Skip to main content
OpenTrials
Not Yet Recruiting

NCT Number: NCT07539402

Searching Patterns In the Robustness of Immunological FVIII Tolerance

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.

Not Yet Recruiting

Trial opening soon.

Get Notified

Key information

Conditions

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

Age range

Up to 18 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Amsterdam UMC, locatie AMC

Amsterdam, North Holland, 1105AZ, Netherlands

Location contact

Lilianne E van Stam, MSc, PhD Candidate

SUB_INVESTIGATOR

Samantha C Gouw, MD, PhD

CONTACT

[email protected]

+31(0)2056629111

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

  • Acquired hemophilia A
  • Any other bleeding disorder

Treatment and study plan

Primary outcomes

  1. FVIII-specific non-neutralizing antibody development

    Time frame: From enrollment up to 5 years

    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.

  2. Characterization of FVIII-specific antibodies (Immunoglobulin isotypes)

    Time frame: From enrollment up to 5 years

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

  3. Characterization of FVIII-specific antibodies (IgG subclasses)

    Time frame: From enrollment up to 5 years

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

  4. Characterization of FVIII-specific antibodies (affinity)

    Time frame: From enrollment up to 5 years

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

  5. Characterization of FVIII-specific antibodies (titer)

    Time frame: From enrollment up to 5 years

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

  6. FVIII inhibitor development (neutralizing antibodies)

    Time frame: From enrollment up to 5 years

    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.

Secondary outcomes

  1. FVIII-specific T and B cell responses

    Time frame: From enrollment up to 5 years

    FVIII-specific T- and B-cell responses will be characterized by assessing differential gene expression profiles and immune activation signatures over time using RNA sequencing. FVIII-specific T- and B-cell responses will be compared between patients with FVIII-specific NNAs and/or inhibitors and patients without FVIII-specific NNAs and/or inhibitors.

  2. Immunomodulatory microbial metabolites (in children <12 years)

    Time frame: From enrollment up to 5 years

    In participants younger than 12 years of age, concentrations of immunomodulatory microbial metabolites (i.e. short chain fatty acids, including butyrate and/or tryptophan catabolites (umol/g)) in fecal samples will be assessed over time using high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Concentrations of immunomodulatory microbial metabolites in fecal samples will be compared between patients with FVIII-specific NNAs and/or inhibitors and patients without FVIII-specific NNAs and/or inhibitors.

  3. Gut microbiota composition (in children <12 years)

    Time frame: From enrollment up to 5 years

    In participants younger than 12 years of age, microbial composition, including diversity indices and diversity indices, in fecal samples will be assessed over time using 16S rRNA gene sequencing. Gut microbiota composition in fecal samples will be compared between patients with FVIII-specific NNAs and/or inhibitors and patients without FVIII-specific NNAs and/or inhibitors.

Study contacts

Contact information is provided by the study sponsor or research team.

Lilianne E van Stam

CONTACT

[email protected]

Samantha C Gouw, MD, PhD

CONTACT

[email protected]

+31(0)2056629111

Sponsors and collaborators

Lead sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Other

Collaborators

  • Amsterdam UMC, location AMC

Registry information

Official study title

Searching Patterns In the Robustness of Immunological FVIII Tolerance (SPIRIT)

Acronym: SPIRIT

Important dates

Study start
2026
Primary completion
2029
Study completion
2029
First posted
Apr 20, 2026
Registry last updated
Apr 20, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.