CTRI Number	CTRI/2020/04/024833 [Registered on: 24/04/2020] Trial Registered Prospectively
Last Modified On:	01/06/2020
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Vaccine
Study Design	Randomized, Parallel Group, Placebo Controlled Trial
Public Title of Study	BCG-Denmark versus no-BCG for COVID 19 prevention
Scientific Title of Study	Effect of BCG-Denmark (Green Signal) on prevention of COVID 19 infection in health care workers – a double blind randomized controlled trial
Secondary IDs if Any	Secondary ID  Registry  NIL  NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study)	Name  Narayanan Parameswaran  Address  Department of Paediatrics, Women and Children Hospital,JIPMER, Dhanvantari Nagar P.O. Dhanvantari Nagar, Puducherry Pondicherry PONDICHERRY 605006 India  Phone  9443458850   Fax     Email  narayanan.p@jipmer.edu.in
Details Contact Person Scientific Query	Name  Narayanan Parameswaran  Address  Department of Paediatrics, Women and Children Hospital,JIPMER, Dhanvantari Nagar P.O. Dhanvantari Nagar, Puducherry Pondicherry PONDICHERRY 605006 India  Phone  9443458850   Fax     Email  narayanan.p@jipmer.edu.in
Details Contact Person Public Query	Name  Narayanan Parameswaran  Address  Department of Paediatrics, Women and Children Hospital,JIPMER, Dhanvantari Nagar P.O. Dhanvantari Nagar, Puducherry Pondicherry PONDICHERRY 605006 India  Phone  9443458850   Fax     Email  narayanan.p@jipmer.edu.in
Source of Monetary or Material Support	Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry
Primary Sponsor Modification(s)	Name  Dr Narayanan Parameswaran  Address  Professor, Department of Paediatrics, JIPMER, Dhanvantari Nagar, Puducherry-605006  Type of Sponsor  Other [Self]
Details of Secondary Sponsor	Name  Address  NIL  NIL
Countries of Recruitment	India
Sites of Study	No of Sites = 1   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Narayanan Parameswaran  Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry  Dhanvantari Nagar P.O., Puducherry -605006 Pondicherry   9443458850 narayanan.p@jipmer.edu.in
Details of Ethics Committee Modification(s)	No of Ethics Committees= 1   Name of Committee  Approval Status  Institute Ethics Committee for Interventional studies  Approved
Regulatory Clearance Status from DCGI	Status  Not Applicable
Health Condition / Problems Studied	Health Type  Condition  Healthy Human Volunteers  Health care workers posted in Covid-19 area to take care of patients with covid-19
Intervention / Comparator Agent	Type  Name  Details  Intervention  BCG-Denmark (Green Signal)  BCG-Denmark (Green Signal), 0.1 ml, intradermal injection in left deltoid area  Comparator Agent  Placebo  Normal saline, 0.1 ml administered intradermally in the deltoid area of left arm
Inclusion Criteria	Age From  18.00 Year(s) Age To  65.00 Year(s) Gender  Both  Details  1. All HCWs (doctors and nurses and housekeeping staff) posted to take care of patients in the designated COVID 19 wards / ICUs for at least one shift (minimum 6 hours). 2. All HCWs (doctors and nurses and housekeeping staff) likely to be posted in Emergency medical services (EMS) for one week (minimum 56 hours). 3. All laboratory workers likely to be posted for at least one week in a Virology laboratory where SARS-CoV-2 testing is being performed.
ExclusionCriteria	Details  1.HCWs not directly involved in patient care (facility manager, supervisory staff not physically present in the patient care areas) 2. A immunodeficiency state (including primary immunodeficiency, HIV infection, chemotherapy or high-dose steroid therapy (more than or equal to 20 mg for more than or equal to 2 weeks),non-biological immunosuppressant (also known as DMARDS), biological agents (such as monoclonal antibodies against tumor necrosis factor (TNF)-alpha) 3. Pregnancy 4.Malignancy 5.Active skin disease such as eczema, dermatitis or psoriasis at or near the site of vaccination. 6.Previously had a SARS-CoV-2 positive test result 7.BCG vaccine received in the past one year
Method of Generating Random Sequence	Stratified block randomization
Method of Concealment	Sequentially numbered, sealed, opaque envelopes
Blinding/Masking	Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome	Outcome  TimePoints  Proportion of HCW with symptomatic COVID 19 disease 6 months after randomization. Symptomatic COVID 19 will be defined as self-reported fever or cough, or shortness of breath, or respiratory distress, or runny or blocked nose plus a positive PCR test and/or antibody test   Six months after randomisation
Secondary Outcome	Outcome  TimePoints  Any adverse effects of intervention (BCG adenitis, disseminated BCG etc)  Six months after randomisation  Mortality if any due to COVID 19 disease   Six months after randomisation  Proportion of HCWs who develop any type of SARS-CoV-2 infection (both asymptomatic and symptomatic)   Six months after randomisation  Proportion of HCWs with Pneumonia (mild and severe) and ARDS requiring hospitalization due to SARS-CoV-2   Six months after randomisation
Target Sample Size	Total Sample Size="1826" Sample Size from India="1826"
Phase of Trial	N/A
Date of First Enrollment (India)	01/05/2020
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)	Not Yet Recruiting
Publication Details	Study protocol not published. Recruitment not yet started
Brief Summary	WHO has declared COVID 19 as a pandemic on 11th March 2020. In addition to the high mortality around the world observed among elderly population and those with chronic comorbidities, exposure of healthcare workers (HCW) to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major concern. In China, more than 3300 HCWs had been infected as of early March 2020 and at least 22 had died. Similarly, in Italy, 20% of frontline HCWs were infected. These figures are alarming as a shortage of HCWs can seriously impede the ability of a country to effectively manage this pandemic. The risk factors for infection in HCWs reported include working in high-risk departments, longer duty hours, and suboptimal hand hygiene after contact with patients. Though some of these risk factors are modifiable, we need to implement all possible strategies to decrease the risk of COVID 19 infection to HCWs. In this context, one promising intervention could be Bacillus Calmette-Guerin vaccine (BCG) vaccination. A couple of recent ecological studies have suggested a possible association between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19 at country level. However, these observations need confirmation in randomised clinical trials.  Live attenuated vaccines, such as measles vaccine, BCG and oral polio vaccine (OPV), have beneficial  effects beyond protection against the targeted infections, through induction of non-specific immunity that protects the recipients from other infections. This observation has been confirmed by several randomized controlled trials. In three randomised trials in low-birth-weight infants, BCG-Denmark reduced neonatal mortality by 38% (95% CI, 17%-54%) in Guinea-Bissau. A meta-analysis of the 3 RCTs of early BCG supported marked reductions in mortality within 3 days after vaccination, and at 28 days and 12 months of age. Further, in a randomised trial in South Africa, revaccination with BCG-Denmark besides reducing sustained tuberculosis infections by 45% (95% CI, 6.4%-68.1%), also reduced the incidence of upper respiratory tract infections by 73% (39%-88%) and all infections by 57% (28%-74%). A recent review by Moorlag et al has specifically looked at the nonspecific effects of BCG on viral infections including influenza A, HPV, RSV in humans as well as animals. Human studies with BCG showed the recipients having decreased episodes of genital herpes infection, improved clearance of viral warts, and enhanced antibody production with influenza A vaccine. Animal studies reviewed had shown the ability of BCG to offer protection against HSV1, Japanese encephalitis, encephalomyocarditis etc.  If this beneficial effect of BCG can be proven to be true, administration of BCG may be used as a novel strategy to protect against viral infections, especially against those infections that cause global pandemics and for which an effective vaccine is currently not available. The potential for this to save the life of millions of people is exciting. Our study hypothesis is that  administration of a single dose of BCG vaccine to health care workers reduce the risk of development of COVID 19 disease in them.