Visual spatial learning outcomes for clinical trials in neurofibromatosis type 1


Cognitive problems are common in children with neurofibromatosis type 1, representing a significant source of lifelong morbidity. Assessment of cognitive function has been challenging in the setting of clinical trials. Spatial learning deficits may be an important target for cognitive interventions. We leveraged a large, international cognitive study in affected children with NF1 treated with lovastatin to assess spatial learning using the “Arena Maze”, a portable, computerized task that allows for retesting in the same environment. As with the parent study, spatial learning assessed with this task did not improve with lovastatin treatment.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders,1 in which more than half of the affected children manifest cognitive impairment. Children with NF1 frequently demonstrate difficulty on various measures of visual spatial skills, visual‐motor integration, and visual learning. One of the major challenges in assessing visual spatial deficits and translating preclinical studies in mice is the lack of a suitable common assessment tool. Mice with germline mutations in the Nf1 gene demonstrate deficits in visual spatial learning, which is traditionally measured using the Morris Water Maze. Based on encouraging preclinical results in mice,the HMG‐CoA reductase inhibitor lovastatin was evaluated in human clinical trials, where no improvements in learning were observed.

Since the standard tests used to measure patient spatial learning and memory in humans differ from the Morris Water Maze used in animal models, the Arena Maze was developed to assess spatial learning strategies in young adults following traumatic brain injury and in a pilot study among children with NF1 and their unaffected siblings.6 The objective of the current study was to evaluate the feasibility of the Arena Maze to assess spatial learning in children with NF1. The secondary objective was to evaluate this tool as an outcome parameter for assessing spatial learning after treatment with lovastatin (NF1 STARS, NCT00853580).

This was an ancillary study to NF1 STARS (n = 146), a multicenter, double‐blind, placebo‐controlled, Phase II randomized trial of lovastatin, conducted by the NF Clinical Trials Consortium to determine the efficacy of lovastatin on visual spatial learning and attention abilities of children with NF1 aged 8–15 years. The same inclusion and exclusion criteria were used for the ancillary study as for the parent study. Participants were recruited from three sites: Boston Children’s Hospital (Boston, MA), The Children’s Hospital at Westmead (Sydney, Australia) and Children’s National Health System (Washington, DC). Informed consent was obtained from all parents/guardians, and age‐appropriate assent was obtained to participate in the ancillary study. Participants were randomized on the parent study to receive lovastatin or placebo daily.

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Managing Editor

Journal of Clinical Trials