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CTRI Number  CTRI/2020/05/025013 [Registered on: 05/05/2020] Trial Registered Prospectively
Last Modified On: 04/05/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Vaccine 
Study Design  Non-randomized, Active Controlled Trial 
Public Title of Study   Evaluation of BCG as potential therapy for COVID-19 
Scientific Title of Study   Phase 2 Clinical Trial for the Evaluation of BCG as potential therapy for CoVID-I9 
Trial Acronym  COVID-19 BCG 
Secondary IDs if Any  
Secondary ID  Identifier 
BIO/CT/20/000049  DCGI 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Rajesh Deshmukh 
Designation  Director, Haffkine Institute 
Affiliation  Haffkine Institute for Training Research and Testing 
Address  Haffkine Institute for Training Research and Testing Acharya Donde Marg Parel, Mumbai 400012
Haffkine Institute for Training Research and Testing Acharya Donde Marg Parel, Mumbai 400012
Mumbai
MAHARASHTRA
400012
India 
Phone  02224160947  
Fax  02224161787  
Email  director@haffkineinstitute.org  
 
Details of Contact Person
Scientific Query
 
Name  Dr Usha Padmanabhan  
Designation  Sr. Sci. Officer Haffkine Institute  
Affiliation  Haffkine Institute for Training, Research & Testing 
Address  Biochemistry Department, Haffkine Institute for Training Research and Testing Acharya Donde Marg Parel, Mumbai 400012 Tel 022-24160947 ext 220, 232 Fax 022-24161787
Same as address 1
Mumbai
MAHARASHTRA
400012
India 
Phone  02224160947  
Fax  02224161787  
Email  u.padmanabhan@haffkineinstitute.org  
 
Details of Contact Person
Public Query
 
Name  Dr Sanjay Mukherjee 
Designation  Hon. Principal Secretary  
Affiliation  Medical Education and Drugs Department 
Address  9th floor, Mantralay, GT Hospital Campus, Fort, Mumbai
9th floor, Mantralay, GT Hospital Campus, Fort, Mumbai
Mumbai
MAHARASHTRA
400001
India 
Phone  022-22622179  
Fax    
Email  psec.mededu@maharashtra.gov.in  
 
Source of Monetary or Material Support  
Medical Education and Drugs Department 9th floor, Mantralay, GT Hospital Campus, Fort, Mumbai 400001 
 
Primary Sponsor  
Name  Medical Education and Drugs Department 
Address  9th floor, Mantralay, GT Hospital Campus, Fort, Mumbai 400001 
Type of Sponsor  Government funding agency 
 
Details of Secondary Sponsor  
Name  Address 
Haffkine Institute for Training Research Testing  Acharya Donde Marg, Parel, Mumbai 400 012 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Sonali Salvi  Sassoon General Hospital  Jai Prakash Narayan Road, Near Pune Railway Station, Pune - 411001
Pune
MAHARASHTRA 
02026126010
02026126868
sonalionly@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
BJ Medical College and SGH  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  B972||Coronavirus as the cause of diseases classified elsewhere, J709||Respiratory conditions due to unspecified external agent,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  BCG plus STANDARD of CARE as suggested by DCGI  DOSE 0.1 ml ROUTE OF ADMINISTRATION Intradermal FREQUENCY Only once during the entire trial DURATION 1-2 min time required to inject subject. It is not continuous therapy.  
Comparator Agent  SALINE plus STANDARD of CARE as suggested by DCGI  DOSE 0.1 ml ROUTE OF ADMINISTRATION Intradermal FREQUENCY Only once during the entire trial DURATION 1-2 min time required to inject subject. It is not continuous therapy. 
 
Inclusion Criteria  
Age From  20.00 Year(s)
Age To  40.00 Year(s)
Gender  Both 
Details  Hospitalized subjects either male or female with confirmed COVID-19 will be included in this as per following criteria:
1. Age 20 - 50 years
2. Symptomatic subjects with fever (using self-reported questionnaire) plus at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire), plus
3. Positive SARS-Cov-2 test in nasopharyngeal sample at admission (using RT-PCR as prescribed by WHO, ICMR and NCDC)  
 
ExclusionCriteria 
Details  Subjects outside the age group
Subjects who test negative for nCOV-19 by RT-PCR as per criteria laid down by ICMR.
Subjects with
1. Any co-morbidities such as renal distress, cardiac malfunction etc. at time of admission
2. Any disorder in which natural immune response is altered,
3. Systemic lupus
4. Hypogamma-globulinemia,
5. Congenital immunodeficiency,
6. Sarcoidosis,
7. Leukaemia,
8. Generalised malignancy,
9. HIV infections or as also those on immunosuppressive therapy, corticosteroids, radiotherapy.
10. Inchronic eczema or other dermatological disease
11. Pregnant women, lactating (breast-feeding) women 
 
Method of Generating Random Sequence   Other 
Method of Concealment   On-site computer system 
Blinding/Masking   Participant Blinded 
Primary Outcome  
Outcome  TimePoints 
Primary Outcome Measures:
1.Total duration of Hospitalization with COVID-19 symptoms such as febrile respiratory distress [Time Frame: from admission until discharge]
2.Decrease in Viral Titer [Time Frame: Measured on day of enrolment, on day 7 and 15 after intervention]
3.Duration of COVID-19 symptoms [Time Frame: At time of admission, following enrollment until discharge] 
Primary Outcome Measures:
1.Total duration of Hospitalization with COVID-19 symptoms such as febrile respiratory distress [Time Frame: from admission until discharge]
2.Decrease in Viral Titer [Time Frame: Measured on day of enrolment, on day 7 and 15 after intervention]
3.Duration of COVID-19 symptoms [Time Frame: At time of admission, following enrollment until discharge] 
 
Secondary Outcome  
Outcome  TimePoints 
1.Local and systemic adverse events to BCG vaccination. [Time Enrolment to 3 months]
2.No. of ICU admissions [Time Enrolment to 3 months]
3.Duration of ICU admission [Time Enrolment to 3 months]
4.Number of participants needing mechanical ventilation [Time Enrolment to 3 months]
5.Duration of Mechanical ventilation [Time Enrolment to 3 months]
6.Mortality [Time From enrolment]
7.Time for resolution of COVID-19 disease [Time From enrollment]
8.Hospitalization cost [Time From enrollment] 
1.Local and systemic adverse events to BCG vaccination. [Time Enrolment to 3 months]
2.No. of ICU admissions [Time Enrolment to 3 months]
3.Duration of ICU admission [Time Enrolment to 3 months]
4.Number of participants needing mechanical ventilation [Time Enrolment to 3 months]
5.Duration of Mechanical ventilation [Time Enrolment to 3 months]
6.Mortality [Time From enrolment]
7.Time for resolution of COVID-19 disease [Time From enrollment]
8.Hospitalization cost [Time From enrollment] 
1. Change in IgG and IgM induced by nCoV-19 in serum [Time Day 0 and days 7 and 15 after BCG intervention]
2. Change in total IgG and IgM levels in serum [Time Day 0 and days 7 and 15 after BCG intervention]
3. Change in Th1 and Th2 cytokines as assessed by RT-PCR using RNA extracted from hematocrit [Time Day 0 and days 7 and 15 after BCG intervention] 
1. Change in IgG and IgM induced by nCoV-19 in serum [Time Day 0 and days 7 and 15 after BCG intervention]
2. Change in total IgG and IgM levels in serum [Time Day 0 and days 7 and 15 after BCG intervention]
3. Change in Th1 and Th2 cytokines as assessed by RT-PCR using RNA extracted from hematocrit [Time Day 0 and days 7 and 15 after BCG intervention] 
 
Target Sample Size   Total Sample Size="60"
Sample Size from India="60" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)   06/05/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="0"
Months="3"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   none 
Brief Summary  

Evaluation of BCG as potential therapy for COVID-19

Summary

Background and Introduction

The novel coronavirus nCoV-19 (or SARS-CoV-2 or 2019-nCoV), responsible for the global pandemic COVID-19 was isolated from human airway epithelial cells from patients from Wuhan, China in December 2019 (Wang et al, 2020; Zhu et al, 2020).  Seven coronaviruses (CoVs) have been described so far infecting humans of which the SARS-CoV (Kuiken et al, 2003), MERS-CoV and nCoV-19 are serious threats to humans. No therapies or vaccines have been approved for SARS or MERS thus far, demonstrating the need to develop effective therapies or vaccines.

 

BacilleCalmette-GuĂ©rin, BCG is a vaccine against tuberculosis that is prepared from a strain of the attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis. The bacilli have retained enough strong antigenicity to become an 80% effective vaccine for the prevention of human tuberculosis. Overall, BCG vaccine reduces the risk of pulmonary and extra-pulmonary tuberculosis (TB) by approximately 50%, but it has 64% efficacy against TB meningitis and 78% against disseminated TB disease.  India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so. BCG as a vaccine is safe to be used in children within a week of their birth and is in the Universal immunization programs of many countries in South East Asia and Africa.

BCG vaccine also provides some protection against leprosyand non-tuberculous mycobacterial infections. In addition, it has been used in the treatment of superficial carcinoma of the bladder.

It has been shown to reduce severe respiratory distress in children from Africa and conferred beneficial immunity and favorable outcomes to malarial infections. Revaccination with BCG has been tried in some populations (Japanese adults). However the longevity of immune protection due to re-vaccination has not yet been confirmed.

 

BCG Strains

Currently, five main strains account for more than 90% of the vaccines in use worldwide with each strain possessing different characteristics. The strains include the Pasteur 1173 P2, the Danish 1331, the Glaxo 1077 (derived from the Danish strain), the Tokyo 172-1, the Russian BCG-I,and the Moreau RDJ strains (Hayashi et al, 2009).

Each strain of BCG has a different reactogenicity profile - The Pasteur 1173 P2 and Danish 1331 strains are known to induce more adverse reactions than the Glaxo 1077, Tokyo 172-1, or Moreau RDJ strains (Hayashi et al., 2009).  The strain is one of the important factors that has been implicated in incidence of adverse events following BCG vaccination (Milstienet al,1990, Lotte et al.,1984). The BCG to be used in this protocol is Tubervac (Serum Institute of India) is derived from the Russian strain, also known as Moscow strain.

Safety of use of BCG

WHO estimates that 80% of the world is covered by BCG i.e. atleast 100 million children with one year of birth are given the vaccine worldwide, a statistic which speaks for the safety of the vaccine.

One of the most common side effects of BCG vaccinations are local complications (injection site reactions and suppurative or non-suppurative lymphadenitis). Management of the same varies between clinicians, and the optimal approach remains uncertain. In addition, the following adverse events have been noted in dispersed populations.

Skin lesions distinct from the vaccination site. Tuberculosis infection can cause a number of cutaneous lesions (such as TB chancre, lupus vulgaris, scrofuloderma, papulonecrotic tuberculids etc). There are case reports of cutaneous lesions, distinct from the site of vaccination, thought to have occurred after BCG vaccination (Bellet et al., 2005). It is important to note that multiple cutaneous lesions may signal disseminated BCG disease usually in an immunocompromised host. There are case reports of lupus vulgaris, scrofuloderma following BCG vaccination.

Lymphadenitis. When severe, this includes nodes which become adherent to overlying skin with or without suppuration. Suppuration has been defined as "presence of fluctuation on palpation or pus on aspiration, the presence of a sinus, or large lymph node adherent to the skin with a caseous lesions on excision" (Lotte et al., 1984). If BCG is administered in the recommended site (deltoid) the ipsilateral axillary nodes are most likely to be affected but supra-clavicular or cervical nodes may also be involved (Hengster et al., 1992). The onset of suppuration may be variable with cases presenting from one week to 11 months following vaccination (de Souza et al., 1983). Lymphadenitis presenting within 2 months of vaccination and larger nodes (+ 1cm) may be less likely to resolve spontaneously (Caglayan et al., 1991). Suppurative lymphadenitis is now rare, especially when BCG inoculations are performed by well-trained staff, with a standardized freeze-dried vaccine and a clearly stated individual dose depending on the age of the vaccinated subjects.

Osteitis and Osteomyelitis. This is a rare and severe complication of BCG vaccination which has primarily been reported in Scandinavia and Eastern Europe and typically associated with changes in BCG vaccine strain. There was a report of an increase in osteitis to 35 per million in Czechoslovakia after a shift from the Prague to Russian strain BCG (Lotte, et al., 1988). Both Finland and Sweden reported increases in osteitis after 1971 when they shifted to a Gothenburg strain produced in Denmark. Sweden reported rates as high as 1 in 3,000 vaccine recipients, which declined rapidly when the national programme shifted to a Danish (Copenhagen, 1331) vaccine strain (Lotte et al., 1988). More recently reports of osteitis have become infrequent.

Disseminated BCG disease or systemic BCG-itis. This recognized but rare consequence of BCG vaccination traditionally has been seen in individuals with severe cellular immune deficiencies. The risk (fatal and non-fatal) is thought to be between 1.56 / million and 4.29 cases / million doses (Lotte et al., 1988). This is based on pre-HIV data. However, the exact incidence is debated because few centers are able to differentiate Mycobacterium Bovis BCG from other forms of Mycobacterium in patients presenting with disseminated disease. In a recent retrospective case series review of Mycobacteriunm tuberculosis complex 5% of cases were found to have the M. Bovis BCG strain (Hesseling et al., 2006). Additional data from studies in South Africa confirm the significantly high risk of disseminated BCG (dBCG) disease in HIV-positive infants, with rates approaching 1% (Hesseling et al., 2009). In one series of 60 cases of BCG-itis the case fatality rate was approximately 50% although other smaller studies have documented a higher mortality rate (Lotte et al., 1988, Talbot et al., 1997). As expected the cellular primary immunodeficiency predisposes to the condition. This includes severe combined immunodeficiency, chronic granulomatous disease, Di George syndrome and homozygous complete or partial interferon gamma receptor deficiency (Jouanguy et al., 1996; Jouanguy et al., 1997; Casanova et al., 1995).

Early recognition and diagnosis is critical to management. In patients with primary immunodeficiency disorders the disease may be fatal without reconstitution of immunity through stem cell transplant.

Immune reconstitution inflammatory syndrome (IRIS). This has recently been identified as a BCG vaccine-related adverse event in immunocompromised individuals due to HIV started on antiretroviral therapy (ART) (DeSimone et al., 2000). It usually presents within 3 months of immune restoration and manifests as local abscesses or regional lymphadenitis usually without dissemination. No fatal cases have yet been documented.  A number of rare events have been reported as case reports or series. These include sarcoidosis, ocular lesions (conjunctivitis, choroiditis, optic neuritis), and erythema nodosum. Tuberculous meningitis (due to the BCG) has been described but is exceptionally rare (Tardieu et al., 1988)

Therefore, as noted above, most of adverse effects of the use of BCG is due to two factors (1) Strain used or change in strain (which has happened in some countries, when they switch suppliers) and (2) Immune status of the individual / population and widespread use of the BCG has demonstrated some advantages, such as excellent immune adjuvant activity, long-persisting effects, safety, and low cost.

Rationale to use BCG as a therapy for COVID-19

Miller et al, 2020 show a negative correlation between BCG immunization status of a country and mortalities due to COVID-19. In particular, Miller et al., 2020 have presented epidemiological data,that suggests that BCG could be effective against nCoV-19 or SARS-CoV-2.  The data (yet to be peer reviewed) found that countries that do not have a BCG immunization policy have more COVID-19 deaths and cases. These countries include the US, the Netherlands and Italy. Countries like Iran which started giving the vaccine late in 1984, had high mortality, suggesting that BCG protected the vaccinated elderly population, whereas countries like Japan have reported lesser cases and mortalities. 

In addition, Two international trials are on for assessing BCG as a prophylactic agent in healthcare workers in Australia and Netherlands against COVID-19.

BCG is known to induce a potent Th1-type response (in particular to increase IFN-gamm) and promote the production of both Th1- and Th2-type cytokines in response to unrelated vaccines. In the latter case, it is likely, however, that BCG stimulates general immune response. This results in faster response to infections that could reduce severity of disease and lead to faster recovery.

This protocol aims to evaluate the effects of BCG used as an interventional therapy on nCoV-19 positive subjects and establish a direct link between BCG inoculation and favorable COVID-19 outcome.

 
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