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

April 16, 2026 updated by: Karin Fijnvandraat, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Study Type

Observational

Enrollment (Estimated)

500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Netherlands
    • North Holland
      • Amsterdam, North Holland, Netherlands, 1105AZ
        • Amsterdam UMC, locatie AMC
        • Contact:
        • Sub-Investigator:
          • Lilianne E van Stam, MSc, PhD Candidate

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

No

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From enrollment up to 5 years
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.
From enrollment up to 5 years
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.
From enrollment up to 5 years
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.
From enrollment up to 5 years
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.
From enrollment up to 5 years
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.
From enrollment up to 5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From enrollment up to 5 years
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.
From enrollment up to 5 years
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.
From enrollment up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Collaborators

Amsterdam UMC, location AMC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2026

Primary Completion (Estimated)

March 1, 2029

Study Completion (Estimated)

March 1, 2029

Study Registration Dates

First Submitted

April 28, 2025

First Submitted That Met QC Criteria

April 16, 2026

First Posted (Actual)

April 20, 2026

Study Record Updates

Last Update Posted (Actual)

April 20, 2026

Last Update Submitted That Met QC Criteria

April 16, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL83658.018.23

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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