Searching Patterns In the Robustness of Immunological FVIII Tolerance (SPIRIT)
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 500
- 试验地点
- 1
- 主要终点
- FVIII-specific non-neutralizing antibody development
研究概览
简要总结
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Congenital hemophilia A of all severities
- •Using NFT for prophylaxis
- •Aged under 18 years
- •Written informed consent
排除标准
- •Acquired hemophilia A
- •Any other bleeding disorder
研究组 & 干预措施
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
结局指标
主要结局
FVIII-specific non-neutralizing antibody development
时间窗: 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.
Characterization of FVIII-specific antibodies (Immunoglobulin isotypes)
时间窗: From enrollment up to 5 years
FVIII-specific antibodies will be characterized by measuring immunoglobulin isotypes (IgA, IgM, and IgG) over time using ELISA.
Characterization of FVIII-specific antibodies (IgG subclasses)
时间窗: 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.
Characterization of FVIII-specific antibodies (affinity)
时间窗: From enrollment up to 5 years
FVIII-specific antibodies will be characterized by measuring the affinity (KA \[M-1\]) over time using ELISA.
Characterization of FVIII-specific antibodies (titer)
时间窗: 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.
FVIII inhibitor development (neutralizing antibodies)
时间窗: 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.
次要结局
- 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)
研究者
Karin Fijnvandraat
Prof. MD PhD
Amsterdam UMC, location AMC