A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1

Study Design

This is a prospective multi-centre randomized, placebo-controlled Phase II study to determine
the efficacy of Lovastatin ™ on visual spatial learning and/or attention abilities of
children with NF1 aged between 8 and less than 16 years. In addition, the effect of
Lovastatin ™ on secondary measures of executive function, visual spatial skills, behavior and
quality of life will be assessed. Participants will be randomized to 16-weeks of treatment
with Lovastatin ™ or a matched placebo. It is plausible and ethical to employ a placebo group
as no standard therapy with established efficacy is being withheld. There is no cross-over in
this study due to a lack of data concerning the length of possible washout effects. The
Lovastatin ™ dose will begin at 20 mg once daily/continuous dosing and escalate over a
two-week period to 40 mg once daily/continuous dosing and continue at this dose for 14 weeks.
Participants will be carefully monitored for side effects. The safety of Lovastatin ™ will be
evaluated using laboratory tests, clinical signs and adverse effects, which will be monitored
at regular intervals over the 16-week period. Primary and secondary outcome measures will be
administered at baseline, 16 weeks post-treatment and at follow-up, 8 weeks after cessation
of treatment to determine any carry-over effects. The safety of Lovastatin ™ will also be
evaluated, with regular monitoring of side-effects during the trial.

Study Population

This is a Phase II study involving children with NF1 (aged between 8 years to 15 years 11
months old at time of enrollment) with evidence of cognitive impairment, defined as having a
score of at least one standard deviation or more below the population mean on a measure of
visual spatial learning and/or attention.

A total of 142 participants with NF1 aged between 8 years and 15 years 11 months will be
enrolled in the study. The age limits were selected on the basis that Lovastatin ™ has been
shown to be safe in children aged between 8 and 17 years old. In addition, one of the primary
outcome measures (attention) only has normative data for up to 15 years 11 months. Therefore,
the maximum age limit for participants at time of enrolment is 15 years 11 months so that
normative data can be used to determine whether participants are impaired. The pediatric NF1
population is an ideal group in which to study the cognitive effects of Lovastatin ™ because
it represents an opportunity for early pharmacological intervention of cognitive deficits.

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.