Key Dates

NOT-HL-19-727

National Heart, Lung, and Blood Institute (NHLBI)

The Division of Blood Diseases and Resources within the National Heart, Lung, and Blood Institute (NHLBI) intends to promote a new initiative by publishing a Funding Opportunity Announcement (FOA) to solicit applications for the following: Generate an Intergenerational Precision Medicine Resource for the Study of Factor VIII Immunogenicity in Severe Hemophilia A: Clinical Coordinating Center ( UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement ( Clinical Trial Not Allowed)).

This Notice of Intent to Publish (NOITP) is being provided to allow potential eligible applicants sufficient time to develop competitive and responsive milestone-driven scientific projects and thus prepare the applicant for the timely submission of an application.

The intended FOA will utilize the UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement (Clinical Trial Not Allowed) activity code to issue a single three-year milestone-driven UG3 award, followed by an up to 4 year award if NHLBI-approved milestones are successfully met, for a total of up to seven year support for this new initiative. A companion award for a Biospecimen and Data Resource Center is anticipated to be made in parallel to the Clinical Coordinating Center to provide data management, laboratory support and expertise for the new initiative (see NOT-HL-19-727).

A key characteristic of the Clinical Coordinating Center application will be completion of core milestones. A core milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be performance-based to achieve completion of the intergenerational severe hemophilia A precision medicine resource on time and on budget. Milestones must be established for both the first three years (the UG3 phase) and subsequent (up to) four years (the UH3 phase) of the program

Satisfactory completion of the milestones for the first three years will be assessed administratively by NHLBI to determine eligibility to continue the award. Due to the collaborative and parallel nature of these FOAs, NHLBI will enter into negotiation with the Clinical Coordinating Center to achieve early phase-out of the award if Clinical Coordinating Center and/ or Biospecimen and Data Resource Center progress is deemed inadequate upon NHLBI administrative review.

Details of the planned FOA are provided below.

The anticipated FOA is expected to create an opportunity for investigators to propose the design of a unique biospecimen resource, derived from a de novo antenatal/ neonatal /pediatric cohort with severe hemophilia A and annotated with robust intergenerational clinical and demographic data, for the purpose of enabling future mechanistic and translational studies of factor VIII immunogenicity and tolerance.

The application for Generate an Intergenerational Precision Medicine Resource for the Study of Factor VIII Immunogenicity in Severe Hemophilia A: Clinical Coordinating Center ( UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement (Clinical Trial Not Allowed)) will propose a detailed scientific plan for clinical project leadership by a critical mass of investigators from different disciplines who will 1) identify the priority research questions; 2) collaborate with the Biospecimen and Data Resource Center (anticipated U24 companion FOA ) in the scientific development, pragmatic implementation, and expert conduct of the hypothesis-driven protocols that will populate the resource with relevant longitudinal data and biospecimens; 3) engage in the interpretation and dissemination of results specific to these protocols; and 4) collaborate with the Biospecimen and Data Resource Center to ensure that the data and biospecimen resource is made accessible to the broader research community within one year of maturity using NIH and NHLBI data and biorepository resources.

A responsive scientific collaboration will be expected to include clinical and/or scientific subject matter expertise in hemophilia, maternal fetal medicine, immunology, multi- and trans-omics, microbiome, psychosocial and environmental sciences, and other relevant fields, as well as demonstrated experience in the conduct of multi-site clinical studies. The proposed Clinical Coordinating Center collaboration would be capacitated to:

• Harness the federally-funded Hemophilia Treatment Center (HTC) infrastructure to target and recruit severe hemophilia A carrier women who are pregnant and anticipating a male offspring;

• Collect biologic (including -omics), demographic, contextual, environmental, and psychological data as well as biospecimens on mothers, by trimester and during labor and delivery, to include biometric data on as well as blood and tissue from the placenta;

• Initiate biometric and phenotypic data collection on affected neonates at delivery, as well as initial specimen collection from umbilical cord tissue/blood and meconium;

• Continue phenotypic data and biospecimen (including -omics) collection in the neonate and toddler to be focused on both non-hemophilia and hemophilia-related immunologic and inflammatory perturbations in the baseline state throughout the 2-year highest risk period for anti-FVIII antibody development;

• Collect biologic (including -omics), demographic, contextual, environmental, and psychological data, as well as biospecimens on the father, when available; siblings, if scientifically appropriate, e.g., monozygotic twin; younger affected sibling born within the study recruitment period;

• Include the option to collect potential scientifically valid control data on male offspring unaffected by hemophilia, e.g., unaffected dizygotic male twin;

• Propose a plan to enrich the statistical power of this cohort through collaborations for data and biospecimens from existing post-natal cohorts.

The strongest applications will propose multiple hypothesis-driven and feasible protocols that scientifically focus on the critical questions to be answered through the future interrogation of the resource. Potentially relevant research questions include, but are not limited to:

• What is the impact of the antenatal physiologic and environmental, as well as the circumstances of labor and delivery, on the hemophilic baby’s innate immune response to the FVIII immunogen?

• How do paternal factors impact maternal microbiome, and/or inform the inherited determinants of neonatal immunoreactivity and inflammatory responses to immunogens, particularly the FVIII immunogen?

• What are the conditions under which fetal exposure to maternal blood and tissue during gestation and at delivery sensitize or tolerize a hemophilic infant to the FVIII immunogen?

• What are the placental structural and immunological determinants of fetal exposure to maternal IgG and FVIII peptides, and the impact of in utero exposure on fetal immune determinants (measured through cord blood and tissue) and subsequent neonatal immunoreactivity to infused FVIII?

• What is the association between maternal infectious, immune, inflammatory and/or microbiome status in the perinatal period and both the neonatal microbiome at delivery, and the immediate and subsequent neonatal immunoreactivity and inflammatory responses to immunogens, particularly the FVIII immunogen?

• How is the propensity for inhibitor development influenced by multi-omic characteristics in severe hemophilia A neonates and children with ongoing immunological perturbations (i.e., infections and immunization)?

• Which characteristics of the hemophilic baby’s immunological/inflammatory baseline inform how disease- specific inflammatory triggers, such as bleeding, potentially combined with exposure to the FVIII immunogen, promote either an immunoreactive or tolerogenic immune response?

• How are biological perturbations specifically related to hemophilic bleeding and/or the infusion of FVIII replacement therapy reflected in transcriptomic, epigenomic, microbiome, proteomic, metabolomic, inflammatory, and immunological changes from the baseline state?

• How are ancestrally-linked risk factors and inhibitor development associated?

• Which social determinants, including ascribed race/ethnicity, are predictors of inhibitor development?

• Are there -omics / environment interactions that may manifest as a risk profile for inhibitor development?

Applicants will be expected to propose milestone- driven activities for:

1. The initial, three-year phase of the project (UG3) to include, in collaboration with the Biospecimen and Data Resource Center:
   1. Scientific and operational protocol development;
   2. The design and conduct of feasibility and pilot studies; and
   3. Initial implementation of feasible scientific and operational protocols to start enrollment into the antenatal/ neonatal /pediatric cohort, and collect data and biospecimens per established procedures.

2. The second, four-year phase of the project (UH3) to include, in collaboration with the Biospecimen and Data Resource Center:
   1. Full implementation of protocols that were developed in Phase 1;
   2. Complete enrollment follow-up and collection of the protocol data and biospecimens for the final build of a sharable, fully annotated biorepository;
   3. Data analyses and dissemination of findings; and
   4. Submission of the public-use data and biospecimens to the NIH repository resources.

Iman K. Martin, PhD, MPH, MS
National Heart, Lung, and Blood Institute (NHLBI)
301-435-0065
[email protected]