Searching Patterns In the Robustness of Immunological FVIII Tolerance

NCT07539402 | Not Yet Recruiting DMC

• 1 other identifier: NL83658.018.23
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 1

Brief Summary

Children with hemophilia A lack clotting factor VIII (FVIII) due to a genetic mutation. It is well known that administration of FVIII concentrate leads to immunological tolerance for the FVIII protein in the majority of children. In 30% of these children tolerance is not achieved leading to the development of anti-FVIII antibodies (i.e. inhibitors). Our knowledge on the underlying immunological mechanisms leading to tolerance is limited. Recently, Non-Factor Therapy (NFT) has become available for prevention of bleeding in patients with hemophilia, i.e. prophylaxis. Currently, many children with severe hemophilia A use NFT as the subcutaneous administration of NFT is very convenient. In children on NFT prophylaxis, intravenous FVIII concentrate is exclusively used on-demand for treatment of bleeding. As NFT is very effective in the prevention of bleeds, patients may not be exposed to the deficient FVIII protein for periods up to a year or longer. It is currently not known how robust immunological tolerance is in the absence of exposure to a deficient antigen. The infrequent exposure to FVIII, enabled by NFT, provides an opportunity to study the immunological tolerance mechanisms for FVIII in children with hemophilia A. The aim of SPIRIT is to investigate the mechanisms of the immunological tolerance to FVIII in patients with hemophilia A aged younger than 18 years using NFT for prophylaxis. In this observational cohort study, children (aged \<18 years) with congenital hemophilia A, who are treated with non-factor therapy as prophylaxis, will be longitudinally followed. Participants will have blood drawn anually, during the regular clinic visits, and additionally following FVIII exposure. Feces samples will be collected and analyzed in children aged \<12 years, following the same scheme as blood sampling. The main study endpoint are the immunological mechanisms underlying tolerance to FVIII, including presence, titers, subtypes and affinities of FVIII-specific (non-)neutralizing antibodies, FVIII-specific T and B cell responses and the role of gut microbiota.

Conditions

Hemophilia A; Hemophilia A, Congenital

Keywords

Hemophilia A; Factor VIII; Tolerance

Outcome Measures

Primary Outcomes (6)

• FVIII-specific non-neutralizing antibody development

  Patients will be longitudinally monitored for the development of FVIII-specific non-neutralizing antibodies (NNAs). The development of FVIII-specific NNAs will be assessed with a direct enzyme-linked immunosorbent assay (ELISA)(Optical Density (OD)), by reporting the presence of FVIII-specific NNAs (Yes/No). Incidence will be calculated as the proportion of patients who develop newly detectable FVIII-specific NNAs during the study period.

  From enrollment up to 5 years

• Characterization of FVIII-specific antibodies (Immunoglobulin isotypes)

  FVIII-specific antibodies will be characterized by measuring immunoglobulin isotypes (IgA, IgM, and IgG) over time using ELISA.

  From enrollment up to 5 years

• Characterization of FVIII-specific antibodies (IgG subclasses)

  FVIII-specific antibodies will be characterized by measuring IgG subclasses (IgG1, IgG2, IgG3, and IgG4) over time using ELISA.

  From enrollment up to 5 years

• Characterization of FVIII-specific antibodies (affinity)

  FVIII-specific antibodies will be characterized by measuring the affinity (KA \[M-1\]) over time using ELISA.

  From enrollment up to 5 years

• Characterization of FVIII-specific antibodies (titer)

  FVIII-specific antibodies will be characterized by measuring inhibitor titers (Bethesda Units (BU)/mL) over time using the Nijmegen-modified Bethesda assay.

  From enrollment up to 5 years

• FVIII inhibitor development (neutralizing antibodies)

  Participants will be longitudinally monitored for the development of FVIII-specific neutralizing antibodies using the Nijmegen-modified Bethesda assay (BU/mL). Inhibitor development will be defined as a titer ≥ 0.6 BU/mL confirmed on at least two consecutive measurements. Incidence will be calculated as the proportion of patients who develop confirmed FVIII inhibitors during the study period.

  From enrollment up to 5 years

Secondary Outcomes (3)

• FVIII-specific T and B cell responses

  From enrollment up to 5 years

• Immunomodulatory microbial metabolites (in children <12 years)

  From enrollment up to 5 years

• Gut microbiota composition (in children <12 years)

  From enrollment up to 5 years

Study Arms (1)

Children with congenital Hemophilia A on NFT

Pediatric patients (aged younger than 18 years), with congenital hemophilia A of all severities, using non-factor therapy

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Children with hemophilia A, who are treated with non-factor therapy as prophylaxis, and who are aged \<18 years. The subjects will be recruited from Hemophilia Treatment Centres (HTCs) in the Netherlanss and internationally.

You may qualify if:

• Congenital hemophilia A of all severities
• Using NFT for prophylaxis
• Aged under 18 years
• Written informed consent

You may not qualify if:

• Acquired hemophilia A
• Any other bleeding disorder

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Amsterdam UMC, location AMC: collaborator

Study Sites (1)

Amsterdam UMC, locatie AMC

Amsterdam, North Holland, 1105AZ, Netherlands

Location

Biospecimen

Retention: SAMPLES WITH DNA

Blood sample Feces sample (If participant \<12 years of age)

MeSH Terms

Conditions

Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Central Study Contacts

Samantha C Gouw, MD, PhD

CONTACT

+31(0)2056629111; s.c.gouw@amsterdamumc.nl

Lilianne E van Stam

CONTACT

l.e.vanstam@amsterdamumc.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 5 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. MD PhD

Study Record Dates

• First Submitted: April 28, 2025
• First Posted: April 20, 2026
• Study Start: May 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029
• Last Updated: April 20, 2026

Record last verified: 2026-04

Locations

NL (1)