Early Interferon-beta Treatment for West-Nile Virus Infection

NCT ID: NCT06510426

Last Updated: 2024-07-23

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-07-14
• Study Completion Date: 2025-12-31

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 (~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.

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 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:

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-IFNa/w 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 JAK1/TYK2 activation and STAT1/STAT2 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 and/or 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: 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;

Conditions

West Nile Virus; West Nile Fever Encephalitis; West Nile Fever Myelitis; West Nile Fever With Other Complications

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Active Treatment

Patients enrolled to participate in the Active Treatment arm will receive 3 subcutaneous injections of 44mcg Interferon b-1a (Rebif), given 48h hours apart.

Group Type: EXPERIMENTAL

Rebif 44 MCG Per 0.5 ML Prefilled Syringe

Intervention Type: DRUG

Rebif 44mcg per 0.5ml administered subcutaneously

Placebo

Patients enrolled to participate in the placebo arm will receive 3 subcutaneous injections of normal saline, given 48h hours apart.

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: DRUG

0.5mL of saline administered subcutaneously

Interventions

Rebif 44 MCG Per 0.5 ML Prefilled Syringe

Rebif 44mcg per 0.5ml administered subcutaneously

Intervention Type: DRUG

Saline

0.5mL of saline administered subcutaneously

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

We aim to focus on three patients' populations:

1. Patients older than 70 years of age, who are at higher risk for the presence of neutralizing anti-Type I IFN auto-antibodies, and therefore at higher risk for developing severe neuroinvasive disease. Only patients who fulfill the diagnostic criteria above will be included.

2. Patients presenting with neuroinvasive WNV disease, including either flaccid paralysis or encephalitis, independent of their age, excluding a presentation consistent with isolated aseptic meningitis (headache, fever, 6th nerve palsy). Only patients who fulfill the diagnostic criteria above will be included.

3. Immunocompromised patients at any age. Immunocompromised patients will be defined as patients with hematologic malignancy (treated or untreated); chemotherapy within previous 4 weeks, stem cell transplant recipient or solid organ transplant recipient; use of any immunosuppressant drug including prednisone greater than or equal to 20 mg/day within the previous 4 weeks; primary / acquired immunodeficiency disorder. Only patients who fulfill the diagnostic criteria above will be included.

Exclusion Criteria

1. Patients younger than 18 years old.

2. Pregnant women.

3. Contraindication for the administration of the drug: Hypersensitivity to natural or recombinant interferon beta, and decompensated liver disease.

4. A patient with neuroinvasive disease showing consistent spontaneous improvement over a period of > 2 days and mRS of below 4.

5. More than 8 days from onset of neurological symptoms in immunocompetent patients and more than 10 days in immunocompromised patients. This time frame will be renewed if a patient with flaccid paralysis develops new onset encephalitis.

6. Patients who are receiving active chemotherapy treatment or suffer concurrent severe viral infection.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tel-Aviv Sourasky Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Tel-Aviv Sourasky Medical Center

Tel Aviv, , Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

David Hagin, MD PhD

Role: CONTACT

Davidha@tlvmc.gov.il

972524792296

Dania Dror, B.Nutr; MPH

Role: CONTACT

Daniad@tlvmc.gov.il

97236974679

Facility Contacts

David Hagin, MD, PhD

Role: primary

davidha@tlvmc.gov.il

972524792296

Dania Dror, B.Nutr, MPH

Role: backup

Daniad@tlvmc.gov.il

97236974679

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Other Identifiers

TLV-0326-24

Identifier Type: -

Identifier Source: org_study_id