CTRI/2020/03/024402 [Registered on: 31/03/2020] Trial Registered Prospectively
Last Modified On:
31/03/2020
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug Preventive
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
Hydroxy Chloroquine, in open labelled, Randomised intervention for prevention of new infection and adverse outcomes following COVID-19 infection -A Tertiary Hospital based study
Scientific Title of Study
Hydroxy Chloroquine, in open labelled, Randomised intervention for prevention of new infection and adverse outcomes following COVID-19 infection- A Tertiary Hospital based study
Secondary IDs if Any
Secondary ID
Registry
NIL
NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)
Name
Dr Remesh Bhasi
Address
Aster Malabar Institute of Medical Sciences (MIMS)
P O Govindapuram
Kozhikode
Kerala
India 673016
Group 2 :
400 mg bd for one day followed by 400 mg weekly for 7 weeks to be taken with meals (or until the epidemic stops) (ICMR Regimen)
Both groups will be advised to follow strict measures of self hygiene, social distancing and other routine protocols issued by IMA and Government bodies to prevent transmission.
Intervention
Hydroxychloroquine
300 mg daily x 7 days followed by 300 mg weekly x 7 weeks
Inclusion Criteria
Age From
18.00 Year(s)
Age To
80.00 Year(s)
Gender
Both
Details
1. Moderate to high risk of exposure to infected patients during the study period.
2. Healthy at the time of enrolment without any symptoms suggestive of any viral infection.
ExclusionCriteria
Details
1. History of known allergy to Hydro ChloroQuine(HCQ) or Chloroquine
2. Known contraindications for HCQ or Chloroquine including Retinopathy, known Cardiac disease like Dysarrythmias, and G6PD deficiency.
3. Pregnancy and Lactation
4. History of recent (within one month) International travel.
5. Features of any ongoing infection including COVID-19
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Sequentially numbered, sealed, opaque envelopes
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Infected Non infected
Time to clinical improvement
Secondary Outcome
Outcome
TimePoints
Mortality, percentage of patients who had clinical improvement, oxygen support days, Mechanical ventilation, ICU stay days, total hospital stay, clinical score, MODs plus or minus
28 days mortality
7 day and 14 day clinical score and all others at the time of discharge
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)
Name
Dr Rajesh Deshmukh
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
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
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.
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. 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]
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]
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-Guérin, 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.
CTRI Number
CTRI/2020/04/024773 [Registered on: 21/04/2020] Trial Registered Prospectively
Albania Argentina Bahamas Bangladesh Belize Bolivia Botswana Brazil Canada Colombia Dominica Dominican Republic Ecuador Egypt Ethiopia Finland Georgia Guyana Honduras India Indonesia Iran (Islamic Republic of) Ireland Italy Jamaica Kenya Kuwait Latvia Lebanon Lithuania Macedonia Malaysia Mali Mexico Mozambique Niger Nigeria Norway Oman Pakistan Panama Paraguay Peru Philippines Portugal Romania Saudi Arabia Sierra Leone Spain Switzerland Trinidad and Tobago Zimbabwe
1. Adults (age ≥18 years) recently hospitalised, or already in the hospital, with definite (diagnosed by RT-PCR) symptomatic COVID admitted for at least moderate or severe illness
2. In the view of the responsible doctor, no contra-indication to any of the study drugs.
3. Providing consent for the participation
ExclusionCriteria
Details
1.Adults (age ≥18 years) with COVID and hospitalised for quarantine purposes or management of other conditions who do not have moderate or severe illness.
2.Laboratory confirmation of SARS Cov -2 infection not available
3.In the view of the randomising doctor, ANY of the AVAILABLE study drugs are contra-indicated
Anticipated transfer to another hospital which is not a study site within 72 hours
4.Pregnant or Lactating Women
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
All-cause mortality, subdivided by the severity of disease at the time of randomization, measured using patient records throughout the study
Throughout the study
Secondary Outcome
Outcome
TimePoints
Measured using patient records:
1. Duration of hospital stay (hours)
2. Time to first receiving ventilation (or intensive care) (hours)
Measured using patient records:
1. Duration of hospital stay (hours)
2. Time to first receiving ventilation (or intensive care) (hours)
Publication and dissemination plan
This international collaboration is co-ordinated through the World Health Organization, which is also a sponsor of the trial. Any wholly reliable interim findings will be disseminated rapidly by the WHO. There will be group authorship recognizing the contribution of all national and local investigators and guided by the International Committee of Medical Journal Editors (ICMJE) recommendations.
IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date.
Now
licensed vaccines are available for COVID-19 which have been shown to protect
from severe disease with variying effectiveness however various strains keep
emerging and there is no treatment that is 100% effective in preventing deaths.
Based on available data and expert consideration, it is felt that certain drugs
used to treat other diseases might be of help for COVID-19 or they might not.
The first (2020) part of Solidarity was completed successfully with 26 actively
recruiting sites across India and 1047 participants were randomised. The final
analysis is ongoing.
Thus after
evaluating 4 repurposed drugs in 2020 (Solidarity), the global trial aims to
study the drugs Artesunate, Imatinib and Infliximab in comparison to Local
Standard of Care in 2021(Solidarity trial Plus). The treatments chosen are
aimed at suppressing specific immune responses occurring during the
inflammatory phase of COVID-19.
The
clinical trial protocol for these new drugs is also referred to as ‘SOLIDARITY
Trial Plus’
However
the Drugs Controller General of India in consultation with the subject Expert
Committee while granting permission (CT-NOC No. CT-ND/89/2021)to the trial in India has recommended removal
of Artesunate arm.
In India
we will test test only In Infliximab and Tab. Imatinib.
CTRI Number
CTRI/2020/04/024858 [Registered on: 25/04/2020] Trial Registered Prospectively
Last Modified On:
25/04/2020
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Non-randomized, Active Controlled Trial
Public Title of Study
“To study the effectiveness of Ivermectin with standard of care treatment
versus standard of care treatment for COVID 19 cases. A Pilot Study
Scientific Title of Study
“To study the effectiveness of Ivermectin with standard of care treatment
versus standard of care treatment for COVID 19 cases. A Pilot Study
Secondary IDs if Any
Secondary ID
Registry
NIL
NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)
Name
Dr Sandeep Budhiraja
Address
Max Super Speciality Hospital (DDF), East Block, Internal Medicine department, 2- Press Enclave Road, New Delhi
Cases of COVID 19 shall be
treated with Ivermectin 200 to 400mcg per kg body weight on day 1 and day 2 along with
standard treatment of the hospital protocol
Comparator Agent
Standard treatment as per hospital protocol for COVID 19
Cases of
COVID 19 shall be treated with standard treatment as per hospital protocol for COVID 19 until the recovery.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
75.00 Year(s)
Gender
Both
Details
1. Subjects within age group between 18 to 75 years
2. With either sex, male or female
3. Confirmed case of COVID-19 at Max Hospitals.
This study aims to confirm the antivirus effectiveness of Ivermectin on coronavirus i.e COVID 19
then to explore its potential use in the combating to the COVID 19 pandemics.
Viral load will be monitored at 1, 3 & 5 days from beginning of trial drug (48 hours interval) Until the report comes negative. Drug will be delivered on daily basis upto eradication of virus or completion of
the trial
Coronavirus disease (COVID-19) is an infectious disease caused by a new virus. The disease
causes respiratory illness (like the flu) with symptoms such as a cough, fever, and in more
severe cases, difficulty breathing. At present, there are no specific treatments for COVID-19.
WHO recommends four treatments for COVID 19 with drugs i.eRemdesivir, Lopinavir/ ritonavir,
Lopinavir/ ritonavir with interferon beta -1a, and chloroquine or hydroxychloroquine. Currently,
there are several ongoing clinical trials evaluating potential treatments. Recently, LeonCaly report here that Ivermectin, an FDA-approved anti-parasitic previously
shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus
(SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARSCoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrant further investigation for possible benefits in humans. The study
rationale is to understand the effect of the drug on eradication of virus. This study aims to confirm the antivirus effectiveness of Ivermectin on coronavirus i.e COVID 19
then to explore its potential use in the combating to the COVID 19 pandemics.
Enrollment of subject into the trial shall only occur after providing written permission to
voluntarily participate into the study by signing and dating the informed consent form before
starting any trial related treatment. 50 cases of COVID-19 will be enrolled into the trial. The trial
shall be divided into two groups. First group with 25 confirmed cases of COVID 19 shall be
treated with Ivermectin 200 to 400mcg per kg body weight on day 1 and day 2 along with
standard treatment of the hospital protocol. The second group with 25 confirmed cases of
COVID 19 shall be treated with standard treatment as per hospital protocol for COVID 19.
Subjects in both the arms shall be followed up for recovery of death with regular monitoring as
per below schedule.
Test for virus at 1, 3 & 5 days from beginning of trial drug started for the patient in the
hospital
Clinical profile of the patient every day of hospitalization
Investigation of pulmonary function and O2 saturation every day of hospitalization
The day a patient is put on ventilator and the day when removed
The day a patient develops acute respiratory distress syndrome and the day when
relieved
All the above data shall be collected on paper case record form for interim and final analysis
from start of the trial i.e enrolment, treatment and follow-up.
Viral test to monitor the eradication of Virus shall be done free of cost from third day of
enrollment and providing the study drug on daily basis upto eradication of virus or completion of
the trial.
