Early Interferon-beta Treatment for West-Nile Virus Infection

NCT06510426 | Recruiting Phase 2 DMC

• 1 other identifier: TLV-0326-24
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

West Nile Virus; WNV; Encephalitis; Flaccid paralysis; WNV neuroinvasive disease

Outcome Measures

Primary Outcomes (2)

• Rates of death or intubation

  Death or intubation within 4 weeks

  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.

  3 and 6 months

Secondary Outcomes (5)

• ICU admission

  4 weeks

• Mechanical ventilation

  4 weeks

• Modified-NIH-stroke-scale (mNIHSS)

  3 months

• Mini-mental state examination (MMSE)

  3 months

• All cause mortality

  12 months

Study Arms (2)

Active Treatment

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Drug: Saline

Interventions

Rebif 44 MCG Per 0.5 ML Prefilled Syringe DRUG

Rebif 44mcg per 0.5ml administered subcutaneously

Active Treatment

Saline DRUG

0.5mL of saline administered subcutaneously

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• We aim to focus on three patients' populations:
• 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.
• 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.
• 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.

You may not qualify if:

• Patients younger than 18 years old.
• Pregnant women.
• Contraindication for the administration of the drug: Hypersensitivity to natural or recombinant interferon beta, and decompensated liver disease.
• A patient with neuroinvasive disease showing consistent spontaneous improvement over a period of \> 2 days and mRS of below 4.
• 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.
• Patients who are receiving active chemotherapy treatment or suffer concurrent severe viral infection.

Sponsors & Collaborators

• Tel-Aviv Sourasky Medical Center: lead

Study Sites (1)

Tel-Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

RECRUITING

Related Publications (11)

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  PMID: 37347462 BACKGROUND

• Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011 Apr 28;472(7344):481-5. doi: 10.1038/nature09907. Epub 2011 Apr 10.

  PMID: 21478870 BACKGROUND

• Samuel MA, Diamond MS. Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol. 2005 Nov;79(21):13350-61. doi: 10.1128/JVI.79.21.13350-13361.2005.

  PMID: 16227257 BACKGROUND

• Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Beziat V, Manry J, Shaw E, Haljasmagi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodriguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Interieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585. doi: 10.1126/science.abd4585. Epub 2020 Sep 24.

  PMID: 32972996 BACKGROUND

• Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Manry J, Michailidis E, Hoffmann HH, Eto S, Garcia-Prat M, Bizien L, Parra-Martinez A, Yang R, Haljasmagi L, Migaud M, Sarekannu K, Maslovskaja J, de Prost N, Tandjaoui-Lambiotte Y, Luyt CE, Amador-Borrero B, Gaudet A, Poissy J, Morel P, Richard P, Cognasse F, Troya J, Trouillet-Assant S, Belot A, Saker K, Garcon P, Riviere JG, Lagier JC, Gentile S, Rosen LB, Shaw E, Morio T, Tanaka J, Dalmau D, Tharaux PL, Sene D, Stepanian A, Megarbane B, Triantafyllia V, Fekkar A, Heath JR, Franco JL, Anaya JM, Sole-Violan J, Imberti L, Biondi A, Bonfanti P, Castagnoli R, Delmonte OM, Zhang Y, Snow AL, Holland SM, Biggs C, Moncada-Velez M, Arias AA, Lorenzo L, Boucherit S, Coulibaly B, Anglicheau D, Planas AM, Haerynck F, Duvlis S, Nussbaum RL, Ozcelik T, Keles S, Bousfiha AA, El Bakkouri J, Ramirez-Santana C, Paul S, Pan-Hammarstrom Q, Hammarstrom L, Dupont A, Kurolap A, Metz CN, Aiuti A, Casari G, Lampasona V, Ciceri F, Barreiros LA, Dominguez-Garrido E, Vidigal M, Zatz M, van de Beek D, Sahanic S, Tancevski I, Stepanovskyy Y, Boyarchuk O, Nukui Y, Tsumura M, Vidaur L, Tangye SG, Burrel S, Duffy D, Quintana-Murci L, Klocperk A, Kann NY, Shcherbina A, Lau YL, Leung D, Coulongeat M, Marlet J, Koning R, Reyes LF, Chauvineau-Grenier A, Venet F, Monneret G, Nussenzweig MC, Arrestier R, Boudhabhay I, Baris-Feldman H, Hagin D, Wauters J, Meyts I, Dyer AH, Kennelly SP, Bourke NM, Halwani R, Sharif-Askari NS, Dorgham K, Sallette J, Sedkaoui SM, AlKhater S, Rigo-Bonnin R, Morandeira F, Roussel L, Vinh DC, Ostrowski SR, Condino-Neto A, Prando C, Bonradenko A, Spaan AN, Gilardin L, Fellay J, Lyonnet S, Bilguvar K, Lifton RP, Mane S; HGID Lab; COVID Clinicians; COVID-STORM Clinicians; NIAID Immune Response to COVID Group; NH-COVAIR Study Group; Danish CHGE; Danish Blood Donor Study; St. James's Hospital; SARS CoV2 Interest group; French COVID Cohort Study Group; Imagine COVID-Group; Milieu Interieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19; Biobank Investigators; COVID Human Genetic Effort; CONSTANCES cohort; 3C-Dijon Study; Cerba Health-Care; Etablissement du Sang study group; Anderson MS, Boisson B, Beziat V, Zhang SY, Vandreakos E, Hermine O, Pujol A, Peterson P, Mogensen TH, Rowen L, Mond J, Debette S, de Lamballerie X, Duval X, Mentre F, Zins M, Soler-Palacin P, Colobran R, Gorochov G, Solanich X, Susen S, Martinez-Picado J, Raoult D, Vasse M, Gregersen PK, Piemonti L, Rodriguez-Gallego C, Notarangelo LD, Su HC, Kisand K, Okada S, Puel A, Jouanguy E, Rice CM, Tiberghien P, Zhang Q, Cobat A, Abel L, Casanova JL. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Sci Immunol. 2021 Aug 19;6(62):eabl4340. doi: 10.1126/sciimmunol.abl4340.

  PMID: 34413139 BACKGROUND

• Zhang Q, Pizzorno A, Miorin L, Bastard P, Gervais A, Le Voyer T, Bizien L, Manry J, Rosain J, Philippot Q, Goavec K, Padey B, Cupic A, Laurent E, Saker K, Vanker M, Sarekannu K; COVID Human Genetic Effort; Etablissement Francais du Sang Study Group; Constances Cohort; 3C-Dijon Study; Cerba HealthCare Group; Lyon Antigrippe Working Group; REIPI INF Working Group; Garcia-Salum T, Ferres M, Le Corre N, Sanchez-Cespedes J, Balsera-Manzanero M, Carratala J, Retamar-Gentil P, Abelenda-Alonso G, Valiente A, Tiberghien P, Zins M, Debette S, Meyts I, Haerynck F, Castagnoli R, Notarangelo LD, Gonzalez-Granado LI, Dominguez-Pinilla N, Andreakos E, Triantafyllia V, Rodriguez-Gallego C, Sole-Violan J, Ruiz-Hernandez JJ, Rodriguez de Castro F, Ferreres J, Briones M, Wauters J, Vanderbeke L, Feys S, Kuo CY, Lei WT, Ku CL, Tal G, Etzioni A, Hanna S, Fournet T, Casalegno JS, Queromes G, Argaud L, Javouhey E, Rosa-Calatrava M, Cordero E, Aydillo T, Medina RA, Kisand K, Puel A, Jouanguy E, Abel L, Cobat A, Trouillet-Assant S, Garcia-Sastre A, Casanova JL. Autoantibodies against type I IFNs in patients with critical influenza pneumonia. J Exp Med. 2022 Nov 7;219(11):e20220514. doi: 10.1084/jem.20220514. Epub 2022 Sep 16.

  PMID: 36112363 BACKGROUND

• Bastard P, Michailidis E, Hoffmann HH, Chbihi M, Le Voyer T, Rosain J, Philippot Q, Seeleuthner Y, Gervais A, Materna M, de Oliveira PMN, Maia MLS, Dinis Ano Bom AP, Azamor T, Araujo da Conceicao D, Goudouris E, Homma A, Slesak G, Schafer J, Pulendran B, Miller JD, Huits R, Yang R, Rosen LB, Bizien L, Lorenzo L, Chrabieh M, Erazo LV, Rozenberg F, Jeljeli MM, Beziat V, Holland SM, Cobat A, Notarangelo LD, Su HC, Ahmed R, Puel A, Zhang SY, Abel L, Seligman SJ, Zhang Q, MacDonald MR, Jouanguy E, Rice CM, Casanova JL. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J Exp Med. 2021 Apr 5;218(4):e20202486. doi: 10.1084/jem.20202486.

  PMID: 33544838 BACKGROUND

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  PMID: 23872679 BACKGROUND

• Kalil AC, Devetten MP, Singh S, Lesiak B, Poage DP, Bargenquast K, Fayad P, Freifeld AG. Use of interferon-alpha in patients with West Nile encephalitis: report of 2 cases. Clin Infect Dis. 2005 Mar 1;40(5):764-6. doi: 10.1086/427945. Epub 2005 Feb 7.

  PMID: 15714427 RESULT

• Reis G, Moreira Silva EAS, Medeiros Silva DC, Thabane L, Campos VHS, Ferreira TS, Santos CVQ, Nogueira AMR, Almeida APFG, Savassi LCM, Figueiredo-Neto AD, Dias ACF, Freire Junior AM, Bitaraes C, Milagres AC, Callegari ED, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Wilson LA, Forrest JI, Ruton H, Sprague S, McKay P, Guo CM, Limbrick-Oldfield EH, Kanters S, Guyatt GH, Rayner CR, Kandel C, Biondi MJ, Kozak R, Hansen B, Zahoor MA, Arora P, Hislop C, Choong I, Feld JJ, Mills EJ, Glenn JS; TOGETHER Investigators. Early Treatment with Pegylated Interferon Lambda for Covid-19. N Engl J Med. 2023 Feb 9;388(6):518-528. doi: 10.1056/NEJMoa2209760.

  PMID: 36780676 RESULT

• Bastard P, Levy R, Henriquez S, Bodemer C, Szwebel TA, Casanova JL. Interferon-beta Therapy in a Patient with Incontinentia Pigmenti and Autoantibodies against Type I IFNs Infected with SARS-CoV-2. J Clin Immunol. 2021 Jul;41(5):931-933. doi: 10.1007/s10875-021-01023-5. Epub 2021 Mar 25. No abstract available.

  PMID: 33763778 RESULT

MeSH Terms

Conditions

West Nile Fever; Encephalitis

Interventions

Interferon beta-1a; Sodium Chloride

Condition Hierarchy (Ancestors)

Encephalitis, Arbovirus; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Infections; Infectious Encephalitis; Arbovirus Infections; Vector Borne Diseases; Mosquito-Borne Diseases; Virus Diseases; RNA Virus Infections; Flavivirus Infections; Flaviviridae Infections; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Interferon-beta; Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Central Study Contacts

David Hagin, MD PhD

CONTACT

972524792296; Davidha@tlvmc.gov.il

Dania Dror, B.Nutr; MPH

CONTACT

97236974679; Daniad@tlvmc.gov.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: Patients at high risk for the development of neuroinvasive WNV disease (age 70 and older or immunocompromised patients) or patients presenting with neurologic symptoms of encephalomyelitis will be randomized to receive the study drug or placebo.

Study Record Dates

• First Submitted: July 14, 2024
• First Posted: July 19, 2024
• Study Start: July 14, 2024
• Primary Completion: July 14, 2025
• Study Completion: December 31, 2025
• Last Updated: July 23, 2024

Record last verified: 2024-07

Locations

IL (1)