Ignite Creation Date:
2024-10-26 @ 3:35 PM
Last Modification Date:
2024-10-26 @ 3:35 PM
Study NCT ID:
NCT06510426
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-07-14
Brief Title:
Early Interferon-beta Treatment for West-Nile Virus Infection
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Early Interferon-beta Treatment for West-Nile Virus Infection
Status:
RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
West Nile virus WNV is a mosquito-borne virus which in majority of cases causes only self-limited disease
Despite that in minority of cases 05 it can infect the brain and cause severe and even life-threatening disease neuroinvasive disease
Recent study has shown that up to 40 of WNV patients who develop neuroinvasive disease have antibodies against Interferons anti-Type I interferon autoantibodies which neutralizes interferons and could explain the development of severe disease
The investigators therefore assume that early treatment with interferon beta the type of interferon against which most patients do not have neutralizing antibodies could prevent the development of severe neuroinvasive WNV disease
Despite that in minority of cases 05 it can infect the brain and cause severe and even life-threatening disease neuroinvasive disease
Recent study has shown that up to 40 of WNV patients who develop neuroinvasive disease have antibodies against Interferons anti-Type I interferon autoantibodies which neutralizes interferons and could explain the development of severe disease
The investigators therefore assume that early treatment with interferon beta the type of interferon against which most patients do not have neutralizing antibodies could prevent the development of severe neuroinvasive WNV disease
Detailed Description:
Scientific Background
West Nile virus WNV is a mosquito-borne neurotropic flavivirus that can infect humans and cause life-threatening disease In recent years WNV infections have been reported in at least 60 countries across all continents and is now a leading cause of mosquito-borne disease globally While most infected individuals remain asymptomatic around 20 develop a self-limited febrile illness and less than 1 require hospitalization for neuro-invasive disease These infrequent yet severe neurologic presentations can include encephalitis 50-70 meningitis 15-35 and acute flaccid paralysis 3-20 which can result in a mortality of about 5-20
Epidemiologically age is the strongest known predictor of neuroinvasive disease and death and the risk of severe disease particularly neuroinvasive disease is about 16 times higher in those over the age of 65 and the risk of death is about 30-45 times higher in those over the age of 70
One possible explanation for the higher risk of older patients to develop more severe disease is the role of Type I interferons IFNs in mediating anti-WNV immunity In-vitro studies using human cell lines and in-vivo murine models have shown that type-I IFNs can inhibit WNV replication in human cells and protect mice against lethal WNV infection Even more compelling evidence for the role of type I IFNs in mediating anti-WNV immunity is a case description of two WNV patients suffering neuroinvasive disease who improved rapidly after initiation of IFNa treatment
Accordingly a recent study has identified very high prevalence of neutralizing anti-Type I IFN autoantibodies in patients with severe WNV neuroinvasive disease Evaluating nearly 450 patients samples anti-Type I IFNs autoantibodies were identified in 35 of WNV admitted patients and in 40 of those with neuroinvasive disease including 31 of encephalitis cases 46 of meningitis cases and 52 of cases of unspecified neurological syndrome This is in comparison with a prevalence of only 3 in asymptomatic mild WNV cases
Of note the prevalence of neutralizing anti-Type I IFNs auto-antibodies was much higher in patients age 65 and older 45 vs 19 and to a lesser extent in male patients In addition the presence of auto-antibodies neutralizing high concentration of Type-I IFNs mostly IFNa2 was associated with 100 fold-increase in the risk of neuroinvasive WNV disease independent of age These finding suggest that the presence of neutralizing anti-Type I IFN autoantibodies play a role in the development of severe and neuro-invasive WNV disease and may explain higher risk of severe disease in older individuals
Regarding the specificity of the anti-Type I IFN autoantibodies most auto-antibodies were able to neutralize high concentration and super-physiologic concentrations of IFNa2 and or IFNw10ngmL As for IFNb no patient had autoantibodies against IFNb only and only 11 of those having neutralizing antibodies against IFNa2 andor IFNw also tested positive for neutralizing anti-IFNb autoantibodies suggesting that IFNb could be potentially used in most patients with WNV disease
High prevalence of neutralizing anti-Type I IFNs were also identified if patients with severe COVID-19 critical influenza pneumonia and severe adverse reaction to live yellow-fever vaccine
Based on these finding a large clinical study showed significant benefit with early administration of a single injection of the Type III IFN IFN-lambda in reducing the risk for the development of severe COVID-19 by 50
In a similar way a case report described the use of IFNb in a patient with early COVID-19 The patient a carrier of an immunodeficiency causing gene was known to have high concentration of neutralizing anti-Type I IFN auto-antibodies against IFNa and IFNw but no anti-IFNb autoantibodies A previous patient carrier of the same immunodeficiency gene suffered life-threatening COVID-19 pneumonia and displayed neutralizing autoantibodies against type I IFNs
In an attempt to prevent severe COVID-19 the second patient was treated with 3 doses of IFNb with rapid resolution of her symptoms
Taken together these data suggest the following
1 Neutralizing anti-Type-I IFN autoantibodies are associated with significantly increased risk for severe and life-threatening viral diseases including WNV neuroinvasive disease
2 The prevalence of neutralizing anti-Type-I IFN increases with age therefore older individuals are at higher risk for developing severe and life-threatening viral diseases
3 Anti-type I IFN autoantibodies can neutralize high and above physiologic concentrations of type-I IFNs
4 Most autoantibodies are directed and neutralize IFNa and IFNw and to a lesser extent IFNb
5 Using alternative non-IFNaw interferons has the potential to bypass this neutralization and prevent progression to severe disease
For these reasons the investigators aim to study the protective effect of early IFNb treatment in patients diagnosed with WNV disease
The rational for using IFNβ is based on the following
1 Patients with severe or neuroinvasive WNV disease were shown to have high titers of neutralizing autoantibodies against most type I IFNs including the 13 individual IFNα and IFNω but less so against IFNβ
2 The signaling pathway of IFNα and IFNβ is similar with both binding to the IFNAR1-IFNAR2 heterodimer complex inducing JAK1TYK2 activation and STAT1STAT2 phosphorylation
3 The known safety profile of subcutaneous injections of IFN-β1a approved and commonly used for the treatment of relapsing remitting multiple sclerosis
4 The previously used IFN-lambda is not available in Israel
Objectives
Primary objective To investigate the clinical effects of IFNb1a treatment in patients with a confirmed WNV disease
Secondary objective To investigate the prevalence of anti-type-I-IFN autoantibodies in patients with WNV and their association with clinical outcome of patients with WNV disease
Research design and methods
This is a clinical prospective double-blinded placebo control trial
Research process
1 Patients will be recruited after being diagnosed with WNV either at the ER or after being admitted
2 Serum urine and CSF samples from WNV suspected patients will be used to confirm WNV diagnosis based on the presence of either anti-WNV IgM antibodies andor positive WNV PCR These samples are collected only for the purpose of establishing a diagnosis and therefore the volume of the sample collected will be the volume required for establishing a diagnosis typically 1-2 blood tubes of 5ml typical urine sample and 1-2 tubes of CSF samples Diagnostic studies will be performed at the infectious disease laboratory Patients will be recruited only after WNV diagnosis is confirmed
3 Positive patients if meets inclusion criteria and after signing an informed consent will be recruited
4 Serum and CSF samples from WNV confirmed patients will be collected and stored for later testing for the presence of neutralizing anti-IFN autoantibodies as well as other potential inflammatory markers For this purpose after the establishing of WNV diagnosis an additional 2 chemistry 6 ml tube 12ml in total will be collected CSF samples will not be collected for the purpose of investigational assays and only if available residual volumes of CSF collected for the purpose of establishing WNV diagnosis will be used These samples will be stored at the Immunology laboratory and testing for the presence of anti-IFN autoantibodies will be performed at the Clinical Immunology Laboratory
5 In order to evaluate duration of viremia blood samples will be collected from the first 30 WNV-confirmed patients for repeated PCR testing on days 0 day 4 and day 10-14
6 Patients will be randomized to receive the intervention drug or placebo based on disease manifestation
7 The intervention drug given will be interferon β1a Treatment protocol would include 3 subcutaneous injections of IFN-β1a Rebif at a dose of 44mcg given every 48h
8 Placebo will be normal saline at an equivalent volume to that of the intervention drug given every 48h
9 In the case a patient is being discharged before receiving the 3 drug doses the patient will be invited to receive the remaining doses at the Neurology Immunology clinic
10 Patients will be followed for a year after disease onset with follow-up visits at the neurology clinic every 3 months Visits would include cognitive and clinical assessments as well as routine blood work for possible delayed effects of the study drug including CBC chemistry with liver and thyroid function as described in the Schedule of Activities table below
11 Data regarding 12-month mortality rate will be collected
Demographics and clinical data will be collected from Chameleon medical record and will be stored coded on local TASMC computers in a password-protected folder Folder pathway WWest Nile
No data will be transferred to outside sources
Randomization process
Patients will be randomly assigned to each of the two arms with a 11 allocation ratio using randomly selected signed enveloped considering clinical presentation and neurologic manifestations For this purpose stratified block randomization will be implemented based on the 3 possible strata generated from the two binary variables presence or absence of neurologic symptoms in case of neurologic symptoms presence or absence of flaccid paralysis A randomization code will be given and maintained for the duration of the study A planned breaking of randomization codes will be performed and reviewed by an independent Data and Safety Monitoring Board as explained below There will be no planned breaking by the blinded researchers Unplanned breaking of codes to team or patient would lead to exclusion of the patient from the analysis
The study drug and placebo will be prepared in the clinical research unit at the pharmacy of the Tel-Aviv Sourasky Medical Center by a certified pharmacist in accordance with procedure 135 of the Pharmaceutics Division Ministry of Health
The study drug placebo will be labeled with the following study title protocol number name of PI name of study drug placebo both randomization number date and time of preparation
West Nile virus WNV is a mosquito-borne neurotropic flavivirus that can infect humans and cause life-threatening disease In recent years WNV infections have been reported in at least 60 countries across all continents and is now a leading cause of mosquito-borne disease globally While most infected individuals remain asymptomatic around 20 develop a self-limited febrile illness and less than 1 require hospitalization for neuro-invasive disease These infrequent yet severe neurologic presentations can include encephalitis 50-70 meningitis 15-35 and acute flaccid paralysis 3-20 which can result in a mortality of about 5-20
Epidemiologically age is the strongest known predictor of neuroinvasive disease and death and the risk of severe disease particularly neuroinvasive disease is about 16 times higher in those over the age of 65 and the risk of death is about 30-45 times higher in those over the age of 70
One possible explanation for the higher risk of older patients to develop more severe disease is the role of Type I interferons IFNs in mediating anti-WNV immunity In-vitro studies using human cell lines and in-vivo murine models have shown that type-I IFNs can inhibit WNV replication in human cells and protect mice against lethal WNV infection Even more compelling evidence for the role of type I IFNs in mediating anti-WNV immunity is a case description of two WNV patients suffering neuroinvasive disease who improved rapidly after initiation of IFNa treatment
Accordingly a recent study has identified very high prevalence of neutralizing anti-Type I IFN autoantibodies in patients with severe WNV neuroinvasive disease Evaluating nearly 450 patients samples anti-Type I IFNs autoantibodies were identified in 35 of WNV admitted patients and in 40 of those with neuroinvasive disease including 31 of encephalitis cases 46 of meningitis cases and 52 of cases of unspecified neurological syndrome This is in comparison with a prevalence of only 3 in asymptomatic mild WNV cases
Of note the prevalence of neutralizing anti-Type I IFNs auto-antibodies was much higher in patients age 65 and older 45 vs 19 and to a lesser extent in male patients In addition the presence of auto-antibodies neutralizing high concentration of Type-I IFNs mostly IFNa2 was associated with 100 fold-increase in the risk of neuroinvasive WNV disease independent of age These finding suggest that the presence of neutralizing anti-Type I IFN autoantibodies play a role in the development of severe and neuro-invasive WNV disease and may explain higher risk of severe disease in older individuals
Regarding the specificity of the anti-Type I IFN autoantibodies most auto-antibodies were able to neutralize high concentration and super-physiologic concentrations of IFNa2 and or IFNw10ngmL As for IFNb no patient had autoantibodies against IFNb only and only 11 of those having neutralizing antibodies against IFNa2 andor IFNw also tested positive for neutralizing anti-IFNb autoantibodies suggesting that IFNb could be potentially used in most patients with WNV disease
High prevalence of neutralizing anti-Type I IFNs were also identified if patients with severe COVID-19 critical influenza pneumonia and severe adverse reaction to live yellow-fever vaccine
Based on these finding a large clinical study showed significant benefit with early administration of a single injection of the Type III IFN IFN-lambda in reducing the risk for the development of severe COVID-19 by 50
In a similar way a case report described the use of IFNb in a patient with early COVID-19 The patient a carrier of an immunodeficiency causing gene was known to have high concentration of neutralizing anti-Type I IFN auto-antibodies against IFNa and IFNw but no anti-IFNb autoantibodies A previous patient carrier of the same immunodeficiency gene suffered life-threatening COVID-19 pneumonia and displayed neutralizing autoantibodies against type I IFNs
In an attempt to prevent severe COVID-19 the second patient was treated with 3 doses of IFNb with rapid resolution of her symptoms
Taken together these data suggest the following
1 Neutralizing anti-Type-I IFN autoantibodies are associated with significantly increased risk for severe and life-threatening viral diseases including WNV neuroinvasive disease
2 The prevalence of neutralizing anti-Type-I IFN increases with age therefore older individuals are at higher risk for developing severe and life-threatening viral diseases
3 Anti-type I IFN autoantibodies can neutralize high and above physiologic concentrations of type-I IFNs
4 Most autoantibodies are directed and neutralize IFNa and IFNw and to a lesser extent IFNb
5 Using alternative non-IFNaw interferons has the potential to bypass this neutralization and prevent progression to severe disease
For these reasons the investigators aim to study the protective effect of early IFNb treatment in patients diagnosed with WNV disease
The rational for using IFNβ is based on the following
1 Patients with severe or neuroinvasive WNV disease were shown to have high titers of neutralizing autoantibodies against most type I IFNs including the 13 individual IFNα and IFNω but less so against IFNβ
2 The signaling pathway of IFNα and IFNβ is similar with both binding to the IFNAR1-IFNAR2 heterodimer complex inducing JAK1TYK2 activation and STAT1STAT2 phosphorylation
3 The known safety profile of subcutaneous injections of IFN-β1a approved and commonly used for the treatment of relapsing remitting multiple sclerosis
4 The previously used IFN-lambda is not available in Israel
Objectives
Primary objective To investigate the clinical effects of IFNb1a treatment in patients with a confirmed WNV disease
Secondary objective To investigate the prevalence of anti-type-I-IFN autoantibodies in patients with WNV and their association with clinical outcome of patients with WNV disease
Research design and methods
This is a clinical prospective double-blinded placebo control trial
Research process
1 Patients will be recruited after being diagnosed with WNV either at the ER or after being admitted
2 Serum urine and CSF samples from WNV suspected patients will be used to confirm WNV diagnosis based on the presence of either anti-WNV IgM antibodies andor positive WNV PCR These samples are collected only for the purpose of establishing a diagnosis and therefore the volume of the sample collected will be the volume required for establishing a diagnosis typically 1-2 blood tubes of 5ml typical urine sample and 1-2 tubes of CSF samples Diagnostic studies will be performed at the infectious disease laboratory Patients will be recruited only after WNV diagnosis is confirmed
3 Positive patients if meets inclusion criteria and after signing an informed consent will be recruited
4 Serum and CSF samples from WNV confirmed patients will be collected and stored for later testing for the presence of neutralizing anti-IFN autoantibodies as well as other potential inflammatory markers For this purpose after the establishing of WNV diagnosis an additional 2 chemistry 6 ml tube 12ml in total will be collected CSF samples will not be collected for the purpose of investigational assays and only if available residual volumes of CSF collected for the purpose of establishing WNV diagnosis will be used These samples will be stored at the Immunology laboratory and testing for the presence of anti-IFN autoantibodies will be performed at the Clinical Immunology Laboratory
5 In order to evaluate duration of viremia blood samples will be collected from the first 30 WNV-confirmed patients for repeated PCR testing on days 0 day 4 and day 10-14
6 Patients will be randomized to receive the intervention drug or placebo based on disease manifestation
7 The intervention drug given will be interferon β1a Treatment protocol would include 3 subcutaneous injections of IFN-β1a Rebif at a dose of 44mcg given every 48h
8 Placebo will be normal saline at an equivalent volume to that of the intervention drug given every 48h
9 In the case a patient is being discharged before receiving the 3 drug doses the patient will be invited to receive the remaining doses at the Neurology Immunology clinic
10 Patients will be followed for a year after disease onset with follow-up visits at the neurology clinic every 3 months Visits would include cognitive and clinical assessments as well as routine blood work for possible delayed effects of the study drug including CBC chemistry with liver and thyroid function as described in the Schedule of Activities table below
11 Data regarding 12-month mortality rate will be collected
Demographics and clinical data will be collected from Chameleon medical record and will be stored coded on local TASMC computers in a password-protected folder Folder pathway WWest Nile
No data will be transferred to outside sources
Randomization process
Patients will be randomly assigned to each of the two arms with a 11 allocation ratio using randomly selected signed enveloped considering clinical presentation and neurologic manifestations For this purpose stratified block randomization will be implemented based on the 3 possible strata generated from the two binary variables presence or absence of neurologic symptoms in case of neurologic symptoms presence or absence of flaccid paralysis A randomization code will be given and maintained for the duration of the study A planned breaking of randomization codes will be performed and reviewed by an independent Data and Safety Monitoring Board as explained below There will be no planned breaking by the blinded researchers Unplanned breaking of codes to team or patient would lead to exclusion of the patient from the analysis
The study drug and placebo will be prepared in the clinical research unit at the pharmacy of the Tel-Aviv Sourasky Medical Center by a certified pharmacist in accordance with procedure 135 of the Pharmaceutics Division Ministry of Health
The study drug placebo will be labeled with the following study title protocol number name of PI name of study drug placebo both randomization number date and time of preparation
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None