A Phase 2 interventional study of Rebif 44 MCG Per 0.5 ML Prefilled Syringe and Saline in West Nile Virus, West Nile Fever Encephalitis and West Nile Fever Myelitis, sponsored by Tel-Aviv Sourasky Medical Center. Recruiting at 1 site in Israel. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-07-23.
Sponsored by Tel-Aviv Sourasky Medical Center · Phase 2, Interventional, and Prevention
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 (\~0.5%) 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.
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 IFNw(10ng/mL). As for IFNb, no patient had autoantibodies against IFNb only, and only 11% of those having neutralizing antibodies against IFNa2 and/or 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:
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:
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:
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: W:\West Nile.
No data will be transferred to outside sources.
Randomization process:
Patients will be randomly assigned to each of the two arms with a 1:1 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;
125 studies on the registry are indexed under Encephalitis; 33 are open to participants now.
This study's planned enrollment of 100 is above the median of 55 across 62 interventional studies indexed under Encephalitis.
Browse Encephalitis studies →Tel-Aviv Sourasky Medical Center is the lead sponsor of 554 studies on the registry; 51 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Diagnosis of WNV infection will be based on the following:
Patients with clinical presentation suspected as compatible with WNV infection, with symptoms including elevated fever, headache or flaccid paralysis or fever with encephalopathy.
And:
Inclusion criteria:
We aim to focus on three patients' populations:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients enrolled to participate in the Active Treatment arm will receive 3 subcutaneous injections of 44mcg Interferon b-1a (Rebif), given 48h hours apart.
Drug: Rebif 44 MCG Per 0.5 ML Prefilled Syringe
Patients enrolled to participate in the placebo arm will receive 3 subcutaneous injections of normal saline, given 48h hours apart.
Drug: Saline
Rebif 44mcg per 0.5ml administered subcutaneously
0.5mL of saline administered subcutaneously
Rates of death or intubation
Death or intubation within 4 weeks
Time frame: 4 weeks
Modified Rankin Scale (mRS) score
Comparison of modified Rankin Scale (mRS) score at 3 and 6 months. The mRS score is a 7 point (0-6) disability scale with higher score suggesting higher level of disability.
Time frame: 3 and 6 months
ICU admission
Rates of ICU admission
Time frame: 4 weeks
Mechanical ventilation
Rates of mechanical ventilation
Time frame: 4 weeks
Modified-NIH-stroke-scale (mNIHSS)
Change in modified-NIH-stroke-scale (mNIHSS) from baseline to 3 months. The scoring range is 0 to 42 points, with higher numbers indicating greater severity.
Time frame: 3 months
Mini-mental state examination (MMSE)
Change in mini-mental state examination (MMSE) from baseline to 3 months. The MMSE has a range score of 0-30. A higher score suggests better performance. Any score of 24 or more (out of 30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.
Time frame: 3 months
All cause mortality
All-cause mortality at 4 weeks, 3 months, 6 months and 12 months
Time frame: 12 months
Started Jul 2024 (actual). Primary completion is estimated for Jul 2025, 12 months after the start.
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Studies of the drug tested here: Interferon beta-1a
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