A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I

Abstract

Objective: Lovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras-MAPK pathway and associated with learning disabilities. We conducted a randomized double-blind placebo-controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1.

Method: Forty-four NF1 patients (mean age 25.7+/-11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent-reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures.

Results: Twelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well-tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f (2) = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f (2) = 0.19, P = 0.02, and adult self-reported internalizing problems, f (2) = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects.

Interpretation: These preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

Figure 1

Regions of Interest for Spatial Capacity Working Memory (SCAP) Functional MRI Task.

Figure 2

Clinical trial flow diagram of study participation. Flow chart depicts the recruitment and follow‐up of all subjects involved in the study. Of the 53 subjects originally screened, four subjects were deemed ineligible. Of the 49 eligible participants, 5 declined to participate prior to randomization. Thus, 44 were randomly assigned to the lovastatin group (n = 21) or the placebo group (n = 23). Four participants (19%) in the lovastatin group and 8 (34.8%) in the placebo group withdrew from the study before completion for personal reasons, resulting in 15 completers in the placebo group and 17 completers in the lovastatin group.

Figure 3

Group x Time Interactions for Measures showing significant treatment‐associated change. Scores at pre‐ and post‐treatment timepoints (baseline and 14‐week follow‐up) for each measure are shown on the Y‐axis. Scores are standardized to z‐scores, for comparability across measures. (A). Letter‐Number Sequencing showed a significant difference in trajectories between the two treatment groups (f ² = 0.70; P < 0.01), with greater improvement seen in the statin group. (B). Hopkins Verbal Learning Test showed a significant difference in trajectories between the two treatment groups (f ² = 0.19; P = 0.02), with greater improvement seen in the statin group. (C). Verbal category fluency showed a significant difference in trajectories between the two treatment groups (f ²= 0.19; P = 0.02), with greater improvement seen in the statin group. (D). YASR Internalizing Problems showed a significant difference in trajectories between the two treatment groups (f ²= 0.26; P = 0.03), with greater improvement seen in the statin group.