutes, centrifuged at 3000 rpm &
serum is separated, collected and coded, stored at – 20o C & sent for estimation of
rabies virus neutralizing antibodies (RVnAb) by rapid fluorescent focus inhibition test
(RFFIT) at the Dept. of Neurovirology, NIMHANS, Bangalore.
A RFFIT result of > 0.5 IU / mL will be considered as an adequate
immunogenic response / protective as per WHO.
f) Statistical analysis
The results obtained for RVnAb will be analyzed by Geometric Mean
concentration (GMC), Geometric Standard Deviation (GSD), 95% Confidence
Interval & p-value will be calculated.
The adverse events will be graded using 4-point scale and variation between
the two groups will be assessed using Mann-Whitney test.
7.3
Has ethical clearance been obtained from your institution:
YES
8.
References:
1. Sudarshan MK, Mahendra BJ, Madhusudana SN, Ashwath Narayana DH, Abdul
Rahaman, Rao NSN, et al. An epidemiological study of animal bites in India:
Results of a WHO sponsored National Multi-centric Rabies Survey, Journal of
Communicable Diseases, 2006;38(1):32-39.
2. Sudarshan MK, Mahendra BJ, Ashwath Narayana DH. Introducing intradermal
rabies vaccination in India: Rationale and Action plan, Journal of APCRI. 2005;
7(1):20-25.
3. Pukamatz Khawplod, Henry Wilde, Siriwan S, Maneerat B, Sukunya L,
Wipaporn J et al. Revision of the Thai Red Cross Intradermal rabies post exposure
regimen by eliminating the 90- day booster injection Vaccine. 2006; 24(1):30843086.
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4. Quiambao B P, Efren M D, Cristina A, Rolan D, Angelika B, Malerczyk C,
Comparison of safety and immunogenicity of Purified Chick Embryo Cell
Vaccine & Purified Vero cell Rabies Vaccine using the updated Thai Red Cross
regimen at a dose of 0.1ml Vaccine. 2005; 23(14):1709-1714.
5. World Health Organization, Expert Consultation on Rabies. Technical Report
Series 931, 2005, Geneva, Switzerland.
6. Weekly Epidemiological record. WHO. 2010; 32(85):309-320.
9.
Signature of the Candidate:
10. Remarks of the Guide:
The present study will prove the safety and immunogenicity of a new
indigenously manufactured PCEC rabies vaccine when administered intradermally,
which will alleviate the deficiency of rabies vaccines used for intradermal
administration in our country.
11. Names and Designation:
11.1
Guide
11.2
Signature
11.3
Head of the Department
11.4
Signature
Dr.Ravish H S MD
Associate Professor
Department of Community Medicine
KIMS, Bangalore -560070.
Dr. B. G. Parasuramalu MD
Professor and Head
Department of Community Medicine
KIMS, Bangalore - 560070.
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12.1
Remarks of Chairman and Principal:
12.2
Signature:
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