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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 1 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. 2 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. 3 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. 4 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. 6 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. 7 12.1 Remarks of Chairman and Principal: 12.2 Signature: 8