NIH/NIDDK – Establishing a Cohort to Clarify Risk and Protective Factors for Neurocognitive Complications of Pediatric Type 1 Diabetes (T1D) – Planning Cooperative Agreements (U34 Clinical Trial Not Allowed)

There is growing evidence that there are neurocognitive complications of T1D, with approximately 28% of middle aged adults and 48% of older adults meeting criteria for clinically significant cognitive impairment (defined as performance =1.5 standard deviations below normative data on =2 cognitive tests). Early age of onset, duration of disease and severity of hyperglycemia (including noctural hyperglycemia), frequency and severity of episodes of hypoglycemia, hypoglycemia unawareness, diabetic ketoacidosis (DKA), and clinical severity at the time of diagnosis may increase risk for impaired neurocognitive and psychological function. However, age-related changes and vascular complications associated with T1D in adults and older adults make isolating mechanisms more complex and clinical targets may be less modifiable as individuals advance in age and disease burden increases. Therefore, research earlier in the developmental spectrum, especially prior to the development of complex disease (e.g., severe complications of T1D, CVD, dementia) may help us better understand mechanisms for neuropsychological complications of T1D, critical periods for prevention and intervention, and strategies to mitigate the risk of neurocognitive complications of T1D in later life.

Early childhood development is characterized by marked changes in brain structure and function at a time when the brain may be especially vulnerable to dysglycemia and T1D. There are limited data from adequately powered, longitudinal studies on the brain and neuropsychological function, especially in pediatric T1D, and the existing longitudinal studies with brain and neuropsychological data have shown mixed results, which has limited our knowledge of how specific parameters associated with T1D (e.g., age of onset, disease duration, glycemic variability and control, timecourse of dysglycemia, frequency and severity of hypoglycemic episodes, DKA) may lead to changes in brain structure and function and deficits in neurodevelopment and neuropsychological function, and how this may impact disease management, clinical course of T1D, and other important outcomes (e.g., academic function).  Moreover, it can be difficult to distinguish the etiology of cognitive impairment from adult cohorts alone since individuals with T1D are at increased risk for other factors that could impact neurocognition later in life (e.g., micro- and macro-vascular disease), but that should be less prevalent in the pediatric and adolescent population. There has also been increased interest in the role of DKA, especially the potential for neurocognitive impairment at the time of diagnosis and following treatment, but there is little long-term (i.e., > 3 months) longitudinal neurocognitive data post-DKA. Recent advances in neuroimaging, computerized neurocognitive assessment, and continuous glucose monitoring and artificial pancreas technologies could lead to improvements in characterizing brain structure/function, cognition, and clinical aspects of pediatric and adolescent T1D and promote understanding of the critical risk or protective factors (e.g., role of DKA, premorbid neurocognition, key developmental periods, effects of treatment regimen) for neurocognitive complications of T1D.  If specific risk or protective factors for adverse or optimal neurocognitive outcomes could be defined, treatment protocols could be developed to limit neurocognitive complications associated with T1D. Artificial pancreas technology may mitigate glycemic excursions and improve glycemic control.  Information on neurocognitive risks and benefits of glycemic control approaches and outcomes may inform algorithms for future closed-loop artificial pancreas systems.

If successful, this observational cohort study is expected to inform the timing and approach for future research to decrease adverse neurodevelopmental outcomes and long-term neuropsychological sequelae of T1D.

Scope

This FOA will utilize the U34 planning cooperative agreement to determine whether a rigorous, adequately powered national, multisite, observational cohort study to prospectively examine the risk and protective factors for neurocognitive complications of pediatric T1D (onset approximately ages 5-10 years) can be designed and what resources would be required. The U34 is a cooperative agreement award mechanism, with the NIH staff being substantially involved as a partner with the Principal Investigator/Program Director. The U34 FOA is designed to: 1) Permit early peer review of the rationale for the proposed cohort study; 2) Permit assessment of the design and protocol of the proposed study; and 3) Provide support for the development of essential elements required for the design and conduct of the cohort study and the management and analysis of the study data.

The U34 is not designed for the collection of preliminary data or for the conduct of pilot studies to support the rationale for an observational cohort study or to test or develop new interventions. The U34 will include the proposed study design (including primary and secondary outcomes) and protocol, but modifications to the study design and protocol will be permitted after peer review.

Contingent on the outcome of the planning cooperative agreements (U34s) and the availability of funds, NIH may fund a consortium to complete the proposed study. As this may require cooperation across some or all U34 awardees, applicants should clearly state that they are willing to work with other U34 awardees to finalize the study design and protocol should a consortium be formed to complete the proposed study, which would be funded through future FOAs.

Purpose

The U34 Planning Cooperative Agreement is intended to support all administrative study group activities that are required in order to begin recruitment of participants and execution of the proposed study, including finalizing study design; protocol development, implementation, and standardization; integration of all core data collection, sharing, processing, storage, and analyses; and coordination of all activities across the consortium. These activities include, but are not limited to: establishing the research team; identifying the clinical research sites and service cores; developing training materials and training/certification plans for study staff; satisfying all regulatory elements of the Food and Drug Administration if an IND/IDE is needed for implementation of the research plan; negotiating agreements with industry, academic centers, and other entities, as needed, for implementation of the research plan; testing and implementation of data collection protocols, including quality assurance and quality control for comparison across research sites where data collection would occur; developing tools for data management and stewardship to ensure they meet FAIR (Findable, Accessible, Interoperable, and Reusable) data principles; developing plans for resource and data sharing and study outcome dissemination; defining recruitment strategies, retention and protocol completion strategies, and contingency plans if recruitment, retention, and protocol completion milestones are not met; finalizing the protocol; writing the Manual of Operations; developing a safety oversight plan (NIDDK will appoint an Observational Study Monitoring Board (OSMB) for the full cohort study); initiating the IRB approval process; and developing an oversight plan for all research activities across the project.

Applicants are expected to provide a detailed description of a proposed study that will accomplish the scientific aims described above, as well as detailed information about the target population and comparison sample for recruitment and enrollment and recruitment capacity and capability for studying this target population and comparison sample. The proposed research study will enable reviewers to evaluate the applicant’s ability to identify the critical issues to be addressed in the study and rigorously design such a study. In addition, the application should include a description of how the cohort study could inform future research to decrease adverse neurodevelopmental outcomes and long-term neuropsychological sequelae of T1D. Preliminary results and background to support the cohort study should be provided. The application should include important details and considerations for the design of the cohort study, including a description of the study population and the comparison group with inclusion and exclusion criteria; study design (including primary and secondary outcomes); and power calculations. Detailed information on neuroimaging protocols and/or a neuropsychological battery, specifically, should be included. Primary outcomes based on neuroimaging or other surrogate markers of brain function and health will need justification. Applicants should address internalizing (i.e., anxiety, depressive) and externalizing symptoms in children and anxiety and depression in parents, and consider these confounding variables in the context of this study. A plan for how the availability of the requisite participant population will be established should be included. A recruitment and retention plan should be a part of that consideration. Issues and challenges related to completing to the proposed studies, including addressing study burden and other barriers and meeting data goals should be addressed. Finally, the application should describe the activities proposed to be conducted during the funding period.

Multidisciplinary teams will be required for these planning grants, including expertise in pediatric T1D, developmental neuropsychology and neuroscience, neuroimaging, diabetes technology, research methods and study designs, and data science for the type of complex study designs and data types expected for the proposed study. A Multiple Principal Investigator (MPI) application should be strongly considered for the type of proposed study expected.

Consultation with NIDDK program staff as soon as possible prior to the application due date is strongly encouraged.

The overall goal of the U34 funding period is to complete all administrative tasks required before recruitment of participants can begin. In the event of an award, the NIDDK and the PD/PI will agree on a list of milestones to be completed during the U34 project period. Successful completion of the U34 may result in an application to conduct the full cohort study, but this is contingent upon the outcome of the U34 and availability of funds. Completion of the full cohort study may require the formation of a consortium, which may require cooperation across some or all U34 awardees. Therefore, applicants should clearly state that they are willing to work with other U34 awardees to finalize the study design and protocol should a consortium be formed to complete the proposed study. As this consortium and the full cohort study would be supported with new FOA(s) issued shortly after completion of the U34, applicants should also clearly state their willingness to submit applications to these future FOA(s) in a timely manner. During the U34 award, NIDDK will appoint an expert panel to review the study design and make recommendations to NIDDK concerning the proposed study, including the study design. Discussions about whether the study should be conducted will include consideration of the following factors: attainment of pre-specified milestones, the expert panel recommendations, scientific landscape, study costs, opportunity cost, and availability of funds. Award of a U34 does not guarantee submission or funding of an application for the full cohort study.

Applicants must state their willingness to comply with the following performance requirements:

  • Engage a broader set of investigators external to the immediate study group to provide opportunities to analyze the data and participate in the parent study by means of ancillary studies
  • Develop opportunities for local analysis of data by study investigators and other qualified researchers at their institutions, and investigators outside the study group (“disseminated data analysis”)
  • Identify fixed and variable costs and establish procedures for negotiation of third party agreements or selection of subcontractors (i.e. clinical sites, clinical/investigational pharmacies, clinical/research laboratories, drug distribution centers, biospecimen repositories, etc.), and develop processes to efficiently administer and manage same throughout the project
  •  The NIDDK Technology Advancement Office must be consulted early in the process when an NIDDK-funded study enters into a collaboration agreement and the NIDDK Regulatory Specialist consulted early in the process when a protocol may be required to operate under an IND/IDE. These consults will be facilitated by the NIDDK Program Official.

Deadline:  March 11, 2019 (letters of intent); April 11, 2019 (full proposals)

URL:  https://grants.nih.gov/grants/guide/rfa-files/RFA-DK-18-007.html