Hemophilia A Research Program (HARP): An Observational Intergenerational Cohort Study of Hemophilia A and Factor VIII Immunogenicity
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 500
- 试验地点
- 1
- 主要终点
- Primary Endpoint(s)/Outcome(s)
研究概览
简要总结
This study longitudinally observes the intergenerational (mother-child) continuum in hemophilia A from pregnancy through early childhood. Because the study follows mother-child pairs, the study includes both a maternal cohort and a pediatric cohort. Each cohort has a primary goal: for the mother with a severe hemophilia genotype, the overarching primary goal is to understand the risks for pregnancy-associated bleeding and postpartum hemorrhage (PPH); for the child, the overarching primary goal is to understand the risks, timing, and circumstances of development of anti-FVIII antibodies. From a longitudinal perspective, risks for both bleeding in the mother and anti-FVIII antibody development in the child are expected to be influenced over time by genetic and environmental factors that begin early in (or before) pregnancy. Enrollment of blood relatives is offered to improve power to better understand inherited contributions to bleeding and inhibitor development in the mother-baby pairs.
详细描述
HARP is a longitudinal observational, decentralized and multisite (with one hybrid site), national prospective cohort study in hemophilia A. Participants will be treated by their HCPs, with no limitations on medical decision-making.
Hemophilia A is an inherited X-linked bleeding disorder caused by deficiency in coagulation factor VIII (FVIII). Severe hemophilia A is defined by a FVIII level < 0.01 IU/dL (or < 1%). A significant complication of hemophilia A is the development of immune responses to FVIII, also known as inhibitors. In pregnancy, mothers who have a hemophilia-causing genotype are at high-risk for postpartum hemorrhage (PPH). Genetics, other health factors, and environment are all thought to contribute to immune responses and bleeding risks. This study seeks to better understand factors involved in inhibitor development and bleeding beginning before birth.
To accomplish the goal of following 50 mother-child pairs with a child affected by severe hemophilia A from pregnancy through at least the first 2 years of life, we expect to enroll approximately 120 pregnant mothers with a pregnancy at-risk of being affected by severe hemophilia A. The biological father, first- and second-degree blood relatives of the child, and other relatives whose data or samples may be informative for the planned genetic studies of hemophilia and inhibitors may be invited to participate in the study and provide data and samples in order to improve power of the study to robustly investigate the heritable causes of bleeding and inhibitors.
Based on incidence and prevalence calculations of hemophilia by the Centers for Disease Control and Prevention, approximately 150 males are born with severe hemophilia A in the United States annually. Because one-third of these patients should not have a prior family history, a conservative estimate for new babies with severe hemophilia A born into a family known to have hemophilia would be 100 males annually. HARP will open 1-2 U.S. fixed sites, with most participants expected to enroll in the decentralized study.
The HARP study design will enable maternal and neonatal/early life sample and data collection for a continuous picture of hemophilia A phenotypes and immunological development. The duration of participation in HARP for each mother-child pair will be from enrollment during pregnancy until the child is at least 2 years old. Mother-child pairs will complete the study when the child reaches 50 cumulative FVIII EDs without an inhibitor or HARP ends, whichever comes first. The expected range of duration of participation for any one mother-child pair will range from 2.2 years up to 5 years, with many participants expected to be followed for < 3 years.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Pregnant individuals who meet the following criteria are eligible for enrollment as study participants:
- •Currently pregnant and prior to 37 weeks gestation
- •Known to have or at-risk of having a severe hemophilia A genotype
- •Pregnant with at least one fetus at-risk of inheriting severe hemophilia A
- •Ability to understand and willingness to provide informed consent
- •18 years of age or older
- •Before the 38th week of pregnancy, enrolled participants must meet all the following criteria to continue to remain in the study:
- •The pregnant mother has a severe hemophilia A genotype.
- •A fetus is determined to have a >/= 25% risk of inheriting severe hemophilia A, or prenatal testing indicates a fetus is affected by severe hemophilia A.
- •No other discontinuation criteria have been identified.
- •Pediatric Continuation / Inclusion Criteria:
- •Eligibility of the child to continue is assessed by age 8 weeks. Mother-child pairs in which a child meets the following criteria will remain in the study:
- •Severe hemophilia A defined by a baseline FVIII:C < 0.01 IU/mL (or FVIII:C < 1%) or a genotype predicted to cause severe hemophilia A
- •Born to a mother participating in the study
- •Thereafter, mothers and their children will continue in the study as long as no new discontinuation criteria occur.
- •Inclusion Criteria for Blood Relatives:
- •Blood relatives of the child may be offered participation if one of the following criteria are met:
- •First-degree blood relatives (e.g., father, sibling) of the child
- •Second-degree blood relatives (e.g., aunt, uncle, grandparent, half-sibling) of the child
- •Any more distant male or female blood relative whose data or samples may be informative for the planned genetic studies of hemophilia and inhibitors
- •Exclusion/Discontinuation Criteria:
- •Maternal: For the pregnant person, exclusion or discontinuation criteria are as follows:
- •Genetic testing is negative for a severe hemophilia A genotype
- •Prenatal clinical diagnostic testing that indicates there is no fetus affected with severe hemophilia A
- •Presence of another clinically significant bleeding disorder
- •Participation in another study for which any blood collection total would exceed safety limits defined in this study
- •Will deliver outside the United States or plans for regular pediatric care for the child to be delivered outside the United States
- •Is a prisoner
- •Any other reason that, in the opinion of the investigator, would render the individual unsuitable for participation in the study
- •Inability for study team to obtain translated study documents in time for participation if participant is not fluent in English
- •Pediatric: For the child, discontinuation criteria are as follows:
- •Infant does not have severe hemophilia A defined by a baseline FVIII:C < 0.01 IU/mL (or FVIII:C < 1%) or does not have a genotype predicted to cause severe hemophilia A
- •Mother or child did not have minimal required study samples or data collected before birth, around the time of delivery, or in the neonatal period
- •Child has another clinically significant bleeding disorder
- •Child has a clinically severe immune disorder
- •Participation in another study for which any blood collection total would exceed safety limits defined in this study
- •Any other reason that, in the opinion of the investigator, would render the individual unsuitable for participation in the study
排除标准
- 未提供
研究组 & 干预措施
Maternal Cohort
Inclusion Criteria (mother):
- Currently pregnant and prior to 37 weeks gestation
- Known or at-risk of having a severe hemophilia A genotype
- Pregnant with a fetus at-risk of inheriting severe hemophilia A
- Ability to understand and willingness to provide informed consent
- 18 years of age or older
Pediatric Cohort Continuation Criteria (Child)
- Severe hemophilia A defined by a baseline factor VIII activity (FVIII:C) <0.01 international units (IU)/mL (or FVIII:C < 1%) or a genotype predicted to result in severe hemophilia A
- Born to a pregnant mother participating in the study
- Absence of discontinuation criteria
Blood Relatives of the Child (may be offered participation)
- First-degree blood relatives (e.g., father, sibling) of the child
- Second-degree blood relatives (e.g., aunt, uncle, grandparent, half-sibling) of the child
- Any more distant male or female blood relative whose data or samples may be informative for the planned genetic studies of hemophilia and inhibitors
结局指标
主要结局
Primary Endpoint(s)/Outcome(s)
时间窗: For mother-child pairs, from enrollment until the child with severe hemophilia A is at least 2 years old*, or until a study discontinuation criteria is met. *This is the minimum duration, the mother-child pairs will be followed for as long as feasible.
The study primary endpoints/outcomes for the maternal and pediatric cohorts are as follows: • Maternal: Rates of primary PPH, defined as * estimated or quantified blood loss \> 1,000 mL in the first 24 hours PP, or * unplanned transfusion of blood products related to blood loss in the first 24 hours PP. As a subset of primary PPH, severe primary PPH is defined as * estimated or quantified blood loss \> 1,500 mL or requirement of \> 2 units packed red blood cells within 24 hours PP, or * primary PPH with estimated or quantified blood loss \> 1,000 mL and evidence of maternal hemodynamic instability (tachycardia, hypotension) or end organ damage with no other etiology (oliguria, creatinine \> 0.8, etc.). • Pediatric: Rate of development of humoral immune response to FVIII and proportion that progress to clinical inhibitors, defined as * clinical FVIII inhibitor, or * detection of an antibody specific to FVIII.
次要结局
- Secondary Endpoint(s)/Outcome(s)(For mother-child pairs, from enrollment until the child with severe hemophilia A is at least 2 years old*, or until a study discontinuation criteria is met. *This is the minimum duration, the mother-child pairs will be followed for as long as feasible.)
研究者
Jill Johnsen
Professor, Division of Hematology and Oncology
University of Washington