Kimford J. Meador - US grants

psychopharmacology; neuropsychology; drug screening /evaluation; pharmacokinetics; anticonvulsants; cognition; carbamazepine; drug adverse effect; clinical research; behavior test; human subject;

The proposed investigation is a continuation of the ongoing NEAD study, which addresses an important health care issue for women and their children. The use of antiepileptic drugs (AEDs) in women of childbearing age for epilepsy and for other indications (e.g., pain and psychiatric disorders) is common, but physicians need additional data, which are critical to adequately advise and direct treatment in these women. Animal studies have clearly demonstrated that commonly employed AEDs impair behavioral neurodevelopment. The potential consequences of such cognitive and behavioral deficits in humans are severe in terms of both personal and societal costs. However, controversy exists on the following issue to be addressed by this proposal. Do the most commonly used AEDs have differential effects on neurobehavioral outcomes in children exposed in utero? The primary objective of this study is to differentiate the relative risks/benefits of the four most commonly used AEDs in the treatment of women with epilepsy in terms of their children's neurobehavioral development after in utero exposure to AED monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate). The NEAD study is a prospective, parallel-group, cohort design, multicenter investigation. The major strength of the NEAD study is that it has enrolled a large and unique cohort of 323 mother/child pairs during pregnancy and collected prospective data on factors, which could affect neurobehavioral outcome. The primary outcome variables are IQ scores of the children and other measures of neurobehavioral development at 6 years/old. This grant extension is designed to follow the children to 6 years/old at which time neurobehavioral measures predict school performance and ultimate adult IQ. Samples have and will be collected for future pharmacogenetic investigations. The NEAD study has an invaluable cohort, and the results of this continuation proposal will impact the clinical management of women receiving these medications, and improve the health of their children.

DESCRIPTION (provided by applicant): Concerns over a crisis in clinical research have been raised for almost two decades. Continuing and increasing problems in this area have adversely impacted the conduct of clinical research, leading to failures in design, recruitment and successful completion of clinical trials. Multiple factors contribute to the existing situation, including scientific, educational, ethical, financial, and regulatory issues. Some of the major problems include: 1) inadequate training in clinical research for many clinicians, scientists, and research coordinators;2) increasing expectations for the quality of clinical research over the las several decades;3) greater difficulty in the control of potential confounding factors compared to basic research;4) increased regulatory requirements related to human assurances and confidentiality of data;5) increased concerns and regulations related to conflicts of interest, which involve interactions with industry as well as non-industry related personal financial and career advantages;6) increased complexity in budgetary issues;and 7) difficulties with academic institutions providing efficient support for clinical trials. Conduct of multicenter clinial research trials is even more challenging due to the need for repeated IRB approvals and contract negotiations at multiple institutions. Recently, there has been a call for academic institutions to assert leadership in clinical trials. Without vigorous academic involvement, criticl issues will continue to be unaddressed, important trials will not be conducted, and the public health will suffer. The NINDS has recognized the serious nature of problems limiting conduct of clinical research, and how these problems impair the translation of basic scientific findings to human populations. In an innovative approach to address existing limitations, the NINDS seeks to develop a Network for Excellence in Neuroscience Clinical Trials (NEXT). Emory University Neurology and collaborators in the Atlanta area seek to participate as a Clinical Site in the NEXT clinical research network. Our group has considerable expertise in neuroscience clinical research across a wide array of diseases, drawing from a diverse regional population with an abundance of subjects to address issues for multiple neurological disorders. Emory University provides excellent research resources and will make a strong commitment to the NEXT project, including agreeing to participate as a Tier I site using a central IRB and to implement protocols according to the budgets approved by the NEXT Steering Committee and the NINDS. PUBLIC HEALTH RELEVANCE: Clinical research is critical to translate discoveries from basic research to routine use in patients. However, multiple problems have impaired the efficient and successful conduct of clinical research. The result adversely affects the public health. The NINDS is developing a Network for Excellence in Neuroscience Clinical Trials (NEXT) to improve clinical neuroscience research. The Emory NEXT site will provide a unique and strong component to this network.

Project Summary: There is a compelling need for prospective, properly controlled studies in women with epilepsy (WWE) during pregnancy to improve maternal and child outcomes. The proposed investigations are pertinent to the NINDS Epilepsy Research Benchmarks, address multiple gaps in our knowledge noted by the American Academy of Neurology, and transform care in WWE. This multicenter investigation employs a prospective, observational, parallel-group, cohort design with an established research team. The FDA requires animal testing of individual AEDs to detect risks of fetal exposure for anatomical teratogenesis (i.e., congenital malformation), but not for functional teratogenesis (i.e., cognitive and behavioral deficits). Further, multiple human AED pregnancy registries are investigating malformations, but not cognitive/behavioral outcomes. Determining the effects of fetal AED exposure on development of neuropsychological abilities requires prospective collection of potential confounding factors and testing of children years after exposure. Thus, it is not surprising that such studies are rare, and the risks for most AEDs have not been assessed. The MONEAD investigation provides a unique cohort of exposed and unexposed children who have been followed prospectively starting in early pregnancy with detailed data collection; MONEAD is the first study to assess the effects of quantitated AED-exposure on neurodevelopment during pregnancy and breastfeeding by directly assessing blood levels in mother, cord blood and infant. This is critical because several commonly used AEDs undergo marked clearance changes during pregnancy with marked individual variability in these changes. Such changes could obscure ?dose? relationships reducing sensitivity of detecting adverse effects. MONEAD is also collecting data on the effects of breastfeeding while taking AEDs which includes blood levels in the child and a breastfeeding diary to directly delineate their exposure. This has never been done previously. The collection of AED levels and other pregnancy related factors is complete. In the proposed continuation grant, the children will undergo detailed neuropsychological testing at 2, 3, 4.5, and 6 years-old. The results will provide clear indications of AED risks to the immature brain for the presently most commonly used AEDs, and provide sentinel data on less commonly used AEDs to direct future studies. The Specific Aims are to determine the long-term effects of in utero and infant AED exposure in the children of WWE on: Aim 1: Cognitive outcomes (e.g., verbal abilities and other cognitive domains including novel measures of cerebral lateralization and creativity), Aim 2: Behavioral outcomes (e.g., adaptive and emotional/behavioral functioning, with measures of autistic behavior, attentional problems and hyperactivity), Aim 3: Determine if breastfeeding when taking AEDs adds additional risks. Hypotheses: Children exposed in utero to certain AEDs will exhibit concentration- dependent impairments in cognitive abilities and abnormal behavior. Continued AED exposure through breastfeeding will not add additional neurodevelopmental risk.

DESCRIPTION (provided by applicant): There is a compelling need for prospective, properly controlled studies in women with epilepsy (WWE) during pregnancy to improve maternal and child outcomes. The proposed investigations are pertinent to the NINDS Epilepsy Research Benchmarks and will address multiple gaps in our knowledge noted by the recent American Academy of Neurology guidelines. This multicenter investigation will employ a prospective, observational, parallel-group, cohort design with an established research team. The specific aims are to: 1) Determine if WWE have increased seizures during pregnancy and delineate the contributing factors; 2) Determine if C-section rate is increased in WWE and delineate contributing factors; 3) Determine if WWE have an increased risk for depression during pregnancy and post-partum period and characterize risks factors; 4) Determine the long- term effects of in utero AED exposure on verbal intellectual abilities and other neurobehavioral outcomes in the children of WWE; 5) Determine if small for gestation age and other adverse neonatal outcomes are increased in children of WWE; 6) Determine if breastfeeding when taking AEDs impairs the child's verbal intellectual and other cognitive abilities. An overall goal f the proposed research is to establish the relationship between AED exposure and outcomes in the mother and child as well as describe and explain the variability in AED exposure and response. Anticonvulsant blood levels (ABLs) and area-under-the- concentration-time-curves (AUCs) will be used as direct measures of drug exposure. The results will enable clinicians to prospectively calculate individual dosing regimens for the mother in order to optimize dosing and limit unnecessary drug exposure to the child. In addition, genetic samples will be collected, which will provide a valuable resource for future pharmacogenetics studies to further delineate individual variability across patients.