A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1
Condition: Neurofibromatosis Type 1
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma
Intervention: Lovastatin ™; placebo
Intervention description: Lovastatin starting at 20mg for 2 weeks, increasing to 40mg for 14 weeks. Total duration of trial is 16 weeks.; Starting at 20mg for 2 weeks, then increasing to 40mg for 14 additional weeks for a total duration of treatment of 16 weeks.
Intervention MeSH terms: Lovastatin; L 647318; Dihydromevinolin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 146.0
Sex: All
Minimum age: 8 Years
Maximum age: 15 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Neurofibromatosis Type 1, Neurocognitive, Phase II

Summary:

      The specific aim of this study is to determine whether Lovastatin ™ significantly improves
      visual spatial learning and/or sustained attention in children with NF1.

      Secondary Aims:

      To evaluate the effect of Lovastatin ™ on measures of executive function, behavior and
      quality of life in children with NF1 and cognitive deficits.

      To further evaluate the toxicity and tolerability of Lovastatin ™ in children with NF1 and
      cognitive deficits.

      Hypotheses

      It is hypothesized that Lovastatin ™ will improve the visual spatial memory and/or attention
      deficits in children with NF1. This is based on studies demonstrating that Lovastatin ™ has
      significantly improved impairments in visual spatial memory and attention in the NF1 murine
      model.

      It is further expected that Lovastatin ™ will be safe and well tolerated over a 16-week
      period.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Males or females aged between 8 years and 15 years 11 months at time of enrollment who
             meet NIH diagnostic criteria for NF1 (Appendix 1)

          -  Participants must have a full-scale IQ of 70 or above. In cases where there is a
             statistically significant difference between verbal IQ and performance IQ (.05 level
             as determined by Table B3 in the WASI manual), participants will be eligible if at
             least one of these quotients is 70 or above

          -  Participants must have a cognitive impairment defined as having a score of at least
             one standard deviation or more below the population mean on one or more of the primary
             objective outcome measures (i.e., impaired on a measure of visual spatial learning
             and/or sustained attention)

          -  Participants must be medically stable

          -  Participants who are on a stable dose of methylphenidate and/or dextroamphetamines for
             at least one month prior to screening and who will remain on the same dose for the
             duration of the study.

          -  Hepatic function: Participants must have a bilirubin within normal limits and AST and
             ALT ± 2 times the upper limit of normal as determined by the standards at their
             institution

          -  Renal function: Participants must have an age-adjusted normal serum creatinine or a
             creatinine clearance of greater than 70 ml/m/1.73m2

          -  Hematologic function: Participants must have an absolute neutrophil count of greater
             than 1,500, a hemoglobin of greater than 9 gms/dl, and a platelet count of greater
             than 100,000 on study entry

          -  Participants must sign all required documents, including informed assent and HIPAA
             documents

          -  Female participants of childbearing age should not be pregnant, must have a negative
             pregnancy test before initiation of treatment, and take appropriate birth control
             precautions to participate in this study.

        Exclusion Criteria:

          -  Full-scale IQ less than 70; In cases where this is a statistically significant
             difference between performance IQ and verbal IQ (.05 level), patients will be excluded
             if both quotients fall below 70

          -  Individuals that are not cognitively impaired on at least one of the primary objective
             outcome measures

          -  Individuals with insufficient English to complete the assessments

          -  Participants taking psychotropic medication other than methylphenidate and/or
             dextroamphetamines. These patients are eligible if, as clinically indicated, they
             cease medication for at least 30 days prior to screening and remain off these
             medication for the duration of the study

          -  Participants with intracranial pathology such as epilepsy, diagnosed head injury,
             hydrocephalus or progressive intracranial tumors (children with asymptomatic or static
             lesions will be eligible)

          -  Participants who are pregnant or breastfeeding; Participants who have received any
             investigational drug, other than sirolimus, within 30 days of initiation of study

          -  Participants who have recently taken Lovastatin. These participants will be eligible
             after a washout period of at least three months.

          -  Participants with significant hepatic, renal or hematologic function as previously
             defined

          -  Participants with a history of neuromuscular disease, excluding hypotonias thought to
             be associated with NF1

          -  Participants with a clinically significant unrelated illness, which in the judgment of
             the principal or associate investigator, would compromise the participant's ability to
             tolerate the medication or potentially interfere with the participant's ability to
             participate in the required testing

          -  Low cholesterol (lower limit of a total cholesterol of 90mg/dl)

          -  Participants who have recently taken sirolimus within three months of enrollment.
             These participants will be eligible after a washout period of at least three months.