Among infants covered by Medicaid in 46 states, from 2004 to 2014, the incidence of neonatal opioid withdrawal syndrome (NOWs) increased 5-fold from 2.8 cases per 1000 hospital births to 14.0 cases per 1000 hospital births.1 In 2014, 82% of births affected by NOWs were covered by Medicaid, at a cost of $462 million. The proportion of neonatal hospital costs due to NOWs increased from 1.6 to 6.7% between 2004 and 2014. NOWs puts children at increased risk of adverse neurodevelopmental outcomes often complicated by family dysfunction. Infants who are exposed prenatally to opioids are a unique population with specific medical and social needs. Finding the best ways to interrupt these cycles for mothers, babies, and families during several critical periods–pregnancy, the newborn period, infancy, childhood, and adolescence–is crucial, yet solution-oriented research in these areas is lacking. To begin to fill these knowledge gaps, the HEAL -supported Antenatal Opioid Exposure Longitudinal Study Consortium program (hereon referred to as the Longitudinal Study Consortium, the Consortium, or the Longitudinal Study, as appropriate) will consist of an observational cohort study to better understand the long-term impacts of antenatal opioid exposure and NOWs, as well as associated environmental, maternal, and neonatal factors, on neuroanatomical, medical, neurodevelopmental, behavioral, and home, social, and family outcomes. It is expected that the results of this observational study will point to targets for intervention trials to improve outcomes for these vulnerable infants.
This study will be part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed the development and implementation of scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment and prevention of opioid misuse and opioid use disorder and (2) enhance pain management. More information and periodic updates about the HEAL Initiative is available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.
Overall Longitudinal Study Consortium Organization
The Longitudinal Study Consortium will be funded as a consortium of a Data Coordinating Center (DCC) and 2 or more Clinical Sites, which together, in a single application, will put forward a common longitudinal study application under the PL1 funding mechanism. The PL1 supports shared resources for categorical research by a number of investigators who focus on a common research problem. Under the PL1 Research Program Project mechanism, the DCC will house 2 Cores: an Administrative Core and a Research Support Core. The collaborating Clinical Sites are organized to increase sample size, accelerate recruitment, and/or increase sample diversity and geographic representation. Ideally, at least 150 in-utero opioid exposed infants are to be included with at least 50 unexposed infants to serve as controls. The DCC may be housed at the same institution as one of the Clinical Sites or may be at a separate institution. The Consortium will collaboratively develop the common protocol prior to application submission. Awardees will work together as a Consortium to implement a multi-site observational, prospective cohort study with multi-modal assessments of children from birth to two years of age to better understand the consequences of in utero opioid exposure. The goal of the program is to compare neuroanatomical (as measured by serial neuroimaging studies), medical, neurodevelopmental, behavioral, and home, social, and family outcomes between children who have been exposed to opioids in utero and those who have not been exposed. Such research is needed to inform development of appropriate care practices and treatments that would benefit exposed infants.
PL1 Activity Code
The PL1 activity code is to support shared resources and facilities for categorical research by a number of investigators who focus on a common research problem. In a single PL1 application for the Longitudinal Study program, a consortium of a DCC and at least 2 Clinical Sites with clinical resources sufficient to conduct a study of this size and complexity form a consortium and work together in the pre-application period to develop a single, shared protocol for the conduct of a multi-site longitudinal cohort study comparing outcomes as delineated below among children from birth to 2 years of age who were either exposed or not exposed to opioids in utero. At the time of award, the PL1 components will be disaggregated, with each Clinical Site being funded through individual but linked research project grants (RL1). The RL1 mechanism supports a discrete, specified, circumscribed project; the grants are linked, and the project is to be performed by the named investigators acting as a consortium. The DCC and its 2 component Cores will be funded as a PL1. The PD/PI for the Research Support Core should be the PD/PI for the PL1 application responding to this announcement. If the PL1 is submitted as a multi-PD/PI application, the Research Support Core PD/PI should be the contact PD/PI.
Key activities of the Longitudinal Study Consortium will be to:
- Communicate effectively with other Consortium members and NIH staff to achieve the objectives of the Longitudinal Study. The Data Coordinating Center and the Clinical Sites are expected to work together as a collaborative Consortium in preparing their application and after award.
- Form and participate on a Steering Committee, composed of the PD/PIs from each of the Clinical Sites and the DCC, as well as a non-voting independent chair, charged with the conduct of the protocol and the preparation of publications. The Steering Committee chairperson should not be affiliated with any of the Consortium institutions. Each full Steering Committee member will have one vote, and a simple majority rules. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee. The Steering Committee will meet within 3 months of award in the Metro DC area to finalize the common protocol, discuss potential common data elements with other HEAL studies, revise the statistical analysis plan and power analysis as needed, and establish the capitation budget.
- Hold conference calls for the Consortium Steering Committee and essential team members at least monthly and travel domestically for face-to-face meetings held in the Bethesda, MD area at least semi-annually during the funding period.
- Implement a single, shared protocol enrolling opioid-exposed and non-exposed newborns, following them over the course of 2 years, and collecting longitudinal assessments in multiple domains.
- Plan how they will collaborate with personnel from other HEAL program studies to implement, for example, common data elements that will facilitate combining data from multiple executed protocols in the future.
- Deposit all patient assessment data and all primary data at the DCC Research Support Core during the project period and make data available to the research community on or before completion of the award.
The Data Coordinating Center (DCC) should plan to address the following items through the activities of the Administrative Core and the Research Support Core:
- How the DCC will collaborate with the Clinical Sites and assist with protocol finalization, preparing study documentation (e.g., manuals and case report forms), training clinical staff in study procedures, coordinating and monitoring study implementation at the Clinical Sites, data collection, and data analysis resulting in publication this longitudinal cohort study.
- A power analysis that will justify the proposed sample size and study outcomes of interest. A statistical analysis plan is also required.
- Evidence of data management and program support capabilities by describing standard operating procedures for data collection, management, analysis and quality control.
- If the DCC is at the same institution as one of the Clinical Sites, describe the conditions and measures that ensure justifiable separation between the two and analytic independence.
- Capability to provide recruitment-based capitation funds to the Clinical Sites as well as logistical support for meetings, teleconferences, and the Steering Committee.
- Developing and maintaining a study website with both public and private features.
- Plans to prepare final study data for deposition in a publicly accessible data repository, such as the NICHD Data and Specimen Hub (DASH).
The Clinical Sites should plan to address the following items:
- Applicants should describe how the Clinical Sites will collaborate with the DCC Cores and participate on the Steering Committee.
- Each Clinical Site in the Longitudinal Study should describe its newborn source population and the prevalence of prenatal opioid exposure in newborns at the site.
- A combined number of at least 200 infants including 150 opioid-exposed and 50 unexposed infants are needed in total from the participating clinical sites.
- Applicants should consider partnering with existing groups or leveraging existing resources to achieve the goals of Longitudinal Study. This could include Clinical and Translational Science Award (CTSA, https://ncats.nih.gov/ctsa) funded by NIH, or the National Center for Advancing Translational Sciences’ Trial Innovation Network (https://trialinnovationnetwork.org/), or other funded perinatal-neonatal research centers as resources for conducting the proposed research.
- Key personnel at the Clinical Sites should participate in the development of the Longitudinal Study including the selection of content for the periodic assessments and their timing based on the scientific literature and/or from their own preliminary data.
An NIH Program Official will:
- Carry out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines.
- Perform other duties required for normal program stewardship of grants.
- Monitor subject recruitment, retention, and dropout, and request and review procedures for adjustment if enrollment targets are not being met.
- Monitor the acquisition of neuroimaging, clinical, and neuropsychological data and request and review procedures for remediation if a research site consistently lags in data acquisition benchmarks.
- Attend site visits and Steering Committee meetings as needed to ensure that progress is being made and to verify the reliability and consistency of data collected across research sites.
- Assure the scientific merit of the study, including the option to withhold support of a participating institution if technical performance requirements such as protocol compliance, enrollment targets, or retention of subjects are not met.
- Initiate a decision to modify or terminate an award based on awardee performance.
Deadline: March 29, 2019 (letters of intent due 30 days prior to deadline)
Filed Under: Funding Opportunities