Conditions: Neurofibromatosis Type 1
Keywords: Neurofibromatosis Type 1, Neurocognitive, Phase II
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 146
Healthy volunteers: yes

Brief 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.

Detailed description:
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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Lovastatin ™ intervention 2: placebo
Intervention descriptions: intervention 1: Lovastatin starting at 20mg for 2 weeks, increasing to 40mg for 14 weeks. Total duration of trial is 16 weeks. intervention 2: Starting at 20mg for 2 weeks, then increasing to 40mg for 14 additional weeks for a total duration of treatment of 16 weeks.

Protocol document:
ICF_002.pdf: 
The University of Alabama at Birmingham 
CONSENT TO PARTICIPATE 
IN A CLINICAL RESEARCH STUDY AND AUTHORIZATION TO USE PROTECTED 
HEALTH INFORMATION 
TITLE OF STUDY: A Randomized Placebo-Controlled Study ofLovastatin in Children 
with N eurofibromatosis Type 1 ("STARS") 
(For purposes of this trial, only children between the ages of 8 years to less than 16 years of 
age will be enrolled) 
IRB Protocol Number: F090202002 
PRINCIPAL INVESTIGATOR: Bruce Korf, MD, PhD 
Co-Principal Investigator: Alyssa Reddy, MD 
Sponsor: The United States Army - The Department of Defense 
"You" refers to "You" or "Your Child" throughout this document 
INTRODUCTION: We would like to invite you to be part of a research study. Before you 
decide if you would like to participate, we want you to know why we are doing the study. We 
also want you to know about any risks (anything unexpected that might happen) and what you 
will be expected to do in the study. 
This form gives you information about the study. Your doctor will talk to you about the study 
and answer any questions you have. We encourage you to discuss this study with your family 
and anyone else you trust before making your decision. We will ask you to sign this form to 
show that you understand the study. We will give you a copy of any forms you sign to keep. 
PURPOSE OF STUDY: You are being asked to participate in this study because you have 
neurofibromatosis type 1 (also called NFl) and are aged 8 to almost 16 years. As many as 
65% of children with NFl have learning disabilities, such as difficulty with memory and 
attention. 
At present, there is no known drug treatment available to treat the majority of these learning 
problems. We would like to use a drug called Lovastatin to see if your learning difficulties 
improve using this medication. Lovastatin has been used in children with other medical problems 
such as increase in the blood cholesterol. This medication has been safe and well tolerated in 
those patients. Some parts of learning that may improve include your ability to pay attention and 
memory. Lovastatin is FDA approved in children for the treatment of high cholesterol and has 
been tolerated well in patients ages 10 to 17. However, Lovastatin has not yet been FDA 
approved for use in children with NFl and learning disabilities, nor do we know if this drug will 
be effective in improving learning, memory and attention. It is an experimental drug for children 
Page 1 ofll 
UAB IRB 
Date of Approval 
( -11-1 Q 
Not Valid On 
1 :Cf-I cf 
Patient's Initials 
07Jan.2013 V.4.2 


with NF 1. We want to know if Lovastatin is as well tolerated in children with NF 1 as it is 
tolerated in children with high levels of cholesterol and if Lovastatin improves learning and 
memory in children with NF 1 and learning disabilities. 
PROCEDURE: A complete medical history and physical examination will be performed 
(including a neurological examination) to confirm each participant's NFl diagnosis and to 
document any complications that they might have from the disease. Height, weight, head 
circumference, blood pressure and pulse will be recorded. 
1. Neuropsychological testing will be performed before initiation of treatment and at 16 
weeks while on the study. 
A final post treatment neuropsychologic test will be 
administered eight weeks after completing medicine requirements for the study. 
2. Prior to entering the study you will have a small amount of blood drawn to measure 
blood counts, blood chemistries, and liver and kidney function. Females of childbearing 
age will have a pregnancy test. Additional labs will be done as needed to monitor side 
effects of medication. This will involve taking 6mL (approximately 1 teaspoon) of blood 
at each draw. All participants will receive Lovastatin or placebo capsule. Both are taken 
orally. You will not know if you are going to be assigned to a particular group. Your 
doctor will also not know, but can find out if necessary. You will take the medication as 
a capsule taken after dinner every day. At the 2°d week you will increase the number of 
capsules as described below. You must be able to swallow the capsule to be part of this 
study. 
Group 
Initial - Week 1 
Start 
Weeks 3-15 
Lovastatin N europsychology 
+ 1 capsule@ 
2 capsules @ 20mg. each 
-Placebo 
Clinical Exam+ Labs 
20mg. 
3. Participants will continue on their assigned dose until the end of the study period which 
is a total of 14 weeks. 
4. While on study each participant will be evaluated at week 2, 4, 8, 12 16 and follow-up. 
At each visit a history and physical will be repeated as well as the blood work described 
above, except for visit 2. Females of childbearing age will also repeat a urine pregnancy 
test at week 8 and 16. Side effects of the medication will be reviewed as well as a drug 
count to make sure the medication is being taken correctly. 
5. Certain medications or foods can affect the levels of Lovastatin in the blood and 
should be avoided. A complete list of medications that need to be avoided will be given 
to you. 
Please consult your doctor if you are taking any of those medications. You should also 
not eat grapefruit or drink grapefruit juice while you are on this study because it can also 
affect the level ofLovastatin in blood. 
YOU MAY BE TAKEN OFF STUDY FOR THE FOLLOWING REASONS: 
• 
You decide to withdraw from the study 
• 
Your doctor may tell you to stop taking part in the study at any time if he/she believes 
it to be in your best interest. 
Page 2 of 11 
Patient's Initials 
07Jan.2013 V.4.2 


• 
You develop significant side effects or medical condition( s) that would be harmful for 
you to continue with the study medication. 
POTENTIAL RISKS/DISCOMFORT: Overall Lovastatin has been well tolerated in children 
ages 10 to 17 as well as in the adult population. The following risks/side effects, which are 
believed to be associated with Lovastatin include: 
Frequency of side effects 
Common (less than 1 person in every 10 but more 
than 1 person in every 100) 
Uncommon (less than 1 person in every 100 but 
more than 1 person in every 1000) 
Rare 0,01 % to 0,1 % (less than 1 person in every 
1,000) 
Rare 0,01 % to 0,1 % (less than 1 person in every 
1,000) 
Page 3 of II 
Side effects description 
Gastrointestinal disorders: constipation, dyspepsia 
(upset stomach) 
Skin and subcutaneous tissue disorders: itching 
(itchy skin) 
Eye disorders: blurred vision (problems seeing) 
Gastrointestinal 
disorders: 
abdominal 
pam, 
diarrhea, dry mouth, flatulence, nausea, vomiting 
General 
disorders 
and 
administration 
site 
conditions: weakness 
Hepatic disorders: yellowing of the skin and eyes 
( choleastic jaundice, hepatitis 
Metabolism and nutrition disorders: loss of 
appetite 
Musculoskeletal, connective tissue and bone 
disorders: 
muscle 
weakness 
(myopathy), 
tenderness and muscle pain, muscle cramps 
Any unexplained muscle pam, tenderness or 
weakness should be reported promptly. Lovastatin 
therapy should be discontinued immediately if 
myopathy is diagnoses or suspected. 
Nervous system disorders: dizziness, absence of 
the sense of taste, headache, tingling sensation, 
tingling and numbness of the feet and legs (losing 
feeling in the feet and legs) 
Psychiatric disorders: insomnia (problems falling 
to sleep), psychic disturbances including anxiety 
(feeling nervous, frustrated or angry), sleep 
disorders 
Skin and subcutaneous tissue disorders: alopecia 
(losing hair), spotted or red, swollen or peeling, 
red skin. 
An apparent hypersensitivity syndrome has been 
reported rarely which has included one or more of 
the following features: 
anaphylaxis (allergic 
reaction), angioedema (swelling beneath the skin), 
lupus-like 
syndrome 
(kidney 
disorder), 
polymyalgia rheumatica (pain and stiffness in the 
hip 
or 
shoulder 
area), 
dermatomyositis 
Patient's Initials 
07Jan.2013 V.4.2 


(inflammation 
and 
skin 
rash), 
vasculitis 
(inflammation 
in 
your 
veins, 
arteries 
and 
capillaries), thrombocytopenia (disorder that can 
causes 
an 
abnormal 
bleeding), 
leucopenia 
(decrease in the number of white blood cells in the 
blood), eosinophilia (high number of white blood 
cells), hemolytic anemia (there are not enough red 
blood cells in the blood), positive ANA (ANA is 
the antinuclear antibody panel is a blood test that 
looks at antinuclear antibodies), ESR increase 
(ESR is a screening test that indirectly measures 
how much inflammation is in the body), arthritis 
(inflammation of the joints, arthralgia (joint pain), 
urticaria (hives, often itchy, red welts on the 
surface of the skin, asthenia (feeling of weakness), 
photosensitivity (sensitivity of the skin to a light 
source), fever, flushing (skin blushing), chills 
(feeling cold), dyspnea (breathing difficulties) and 
malaise (generalized feeling of discomfort) 
Uncommon: elevated transminases (this may be 
an indicator of liver damage) 
Rare: other liver function test abnormalities 
including elevated alkaline phosphatase and 
bilirubin; increase in serum CK levels. 
ADDITIONAL ELEMENTS: (Unforeseeable risks to participant or embryo). It is not 
known if this study treatment can cause serious harm to unborn children or children who are 
breast-feeding. For this reason, if you are pregnant or breastfeeding, you will not be allowed to 
participate in this study. It is advisable that you should not become pregnant while you are on 
the study treatment and for at least six months after completing your study treatment. If you are 
of childbearing age and sexually active, you must agree to use birth control (birth control pills, 
contraceptive implants, condoms or not having sex) while taking the medication and for 6 
months after stopping the medication. If you become pregnant while enrolled in this study, your 
participation will be ended and you should understand that there is an unknown risk to an unborn 
baby. If you are able to become pregnant, you will be given a pregnancy test before starting the 
study and possibly at other times during the study. 
Since the long-term effect of lower lipid levels in children on Lovastatin is unknown at this time, 
having normal range cholesterol is a criterion for enrollment. Your cholesterol levels will be 
checked several times during this trial. 
Please be aware that you could miss approximately six ( 6) whole or half days of school to 
participate in this trial. You are encouraged to discuss your decision to participate with your 
school to comply with the absenteeism policies and to arrange to make-up any missed work. 
Page 4 ofll 
Patient's Initials 
07Jan.2013 V.4.2 


VOLUNTARY PARTICIPATION: There will be no penalty or loss of benefits to which you 
are otherwise entitled if you decide to withdraw from the study. You may choose not to 
participate in this study. If your doctor thinks that any treatment other than what you will get in 
this study would be better for you, your doctor will inform you of other options. At present, 
however, there is no other standard treatment available for learning disabilities in children with 
NF 1. It is important that you know: 
• 
The study is voluntary - you do not have to join the study. 
• 
You may change your mind and stop being in the study any time you want. 
However, as with any medication, you must discuss with your doctor if you decide 
to withdraw and stop taking the medication. 
• 
You will be notified if any important changes are made to the study. In some 
cases we may need your signature on an updated consent form. 
POTENTIAL BENEFITS: If you agree to take part in this study, there may or may not be 
direct benefit to you. It is possible that the medicine may improve your learning skills. However 
this may not occur. We hope that the information learned from this study will benefit you and 
other children with NF 1 and learning disabilities in the future. You will receive a summary of 
the neuropsychological testing before and after treatment. If there is any specific alteration that 
will need intervention, you will receive recommendations. The results of the neuropsychological 
testing will provide useful information about your cognitive profile. If you are one of the 
patients to receive the placebo drug on this study, you could benefit from a detailed, cognitive 
consultation to further understand your cognitive functions. 
ALTERNATIVES TO PARTICIPATION: No alternative treatment is offered or recommended 
for participants in this study. We recommend that you please speak with your doctor regarding 
your individual treatment needs if you decide not to participate. If you decide not to participate it 
will not affect your regular health care. You should also discuss your decision to participate with 
your doctor prior to taking part in this trial. 
QUESTIONS - WHO TO CALL: Please contact the Principal Investigator (PI), Dr. Bruce 
Korf, The University of Alabama at Birmingham, Genetics (Kaul Building), 205.934.1154 or 
205.427.3818 (Emergency) ofthis study if: 
Page 5of11 
• If you have questions about any part of this study or consent form either now or at 
any time in the future. 
• If you believe you have been injured as a result of being in this study. 
• If you have questions about your rights as a research participant, or concerns or 
complaints about the research, you may contact the Office of the IRB (OIRB) at 
(205) 934-3789 or 1-800-822-8816. If calling the toll-free number, press the 
option for an operator/attendant and ask for extension 4-3789. Regular hours for 
the OIRB are 8:00 a.m. to 5:00 p.m. CT, Monday through Friday. You may also 
call this number in the event the research staff cannot be reached or you wish to 
talk to someone else. 
Patient's Initials 
07Jan.2013 V.4.2 


COST AND COMPENSATION: The University of Alabama at Birmingham cannot promise 
that the risks we have told you about or other unknown problems will not happen. If emergency 
treatment is deemed necessary as a result of this trial, it will be provided. 
Additional costs to participants to take part: The University of Alabama at Birmingham will 
give you the medicine used in this study for free. You will not be charged for anything else we 
do that is part of the study. You will still have to pay for any medical care or costs (parking, etc.) 
that are not part of the study. 
What compensation is available in case of injury: The University of Alabama has made no 
provision for monetary compensation in the event of injury from the research, and in the event of 
such injury, treatment will be provided, but is not free of charge. 
The Principal Investigator or his/her designee will assist you and your child in obtaining 
appropriate medical treatment if it is required. If you have any questions, please discuss this 
issue thoroughly with the Principal Investigator or his/her designee prior to enrolling in this trial. 
This is not a waiver or release of any of your legal rights. 
CONFIDENTIALITY: We will keep the records of this study confidential. Only the people 
working on the study will know your name. They will keep this information in case we have to 
find you later to let you know of any new information that may affect and/or benefit your health. 
The federal governrnent can review the study records and medical records to make sure we are 
following the law and protecting the children in the study. Your medical record is confidential, 
but just like any medical record; there are some exceptions under state and federal law. 
Every effort will be made to maintain the confidentiality of your medical and research 
information ("Protected Health Information" or "PHI") consisting of name, address (including 
city and zip code), date of birth, telephone numbers, social security numbers, new and existing 
medical records, medical record numbers, health plan numbers, types, dates, and results of 
various tests and procedures, and blood and /or tissue sample analysis. Protected Health 
Information is defined as health information, whether verbal or recorded in any form (such as on 
a piece of paper or entered in a computer), that identifies you as an individual or offers a 
reasonable basis to believe that the information could be used to identify you. 
If you agree to participate in this research study, the research team, the research sponsor (when 
applicable) and the sponsor's representatives, may use Personally Unidentified Study Data. The 
Personally Unidentified Study Data does not include your name, address, telephone, or social 
security number. Instead, the researcher assigns a code to the Personally Unidentified Study 
Data. Personally Unidentified Study Data may include your date of birth, initials, and dates you 
received medical care. Personally Unidentified Study Data may also include the health 
information used, created, or collected in the research study. 
The research team or the research sponsor may share the Personally Unidentified Study Data 
with others to perform additional research, place it into research databases, share it with 
researchers in the U.S. or other countries, or use it to improve the design of future studies. They 
Page 6 ofll 
Patient's Initials 
07Jan.2013 V.4.2 


may also publish it in scientific journals, or share it with business partners of the sponsor and to 
file applications with U.S. or foreign government agencies to get approval for new drugs or 
health care products. 
By signing this consent form you are giving permission for representatives of Bruce Korf, MD, 
the Investigator and UAB employees involved with the research study including the Institutional 
Review Board and the Office for Research Compliance, and any sponsoring company or their 
appointed agent as well as representatives and staff of: the NF Consortium Operations Center the 
Department of Defense (DOD), National Cancer Institute (NCI), the National Institutes of Health 
(NIH) and the Office for Human Research Protection (OHRP), the Federal Food and Drug 
Administration (FDA), the National Cancer Data Base (NCDB), the Medical Monitor and 
referring institutions involved with the research study, including participating labs and pharmacy 
personnel, to be allowed to inspect sections of your medical and research records related to this 
study. It should be noted that representatives of the U.S. Army Medical Research and Material 
Command are eligible to review research records as part of their responsibility to protect human 
participants in research. 
A Data and Safety Monitoring Board and a site monitor will be reviewing the data from this 
research throughout the study. The investigator will tell you about new information from this or 
other studies that may affect your health, welfare, or willingness to stay in this study. 
The information from the research study may be published; however, you will not be identified 
in such publication. The publication will not contain information about you that would enable 
someone to determine your identity as a research participant without your authorization. 
UAB and/or the Investigator will take the following precautionary measures to protect your 
privacy and confidentiality of your research and/or medical records: 
Your individual identifiers (name, address, date of birth, etc.) will not be used in any 
publications or reports. All your study records will be kept in secure areas with limited access. 
A copy of this consent form will be included in your medical research record. 
Organizations that may inspect/or copy you medical and research records for quality assurance 
and data analysis include: 
• 
The local Institutional Review Board 
• 
Administration (FDA), involved in keeping research safe for people 
• 
Department of Defense (USAMRMC) 
• 
Office of the Congressionally Directed Medical Research Programs (CDMRP) 
Names of participants or material identifying participants (except as described above) will not be 
released without written permission, unless required by law. 
I. 
ADDITIONAL ELEMENTS 
Page 7of11 
Patient's Initials 
07Jan.2013 V.4.2 


By signing this form you are authorizing Dr. Bruce Korf, and his/her research staff to create, access, 
use, and disclose my PHI for the purposes described below. 
Protected Health Information that may be used and shared includes: 
~Information that identifies you such as name, address, telephone number, date of birth, Social 
Security number and other details about you. 
~ Information that relates to your health or medical condition from your medical records 
~ Information obtained from the study procedures outlined in this consent form, for 
example: things done to see if you can join the study such as physical exams, blood 
and urine tests, x-rays and other tests, and any other medical information we learn 
from you about your health history and family history 
~ Laboratory results obtained on specimens collected from you (blood, urine, tissue) 
~ Questionnaires or surveys you complete 
~ Interviews conducted with you by members of the research team 
The Researchers may use and share my Protected Health Information with: 
+The Principal Investigator, other Investigators, Study Coordinators, and all 
administrative staff in charge of doing work for the study; 
+Government agencies that have the right to see or review your PHI, including but not 
limited to the Office of Human Research Protections and the Food and Drug 
Administration; 
+ The University of Alabama at Birmingham, includes, but not limited to pharmacy, IRB and 
regulatory governing groups, and clinical staff. 
+Audit Committee of The University of Alabama at Birmingham. 
+Quality Improvement Program Coordinator and other staff in the Office for the 
Protection of Human Subjects of the University of Alabama at Birmingham. 
In addition to the above people and organizations, the Researchers may also use and share my 
Protected Health Information with: 
~ Doctors and staff at other places that are participating in the study. The name( s) of the other 
place(s) that are participating in this study are: National Institutes of Health (NIH), National 
Cancer Institute (NCI), The University of Alabama at Birmingham, University of Chicago, 
University of Utah, and Washington University. 
~ Laboratories and other people or organizations that look at your health information in 
connection with this study. 
~The Sponsor of the study and people that the Sponsor may contract with for the study. 
Page 8of11 
Patient's Initials 
07Jan.2013 V.4.2 


[8J The Contract Research Organization (an organization that helps the Sponsor run the 
study). 
[8J The Data Safety Monitoring Board (a group of people who examine the medical 
information during the study) 
[8J The Medical Monitor for the Study (a person who reviews medical information during 
the study) 
[8J The Patient Advocates (person( s) who watches out for your best interest) 
[8J Any other outside entity who will receive health information deemed necessary, i.e. 
the drug distribution facility, your primary physician, etc. 
Note: should your health information be disclosed to anyone outside of the study by you, your 
information may no longer be protected by HIP AA and this Authorization. However, the use of 
your health information will still be regulated by applicable federal and state laws. 
Storage of PHI in a Database: Your PHI (Personal Health Information) will be stored in a 
database for this research and future research. Please indicate your approval of any or all of the 
following by initialing next to the statement: 
My PHI may be stored in the above-named database for future analysis related to this study 
Yes 
No 
Initials 
My PHI may be stored in the above-named database. Researchers may contact me to request my 
authorization for future studies that are not related to this study 
Yes 
No 
Initials 
My PHI may be stored without any of my identifying information for use in other studies of 
other diseases 
Yes 
No 
Initials 
You do not have to sign this Consent/Authorization. If you decide not to sign the Authorization, 
you will not be allowed to participate in the research study. After signing the Consent I 
Authorization, you can change your mind and: 
+ Revoke this Authorization. After withdrawal you will not be allowed to participate in the study. 
+ If you revoke this Authorization, researchers may only use and disclose the PHI that was 
collected for this research study before you revoked the Authorization. 
+ If you revoke this Authorization your information/data may still be used and disclosed if you 
should have an adverse event (unexpected side effect). 
Page 9of11 
Patient's Initials 
07Jan.2013 V.4.2 


You will not be allowed to review the information collected for this research study until after the 
study is completed. If you are not allowed to review your information during participation in the 
study, when the study is over you will have the right to access the information. 
If you have not already received a Notice of Privacy Practices, you may request a copy and will be 
given one. If you have any questions or concerns about your privacy rights, you may contact Dr. 
Bruce Korfs office or the IRB. It is necessary for you to understand that by signing this form you 
are not giving up any legal rights. 
CONSENT/AUTHORIZATION: I am the participant or I am authorized to act on behalf of the 
participant. I have read this information and will receive a copy of this form after it is signed. By 
signing this form, you agree that you have talked to your doctor about the study and understand it, 
and you want to be in the study. You agree that we have talked to you about the risks and benefits 
of the study, and about other choices. You may decide to stop being in this study at any time and 
no one will mind and nothing will change about your medical care other than not being in the 
study. Copies ofthis form will be: 
(1) 
Kept in the study file by the Principal Investigator; 
(2) 
Put in your medical record; and 
(3) 
Given to you to keep. 
Printed Name of Participant: ____________________ _ 
Printed Name of Parent(s)/Guardian(s): ___________________ _ 
Signature of Parent(s)/Guardian(s): _________ __ 
Date: _ ____ _ 
[Signature of one parent required} 
[Note: Legal authorization in this order: (1) Parent for child/minor under 19 years of age; (2) Judicially 
Appointed guardian or individual named in a durable power of attorney; (3) Spouse; (4) Son or daughter over I 9 
years of age; (5) Either parent; (6) Brother or sister over 19 years of age; (7) Other nearest kin over I 9 years of 
age}. 
Witness (to signatures): ______ _ _ ___________ Date: _____ _ 
(may be investigator) 
I certify that I have explained to the above individual(s) the nature and purpose of the study, 
potential benefits, and possible risks associated with participation in this study. I have answered 
any questions that have been raised. 
Printed Name oflndividual Obtaining Consent: _________ _ _ _ ______ _ 
Title: ___ Signature: _____________ _____ Date: _____ _ 
Page 10of11 


University of Alabama at Birmingham 
AUTHORIZATION FOR USE/DISCLOSURE OF HEALTH INFORMATION 
FOR RESEARCH 
What is the purpose of this form? You are being asked to sign this form so that UAB may use and release 
your health information for research. Participation in research is voluntary. If you choose to participate in the 
research, you must sign this form so that your health information may be used for the research. 
Participant name: 
Research Protocol: A Randomized Placebo-Controlled 
Study of Lovastatin in Children with Neurofibromatosis 
Type 1 (STARS) 
UAB IRB Protocol Number: F090202002 
Principal Investigator: Dr. Bruce Korf 
Sponsor: The US Army - Depart. Of Defense 
What health information do the researchers want to use? All medical information and personal identifiers 
including past, present, and future history, examinations, laboratory results, imaging studies and reports and 
treatments of whatever kind related to or collected for use in the research protocol. 
Why do the researchers want my health information? The researchers want to use your health information 
as part of the research protocol listed above and described to you in the Informed Consent document. 
Who will disclose, use and/or receive my health information? The physicians, nurses and staff working on 
the research protocol (whether at UAB or elsewhere); other operating units ofUAB, HSF, UAB Highlands, The 
Children's Hospital of Alabama, Callahan Eye Foundation Hospital and the Jefferson County Department of 
Public Health, as necessary for their operations; the IRB and its staff; the sponsor of the research and its 
employees; and outside regulatory agencies, such as the Food and Drug Administration. 
How will my health information be protected once it is given to others? Your health information that is 
given to the study sponsor will remain private to the extent possible, even though the study sponsor is not 
required to follow the federal privacy laws. However, once your information is given to other organizations 
that are not required to follow federal privacy laws, we cannot assure that the information will remain protected. 
How long will this Authorization last? 
Your authorization for the uses and disclosures described in this 
Authorization does not have an expiration date. 
Can I cancel the Authorization? You may cancel this Authorization at any time by notifying the Director of 
the IRB, in writing, referencing the Research Protocol and IRB Protocol Number. If you cancel this 
Authorization, the study doctor and staff will not use any new health information for research. However, 
researchers may continue to use the health information that was provided before you cancelled your 
authorization. 
Can I see my health information? You have a right to request to see your health information. However, to 
ensure the scientific integrity of the research, you will not be able to review the research information until after 
the research protocol has been completed. 
Signature of participant: _ _ _ _ _ _ _ _ ___ _ _ _ _ 
Date: -
-
-
-
-
or 
participant's legally authorized representative: ____ _ _ _ _ ____ Date: _ _ _ _ _ 
Printed Name of participant's representative: _ _ _ _ _ _ _ _ _ _ _ ___ _ _ __ _ 
Relationship to the participant: _________ _ _ _______ _ _ ____ _ 
Page 11of11 

Prot_000.pdf: 
 
STARS April 13, 2011   
V 5.0 
 
 
 
1
 
 
 
 
 
Neurofibromatosis Type 1 (NF1) Clinical Trials Consortium 
 
Protocol for the  
The NF1 STAtin Randomized Study (NF1 STARS) 
 
  
 
A Randomized Placebo-Controlled Study of Lovastatin in Children 
with Neurofibromatosis Type 1 
 
 
  
 
Sponsored by: 
USMRMC, Office of the Congressionally Directed 
Medical Research Programs (CDMRP) 
Department of Defense (DOD) 
 
 
Contract Number W81XWH-05-1-0615 
 
 
Version 5.0 - April 2011 
Medical Monitor 
Tena Rosser, MD  
 
 
 
 
 
 
 
 
 


 
 
 
STARS April 13, 2011   
V 5.0 
2
Table of Contents 
1.0 
BACKGROUND AND SIGNIFICANCE ..................................................................................................... 4 
1.1 
NEUROFIBROMATOSIS AND COGNITIVE DEFICITS ................................................................................... 4 
1.2. 
BIOLOGICAL BASIS OF COGNITIVE DEFICITS IN NF1 .............................................................................. 5 
1.3 
RATIONALE FOR THE USE OF LOVASTATIN  IN CHILDREN WITH NF1 ..................................................... 6 
1.4 
THE TOLERABILITY AND SAFETY OF LOVASTATIN IN CHILDREN WITH NF1 ......................................... 7 
1.5 
LOVASTATIN FOR TREATMENT OF FAMILIAL HYPERCHOLESTEROLEMIA IN CHILDREN ...................... 8 
1.6 
POTENTIAL COGNITIVE EFFECTS OF LOVASTATIN IN INDIVIDUALS WITH HYPERCHOLESTEROLEMIA 9 
1.7 
USE OF LOVASTATIN FOR THE TREATMENT OF OTHER CONDITIONS ................................................... 10 
1.8 
COMPARISONS BETWEEN THE NF1 MURINE MODEL AND CHILDREN WITH NF1 ................................. 10 
1.9 
RATIONALE FOR OUTCOME MEASURES: NEUROPSYCHOLOGICAL ASSESSMENT................................. 11 
1.10 
SUMMARY AND OVERVIEW OF STUDY .................................................................................................... 13 
2.0 
RESEARCH PLAN ..................................................................................................................................... 13 
2.1 
SPECIFIC AIM ........................................................................................................................................... 13 
2.2 
SECONDARY AIMS .................................................................................................................................... 13 
2.3 
HYPOTHESES ............................................................................................................................................ 13 
3.0 
RESEARCH DESIGN AND METHODS.................................................................................................. 14 
3.1 
STUDY DESIGN ......................................................................................................................................... 14 
4.0 
STUDY POPULATION .............................................................................................................................. 14 
4.1 
HUMAN SUBJECT SELECTION .................................................................................................................. 14 
4.2 
INCLUSION CRITERIA .............................................................................................................................. 17 
4.3 
EXCLUSION CRITERIA ............................................................................................................................. 18 
5.0 
STUDY PROCEDURES ............................................................................................................................. 18 
5.1 
PRE-TREATMENT ..................................................................................................................................... 18 
5.2 
TREATMENT VISITS ................................................................................................................................. 24 
5.3 
POST-TREATMENT ................................................................................................................................... 25 
5.4 
FOLLOW-UP .............................................................................................................................................. 25 
6.0 
PHARMACEUTICAL INFORMATION ................................................................................................. 26 
6.1 
PHARMACOKINETICS ............................................................................................................................... 26 
6.2 
DRUG COMPANY/SUPPLY/DISTRIBUTION ............................................................................................... 27 
6.3 
PROCEDURES/RECOMMENDATIONS FOR DRUG SUPPLY AND DISTRIBUTION........................................ 27 
6.4 
DRUG DOSAGE AND POSSIBLE INTERACTIONS ....................................................................................... 27 
6.5 
TOXICITY AND ADVERSE EVENT MONITORING ..................................................................................... 28 
6.6 
MODIFICATIONS FOR TOXICITY .............................................................................................................. 30 
6.7 
ADVERSE EVENT MONITORING .............................................................................................................. 30 
6.8 
ADVERSE EVENT REPORTING ................................................................................................................. 31 
6.9 
CLASSIFICATION OF ADVERSE EVENTS BY SEVERITY AND RELATIONSHIP TO STUDY DRUG 
ADMINISTRATION ................................................................................................................................................... 32 
6.10 
 EXPEDITED ADVERSE EVENT REPORTING ............................................................................................. 32 
6.11 
RISKS AND PROTECTION FROM RISKS .................................................................................................... 32 
7.0 
STATISTICS ............................................................................................................................................... 34 
8.0 
DATA MANAGEMENT ............................................................................................................................ 35 
8.1 
MEDICAL MONITOR AND DATA SAFETY MONITORING PLAN ............................................................... 35 
8.2 
CONFIDENTIALITY ................................................................................................................................... 36 


 
 
 
STARS April 13, 2011   
V 5.0 
3
9.0 
ETHICAL AND REGULATORY CONSIDERATION .......................................................................... 36 
9.1 
CONSENT/ASSENT/HIPAA PROCESS AND DOCUMENTATION ................................................................ 36 
9.2 
BENEFITS .................................................................................................................................................. 37 
9.3 
POTENTIAL BIASES AND PROBLEMS ....................................................................................................... 37 
9.4 
COSTS TO SUBJECTS ................................................................................................................................ 38 
9.5 
CONFLICTS OF INTEREST ........................................................................................................................ 38 
9.6 
SUBJECT COMPENSATION........................................................................................................................ 38 
9.7 
OUTSIDE CONSULTANTS/COLLABORATORS ........................................................................................... 38 
9.8 
CONTRACTUAL AGREEMENTS................................................................................................................. 38 
10.0 
REFERENCES ............................................................................................................................................ 39 
APPENDIX 1:  NATIONAL INSTITUTE OF HEALTH CRITERIA FOR NEUROFIBROMATOSIS 1 
(1988) .......................................................................................................................................................................... 45 
APPENDIX 2: LIST OF COMMON PSYCHOTROPIC MEDICATIONS ........................................................ 46 
APPENDIX 3:  STUDY EVALUATION BEFORE, DURING, POST TREATMENT AND FOLLOW-UP ... 48 
APPENDIX 4: CONSENT/ASSENT ....................................................................................................................... 49 
APPENDIX 5:  OUTCOME MEASURES: NEUROPSYCHOLOGICAL ASSESSMENT ............................... 50 
APPENDIX 6:  DRUGS & OTHER COMPONENTS THAT INTERACT WITH LOVASTATIN.................. 51 
APPENDIX 7:  COMMON TERMINOLOGY, CRITERIA FOR ADVERSE EVENTS (CTCAE) ................. 52 
APPENDIX 8:  LIST OF ARREVIATIONS ........................................................................................................... 54 
APPENDIX 9:  PROTOCOL ROSTER .................................................................................................................. 57 
APPENDIX 10: ADDENDUM FOR MANCHESTER, UK …………………………………………………….. 60 
  


 
 
 
STARS April 13, 2011   
V 5.0 
4
1.0 
Background and Significance     
 
1.1 
Neurofibromatosis and Cognitive Deficits 
 
NF1 is a common autosomal dominant disorder with an incidence of 1 in 3,000 and is 
characterized by diverse cutaneous, neurological, skeletal and neoplastic manifestations (North, 
1998). The most common neurological complication of NF1 in childhood is cognitive 
dysfunction (North, Hyman & Barton, 2002). Knowledge regarding the cognitive profile of 
children with NF1 has dramatically increased over the past 15 years.  Many studies have shown 
a slight yet robust reduction of general intellectual function, with a downward shift in the 
distribution of IQ scores when compared to unaffected siblings, controls and normative data 
(Levine, Materek, Abel, O‟Donnell & Cutting, 2006; Ozonoff, 1999).  While general 
intellectual functioning is only mildly affected, one of the most telling areas indicative of 
cognitive deficits in NF1 is academic achievement, with up to 70 percent of school-aged 
children with NF1 underachieving (Brewer, Moore & Hiscock, 1997) and learning disabilities 
estimated to be present in 30 to 65 percent of children (North et al., 1997). Areas of difficulty 
appear to encompass a range of academic skills including reading, spelling and mathematics, 
with no one area predominately more affected.   
 
As well as academic difficulties, studies consistently show children with NF1 have impaired 
performance on tasks of visual spatial function such as the Judgment of Line Orientation, a task 
associated with activation of the parietal and occipital lobes (Hyman, Shores & North, 2005; 
Kesler, Haberecht, Menon, Warsofsky & Dyer-Friedman et al., 2004; Levine et al., 2006).  In 
addition, there is also a high incidence of executive dysfunction, including reduced cognitive 
flexibility, attention, working memory capacity, inhibition and planning; all functions thought to 
be mediated by the prefrontal cortex (Anderson, Anderson, Northam, Jacobs & Mikiewicz, 
2002; Hyman et al., 2005).  There is also a high incidence of attention deficit hyperactivity 
disorder (ADHD; Mautner, Kluwe, Thakker & Leark, 2002) and results from a recent study 
found that 63% of children with NF1 have poor sustained attention (Hyman et al., 2005). Other 
reported areas of impairment include verbal memory, language and psychomotor deficits 
(Ferner, Hughes & Weinman, 1996; Mazzocco, Turner, Denckla, Hofman, Scanlon et al., 
1995).  
 
Given that general intellectual functioning is not the key explanation for the pattern of observed 
academic failure, it is likely that these specific neurocognitive deficits contribute to or are 
responsible for the characteristic profile of children with NF1.  As such, these NF1 associated 
deficits may negatively impact on daily living skills, academic performance, employment 
opportunities and quality of life (Graf, Landolt, Mori & Boltshauser, 2006; Page, Page, Ecosse, 
Korf, Leplege et al., 2006).  Despite the significant negative impact of this disorder on cognitive 
and behavioral functioning, only one study has reported on treatment outcomes (Mautner et al., 
2002). The results of this study demonstrated that stimulant medication was effective in treating 
the behavioral symptoms of ADHD in children with NF1. To date, no studies have examined 
the  


 
 
 
STARS April 13, 2011   
V 5.0 
5
effects of interventions on the cognitive functioning of children with NF1. Clearly, there is a 
need to investigate interventions that can improve cognitive impairments associated with NF1. 
 
1.2. 
Biological Basis of Cognitive Deficits in NF1  
 
Understanding the underlying genetic defect of NF1 has become critical in explaining the 
spectrum of clinical manifestations of this disorder, from benign and malignant tumor growth to 
cognitive dysfunction.  The NF1 gene encodes a 250kDa protein called neurofibromin which is 
expressed in many tissues, including neurons, Schwann cells, and oligodendrocytes as well as in 
many non-neural cell types (Daston & Ratner, 1992; Daston, Scrable, Nordlund, Sturbaum, 
Nissen et al., 1992).  Although the function of neurofibromin is not clearly understood, 
neurobiological evidence shows it plays a role in several biochemical processes, including 
adenylyl cyclase modulation (Guo, The, Hannan, Bernards & Zhong, 1997), microtubule 
binding (Xu & Gutmann, 1997) and mammalian target rapamycin signaling (Dasgupta, Yi, 
Chen, Weber & Gutmann, 2005; Johannessen, Reczek, James, Brems, Legius et al., 1995).   
It is the effect of neurofibromin on ras, a protein implicated in cell proliferation and 
differentiation that has been most extensively investigated (e.g., Martin, Viskochil, Bollag, 
McCabe, Crosier et al., 1990; Weiss, Bollag & Shannon, 1999; Xu, Lin, Tanaka, Dunn, Wood 
et al., 1990).  These studies suggest that neurofibromin contains a GTPase-activating protein 
domain that functions to accelerate the conversion of active GTP-bound ras to its inactive GDP-
bound form.  Loss of neurofibromin within a cell would thus result in constitutive activation of 
the ras signaling pathway, ultimately resulting in increased ras activity and unregulated cell 
proliferation and differentiation (Bollag, Clapp, Shih, Adler, Zhang et al., 1996; DeClue, 
Papageorge, Fletcher, Diehl, Ratner et al., 1992; Hiatt, 2001; Martin et al., 1990). 
An important experimental model used to study the effects of diminished amounts of 
neurofibromin on cognitive functioning is the Nf1 mouse model. Importantly, human and mouse 
forms of neurofibromin are highly homologous (98% sequence similarity) as are the promoter 
sequences of the gene, suggesting that both the biochemistry of the protein and the 
transcriptional regulation of the gene are conserved across species (Bernards, Snijders, 
Hannigan, Murthy & Gusella, 1993; Hajra, Martin-Gallardo, Tarle, Freedman, Wilson-Gunn et 
al., 1994).  Silva and colleagues have demonstrated that mice heterozygous for a targeted 
mutation in the Nf1 gene (Nf1 +/- mice) exhibit cognitive deficits associated with enhanced 
GABA inhibition and reduced long-term potentiation (LTP; Costa, Federov, Kogan, Murphy, 
Stern et al., 2002; Costa & Silva, 2002; Silva, Frankland, Marowitz, Friedman, Laszlo et al., 
1997). The Nf1 +/- mouse model of cognitive dysfunction appears to mimic aspects of certain 
cognitive deficits in children with NF1 and is not related to tumor formation (Costa, Yang, 
Huynh, Pulst, Viskochil et al., 2001).  These deficits primarily involve enhanced GABA-
mediated inhibition affecting hippocampal-dependent and prefrontal-mediated tasks, including 
spatial memory and new learning, visual spatial attention, working memory and contextual 
discrimination (Costa et al., 2002; Li, Cui, Kushner, Brown, Jentsch et al., 2005).   


 
 
 
STARS April 13, 2011   
V 5.0 
6
1.3 
Rationale for the Use of Lovastatin in Children with NF1  
 
Lovastatin, a fungal antibiotic, is a specific inhibitor of the rate-limiting enzyme in cholesterol 
biosynthesis (a non-selective HMG-CoA reductase inhibitor), and is widely used in the treatment 
of hyperlipidemia in humans (Xu, McGuire, Blaskovich, Sebti & Romero, 1996). It is one of the 
first-generation statins and therefore has a large body of safety and pharmacokinetic data from 
clinical trials and general use for hyperlipidemia (Corsini, Maggi & Catapano, 1995b). Previous 
studies have shown that Lovastatin can inhibit small GTPase (including ras) isoprenylation and 
activity (Sebti, et al., 1991; Mendola and& Backer, 1990; Sebti, Tkalcevic & Jani, 1991).  
 
Although it is difficult to draw direct correlations between the murine Nf1 model and the 
neurocognitive changes in children, excessive ras activity and learning impairment observed in 
Nf1+/- mice suggests a possible substrate in part for the cognitive deficits demonstrated in 
children with NF1.  As such, therapeutic interventions designed to decrease ras function have 
been proposed as treatments for NF1 (Weiss et al., 1999).   
 
A recent study by Li and colleagues (2005) used Lovastatin to evaluate its benefit on cognitive 
deficits in Nf1+/- mice.  Nf1+/- and wild-type mice were treated with either Lovastatin or 
placebo before completing a task of attention, visual spatial learning or pre-pulse inhibition. 
Mice completing the pre-pulse inhibition or visual spatial learning tasks were injected with 10 
mg/kg of Lovastatin subcutaneously for three days before training and Nf1+/- mice completing 
the attention task were administered 0.15 mg of Lovastatin orally, once per day.  Nf1+/- mice 
treated with Lovastatin demonstrated improved performance relative to mice on placebo on all 
cognitive and behavioral measures as follows: 
 
 
Attention – using a lateralized reaction time task, mice treated with Lovastatin were 
significantly more accurate at detecting the location of an unpredictable target stimulus 
than mice in the placebo group.  This measure of divided visuospatial attention is 
dependent on the pre-frontal cortex; 
 
Spatial learning – using the hidden version of the Morris Water Maze (Morris, 1984), 
mice treated with Lovastatin spent significantly more time searching in the target 
quadrant of the maze compared with Nf1+/- mice given the placebo.  This task is 
sensitive to lesions in the hippocampus as well as other structures within the limbic 
system (Mogensen, Moustgaard, Khan, Wortwein & Nielsen, 2005; Steffenach, Witter, 
Moser & Moser, 2005), suggesting the observed improvement in the Lovastatin group 
maybe due to increased LTP (a hippocampus-related learning process; Lynch, 2004), 
which has been shown to be defective in Nf1 +/- mice (Costa et al., 2002; Silva et al., 
1997); 
 
Pre-pulse inhibition (PPI) – Nf1+/- mutant mice treated with Lovastatin had an increased 
PPI when compared to the placebo group.  PPI is a measure of sensory gating of 
environmental stimuli, so that a startle reflex is inhibited if it is preceded by a weak 
prestimulus.  PPI has been shown to be significantly reduced in children with ADHD 
(Castellanos, Fine, Kaysen, Marsh, Rapoport et al., 1996), which has a high co-morbidity 


 
 
 
STARS April 13, 2011   
V 5.0 
7
with NF1 (38-46% of NF1 children satisfy DSM-IV diagnostic criteria for ADHD; 
Hyman et al., 2005; Hyman, Shores & North, 2006). 
 
Interestingly, the dose of Lovastatin effective in Nf1+/- mice did not affect cognitive function in 
control mice, suggesting Lovastatin (which inhibits ras activation) has a beneficial effect on 
cognitive function in the setting of abnormal ras activation (as in NF1), but not when normal 
inhibition of ras activation is intact. 
 
In addition to these cognitive experiments, Li and colleagues (2005) examined the effects of 
Lovastatin at a biochemical level. Treatment with Lovastatin was found to decrease ras activity 
in Nf1+/- mice as well as reverse LTP deficits.   
 
Collectively, these results provide strong evidence that Lovastatin can reverse the cognitive and 
physiological deficits observed in Nf1+/- mice to levels comparable to wild-type control mice (Li 
et al., 2005).  Critically, this indicates that the cognitive deficits observed in Nf1+/- mice are not 
caused by irreversible developmental abnormalities since they have been reversed with acute 
Lovastatin treatment in mutant mice.  These experiments outline important parallels between the 
cognitive deficits in mice and humans with NF1 and have relevant implications for the 
development of treatment strategies for these deficits through modification of ras activity or 
GABA mediation (Costa, et al., 2002, 2001).   
 
In summary, the highly homologous nature of neurofibromin in mice and humans make murine 
models of NF1 an appealing medium to study the pathologies associated with NF1, such as 
altered molecular pathways and cognitive function.  Studies employing mouse models of NF1 
have been crucial in identifying an increase in ras activity and GABA-mediated inhibition as key 
mechanisms behind the observed cognitive deficits (Weeber & Sweatt, 2002).  Crucially, studies 
have also shown that pharmacological intervention (Lovastatin) not only decreased ras activity 
and GABA-mediated inhibition, but also reversed cognitive deficits.  This suggests that similar 
effects of Lovastatin may also be observed in children with NF1-associated cognitive deficits. 
The aim of this study is to examine the efficacy of Lovastatin on the cognitive deficits of 
children with NF1. The use of oral Lovastatin in this study will be the first biologically-based, 
molecularly targeted treatment for children with NF1 and cognitive deficits.  
 
1.4 
The Tolerability and Safety of Lovastatin in Children with NF1 
  
The safety and tolerability of Lovastatin in children with NF1 has recently been examined in a 
Phase I open label study. Lovastatin was orally administered to children with NF1 aged 10-17 
years with normal cholesterol levels. Doses of 20, 30 or 40 mg/day were administered using a 
conventional Phase I design, with dose escalation to determine maximum tolerated dose. This 
study enrolled a total of 23 children with a diagnosis of NF1 aged between 10-17 years. The 
20mg and 30mg cohorts included 3 patients each and the 40mg cohort contained 17 patients.  All 
patients were clinically stable and those with symptomatic intracranial lesions were excluded.  
All three groups were found to tolerate the dose well for the duration of the study (3 months) and 
no significant side effects specifically related to Lovastatin were reported. Medication was very 


 
 
 
STARS April 13, 2011   
V 5.0 
8
well tolerated in all patients with minimal side effects. Side effects described include: headache, 
nausea and dizziness. Quantitatively, Lovastatin did not have a significant effect on liver or 
pancreatic enzymes, creatine phosphokinase (CPK), myoglobinuria, complete blood count 
(CBC), renal function, or lipid profiles, with all laboratory results within normal parameters for 
all patients. Lovastatin did have a significant effect on total cholesterol levels, with a 18% 
decrease in mean levels (range 
28% to 
8%) from the pre-treatment to post-treatment. 
However, different subtypes of cholesterol (LDL, HDL, VLDL) stayed within the normal limits. 
The most significant changes were observed in LDL levels, with changes between increments of 
11% to decrease in 45% compared with the initial value. The decrease in cholesterol levels were 
independent of dosage levels and all groups remained within the normal limits (Acosta et al, 
submitted 2010) 
 
1.5 
Lovastatin for Treatment of Familial Hypercholesterolemia in Children 
 
Evidence from clinical studies indicates the safety of Lovastatin (up to 40mg/day) for the 
treatment of familial hypercholesterolemia (heFH) in children. The safety and effectiveness of 
Lovastatin in 132 adolescent boys (10 to 17 years of age) with heFH has been evaluated in a 
doubled-blind, placebo-controlled study of 48 weeks duration (Stein, Illingworth, Kwiterovich 
Jr., Liacouras, Siimes et al., 1999). Adolescent boys were randomized to Lovastatin (n=67) or 
placebo (n=65).  The dose of Lovastatin was started at 10 mg/day and increased at eight week 
intervals (8 weeks and 16 weeks) to 20 and 40 mg/day. Treatment with Lovastatin was 
considered safe, and the side-effect profile of the two groups (Lovastatin and placebo) was not 
significantly different.  Additionally, Lovastatin did not have a significant effect on growth 
hormonal, and nutritional status at 24 and 48 weeks.  No significant differences in increase 
serum levels of CPK and/or aspartate amino transferase (AST) were observed between the 
groups. Compared to placebo, the low density lipoprotein (LDL) cholesterol levels of boys 
receiving Lovastatin decreased significantly by 17%, 24%, and 27% receiving dosages of 10, 20, 
and 40 mg/d respectively (Kwiterovich, Jr., 2001; Stein et al., 1999). 
 
The safety, tolerability and efficacy of Lovastatin was also evaluated in 54 adolescent girls (10 to 
17 years) who were enrolled in a double-blind, randomized, placebo-controlled study over 24 
weeks (Clauss, Holmes, Hopkins, Stein, Cho et al., 2005). Similar to the findings in boys, 
Lovastatin was efficacious at reducing LDL cholesterol by 23% to 27%, total cholesterol by 17% 
to 22% and apolipoprotein B (Apo B) by 20% to 23% at weeks 4 and 24 respectively.  
Importantly, Lovastatin was also found to be safe and well tolerated with no clinically significant 
alterations in vital signs, anthropomorphic measurements, hormone levels, menstrual cycle 
length or tests of liver and muscle function.   
 
In another randomized double-blind trial, the efficacy, safety, and tolerability of Lovastatin was 
evaluated in 69 adolescent boys (9 to 17 years) with heFH (Lambert, Lupien, Gagne, Levy, 
Blaichman et al., 1996). Following a four-week placebo run-in period, the participants were 
randomized to receive active treatment with Lovastatin (10, 20, 30, or 40 mg/day) for eight 
weeks.  Three children who received 30 or 40 mg/day of Lovastatin experienced transient AST 
elevations.  A total of 10 children reported 13 adverse clinical events while receiving Lovastatin 


 
 
 
STARS April 13, 2011   
V 5.0 
9
including headache, fatigue, heartburn, jaundice, muscle cramps, chest pain, lymph node 
enlargement, and cold-and flu-like symptoms. Adverse events did not appear to be dose related 
(Lambert et al., 1996). There were no serious adverse experiences reported.  None of the 
reported clinical adverse events or laboratory abnormalities required early withdrawal from the 
study. 
 
In general, Lovastatin is considered a safe medication, and has been approved for the treatment 
of familial heFH in children 10 to 17 years old (Clauss et al., 2005; Stein et al., 1999).  These 
studies, combined with results from the aforementioned Phase I study (Acosta et al., submitted), 
indicate that Lovastatin in doses of 40mg/day should be safe and well-tolerated in children with 
NF1.  
1.6 
Potential Cognitive Effects of Lovastatin in Individuals with Hypercholesterolemia 
 
Very few studies have examined the potential cognitive effects of Lovastatin in humans. In one 
study, cognitive effects were assessed in adults with heFH who were randomized to receive 20 
mg Lovastatin (n=98) or placebo (n=96) over a 6-month period (Muldoon, Barger, Ryan, Flory, 
Lehoczky et al., 2000). Results from this blinded randomized control trial indicated that at 6 
months follow-up, control participants had improved on all five domains of cognitive 
functioning (attention, psychomotor speed, mental flexibility, working memory and memory 
recall), most likely due to practice and/or learning effects. Participants on Lovastatin improved 
only on measures of memory recall. Further sub-analysis indicated that only participants treated 
with Lovastatin with a lower mean LDL cholesterol level at follow-up (mean 109  11mg/dL 
(2.79  0.28mmol/l)) had a small decrease in cognitive function from baseline. However, total 
serum cholesterol in the lower range (<200mg/dL (5.13mmol/l)) has been associated with poorer 
performance on cognitive measures which place demands on abstract reasoning, 
attention/concentration, word fluency and executive functioning (Elias, Elias, D‟Agostino, 
Sullivan, Wolf et al., 2005). Therefore, it plausible that lower cholesterol levels contributed to 
poorer cognitive performance observed by Muldoon et al. (2000).  
 
Other studies that have examined cognitive performance of adults with heFH when treated with 
Lovastatin generally report no significant effect on measures of cognitive performance (Kostis, 
Rosen & Wilson, 1994; Gibellato, Moore, Selby & Bower, 2001). However, one study found that 
after four weeks of treatment with Lovastatin, patients with heFH performed significantly better 
on one cognitive task (digit symbol substitution) when compared to baseline (Gengo, 
Cwudzinski, Kinkel, Block, Stauffer et al., 1995). There were no significant changes for other 
cognitive tasks.  
 
In summary, no studies have examined the potential cognitive effects of Lovastatin in individuals 
without heFH. The results from studies of individuals with heFH suggest no significant cognitive 
effects of Lovastatin. This is consistent with observations in control mice, in that the dose of 
Lovastatin effective in reversing cognitive deficits in Nf1+/- mice did not affect cognitive 
function in control mice (Li et al., 2005). However, it is important to consider that our current 
study is targeting a population that has a metabolic alteration that is susceptible to modification 


 
 
 
STARS April 13, 2011   
V 5.0 
10 
from Lovastatin. Thus, the anticipated cognitive benefits of Lovastatin in children with NF1 are 
not necessarily expected in individuals with a normal metabolic pathway. 
 
1.7 
Use of Lovastatin for the Treatment of Other Conditions 
 
Lovastatin has been used in several other clinical trials, including Phase I studies of adult 
participants with recurrent or metastatic squamous cell carcinoma of the head, neck, or cervix  
and in other solid tumors with maximum doses of between of 7.5 mg/kg  and 45mg/kg/day 
(Knox, Siu, Chen, Dimitroulakos, Kamel-Reid et al., 2005; Thibault, Samid, Tompkins, Figg, 
Cooper et al., 1996). Thibault and colleagues (1996) conducted a Phase I trial to characterize the 
tolerability of Lovastatin administered at progressively higher doses to cancer patients.  They 
were treated with a 7-day course of Lovastatin given monthly (over a 20 month period), with 
doses ranging from 2 to 45 mg/kg/day.  They found cyclical treatment with Lovastatin reduced 
cholesterol concentrations by up to 43% when compared with pre-treatment levels. Very high 
doses of Lovastatin (25 mg/kg/day) were very well tolerated for seven days. Myopathy was the 
dose limiting toxicity and found to be prevented by ubiquinone supplementation (Thibault et al., 
1996). In another Phase I study for treatment of cancer in adults, Lovastatin has been used in 
doses up to 7.5 mg/kg/day for up to 28 days with a good tolerability and limited side effects 
(Knox et al., 2005).  In this study, the major side effects were related to myopathy and renal 
insufficiency (Knox et al., 2005). Doses even higher up to 45 mg/kg/day have been used for a 
seven day cycle per month up to 20 months with similar findings (Thibault et al., 1996). Current 
studies are not conclusive about the benefits of Lovastatin in cancer however in most of the 
cases, the dosage exceeded the maximum recommended dose for the standard treatment of heFH 
(current dose recommended in adults is up to 80 mg/day). Doses used in the aforementioned 
studies have been calculated in most cases by kg/weight (up to 45 mg/kg/day).  
 
Lovastatin also has been used in patients with adrenoleukodystrophies to decrease very long 
chain fatty acids, where dosage was increased from 20mg to 40mg in two weeks (Pai, Khan, 
Barbosa, Key, Craver et al., 2000). No significant changes in cholesterol levels and no 
correlation between the dose and decrease of cholesterol levels were shown (Pai et al., 2000). 
Side effects were reported in 2-3%, including weakness, abdominal pain, constipation, diarrhea, 
dyspepsia, flatulence, nausea, myalgia, muscle cramps, dizziness, headache, skin rash, and 
blurred vision (Pai et al., 2000). One patient had adverse events severe enough to discontinue 
Lovastatin. Lovastatin-induced myopathy or marked elevation of CPK is expected to occur in 
<1:500 participants undergoing such therapy for heFH (Pierce, Wysowski & GrossPierce, 1990; 
Marais & Larson, 1990). 
 
1.8 Comparisons between the Nf1 Murine Model and Children with NF1  
 
While results from Nf1+/- mice provide evidence that Lovastatin may be effective in treating 
cognitive deficits in children with NF1, it is difficult to make direct comparisons between the 
Nf1 murine model and the neurocognitive functioning of children with NF1. The precise 
mechanism underlying the Lovastatin reversal of the cognitive phenotype in Nf1+/- mice is not 
completely understood. In addition, results from animal studies are limited in their direct 


 
 
 
STARS April 13, 2011   
V 5.0 
11 
application to humans due to biological and cognitive differences. A recent systematic review of 
the treatment effects between animal experiments and human clinical trials for six different 
interventions found disconcordance for three interventions (Perel, Roberts, Sena, Wheble, 
Briscoe et al., 2006). The lack of concordance may be due to bias, random error or the failure of 
animal models to mimic human disease adequately (Perel et al., 2006).  
Cognitively, the capabilities of mice are limited to basic levels of functioning and it is not 
possible to assess the full effects of Lovastatin using this model.  Thus, the potential effects of 
Lovastatin in children with NF1 may not be fully realized by the evidence provided by animal 
studies. It is possible that the neurocognitive functions targeted by Lovastatin could be 
underestimated in children with NF1.  For example, it is possible that the action of Lovastatin on 
LTP (i.e., it has shown to increase LTP in Nf1 +/- mice relative to placebo controls) could form 
and strengthen neural connections not only in the hippocampus (associated with learning and 
memory), but also induce similar effects of neural connectivity and plasticity throughout the 
brain of children with NF1, resulting in significant improvements across a variety of cognitive 
domains. 
 
1.9 
Rationale for Outcome Measures: Neuropsychological Assessment 
  
Neuropsychological assessment plays a critical role in identifying and monitoring central 
nervous system (CNS) dysfunction in children with developmental, acquired, and medical 
disorders, including NF1.  Objective standardized tests assessing general cognitive ability and 
specific neuropsychological domains are reliable and valid measures that are sensitive to changes 
in CNS function, including cognitive improvements from pharmacological treatments (e.g. 
Bedard, Martinussed, Ickowicz & Tannock, 2004; Tucha, Mecklinger, Laufkotter, Klein, Walitza 
et al., 2006). As a result, neuropsychological test scores have been extensively used as cognitive 
outcome measures in clinical trials, including those with children (e.g., Bedard et al., 2004; 
Kempton, Vance, Maruff, Luk, Costin et al., 1999; Mehta, Goodyer & Sahakian, 2004; Mohr & 
Brouwers, 1991).  When selecting neuropsychological tests to be used in clinical trials, various 
guidelines should be followed (Ruff & Crouch, 1991).  First, tests should be selected that will 
assess the specific cognitive domains that are affected and may be changed by treatment.  
Second, as the tests need to be administered repeatedly, it is optimal that alternate forms be used 
where possible to minimize test-retest effects.  Finally, the tests should be standardized measures 
with documented reliability and validity. 
 
The selected measures in this study are drawn from both traditional pencil-and-paper 
neuropsychological tests as well as two computerized tasks which are sensitive to detecting 
treatment effects – the Cambridge Neuropsychological Testing Automated Battery (CANTAB, 
reviewed by Luciana, 2003) and the Conners‟ Continuous Performance Test-II (CPT-II; 
Conners, 2000).  The CANTAB is a neuropsychological assessment battery that consists of 22 
stand-alone subtests (we will administer 4 subtests only), developed to assess aspects of visual 
spatial learning, executive function, attention, semantic/verbal memory, decision making and 
response control.  The CANTAB was selected as an outcome measure for a number of reasons. 
First, it has a number of subtests, including a visual spatial learning task that may potentially be 


 
 
 
STARS April 13, 2011   
V 5.0 
12 
affected by Lovastatin. Second, the CANTAB has evolved from animal behavior paradigms to 
facilitate cross-species studies of cognition.  As such, it has strong theoretical underpinnings.  
Third, it has been designed with a neural systems approach in mind, being extensively validated 
in patients with damage in specific areas of the brain.  Fourth, it has extensive functional 
neuroimaging data available, outlining the neural substrates involved in many of the subtests, 
providing a useful confirmation of the neuroanatomical basis of the tests. Fifth, the tests are 
entirely computerized, enabling automatic recording of response accuracy and latencies via a 
touch-screen apparatus.  This increases the consistency of data collection between sites.  In 
addition, there are five equivalent forms available, minimizing retest practice effects.  Subtests 
from the CANTAB start at a simple level and gradually increase in difficulty. Finally, research 
suggests that computerized batteries, in particular the CANTAB, are sensitive to subtle 
neurocognitive changes and may be better able to detect subtle cognitive dysfunction and 
changes over time than traditional paper-and-pencil neuropsychological measures (Bedard et al., 
2004; Froestl, Gallagher, Jenkins, Madrid, Melcher et al., 2004; Makdissi, Collie, Maruff, Darby, 
Bush et al., 2001; Nestor, Scheltens & Hodges, 2004).  
 
In this study, the primary outcome measures have been selected based on the effects of 
Lovastatin in murine models of NF1 and the cognitive functions that are frequently impaired in 
children with NF1.  Therefore, the primary outcome measures assess visual spatial learning and 
sustained attention. Visual spatial learning will be assessed using the Paired Associate Learning 
(PAL) subtest from the CANTAB (see Section 5.1.4.1). Preliminary findings indicate that 46% 
(13/28) of children with NF1 performance on the PAL is impaired (>1SD below normative 
mean; Payne, Barton & North, unpublished data). Sustained attention will be assessed using the 
Score! subtest from the Test of Everyday Attention for Children (TEA-Ch). Previous findings 
indicate that 63% (50/80) of children with NF1 have impaired performance (>1SD below 
normative mean) on the Score! subtest (Hyman et al., 2005). 
 
Since evidence from the murine model of NF1 suggests that Lovastatin may improve functions 
that rely on prefrontal cortex, such as response inhibition and the effect of Lovastatin on 
cognitive impairments is not known, a broader battery of neuropsychological tests have been 
included as secondary outcome measures.  These include multidimensional measures of attention 
(selective, divided and switching attention from the TEA-Ch; see Hyman et al., 2003, 2005, 
2006), executive functioning (e.g. response inhibition, planning and organization) and 
visuospatial ability, as well as quality of life. 
  
The other computer-based measure, the CPT-II, has a significant history of use in identifying 
attentional deficits and the effects of stimulant medication (e.g., Boonstra, Kooij, Oosterlaan, 
Sergeant, & Buitelaar, 2005; Conners, Epstein, Angold, & Klaric, 2003). CPTs have been used 
in previous studies of children with NF1 (Ferner et al., 1996; Mautner et al., 2002; Mazzocco et 
al., 1995). Results from a recent study using the Kiddie‟s CPT, indicated that children with NF1 
made significantly more omission (inattentive) errors than the control group (Irle, Shores, Watt 
& North, unpublished data). 
 


 
 
 
STARS April 13, 2011   
V 5.0 
13 
1.10 
Summary and Overview of Study 
 
The most common neurological complication of NF1 in childhood is cognitive deficits for which 
there are no effective specific pharmacological treatments. Studies indicate that Lovastatin can 
reverse the biochemical, electrophysiological and cognitive deficits observed in Nf1+/- mice to 
levels comparable to wild-type control mice. Nf1+/- mice treated with Lovastatin demonstrated 
improved performance on tasks of spatial learning and memory (as measured by the Morris 
Water maze), attention, and pre-pulse inhibition. These tasks are hypothesized to reflect the 
cognitive deficits observed in children with NF1. The Morris Water Maze involves mechanisms 
of learning and memory, which relies on hippocampal functioning. While visual-spatial deficits 
have been reported in children with NF1 (e.g., Schrimsher, Billingsley, Slopis & Moore, 2003), 
no studies have reported on the visual spatial learning abilities in this cohort. 
 
Lovastatin, which targets the inhibition of ras, is a logical choice as a potential therapeutic 
intervention for children with NF1 and cognitive deficits. Clinical trials indicate that Lovastatin 
is effective and safe to treat heFH in adults and children. Results from a recently completed 
Phase I trial indicate that Lovastatin is safe to be used in children (10-17 years) with NF1 
(Acosta et al., submitted).  
 
Currently, no studies have examined the effect of Lovastatin on cognitive functioning in 
individuals with NF1. This study will determine the efficacy of Lovastatin as a treatment for the 
cognitive deficits observed in children with NF1. We will conduct a multi-center randomized, 
double-blind, Phase II trial with two treatment arms (Lovastatin/placebo) for 16 weeks. Based on 
predictions from the NF1 murine mouse model, it is expected that children with NF1, who are 
impaired on a visual spatial learning task and/or an attention task, will benefit from Lovastatin.  
 
2.0 
Research Plan  
 
2.1 
Specific Aim 
 
The specific aim of this study is to determine whether Lovastatin significantly improves visual 
spatial learning and/or sustained attention in children with NF1. 
 
2.2 
Secondary Aims 
 
2.2.1. To evaluate the effect of Lovastatin on measures of executive function, behavior and 
quality of life in children with NF1 and cognitive deficits; 
2.2.2. To further evaluate the toxicity and tolerability of Lovastatin in children with NF1 and 
cognitive deficits. 
 
2.3 
Hypotheses 
 


 
 
 
STARS April 13, 2011   
V 5.0 
14 
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. 
 
3.0 
Research Design and Methods  
 
3.1 
Study Design 
 
This is a prospective multi-center; 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 8 to 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. 
 
4.0 
Study Population 
 
4.1 
Human Subject Selection 
 
This is a Phase II study involving children with NF1 (aged 8 years to less than 16 years at time of 
screening) 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 8 years to less than 16 years will be enrolled in the 
study. The age limits were selected on the basis that Lovastatin has been shown to be safe and 
well tolerated in children aged between 10 and 17 years old. Lovastatin has been extensively 
used in children 10-17 years of age with hypercholesterolemia, with minimal side effects. Also, 
results from Phase 1 study indicate that Lovastatin is safe and well tolerated in children with NF1 
aged 10-17 years (see section 1.4). Despite the lack of preliminary data in terms of safety using 
Lovastatin in children aged 8 and 9 years of age, we do not anticipate higher risk of side effects 
in this age group compared with children 10 years and older. During the phase 1 study (Acosta et 
al., submitted), 4 patients aged 10 years participated in the study. In all cases, no side effects or 


 
 
 
STARS April 13, 2011   
V 5.0 
15 
significant changes in metabolic parameters were observed in this group compared with the older 
patients. In addition, metabolic pathways related to the metabolism of drugs, including 
Cytochrome P450 complex, are approximately developed up to 70% after the perinatal period 
(Lange, Pharmacology). It is considered fully developed by 5 years of age (Anderson et al 2009). 
Adjustments in the doses are related with changes in weight mainly. We do not expect changes 
in toxicity in this younger age group and those patients will be monitored closely as per study 
protocol during the study for immediate identification of any risk(s) or side effect(s). 
 
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. 
 
 Participants will be recruited from the following sites*: 
 
 
Neurogenetics Clinic, The Children‟s Hospital at Westmead, Sydney, Australia.  The 
Neurogenetics Clinic in Sydney caters for families with NF1 and services a population base of 
approximately 4 million.  There is a wide referral base and the clinic caters for over 1300 
individuals with NF1, 70% of whom are under 20 years of age, with all socioeconomic groups 
represented.  
 
 
Children‟s Hospital Boston/Dana-Farber Cancer Center.  The multidisciplinary NF1 
Program at CHB/DFCI works towards the overall goal of conception, development and 
conduction of collaborative pilot, Phase I and II clinical evaluations of promising therapeutic 
agents and approaches for the prevention, diagnosis, management and treatment of NF1, 
committed to: 1) ensuring that more than 12 patients with NF1 are available yearly for 
Consortium studies, 2) acting as a resource in areas where our expertise will ensure success of 
the Consortium, 3) proposing novel studies that meet the Consortium‟s goals, and, 4) developing 
and expanding a genomic and tissue bank. 5) Continuing to develop expertise in clinical and 
basic science research that will lead to new areas of treatment and management of patients with 
NF1.  
 
 
Children‟s National Medical Center.  The Neurofibromatosis Program of the Children‟s 
National Medical Center (CNMC), designated as a Center of Excellence by the Children‟s 
Tumor Foundation, is a well-established, multi-disciplinary program caring for children and 
adults with NF1. The program is multi-faceted and has proven expertise in clinical care, 
clinical/translational research, basic research and advocacy.  Commitment/Experience in NF1 
Clinical Research: The CNMC program‟s personnel have extensive experience in coordinating 
care in clinical trials for children with neurofibromatosis.  
 
 
Cincinnati Children‟s Hospital Medical Center.  The Cincinnati Neurofibromatosis 
Center, founded in 1986, is a multidisciplinary center dedicated to the diagnosis, clinical care, 


 
 
 
STARS April 13, 2011   
V 5.0 
16 
and medical management of adults and children with NF1 and NF2. It is one of the largest NF 
centers in the country, with over 600 patients with NF1 evaluated and over 400 annual patient 
visits. The NF Center is housed at Cincinnati Children‟s Hospital Medical Center (CCHMC), 
with an adult program based in the Internal Medicine/Pediatrics 
 
 
Children‟s Hospital of Philadelphia.  The Penn Joint Neurofibromatosis Program (NFP) 
constitutes a multi-institutional, multidisciplinary approach to the diagnosis and management of 
children and adults with neurofibromatosis type 1 (NF1) at The Children's Hospital of 
Philadelphia (CHOP) and the Hospital of the University of Pennsylvania (HUP). 
 
 
The University of Alabama at Birmingham.  The UAB Neurofibromatosis Center 
includes both clinical and research activities dedicated to all forms of neurofibromatosis.  
Components include a Neurofibromatosis Clinic that serves individuals with NF1, NF2, and 
schwannomatosis at all ages; a full range of consultation services; expertise in conduct of clinical 
trials and natural history studies; a unique NF1 and NF2 genetic testing laboratory that serves the 
entire NF community; basic research focusing on mouse models and drug discovery.  
 
 
University of Chicago.  The NF Program at the University of Chicago, established in 
1989, is a large multi-disciplinary program for children and adults. The program offers 
exceptional care to patients of all ages and continues to demonstrate expertise in clinical care, 
clinical/translational research, basic research, and patient education and advocacy.  
Commitment/Experience in NF1 Clinical Research. 
 
 
University of Utah.  The neurofibromatosis type 1 (NF1) research program and NF Clinic 
at the University of Utah have been established for over 20 years. The NF Clinic primarily 
focuses on the pediatric population seen at Primary Children‟s Medical Center, but adult patients 
are routinely managed by oversight of their health supervision and collaboration with an 
integrated network of experienced subspecialists. 
 
 
Washington University.  Washington University School of Medicine (WUSM) has a 
multidisciplinary NF Center with a long history of commitment to and expertise in NF1 research 
and clinical care. The NF Center is focused on promoting pioneering laboratory research, 
facilitating collaborative basic science and clinical research, and translating innovative scientific 
discoveries to improved care for individuals with NF.  
 
 
Central Manchester University Hospitals. – Central Manchester University Hospitals 
NHS Foundation Trust, England – The Manchester Neurofibromatosis Centre was established in 
1990 and has been providing diagnosis and management advice for families with all kinds of 
neurofibromatosis since then. The center has a long history of clinical and epidemiological 
research in NF1 and NF2, alongside molecular genetic research in NF2 and Schwannomatosis. 
The centre was nationally commissioned in April 2009 to be one of two English centers 
providing multidisciplinary care for patients with complex NF1. In April 2010, this was followed 
by national funding for NF2 care with 3 other English centers. 
 


 
 
 
STARS April 13, 2011   
V 5.0 
17 
 
 
University of Texas Southwestern Medical Center. – UTSW is a multidisciplinary clinic 
for patients with all types of neurofibromatosis throughout their lifetimes.  Pediatric patients are 
seen at Children‟s Medical Center Dallas, one of the foremost pediatric hospitals in the nation, 
while adult patients are seen in the NCI designated Simmon‟s Cancer Center.  UTSW has a 
strong history of basic laboratory, translational and clinical research in patients with 
neurofibromatosis.   
 
*other sites may be added to help with accrual. 
 
4.2 
Inclusion Criteria 
 
 
Males or females aged between 8 years to less than 16 years at time of screening 
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 (see Section 4.3 for exclusion criteria 
regarding other psychotropic medication, i.e. medication capable of affecting the 
mind, emotions or behavior) 
 
Hepatic function:  Participants must have adequate liver function defined as at least 
3 of the 4 liver function tests to be < 2 x upper limit of normal for age according to 
institution standards (AST, ALT, Direct bilirubin, Indirect bilirubin [computed from 
total bilirubin and direct bilirubin]) and no tests should be >5x upper limit of normal 
for age; 
 
Renal function:  Participants must have adequate renal function defined as serum 
creatinine ≤ 1.5x upper limits of normal for age, and BUN ≤ 1.5x upper limits of 
normal for age or a creatinine clearance of greater than 70 ml/m/1.73m2; 
 
Hematologic function:  Participants must have an absolute neutrophil count of > 
1,000, a hemoglobin ≥10 gms/dl, and a platelet count > 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. 
 


 
 
 
STARS April 13, 2011   
V 5.0 
18 
4.3 
Exclusion Criteria 
 
 
Full-scale IQ less than 70. In cases where there 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 (see Section 4.2). Appendix 2 contains a list of common 
psychotropic medications. These patients are eligible if, as clinically indicated, they 
cease medication for at least 30 days prior to screening and remain off these 
medications 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 screening; 
 
Participants who have recently taken sirolimus. These participants will be eligible 
after a washout period of at least three months; 
 
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). 
 
 
5.0 
Study Procedures 
 
An overview of the study procedures can be found in Appendix 3. 
 
5.1 
Pre-Treatment 
 
The pre-treatment phase of this study consists of obtaining informed consent, an initial 
evaluation and enrollment process, as well as a screening for eligibility.  
 
5.1.1 Screening and Informed Consent 


 
 
 
STARS April 13, 2011   
V 5.0 
19 
  
The study will be described in detail to participants and their parents/legal guardians at an initial 
visit. If the participant and family agree to participate in the study, the applicable assent, consent 
and HIPAA documents will be signed (see Appendix 4). After informed consent has been 
obtained, a screening assessment will be performed.  The screening assessment will include a 
medical history, physical examination and laboratory tests. The site psychologist will also 
administer the primary outcome measures (see section 5.1.4.1) and an abbreviated IQ measure 
which is estimated to take 50 minutes to complete. To be eligible to participate in the treatment 
phase, patients must have an impairment on at least one of the primary outcome measures of 
visual spatial learning or sustained attention (≥ 1SD below the normative mean) and an IQ equal 
to or above 70. Unless the patient has undergone an IQ test within six months of screening, IQ 
will be assessed using the Wechsler Abbreviated Scale of Intelligence (WASI; Wechsler, 1999). 
If the participant has recently completed an IQ test (within six months of screening), then this 
score will be used for the purposes of screening. Examples of acceptable IQ tests include (but are 
not limited to) the WASI, the Wechsler Intelligence Scale for Children 4th Edition (WISC-IV), 
and the Stanford-Binet Intelligence Scales 5th Edition (SB-V). 
 
If the child fails to satisfy the screening criteria, parents will be verbally informed of the reason 
why the child did not meet the criteria. If the reason for exclusion was a Full-Scale IQ less than 
70, parents will be verbally informed of the range of the child‟s IQ score and that it may indicate 
the presence of an intellectual disability. Parents will be advised that only a brief assessment of 
IQ was conducted and that the child‟s performance may vary due to motivation, attention and 
fatigue. It will be recommended to parents that their child undergo a full IQ assessment to obtain 
further information about their child‟s intellectual functioning. Upon request, results of the IQ 
test will be provided to parents in a written report. 
 
5.1.2 
History and Physical Examination 
A complete medical history and physical examination (including neurological examination) will 
be performed initially to confirm each participant‟s NF1 diagnosis and to document any 
complications that they might have from the disease. Height, weight, head circumference, blood 
pressure, and pulse will be recorded. Patients will also be given a list of medications to avoid 
while on this study.  To be eligible participants must have not taken any stimulant medications 
for at least 30 days or more and agree to remain off stimulant medication for the duration of the 
study.  
 
5.1.3 Laboratory Studies 
 
A pre-treatment enrollment laboratory test will be performed at least two weeks prior to 
commencing the study medication.  The following studies will be performed: 
 
Hematology: Complete blood count (CBC); 
 
Chemistries: Blood urea nitrogen (BUN), creatinine, alanine aminotransferase 
(ALT), asparate aminotransferase (AST), CPK and, Lipid profile (HDL, Cholesterol, 
LDL, Triglycerides), total bilirubin and direct bilirubin (indirect bilirubin will be 
computed from total and direct bilirubin serum measurements); 


 
 
 
STARS April 13, 2011   
V 5.0 
20 
 
Urine Pregnancy Test: A urine pregnancy test will be performed on all females of    
childbearing age before commencing study medication and at weeks 8 and 16.  
 
In order to ascertain an accurate lipid profile, participants will fast overnight before their 
laboratory tests are performed. This will apply to all lipid assessments conducted during the 
study period.  
 
5.1.4 
Baseline Assessment - Neuropsychological Outcome Measures 
 
Within one month of enrollment and before initiation of treatment, participants will be 
administered all primary and secondary outcome measures as outlined in section 5.1.4.1. The 
child‟s history will also be reviewed with the family to gather information about the child‟s 
cognitive development and behavior. 
 
5.1.4.1 Primary Outcome Measures   
 
The effect of Lovastatin on cognitive functioning in children with NF1 has not been examined. 
Evidence from a murine model of NF1 suggests Lovastatin improves visual spatial learning and 
memory, and attention.  As such, the following primary outcome measures are:  
 
 Visual Spatial Learning and Memory 
*CANTAB Paired Associate Learning (PAL) 
PAL is a measure of arbitrary visuospatial associations. It involves the randomized „opening‟ of 
six boxes that are displayed on the screen, each revealing a different pattern. Immediately after 
presentation of the six patterns, each item reappears in the central box in random order and the 
participant has to indicate where each item was first seen.  Measures include the number of 
patterns placed correctly on the first trial and the number of repeat presentations needed to learn 
all the associations correctly. Administration time for this measure is approximately 10 minutes. 
 
 Attention 
*Score! Subtest from the Test of Everyday Attention for Children (TEA-Ch: Manly, Robertson, 
Anderson & Nimmo-Smith, 1999).  
The TEA-Ch is a normed and standardized multi-subtest battery that assesses various aspects of 
attentional function in children aged between 6 years and 15 years 11 months. The Score! subtest 
requires children to keep count of sounds they hear on a tape.  This task does little to „grab‟ the 
child‟s attention and is a measure of their ability to self-sustain his or her own attention. Previous 
findings indicate that approximately 63% of children with NF1 are impaired on Score! (Hyman 
et al., 2005).  There are two alternate forms for this subtest and it takes approximately 8 minutes 
to complete.  
 
5.1.4.2   Secondary Outcome Measures 
 
 Attention 
*Test of Everyday Attention for Children (TEA-Ch: Manly et al., 1999) 


 
 
 
STARS April 13, 2011   
V 5.0 
21 
In addition to the Score! subtest, three other subtests from the TEA-Ch will also be used in this 
study: Sky Search (visual selective attention), Sky Search Dual Task (divided attention between 
visual and auditory information), and Creature Counting (attentional control/switching). The test 
is normed for children 6 to 15 years 11 months and there are two alternate forms available. 
Administration time for these three subtests is approximately 20 minutes. 
 
*Conners‟ Continuous Performance Task – II (CPT-II: Conners, 2000) 
CPT-II is a computerized measure of sustained attention and concentration.  It is a 14-minute 
computerized test that requires the child to discriminate targets (X‟s) from nontargets (letters of 
the alphabet).  Various measures calculated by the program include hit reaction time, omission 
and commission errors, change in reaction time speed and consistency.  This test takes 
approximately 14 minutes to administer. 
 
Parent version of the Conners ADHD/DSM-IV Scales (CADS: Conners, 1997) 
The CADS-P is a published questionnaire that uses observer ratings to help assess the presence 
of inattentive and hyperactive/impulsive behaviors in children and adolescents and directly 
corresponds to the DSM-IV criteria for ADHD. The parent version of the questionnaire will be 
administered, which contains 26 items (12 items ADHD index, 9 inattentive items and 9 
hyperactive-impulsive items).  It takes approximately 5 to 10 minutes to complete. The CADS-P 
is a subjective outcome measure of attention. 
 
 
Executive Functions 
*CANTAB Spatial Working Memory (SWM) 
This is a test of the participant‟s ability to retain spatial information and to manipulate 
remembered items in working memory.  It is a self-ordered task that also assesses heuristic 
strategy.  Administration time for this test is approximately 10 minutes. 
 
*CANTAB Stockings of Cambridge (SOC) 
This is a test of spatial planning and problem solving (aspect of executive function), which is 
based on the „Tower of London‟ test (Shallice, 1982).  Administration time for this measure is 
approximately 10 minutes. 
 
*CANTAB Stop Signal Task (SST) 
This is a classic stop signal response inhibition test that uses interleaved staircase functions to 
generate an estimate of stop signal reaction time.  SST gives a measure of the participant‟s 
ability to inhibit a response.  Administration time for this task is approximately 15 minutes. 
 
Controlled Oral Word Association Test (COWAT; Benton & Hamsher, 1989) 
The COWAT assesses the executive aspects of language processing, including verbal fluency 
and concept formation.  It requires children to rapidly make verbal associations to specific 
letters of the alphabet (i.e., F, A and S). The test is normed for children between 7 to 16 years of 
age (Anderson, Lajoie & Bell, 1995).  Administration time for the COWAT is approximately 5 
minutes. 
 


 
 
 
STARS April 13, 2011   
V 5.0 
22 
Behavior Rating Inventory of Executive Function-Parent - Report Form (BRIEF; Gioia, Isquith, 
Guy & Kenworthy, 2000; Guy, Isquith & Gioia, 2004)  
The BRIEF is a published clinical questionnaire assessing executive function in the home and 
school setting.  The Parent Form is completed by the child‟s parent or guardian.  It contains 86 
items, with eight clinical scales and two validity scales. Behavior descriptors of a child are rated 
on a three-point Likert scale: “never,” “sometimes,” “always.”  Items were developed to capture 
everyday behaviors associated with executive functions, and tap eight domains including: 
initiate, inhibit, shift, plan, organize, self-monitor, emotional control, and working memory.  
These scales are combined to form two broader indices (Behavioral Regulation and 
Metacognition) and a Global Executive Composite score. The Parent Form is normed for 
parents of children aged 5-18 years old.  This questionnaire takes approximately 15 minutes to 
complete. 
 
 
Visual Spatial Skills 
*Judgment of Line Orientation (JLO: Benton, Varney & Hamsher, 1976) 
The JLO is a motor-free untimed measure of spatial perception and orientation. JLO requires 
participants to judge the spatial directionality and size of angles. Two alternative forms of this 
test are available.  These tests take approximately 10 minutes to administer. 
 
 
Visual Perceptual Skills  
Object Assembly (Wechsler Scale for Intelligence – Third Edition; WISC-III; Wechsler, 1991)  
The Object Assembly test is a perceptual organization timed task, that is, a task that requires 
mentally organizing spatial information into meaningful part-whole relationships. For this task, 
participants are required to put together puzzle pieces to form line drawings of common objects. 
This test takes approximately 13 minutes to complete.  
 
 
Behavior 
Behavior Assessment System for Children - Second Edition (BASC-II; Reynolds & Kamphaus, 
2004) 
The BASC-II is a multidimensional system used to evaluate the behavior and self-perceptions 
of children and young adults aged two through 25 years.  The Parent Rating Scales is a 
comprehensive measure of the child‟s adaptive and problem behaviors in community and home 
settings, which takes 10 to 20 minutes to complete.  It assesses various internalizing and 
externalizing problem behaviors as well as adaptive skills.  The Self-Report of Personality is a 
personality inventory for children and adolescents, and young adults, which takes about 30 
minutes to complete.  It assesses various internalizing problems, hyperactivity/inattention, 
personal adjustment and school problems. 
 
 
Quality of Life 
The Pediatric Quality of Life Scale (PedsQL: Varni, Seid & Kurtin, 2001) 
The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and parent proxy-
report scales to assess health-related quality of life in children and adolescents aged 2 to18 
years. There are parallel child and parent scales, which include self-report forms for children, 


 
 
 
STARS April 13, 2011   
V 5.0 
23 
and proxy-report forms for parents.  The PedsQL consists of four core scales: physical, 
emotional, social, and school.  It takes 5 to 10 minutes to complete. 
 
 
Visuospatial Learning and Memory 
Computer Generated Arena (CGA: Astur, Taylor Mamelak, Philpott & Sutherland, 2002) 
The CGA is an optional computerized clinical outcome measure that will be performed after 
completion of all secondary outcome measures. It is a virtual environment task that has been 
developed as a “Human Morris Water Maze” (Astur et al., 2002; Kallai, Makany, Karadi & 
Jacobs, 2005). The task requires children to use a joystick controller to navigate a circular 
“arena” to locate an invisible target hidden on the floor. The walls of the arena contain cues, such 
as windows that remain in place. The fixed target must be located in subsequent trials, each time 
starting from a new location. This test takes 10-15 minutes to administer and will only be 
conducted at the following sites: The Children‟s Hospital at Westmead, Children‟s Hospital 
Boston and Children‟s National Medical Center. 
 
In addition to these measures, Motor Screening (MOT) from the CANTAB will also be 
administered.  MOT is a simple pointing task that measures psychomotor speed and introduces 
the participant to the touch-screen apparatus, ensuring they can touch the screen accurately, and 
can hear, understand and follow instructions. The mean latency to touch a cross is measured. 
MOT takes approximately 5 minutes to administer.   
 
All primary measures will be administered at screening. The length of time required for the 
child to complete the remainder of the baseline neuropsychological assessment is estimated to 
be 128 minutes (98 minutes testing and 30 minutes to complete self-report questionnaires). It is 
estimated that parent questionnaires will take 55 minutes to complete (see Appendix 5). All 
neuropsychological assessments that will be used in this study are published tests that have 
normative data that is both reliable and valid for the age range in this study. These tests are all 
extensively used in clinical and/or research settings. All tests have standardized instructions for 
administration ensuring there will be no site variation in administration.  
 
To minimize any test-retest effects for neuropsychological outcome measures, alternate forms 
(indicated by „*‟ in the above sections 5.1.4.1 and 5.1.4.2) will be used where possible, to 
minimize potential practice effects. Furthermore, the use of a placebo group will allow us to 
identify any potential practice effects and distinguish whether any changes in the treatment 
group are larger than those accounted by practice effects i.e. a treatment effect. In addition, 
statistical analysis of the data will be conducted to account for confounding variables such as 
practice effects (see Section 8). 
   
5.1.5 Randomization 
 
Following a successful screening period, the participant will be randomized to one of the two 
treatment groups: Lovastatin or placebo. Randomization will be implemented by the Data 
Coordinating Center for this trial utilizing a permuted blocks approach.  
 


 
 
 
STARS April 13, 2011   
V 5.0 
24 
Randomization will be stratified by clinical site, to ensure adequate balance between the treatment 
groups, overall and at each site.  Password protection will be implemented to ensure that only 
certified clinical center personnel are allowed to randomize patients and access the database.  At the 
time of randomization, each participant will be assigned a unique medication kit identification 
number that will be used throughout the duration of the study.  
 
5.1.6 Masking Procedure and Labeling 
 
In order to preserve the double-masking of the trial, only the Data Coordinating Center, the drug 
distribution center, and the pharmacist at each participating site will be unmasked. The drug 
distribution center will be provided with the randomization sequence and treatment assignment 
directly by the Data Coordinating Center. 
 
Both treatments (Lovastatin and placebo) will be distributed from the Pharmacy Department at each 
site. Except for the pharmacist, all staff will be blinded to the treatment sequence at each site.  
 
The success of blinding will not be evaluated. While the CONSORT checklist previously stated 
that the success of blinding should be evaluated this statement has recently been removed from 
the CONSORT checklist as it was deemed that testing for blindness may not generate valid 
answers (Sackett, 2007). 
 
5.2 
Treatment Visits 
 
5.2.1 Dose Schedule and Prescription 
 
Eligible participants will be dispensed 20mg of Lovastatin or the placebo at the initiation of 
treatment.  Participants will be given directions to take the medication once daily after dinner 
time. Given that Lovastatin has a strong odor; participants will be required to swallow the 
capsule whole without breaking the seal. Participants will take one tablet (20mg Lovastatin) per 
dose for two weeks; and increase to two tablets per dose during the following weeks (40 mg 
Lovastatin). Participants will continue on the same dosage for a total of 14 weeks. In order to 
assess medication compliance, participants will be required to complete pill diary forms. All 
participants will be provided with a complete list of medications and products that have 
detrimental interactions with Lovastatin that must be completely avoided while being treated 
with Lovastatin (see Appendix 6). 
 
5.2.2 Clinical Evaluation 
 
Throughout the treatment phase of the study, participants will be clinically evaluated every 4 
weeks ( 4 days) by a neurologist or a qualified physician at each site.  At each visit, an interim 
medical history and physical examination (including a neurological examination) will be 
performed. Height, weight and body surface area will be obtained. Participants will be assessed 
for toxicity/side effects and safety labs will be performed as specified in section 5.1.3 every 4 
weeks ( 4 days). Medication compliance will also be assessed at these visits. Pill diaries will be 


 
 
 
STARS April 13, 2011   
V 5.0 
25 
reviewed and a pill count will be performed and recorded.  At the end of the study or the 
treatment period, all unused medication will be collected and dispensed of properly on a per site 
basis according to clinical procedures and guidelines. 
 
5.2.3 Off-Study Criteria (Note: See Section 6.6 for modifications for toxicity information) 
 
A participant will be taken off the study for the following reasons: 
 The participant refuses further treatments and/or wishes to withdraw from the study;  
 For participants concurrently taking stimulant medications (methylphenidate and/or 
dextroamphetamines), they will be withdrawn from the study if they stop or change the dose 
or type of  stimulant medication before their final study visit; 
 It is deemed in the best interest of the participant to stop the study by the research team; 
 Serious protocol violation or non-compliance as determined by the principal investigator or 
research team;  
 The development of significant drug toxicity, such as recurrent grade 3 or 4 toxicity after dose 
reduction; and/or persistent grade >2 toxicity for >10 days without administration of the drug;  
 The development of a concurrent serious medical condition that might preclude or 
contraindicate the administration of Lovastatin; 
 Death.  
 
5.3 
Post-Treatment 
 
The following tests and procedures will be performed at the end of the 16-week treatment period 
(unless participants have come off treatment early): 
 Medical history and physical examination;  
 Laboratory studies as specified in section 5.1.3 including CBC, BUN, creatinine, ALT, AST, 
direct and total bilirubin, CPK and complete lipid profile; 
 All outcome measures will be re-administered 16 weeks (± 4 days) after treatment 
commenced (and the day it is terminated). In exceptional situations where participants are 
unable to attend the post-treatment assessment at week 16 (± 4 days), the post-treatment 
assessment will be conducted earlier, but as close to week 16 as possible. If a participant is 
withdrawn from the study early, the battery will still be given, if it is at least four weeks since 
the baseline assessment (unless the reason is non-compliance of medication). It is estimated 
that it will take the child approximately 148 minutes (118 minutes testing and 30 minutes 
self-report questionnaires) to complete the primary and secondary outcome measures. It is 
estimated that parent questionnaires will take 55 minutes to complete.   
 
5.4 
Follow-up 
 
To determine any carry-over effects in the present study, a follow-up assessment will be 
conducted 8 weeks (± 7 days) post cessation of treatment. As treatment status will be blinded, all 
participants will be re-administered all outcome measures and laboratory tests (excluding 
pregnancy test) at follow-up. While no existing data exist on the carry-over effects of Lovastatin, 
in patients with cancer who were given high dosages of Lovastatin (2-45mg/kg/day) 


 
 
 
STARS April 13, 2011   
V 5.0 
26 
approximately 30 days after the cessation of Lovastatin, cholesterol levels returned back to 
normal levels (Thibaulet et al., 1996).   
 
All study personnel that have responsibility for direct participant related activities will be 
intensively trained in the relevant specific procedures before contact with participants, which 
includes providing informed consent/assent, family/child interviews, the administration and 
scoring of tests, maintenance of confidentiality, data collection and handling, and procedures for 
handling difficulties that might arise during the study. All study personnel who have direct 
contact with study participants or their data, will sign a confidentiality form, indicating their 
understanding of appropriate procedures for maintaining participant confidentiality. Doctoral-
level neuropsychology staff and physicians will provide the relevant training and ongoing 
supervision of all study personnel. 
 
6.0 
Pharmaceutical Information 
 
6.1 
Pharmacokinetics 
 
Lovastatin is one of the first-generation statins and therefore has a large body of safety and 
pharmacokinetic data from clinical trials and general use for hyperlipidemia (Corsini, et al., 
1995a).  
1. 
It is a lactone that is readily hydrolyzed in vivo to the corresponding b-hydroxyacid, a 
potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for 
an assay in pharmacokinetic studies of the b-hydroxyacid metabolites (actives inhibitors) 
and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma 
following administration of Lovastatin;  
2. 
Following an oral dose of 14C-labeled Lovastatin in men, 10% of the dose was excreted in 
urine and 83% in feces. Plasma concentrations peaked at two hours and declined rapidly to 
about 10% of peak by 24 hours post dose;  
3. 
Lovastatin is highly bounded (>95%) to human plasma proteins. Animal studies 
demonstrated that Lovastatin crossed the blood brain and placental barriers;  
4. 
The major active metabolites present in human plasma are the b-hydroxyacid of Lovastatin, 
its 6‟-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of 
both active and total inhibitors were obtained within two to four hours of dose 
administration;  
5. 
The recommended dose in children 10 to 17 years old is 10-40 mg/day (Merck & Co., Inc, 
2007); 
6. 
It is metabolized in the liver by the cytochrome P450 isoenzyme CYP3A4, with less than 
10% being excreted renally (Kantola, Kivisto & Neuvonen, 1998); 
7. 
With a once a day dose regimen, plasma concentrations of total inhibitors over a dosing 
interval achieved a steady state between the second and third days of therapy and were 
about 1.5 times those following a single dose (Vree, Dammers, Ulc, Horkovics-Kovats, 
Ryska et al., 2003). When Lovastatin is given under fasting conditions, plasma 
concentrations of total inhibitors were on average about two thirds those found when 


 
 
 
STARS April 13, 2011   
V 5.0 
27 
Lovastatin was administered immediately after a standard test meal (Hsu, Spinler & 
Johnson, 1995; (Merck & Co., Inc, 2007). 
 
6.2 
Drug Company/Supply/Distribution 
 
Based on an estimate from Eminent Corporation, funds included in the budget will be used to 
purchase Lovastatin and its matching placebo and distribute Med Kits to participating sites.  
Eminent Corporation will also be responsible for study medication reconciliation and shipping. 
 
6.3 
Procedures/Recommendations for Drug Supply and Distribution 
 
Lovastatin and its matching placebo will be obtained and distributed to participating sites by a 
subcontractor to the Operations Center.  A 20mg tablet of Lovastatin or an identical tablet 
(placebo) will be provided for each participant.  Medications, including the placebo, will be 
provided to the participants free of charge.  Participants will be instructed to return all unused 
medications as well as empty bottles at each clinic visit.  All unused medicine will be disposed of 
properly at each individual site.  
 
Lovastatin is administered orally.  The bioavailability of the tablet increases under the influence 
of a meal. Based on these findings, it is advised to take the tablets immediately after a meal. One 
dose per day after dinner time will be instructed to parents, since evening doses are more 
effective than the same dose given in the morning (Merck & Co., Inc, 2007). Lovastatin is a 
substrate for cytochrome P450 isoform 3A4 (CYP3A4). Grapefruit juice contains one or more 
components that inhibit CYP3A4 and can increase the dose concentration. Participants will be 
instructed to avoid the consumption of grapefruit juice during the treatment. A complete list of 
drug interactions/contraindications will be described to parents and participants.  
 
Compliance will be monitored by recording the number of pills dispensed to families from the 
pharmacy and then comparing that to the number of pills that are returned at each monthly visit.  
Participants will be asked to return all unused pills at each visit. A pill diary will also be 
maintained by each participant and reviewed at each follow-up visit to ensure compliance with 
the medication. 
 
6.4 
Drug Dosage and Possible Interactions 
 
The selection of the maximum dose of Lovastatin to be used in this study, 40 mg/day, is based on 
the tolerability of the drug when used for heFH and the results of the Phase I study examining 
safety and tolerability of Lovastatin in children with NF1 (Acosta et al., submitted).  Participants 
will commence at 20 mg/day for two weeks and escalate to the 40 mg/day dose in week 3.   
 
Approximately 40% of children with NF1 are diagnosed with comorbid ADHD, many of whom 
are 
treated 
with 
psychostimulant 
medication 
such 
as 
methylphenidate 
and/or 
dextroamphetamines. In order to minimize recruitment bias and ensure recruitment targets are 
met, patients taking methylphenidate and/or dextroamphetamines will be eligible for this study. 


 
 
 
STARS April 13, 2011   
V 5.0 
28 
The predominant metabolic pathway of methylphenidate is de-esterification to form 
pharmacologically inactive d- or l-ritalinic acid (Patrick et al 1987). Metabolism of 
methylphenidate when used by oral administration undergoes a stereoselective clearance to 
ritalinic acid (CES1A1 is the major enzyme responsible) before entering systemic circulation 
(Sun et al, 2004). Methylphenidate does not use the microsomal cythochrome P450 in the liver 
for its metabolism (Sun et al 2004; Patrick et al 1987). Dextroamphetamines are metabolized by 
the cythrochrome P450 in liver. However the isoenzyme responsible for its metabolism is the 
CYP2D6 (Adderall Medication Guide, Shire, Nov. 2010). Instead, lovastatin is metabolized by 
the CYP3A4 (Ritalin® Medication Guide, Novartis, 2010). There are not described interactions 
or competitive mechanism between dextroamphetamines and lovastatin.  
 
Although limited by a small sample size, results of the Phase I study provide some evidence for 
the inclusion of patients on stimulant medication (Acosta et al., submitted). A total of 23 patients 
with NF1 (10-17 years of age) completed 12 weeks of treatment with Lovastatin. Nine patients 
had a diagnosis of ADHD and five of these patients were taking a stable dose of stimulant 
medication during the course of the study. Calculation of Reliable Change Index for individuals 
indicated significant improvements on both verbal and nonverbal memory measures in 
approximately 40% of participants regardless of whether they were off or on methylphenidate.  
 
The list of psychotropic medications is quite extensive. As many psychotropic medications may 
interact with the metabolism of Lovastatin, e.g. Fluoxetine, patients taking psychotropic 
medications other than stimulant medications will be excluded from the study. Also, participants 
on other medications to control behavior (including Straterra) and anticonvulsants will not be 
eligible to participate in the study as these medications are known to affect cognition and 
learning and, thus, confound the results of the study. However, these participants may be eligible 
if they cease medication for at least 30 days prior to screening and remain off these medications 
for the duration of the study. Importantly, all participants must still demonstrate impairment on 
either of the primary outcome measures at the screening assessment and satisfy all other 
inclusion criteria to be enrolled in the study.    
 
6.5 
Toxicity and Adverse Event Monitoring 
 
6.5.1 Lovastatin Side Effects 
 
Lovastatin has been shown to be safe and effective in a pediatric population for treatment of 
familial heFH with minimal toxicity. The FDA has approved it for treatment in children and it is 
believed to be safe to extend to other potential uses. Side effects reported have been considered 
reversible once the medication has been discontinued.  The most frequent side effects of 
Lovastatin are described below by systems.  Presentation is less common in children than in 
adults, and includes: 
 
Muscular: Muscle pain, tenderness, weakness, increase of CPK, cramps, rhabdomyiolisis 
(rare) 
Hematologic: Thrombocytopenia 


 
 
 
STARS April 13, 2011   
V 5.0 
29 
Gastrointestinal: Abdominal pain, flatulence, diarrhea, constipation 
Hepatic: Transient elevation in serum transaminases 
Dermatologic: Rash (rare) 
Constitutional: Fatigue, asthenia, flu-like symptoms, headache, dizziness, insomnia 
 
6.5.2 Frequencies of side effects 
 
The frequencies of adverse events are ranked according to the following: Very Common 
(>1/10), Common (>1/100, <1/10), Uncommon (>1/1,000, <1/100), Rare (≥1/10,000, 
<1/1000), and Very Rare (<1/10,000).  
 
Common >1% and < 10% (less than 1 person in every 10 but more than 1 person in 
every 100):  Gastrointestinal disorders: constipation, dyspepsia 
 
Uncommon 0.1% to 1% (less than 1 person in every 100 but more than 1 person in 
every 1,000):   Skin and subcutaneous tissue disorders: itching; elevated transaminases. 
 
Rare 0.01% to 0.1% (less than 1 person in every 1,000): 
 
Eye disorders: blurred vision. 
 
Gastrointestinal disorders: abdominal pain, diarrhea, dry mouth, flatulence, 
nausea, vomiting. 
 
General disorders and administration site conditions: weakness. 
 
Hepatic disorders: yellowing of the skin and eyes (cholestatic jaundice), hepatitis. 
 
Metabolism and nutrition disorders: loss of appetite. 
 
Musculoskeletal, connective tissue and bone disorders: muscle weakness 
(myopathy), tenderness and muscle pain, muscle cramps. Participants will be told 
to promptly report any unexplained muscle pain, tenderness or weakness. If 
myopathy is diagnosed or suspected, then Lovastatin therapy will be immediately 
discontinued. 
 
Nervous system disorders: dizziness, absence of the sense of taste, headache, 
tingling sensation, tingling and numbness of the feet and legs. 
 
Psychiatric disorders: insomnia, psychic disturbances including anxiety, sleep 
disorders. 
 
Skin and subcutaneous tissue disorders: alopecia, spotted or diffuse redness of the 
skin including Stevens - Johnson syndrome, redness and swelling of the skin, 
shedding of the skin. 
 
An apparent hypersensitivity syndrome has been reported rarely which has 
included one or more of the following features: anaphylaxis, angioedema, lupus-
like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, 
thrombocytopenia, leukopenia, eosinophilia, hemolytic anemia, positive anti-
nuclear antibodies, erythrocyte sedimentation rate increase, arthritis, arthralgia, 
urticaria, asthenia, photosensitivity, fever, flushing, chills, dyspnea and malaise, 
and other liver function test abnormalities including elevated alkaline phosphatase 
and bilirubin; increase in serum CPK levels.  


 
 
 
STARS April 13, 2011   
V 5.0 
30 
 
6.5.3 Breaking the Blind 
Treatment assignment may be revealed only for reasons relating to the participant‟s safety or when 
critical therapeutic decisions are contingent on knowing the assigned study medication.  Except in 
the most pressing circumstances, a decision to break the blind must be discussed with the 
Operations Center, Chair of the Protocol Committee or the Chair‟s designee from the Protocol 
Committee and permission in writing must be obtained before the blind may be broken.  
Withdrawal of a participant from the study is not a sufficient reason to break the study blind. 
 
If the blind is broken, the pharmacist will record key information at the time the blind is broken.  
Information to be collected includes the participant number and initials, medication kit number, date 
the blind was broken, reason for breaking the blind, the name of the investigator who requested the 
blind be broken, the name of the pharmacist who broke the blind, and the names of the Clinical 
Review Committee members who authorized breaking the blind.  A member of the Clinical Review 
Committee will fax or e-mail written permission to break the blind to the pharmacist and to the 
Operations Center. 
 
6.6 
Modifications for Toxicity 
 
Participants who experience grade 2 toxicity related to Lovastatin will have Lovastatin withheld 
until the toxicity resolves (grade <1) and then restarted at the same dose level. If the grade 2 
toxicity recurs, the dose will be withheld again until the toxicity resolves (grade <1) and then 
reduced to 50% of the dose. If the grade 2 toxicity recurs, the participant will be taken off the 
protocol. The participant will be evaluated by the principal investigator.  
 
Participants who experience grade 3 or 4 toxicity related to Lovastatin will have their dose 
withheld. If the toxicity returns to grade <1 within 10 days, the participant may resume 
Lovastatin at a dose reduced by 50%. If the toxicity persists at grade >2 for >10 days without 
administration of Lovastatin or the grade 3 or 4 toxicity recurs at the lower dose, the participant 
will be removed from the study. 
 
6.7 
Adverse Event Monitoring (UK sites please refer to Appendix 10) 
 
Participants will be monitored closely for medication side effects with a diary and with 
laboratory testing as indicated in the Study Procedures section (see of the protocol (see Section 
5). Adverse events will be addressed immediately as described in Section 6.8.  Participants will 
also be closely followed clinically at least once per month while on the study medication by the 
site physician. The Side Effects Checklist and Adverse Event Monitoring Form will be used to 
assess participants at every visit or phone contact. 
 
Participants will be monitored for adverse events regularly throughout the study. Adverse events 
are any unfavorable or unintended sign (including abnormal laboratory findings), symptom or 
disease temporarily associated with the use of medical treatment or procedure regardless of 
whether it is considered related to the medical treatment or procedure (attribution of unrelated, 


 
 
 
STARS April 13, 2011   
V 5.0 
31 
unlikely, possible, probable, or definite). Life-threatening adverse events are any adverse event 
that places the participant at an immediate risk of death from the reaction. Serious adverse events 
are any event occurring at any dose level that results in any of the following outcomes: death, a 
life-threatening adverse event, inpatient hospitalization, prolongation of an existing 
hospitalization, a persistent/significant disability/incapacity, and other medically significant 
events. Unexpected adverse events not listed above may also occur. 
 
All observed or volunteered adverse events will be recorded on the Adverse Event form. Events 
involving adverse drug reactions, illnesses with onset during the study or exacerbation of pre-
existing illnesses will be recorded. Objective test findings, such as abnormal lab values, that 
result in drug dosage changes will also be recorded. 
 
6.8 
Adverse Event Reporting 
 
Adverse events will be graded according to the Cancer Therapy Evaluation Program‟s; Common 
Terminology Criteria for Adverse Events Version 4 (CTCAE), which can be downloaded from 
http://ctep.cancer.gov. A severity grading of side effects related to Lovastatin use can be found in 
Appendix 7. The principal investigator at each site will determine whether the adverse event is 
related or unrelated to the medical treatment. If deemed to be related, the principal investigator 
will determine whether the adverse event is expected or unexpected. Details of the event 
(expected or unexpected), and whether the side effect and severity (i.e. toxicity) were included in 
informed consent (yes/no), will be recorded on the adverse event module form. 
 
A justification will be recorded on the adverse event module if the observed toxicity was not 
included in the informed consent. For all adverse events, the investigator must pursue and obtain 
information to determine the outcome of adverse events and to assess whether it meets the 
criteria for classification of a serious adverse event. All serious adverse events require immediate 
notification to the Operations Center. All adverse events, whether serious or otherwise, will be 
followed until resolution (the patients health has returned to his/her baseline status) or until the 
event has stabilized (investigator does not expect any further improvement or worsening of the 
adverse event). Participants withdrawn from the study due to adverse events will be followed by 
the investigator until resolution. All grade 3, 4 and 5 adverse events will be reviewed by the 
Clinical Review Committee. 
 
All adverse events will be tabulated by treatment arm, severity grade and reported to the NF1 
Data and Safety Monitoring Board (DSMB).  The occurrence of adverse events will be reviewed 
by the DSMB at 2-month intervals to monitor patient safety. Summary details of the occurrences 
and grade of adverse events will be distributed to each site at 2-monthly intervals. It will be the 
responsibility of the site principal investigator to disclose this information to the site‟s 
institutional review board. In addition, all unexpected and serious adverse events will be 
forwarded to the medical monitor, Tena Rosser, M.D. She will serve as a patient advocate, will 
be independent of the clinical study team, and will report to the DSMB. She will oversee the 
progress of the protocol, especially issues of individual subject/patient management and safety. 
The monitor will provide an unbiased written report of each event. 


 
 
 
STARS April 13, 2011   
V 5.0 
32 
 
6.9 
Classification of Adverse Events by Severity and Relationship to Study Drug 
Administration 
 
 Adverse Event – Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease regardless of whether it is considered related to the study 
medications (attribution of unrelated, unlikely, possible, probable, or definite). 
 Life-Threatening Adverse Event – Any adverse event that places the participant, in view of 
the investigator, at immediate risk of death from the reaction. 
 Serious Adverse Event – Any adverse event occurring that results in any of the following 
outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, or a persistent or significant disability/incapacity.  Important medical 
events that do not result in death, are not life-threatening, or do not require hospitalization 
may be considered serious adverse experiences when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
 Hospitalization - All hospitalizations (or prolongation of existing hospitalization) for 
medical events equivalent to CTCAE grade 3, 4 or 5 must be reported.  
 Attribution – The determination of whether an adverse event is related to a study treatment. 
Attribution categories: 
 Definite – The adverse event is clearly related to the study medication. 
 Probable – The adverse event is likely related to the study medication. 
 Possible – The adverse event may be related to the study medication. 
 Unlikely – The adverse event is doubtfully related to the study medication. 
 Unrelated – The adverse event is clearly NOT related to the study medication. 
 
6.10 
 Expedited Adverse Event Reporting 
 
All serious adverse events or unexpected adverse events that are life threatening or fatal 
regardless of attribution, including death within 30 days of the last dose of study treatment, 
should be reported to the DCC within 24 hours or by the next business day. 
All reportable adverse events must be reported to the Operations Center within 10 working days. 
All fatal or life-threatening events will be reported to the Operations Center within 24 hours with 
a written report to follow within 10 working days. 
 
6.11 
Risks and Protection from Risks 
 
Individual risks in this study are associated with the use of Lovastatin, laboratory tests (blood 
drawn) and with neuropsychological testing.   
 
Lovastatin has been shown to be safe and effective in a pediatric population for treatment of 
familial HeFH. The FDA has approved Lovastatin (40mg/day) for treatment of HeFH in children 
and it is believed to be safe to extend to other potential uses. The most frequent side effects of 
Lovastatin are muscular pains, weakness and tenderness, and gastrointestinal conditions such as 


 
 
 
STARS April 13, 2011   
V 5.0 
33 
abdominal pain, flatulence, diarrhea and constipation, and are reversible once the medication has 
been discontinued. Participants will be provided with a list of drug and food items that they 
should avoid while on study medication. All participants will be monitored for adverse events as 
described in Section 6.7. Participants who experience adverse events related to the study 
medication will have study medication withheld and/or modified as outlined in Section 6.6. 
Additionally, there will be regular monitoring and clinical evaluation. 
 
In the 24 patients that were evaluated for the Phase 1 Lovastatin study, few patients‟ total 
cholesterol dropped below 100, and in all cases, the HDL:LDL ratio was within normal limits. In 
all cases total cholesterol returned to baseline after the treatment.  From a clinical perspective, 
decreased LDL is one of the desirable outcomes of using Lovastatin. There is no evidence of 
increase risk or harmful consequences for a temporal decrease of LDL levels. Since this is a 16 
week study (plus follow-up), transient decrease in lipid profile levels will not change the risk for 
this patient population. 
 
Since the long-term effects of lowering lipid levels in the children on Lovastatin are unknown at 
this time, having normal range cholesterol (cholesterol > 90 mg/dL) is a criteria for enrollment.  
In addition, a lipid profile is checked at baseline and at weeks 4, 8, 12, 16 and 24.  If levels drop 
below 80 mg/dL, the site should notify the protocol team for guidance. If other lipid profile 
levels drop below normal values, the site should also notify the protocol team for guidance. 
 
Despite the lack of preliminary data in terms of safety using Lovastatin in children aged 8 or 9 
years of age, we anticipate no changes or higher risk of side effects, compared with the older 
children. Date from a phase 1 mentioned before (Acosta et al., submitted), demonstrated no 
differences in tolerability or side effects in children 10 years of age compared with older 
children. In addition, metabolic pathways related with metabolism of drugs, including Cythrome 
P450 complex, are fully developed by 5 years of age (Anderson et al 2009). We do not expect 
changes in toxicity in this younger age group and those patients will be monitored closely during 
the study to early identify any risk(s) or side effect(s). Any metabolic alteration or adverse event 
observed in this specific group age will be notified to the Protocol team for careful evaluation. 
 
There is some pain and a small risk of bruising associated with blood collection, which can be 
minimized by applying a topical anesthetic cream and having experienced blood collectors. 
 
There are minimal risks associated with neuropsychological assessments. All the tests in this 
study are routinely used in clinical and/or research neuropsychological evaluations. As such, they 
are not expected to result in any undue stress in the child. Some children, particularly younger 
children, may become tired during the assessment. If this happens, the child can take short 
breaks. At the beginning of the session, the child will be told by the psychologist that they should 
try their best. They will also be told that they may find some questions easy and others a little 
harder, but not to worry if they cannot answer all questions, as some are for older children. The 
majority of tests have a discontinue rule, so that testing is stopped if the child makes a certain 
number of consecutive errors. This ensures that the child does not become anxious or frustrated. 
If a participant worries that they are unable to answer a question, the test administrator will 


 
 
 
STARS April 13, 2011   
V 5.0 
34 
reassure the child that he/she is not expected to answer all the questions and it is only expected 
that he/she try his/her best on the task. All test administrators will have psychological training 
and experience with interacting and assessing children. If for some reason the child states that 
he/she does not want to continue, the assessment will cease. We will then consult with the parent 
and child to ascertain whether the testing will continue. 
 
There are an estimated six partial or whole days that a child could miss school while 
participating in this trial.  We will recommend to the parent (parents, legal guardians) that he/she 
should discuss school policies for excused absences and make necessary arrangements for make-
up work. 
 
 
 
7.0 
Statistics 
 
Determination of sample size: No data exist on the effects of Lovastatin in children with NF1. 
A clinical and meaningful difference for primary efficacy measures is defined as an effect size of 
one half of a standard deviation, which is classified as a treatment effect of medium magnitude 
(Cohen, 1988). A sample size of 64 participants per treatment group (128 total) will be sufficient 
to detect an effect size of half a standard deviation at the two-sided 0.05 significance level with 
power of 0.80 (Peat, Mellis, Williams & Xuan, 2001).  To allow for a 10% dropout rate prior to 
the 16-week point, a total of 142 participants will be enrolled.  
 
Interim analyses: Interim analyses will be done under the purview of the DSMB, which will set 
the content and frequency of analyses.  We will propose a Charter containing a data monitoring 
plan that will include stopping guidelines.  We expect these to be the Lan DeMets modifications 
of the O‟Brien Fleming boundaries (Lan & DeMets, 1983; O‟Brien & Fleming, 1979)).  It is 
expected that the DSMB will review this charter during its first meeting. 
         
Data analysis: Demographic and baseline characteristics will be summarized for each group 
using descriptive statistics. Intention-to-treat analyses will be conducted for the primary 
outcomes measures. An intention-to-treat analysis provides an unbiased, conservative and 
consistent estimate of a treatment effect (Heritier, Gebski & Keech, 2003).  
 
Analyzing change scores from baseline to post-treatment does not control for baseline imbalance 
because of the regression to the mean (Vickers & Altman, 2001). Also, with changes scores, if 
the treatment is effective, the statistical significance of the treatment effect will depend upon the 
correlation between baseline and follow-up scores. Therefore, to determine whether there has 
been a significant change from baseline to post-treatment, primary and secondary outcomes will 
be analyzed using ANCOVA, which is a better approach than analyzing change scores with 
independent t-tests (Vickers & Altman, 2001). 
 
In addition, at an individual case level to determine whether test-retest change scores from 
baseline to post-treatment are reliable and clinically meaningful, standardized regression based 


 
 
 
STARS April 13, 2011   
V 5.0 
35 
change scores (RBC) will be also be calculated. RBC can account for measurement error, 
differential practice effects and regression to the mean (Sherman et al., 2003). However, RBC 
scores do not necessarily indicate whether a significant change from baseline has occurred 
(Sherman et al., 2003).  Similar statistical analysis will be conducted for scores from post-
treatment to follow-up. Linear mixed models may also be conducted to examine changes over 
time. In addition, a number of sub-group analyses are planned to help identify individuals more 
likely to benefit from, or be harmed by, the treatment. In regard to treatment effects, definition of 
subgroups will rely on baseline data, not data measured after randomization. Such subgroups 
might include age (including comparison of 8-9 years to 10 years and older), gender, and 
presence of ADHD (on or off stimulant medication) (if there are sufficient cases). Exploratory 
data derived through subgroup analyses will serve primarily to generate new hypothesis for 
subsequent studies.  
 
8.0 
Data Management 
 
Data sets will follow all standards as per Data Coordinating Center‟s guidelines and 
recommendations. All paper charts, forms, and information associated with this study will be 
kept in a locked cabinet at the clinical sites. Access to this cabinet is available only to 
investigators on the study and research assistants. All participant information from this study will 
be strictly confidential. On entry to the study, participants will be assigned a unique PIN that will 
be used throughout the study. All data stored in computer systems will be password protected 
and stored using participant PINs only (see next section for more information regarding database 
security). Participant names will not be used in any computer databases associated with this 
project. A list of participant names and coordinating PINs will be kept separately on the 
password-protected principal investigator‟s computer. This information will be kept in 
accordance with the requirements of the Department of Defense. 
 
8.1 
Medical Monitor and Data Safety Monitoring Plan 
The Data Safety and Monitoring Plan for this study will follow the NIH guidelines. The External 
Advisory Board (EAB) will serve as external reviewers and advisors to DoD and the Governing 
Body.  The EAB will review and approve the protocol with respect to ethical and safety standards. 
Its primary responsibility will be to monitor the emerging results of the trial to assess treatment 
representatives are ex officio members of the EAB. The EAB will determine the content and 
frequency of safety reports it will review and will periodically review interim analyses of data 
collected for this study. 
 
In addition, the DSMB will protect the integrity of the study by ensuring that recruitment targets 
can be met within the study timelines. This will be achieved by comparing actual recruitment 
against planned and by monitoring participant drop-out rates. In the event that the number of 
accrued patients is less than 20% of the planned value, the DSMB will advise on appropriate 
remedial action. Possible remedial actions may include, but are not limited to, the extension of 
the recruitment period, review and amendment of inclusion criteria. 
 


 
 
 
STARS April 13, 2011   
V 5.0 
36 
Dr. Tena Rosser will be the medical monitor for this study. She is a qualified physician and is not 
associated with this protocol. She will work closely with the Principal Investigator to monitor the 
participants‟ treatment while on this study. The medical monitor is required to review all 
unanticipated problems involving risk to subjects or others, serious adverse events and all subject 
related deaths associated with the protocol, providing an unbiased written report of the event. At 
minimum, the medical monitor should comment on the outcomes of the event or problem, and in 
the case of a serious adverse event or death, comment on the relationship to participation in the 
study. The medical monitor should also indicate whether she concurs with the details of the 
report provided by the study investigator. Reports for events determined by either the 
investigator or the medical monitor to be possibly or definitely related to participation and 
reports of events resulting in death should be promptly forwarded to the USAMRMC ORP 
HRPO. 
 
It is expected that summaries of accrual, retention, and adverse events will be disseminated to the 
clinical centers periodically.  To maintain the blind, adverse events will be aggregated across 
treatment arms.  
 
8.2 
Confidentiality 
 
Data will be obtained and stored consistent with IRB and HIPAA guidelines. All participant 
charts, standardized study forms, and information associated with this study will be kept in a 
locked cabinet in the principal investigator‟s office. Access to this cabinet is available only to the 
principal investigator and the research team. All participant information from this study will be 
strictly confidential. On entry to the study, participants will be assigned a unique participant PIN 
that will be used throughout the study. All data stored in computer systems will be password 
protected and stored using PINS only. Participant names will not be used in any computer 
databases associated with this project. A list of participant  names and coordinating PINs will be 
kept separately on the password protected principal investigator‟s computer. This information 
will be kept in accordance with the requirements of the Department of Defense.  
 
9.0 
Ethical and Regulatory Consideration 
 
9.1 
Consent/Assent/HIPAA Process and Documentation 
 
The investigational nature and objectives of the study, procedures involved, treatments involved, 
medication side effects, risks, benefits and alternative therapies will be carefully explained to 
potential participants and their parents/legal guardians. Potential participants will be allowed to 
take their time in deciding whether to join the trial and will be given privacy to make their 
decision. They will also be encouraged to discuss their concerns or questions about joining the 
trial with their parents/guardian.  Consent will be obtained from parents/legal guardians and 
assent will be obtained from children aged 8 years to less than 16 years, with signatures obtained 
as appropriate.  This trial will be conducted in compliance with the Good Clinical Practice 
guidelines and the applicable regulatory requirements.  
 


 
 
 
STARS April 13, 2011   
V 5.0 
37 
9.2 
Benefits 
 
For participants receiving Lovastatin, it may have a direct benefit on their cognitive abilities 
(namely their visual spatial learning and/or attention). It is possible that Lovastatin may 
additionally have a positive effect on secondary outcome measures. After the participant has 
completed the trial, a report of their neuropsychological assessment will be provided to the 
parents to assist the child in the school environment. This will include a summary of the child‟s 
cognitive strengths and weaknesses based on the neuropsychological assessments. If cognitive 
weaknesses are found, strategies will be offered with the aim to help parents and educators 
manage the cognitive difficulties. Recommendations for additional support/services will also be 
provided as necessary. At the conclusion of the trial, participants will be sent a summary of the 
research findings with no personal identifying information. If the results show that Lovastatin is 
efficacious in treating cognitive impairments, this will lead to a Phase III study to determine its 
effectiveness in the general NF1 community. 
 
The current study will contribute to the treatment of cognitive impairments associated with NF1. 
It will provide additional information regarding the safety of Lovastatin in children with NF1 and 
cognitive deficits. As mechanisms related with cholesterol metabolism and similar pathways that 
imply Ras pathway activation has been implicated in other models of learning.  These results 
may have a more generalized benefit.  Through this study, there is the hope to gain a better 
understanding of the neurobiology and extent of cognitive difficulties in children with NF1. 
  
9.3 
Potential Biases and Problems 
 
Challenges may exist in recruiting participants.  The Recruitment section of the proposal details 
participant availability and recruitment measures for the clinical trial. At recruitment, the side 
effects of the medication, as well as its use in children with NF1 (Phase I), will be reviewed with 
parents. The system for monitoring side effects will also be discussed. Parents and children will 
have the opportunity to ask questions regarding use of the medication and will be able to 
withdraw from the study at any time.  
 
Participants will be stratified to study medication by clinical site to minimize systematic 
differences in important or unknown confounders between the groups. The requirement for 
multiple visits may result in some attrition in the sample due to difficulties keeping each of the 
scheduled appointments. We have included a 10% attrition rate in the calculation of a sample 
size. To assist in the retention of participants, we will have regular contact with participants 
throughout the entire study.  The investigators, study coordinator, and research assistant will 
work closely with the families to facilitate their return and maximize participation. All 
participants will be required to attend scheduled visits. This will allow us to monitor any side 
effects and may also indirectly assist in maintaining treatment compliance.  
 
Lovastatin has been shown to be safe and effective in a pediatric population for treatment of 
familial heFH. Although unexpected adverse events may occur, frequent monitoring as well as 
phone contact with participants and their families will be done throughout the study.  


 
 
 
STARS April 13, 2011   
V 5.0 
38 
 
9.4 
Costs to Subjects 
 
The study will not imply cost for participants and families. We will provide study medication 
during the trial; laboratories and neuropsychological testing that are part of the present study. 
Participants still have to pay for any other medical care that is not part of the study. 
 
9.5 
Conflicts of Interest 
 
None. 
 
9.6 
Subject Compensation 
 
Medication, laboratories and neuropsychological testing will be free of charge. Additional 
medical expenses not related with the study will not be covered.  
  
9.7 
Outside Consultants/Collaborators  
 
9.8 
Contractual Agreements  
 
 
None.     
 


 
 
 
STARS April 13, 2011   
V 5.0 
39 
10.0 
References 
 
Acosta MT, Gioia G, Seldin-Sommer L, Marcus D Lovastatin, and Shapiro M et al. Lovastatin as a 
pharmacological treatment for learning disabilities in patients with NF1: Safety and 
neuropsychological data from Phase 1 study. Accepted at the 36th Annual Meeting Child 
Neurology Society, October 10-13 2007, Quebec, Canada. 
Acosta MT, Kardel P, Walsh KS, Rosenbaum KN, Gioia GA, Packer RJ (submitted). Lovastatin 
improves cognitive deficits in neurofibromatosis type 1: safety and efficacy Study. 
Anderson GD, Lynn AM.Optimizing pediatric dosing: a developmental pharmacologic approach. 
Pharmacotherapy. 2009 Jun;29(6):680-90. 
Anderson V, Anderson P, Northam E, Jacobs R, and Mikiewicz O (2002). Relationships between 
cognitive and behavioral measures of executive function in children with brain disease. Child 
Neuropsychology, 8: 231-240. 
Anderson V, Lajoie G, and Bell R (1995). Neuropsychological assessment of the school-aged child. 
Department of Psychology, University of Melbourne. 
Armstrong PW and Furberg CD (1995). Clinical trial data and safety monitoring boards. Circulation, 91: 
901-904. 
Astur RS, Taylor LB, Mamelak AN, Philpott L, Sutherland RJ (2002). Humans with 
hippocampus damage display severe spatial memory impairments in a virtual Morris 
water task. Behavioural Brain Research, 132: 77-84. 
Bedard A-C, Martinussen R, Ickowicz A, and Tannock R (2004). Methylphenidate improves visual-
spatial memory in children with attention-deficit/hyperactivity disorder, Journal of the American 
Academy of Child & Adolescent Psychiatry, 43: 260-268. 
Benton A, and Hamsher K (1989). Multilingual aphasia examination. Iowa City: AJA Associates. 
Benton A, Varney N, and Hamsher K (1976). Judgement of Line Orientation. Iowa City: Department of 
Neurology, University of Iowa. 
Bernards A, Snijders AJ, Hannigan GE, Murthy AE, and Gusella JF (1993). Mouse neurofibromatosis 
type 1 cDNA sequence reveals high degree of conservation of both coding and noncoding mRNA 
segments. Human Molecular Genetics, 2: 645-650.  
Bollag G, Clapp DW, Shih S, Adler F, Zhang YY et al. (1996). Loss of NF1 results in activation of the 
Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nature Genetics, 12: 
144-148. 
Boonstra A M, Kooij JJS, Oosterlaan J, Sergeant JA, and Buitelaar JK (2005). Does Methylphenidate 
Improve Inhibition and Other Cognitive Abilities in Adults with ADHD? Journal of Clinical & 
Experimental Neuropsychology, 27: 278-298. 
Brewer VR, Moore BD, and Hiscock M (1997). Learning disability subtypes in children with 
neurofibromatosis. Journal of Learning Disabilities, 30: 521-533. 
Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL et al. (1996). Sensorimotor gating in boys 
with Tourette‟s syndrome and ADHD: preliminary results.  Biological Psychiatry, 39: 33-41. 
Clauss SB, Holmes KW, Hopkins P, Stein E, Cho M et al. (2005). Efficacy and safety of Lovastatin 
therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics, 16: 682-
688. 
Cohen J (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Lawrence 
Earlbaum Associates. 
Conners DK (1997). Conners‟ Rating Scale-Revised Technical Manual. Canada: Multi-Health Systems 
Inc.   
Conners DK (2000). Conners‟ continuous performance test II (CPT II) Version 5.1 for Windows. Canada: 
Multi-Health Systems Inc. 


 
 
 
STARS April 13, 2011   
V 5.0 
40 
Conners CK, Epstein JN, Angold A, and Klaric J (2003). Continuous Performance Test Performance in a 
Normative Epidemiological Sample. Journal of Abnormal Child Psychology, 31: 555-562. 
Corsini A, Maggi FM, and Catapano AL (1995). Pharmacology of competitive inhibitors of HMG-CoA 
reductase. Pharmacological Research, 31: 9-27. 
Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J et al. (2002). Mechanism for the learning 
deficits in a mouse model of neurofibromatosis type 1. Nature, 415: 526-530. 
Costa RM and Silva AJ (2002). Molecular and cellular mechanisms underlying the cognitive deficits 
associated with neurofibromatosis 1. Journal of Child Neurology, 17: 622-626. 
Costa RM, Yang T, Huynh DP, Pulst SM, Viskochil DH et al. (2001). Learning deficits, but normal 
development and tumor predisposition, in mice lacking exon 23a of Nf1. Nature Genetics, 27: 
399-405. 
Dasgupta B, Yi Y, Chen DY, Weber JD, and Gutmann DH (2005). Proteomic analysis reveals 
hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated 
human and mouse brain tumors. Cancer Research, 65: 2755-2760. 
Daston MM and Ratner N (1992). Neurofibromin, a predominantly neuronal GTPase activating protein in 
the adult, is ubiquitously expressed during development. Developmental Dynamics, 195: 216-226. 
Daston MM, Scrable H, Nordlund M, Sturbaum AK, Nissen LM et al. (1992). The protein product of the 
neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and 
oligodendrocytes. Neuron, 8: 415-428. 
DeClue JE, Papageorge AG, Fletcher JA, Diehl SR, Ratner N et al. (1992). Aberrant regulation of 
mammalian p21ras contributes to malignant tumor growth in con Recklinghausen (type 1) 
neurofibromatosis. Cell, 69: 265-273. 
DeMets DL, Pocock S, and Julian DG (1999). The agonising negative trend in monitoring clinical trials. 
Lancet, 354:1983-1988. 
Elias PK, Elias MF, D‟Agostino RB, Sullivan LM, Wolf PA et al. (2005). Serum cholesterol and 
cognitive performance in the Framington Heart Study. Psychosomatic Medicine, 67: 24-30. 
Ferner RE, Hughes RAC, and Weinman J (1996). Intellectual impairment in neurofibromatosis 1. Journal 
of the Neurological Sciences, 138: 125-133. 
Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T et al. (2004). SGS742: the first GABAb 
receptor antagonist in clinical trials. Biochemical Pharmacology, 68: 1479-1487. 
Gengo F, Cwudzinski D, Kinkel P, Block G, Stauffer L et al. (1995). Effects of treatment with Lovastatin 
and pravastatin on daytime cognitive performance. Clinical Cardiology, 18: 209-214. 
Gibellato MG, Moore JL, Selby, and Bower (2001). Effects of Lovastatin and pravastatin on cognitive 
function in military aircrew. Aviation, Space & Environmental Medicine, 72: 805-812. 
Gioia GA, Isquith PK, Guy SC, and Kenworthy L (2000). Behavior Rating Inventory of Executive 
Function. Odessa: Psychological Assessment Resources. 
Graf A, Landolt MA, Mori AC, and Boltshauser E (2006). Quality of life and psychological adjustment in 
children and adolescents with neurofibromatosis type 1.  Journal of Pediatrics, 149: 348-353A. 
Guo, HF, The I, Hannan F, Bernards A, and Zhong Y (1997). Requirement of Drosophila NF1 for 
activation of adenylyl cyclase by PACAP38-like neuropeptides. Science, 276: 795-798. 
Guy SC, Isquith PK, and Gioia GA (2004). Behavior rating inventory of executive function - self report 
version professional manual. Lutz, FL: Psychological Assessment Resources. 
Hajra A, Martin-Gallardo A, Tarle SA, Freedman M, Wilson-Gunn S et al. (1994). DNA sequences in the 
promoter region of the NF1 gene are highly conserved between human and mouse. Genomics, 21: 
649-652. 
Heritier SR, Gebski VJ, and Keech AC (2003). Inclusion of patients in clinical trial analysis: the 
intention-to-treat principle. Medical Journal of Australia, 179: 438–440. 


 
 
 
STARS April 13, 2011   
V 5.0 
41 
Hsu I, Spinler SA, and Johnson NE (1995). Comparative evaluation of the safety and efficacy of HMG-
CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Annals of 
Pharmacotherapy, 29: 743-759. 
Hyman SL, Shores EA, and North KN (2005). The nature and frequency of cognitive deficits in children 
with neurofibromatosis type 1. Neurology, 65: 1037-1044. 
Hyman SL, Shores EA, and North KN (2006). Learning disabilities in children with NF1: subtypes, 
cognitive profile, and attention deficit/hyperactivity disorder. Developmental Medicine and Child 
Neurology, 48: 973-977. 
Sangester J, Shores EA, Watt S, and North KN (2011). The cognitive profile of young children with 
neurofibromatosis type 1. Child Neuropsychology, 17: 1-16. 
Johannessen CM, Reczek EE, James MF, Brems H, Legius E et al. (1995). The NF1 tumor suppressor 
critically regulates TSC2 and mTOR. Proceedings of the National Academy of Sciences USA, 
102: 8573-8578. 
Kallai J, Makany T, Karadi K, Jacobs WJ. Spatial orientation strategies in Morris-type virtual 
water task for humans (2005). Behavioural Brain Research;159: 187-96. 
Kantola T, Kivisto KT, and Neuvonen PJ (1998). Grapefruit juice greatly increases serum concentrations 
of Lovastatin and Lovastatin acid. Clinical Pharmacology & Therapeutics, 63: 397-402. 
Kempton S, Vance ALA, Maruff P, Luk E, Costin J et al. (1999). Executive function and attention deficit 
hyperactivity disorder: stimulant medication and better executive function performance in 
children. Psychological Medicine, 29: 527-538. 
Kesler SR, Haberecht MF, Menon V, Warsofsky IS, Dyer-Friedman J et al. (2004).  Functional 
Neuroanatomy of Spatial Orientation Processing in Turner Syndrome. Cerebral Cortex, 14: 174-
180. 
Knox JJ, Siu LL, Chen E, Dimitroulakos J, Kamel-Reid S et al. (2005).  A Phase I trial of prolonged 
administration of Lovastatin in patients with recurrent or metastatic squamous cell carcinoma of 
the head and neck or of the cervix. European Journal of Cancer, 41: 523-530. 
Kostis JB, Rosen RC, and Wilson AC (1994) Central nervous system effects of HMG CoA reductase 
inhibitors: Lovastatin and pravastatin on sleep and cognitive performance in patients with 
hypercholesterolemia. Journal of Clinical Pharmacology, 34: 989-996. 
Kwiterovich PO, Jr. (2001). Safety and efficacy of treatment of children and adolescents with elevated 
low density lipoprotein levels with a step two diet or with Lovastatin. Nutrition, Metabolism & 
Cardiovascular Diseases, 11(S5): 30-34. 
Lambert M, Lupien PJ, Gagne C, Levy E, Blaichman S et al. (1996). Treatment of familial 
hypercholesterolemia in children and adolescents: effect of Lovastatin. Canadian Lovastatin in 
Children Study Group. Pediatrics, 97: 619-628. 
Lan, KKG. and DeMets, DL.  Discrete sequential boundaries for clinical trials, Biometrika, 70 (1983), 
659-663 
Lange Pharmacology: http://www.amazon.com/Basic-Clinical-Pharmacology-ninth-
science/dp/0071410929 
Levine TM, Materek A, Abel J, O‟Donnell M, and Cutting LE (2006). Cognitive profile of 
neurofibromatosis type 1. Seminars in Pediatric Neurology, 13: 8-20 
Li W, Cui Y, Kushner SA, Brown RAM, Jentsch JD et al. (2005). The HMG-CoA reductase inhibitor 
Lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 
1. Current Biology, 15: 1961-1967. 
Luciana M (2003) Practitioner review: computerized assessment of neuropsychological function in 
children: clinical and research applications of the Cambridge Neuropsychological Testing 
Automated Battery (CANTAB). Journal of Child Psychology and Psychiatry, 44: 649-663. 
Lynch, MA (2004). Long-term potentiation and memory. Physiological Reviews, 84: 87-136. 


 
 
 
STARS April 13, 2011   
V 5.0 
42 
Makdissi M, Collie A, Maruff P, Darby DG, Bush A et al. (2001). Computerised cognitive assessment of 
concussed Australian Rules footballers. British Journal of Sports Medicine, 35: 354-360. 
Manly T, Robertson IH, Anderson V, and Nimmo-Smith I (1999). The Test of Everyday Attention for 
Children. London; Battley Brothers. 
Marais GE and Larson KK (1990). Rhabdomyolysis and acute renal failure induced by combination 
Lovastatin and gemfibrozil therapy. Annals of Internal Medicine, 112: 228-230. 
Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ et al. (1990). The GAP-related domain of 
the neurofibromatosis type 1 gene product interacts with ras p21. Cell, 63: 843-849 
Mautner VF, Kluwe L, Thakker SD, and Leark RA (2002). Treatment of ADHD in neurofibromatosis 
type 1. Developmental Medicine & Child Neurology, 44: 164-170. 
Mazzocco MMM, Turner JE, Denckla MB, Hofman KJ, Scanlon DC et al. (1995). Language and reading 
deficits associated with neurofibromatosis type 1: evidence for not-so-nonverbal learning 
disability. Developmental Neuropsychology, 11: 503-522. 
Mendola CE and Backer JM (1990). Lovastatin blocks N-rasoncogene-induced neuronal differentiation. 
Cell Growth & Differentiation, 1: 499-502. 
Merck & Co., Inc. (2007). Mevacor (Lovastatin) fact sheet. Merck & Co., Inc., Whitehouse Station: NJ. 
http://www.merck.com/product/usa/pi_circulars/m/mevacor/mevacor_pi.pdf 
Mehta MA, Goodyer IM, and Sahakian BJ (2004). Methylphenidate improves working memory and set-
shifting in AD/HD: relationships to baseline memory capacity. Journal of Child Psychology & 
Psychiatry, 45: 293-305. 
Mogensen J, Moustgaard A, Khan U, Wortwein G, and Nielsen KS (2005). Egocentric spatial orientation 
in a water maze by rats subjected to transection of the fimbria-fornix and/or ablation of the 
prefrontal cortex. Brain Research Bulletin, 65: 41-58. 
Mohr E and Brouwers P (1991). Handbook of Clinical Trials: The Neurobehavioural Approach. 
Amsterdam: Swets & Zeitlinger. 
Morris R (1984). Developments of a water-maze procedure for studying spatial learning in the rat. 
Journal of Neuroscience Methods, 11: 47-60. 
Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP et al. (2000). Effects of Lovastatin on 
cognitive function and psychological well-being. American Journal of Medicine, 108: 538-547. 
National Institutes of Health [NIH] (1988) Neurofibromatosis. Conference statement. National Institutes 
of Health Consensus Development Conference. Archives of  Neurology, 45: 575-578. 
Nestor PJ, Scheltens P, and Hodges JR (2004). Advances in the early detection of Alzheimer‟s disease. 
Nature Medicine 10 Suppl: 34-41. 
North KN (1998). Clinical aspects of neurofibromatosis 1. European Journal of Paediatric Neurology, 2: 
223-231. 
North KN, Hyman SL, and Barton B (2002). Cognitive deficits in neurofibromatosis type 1. Journal of 
Child Neurology, 17: 605: 612. 
North KN, Riccardi V, Samango-Sprouse C, Ferner R, Moore B, Legius E, Ratner N, and Denckla MB 
(1997). Cognitive function and academic performance in neurofibromatosis 1: consensus 
statement from the NF1 Cognitive Disorders Task Force. Neurology, 48: 1121-1127. 
Novartis. Ritalin® Medication Guide. December, 2010. 
O'Brien PC, Fleming TR.  A multiple testing procedure for clinical trials.  Biometrics 35 (1979), pp. 549-
556. 
Ozonoff S (1999). Cognitive impairment in neurofibromatosis type 1. American Journal of Medical 
Genetics, 89: 45-52. 
Page PZ, Page GP, Ecosse E, Korf BR, Leplege A et al. (2006). Impact of neurofibromatosis 1 on quality 
of life: a cross-sectional study of 176 American cases. American Journal of Medical Genetics, 
140A: 1893-1898. 


 
 
 
STARS April 13, 2011   
V 5.0 
43 
Patrick KS, Caldwell RW, Ferris RM and Breese GR. Pharmacology of the enantiomers of threo-
methylphenidate. J  Pharmacol Exp Ther 1987;241:152-158 
Payne JM, Barton B, and North KN (unpublished data). Computerised assessment of neuropsychological 
function in children with NF1. 
Pai GS, Khan M, Barbosa E, Key LL, Craver JR et al. (2000). Lovastatin therapy for X-linked 
adrenoleukodystrophy: clinical and biochemical observations on 12 patients. Molecular Genetics 
& Metabolism, 69: 312-322. 
Peat J, Mellis C, Williams K, and Xuan W (2001). Health science research: a handbook of quantitative 
methods. Sydney: Allen & Unwin. 
Perel P, Roberts I, Sena E, Wheble P, Briscoe C et al. (2006). Comparison of treatment effects between 
animal experiments and clinical trials: systematic review. British Medical Journal (BMJ), doi: 
10.1136/bmj.39048.407928.BE. 
Pierce LR, Wysowski DK, and Gross TP (1990). Myopathy and rhabdomyolysis associated with 
Lovastatin-gemfibrozil combination therapy. Journal of the American Medical Association 
(JAMA), 264: 71-75. 
Pocock, SJ (1977). Group sequential methods in the design and analysis of clinical trials. Biometrika, 64: 
191-199. 
Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients 
(2000). New England Journal of Medicine; 342: 1266-71. 
Reynolds, CR, and Kamphaus RW (2004). Behavior Assessment System for Children - Second Edition. 
Circle Pines: AGS Publishing. 
Ruff RM, and Crouch JA (1991). Neuropsychological test instruments in clinical trials. In E. Mohr & P. 
Brouwers (Eds.), Handbook of clinical trials: The neurobehavioural approach (pp. 89-119. 
Amsterdam: Swets & Zeitlinger. 
Sackett DL (2007). Commentary: Measuring the success of blinding in RCTs: don‟t, must, can‟t or 
needn‟t? International Journal of Epidemiology, 36: 664-665. 
Schrimsher GW, Billingsley RL, Slopis JM, and Moore BD (2003). Visual-spatial performance deficits in 
children with neurofibromatosis type-1. American Journal of Medical Genetics, 120A: 326-330. 
Sebti SM, Tkalcevic GT, and Jani JP (1991). Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the 
growth of human H-rasoncogene transformed cells in nude mice. Cancer Communications, 3: 
141-147. 
Shallice T (1982). Specific impairments of planning. Philosophical Transactions of the Royal Society of 
London B, 298: 199-209. 
Sherman EMS, Slick DJ, Connolly MB, Steinbok P, Martin R et al. (2003). Reexamining the effects of 
epilepsy surgery on IQ in children: use of regression-based changes scores. Journal of the 
International Neuropsychological Society, 9: 879-886. 
Shire. Adderall Medication Guide.  2010 Nov.  
Silva AJ, Frankland PW, Marowitz Z, Friedman E, Laszlo GS, Cioffi D, Jacks T, and Bourtchuladze R 
(1997). A mouse model for the learning and memory deficits associated with neurofibromatosis 
type I. Nature Genetics, 15: 281-284. 
Steffenach HA, Witter M, Moser MB, and Moser EI (2005). Spatial memory in the rat requires the 
dorsolateral band of the entorhinal cortex. Neuron 45: 301-313. 
Stein EA, Illingworth DR, Kwiterovich PO, Jr., Liacouras CA, Siimes MA et al. (1999).  Efficacy and 
safety of Lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a 
randomized controlled trial. Journal of the American Medical Association (JAMA), 281: 137-144. 
Sun Z, Murry DJ, Sanghani SP, et al. Methylphenidate is Stereoselectively Hydrolized by 
Human 
            Carboxylestereasa CES1A1. J Pharmacol Experim Therapeut 2004:310;469-476 


 
 
 
STARS April 13, 2011   
V 5.0 
44 
Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR et al. (1996).  Phase I study of Lovastatin, an 
inhibitor of the mevalonate pathway, in patients with cancer. Clinical Cancer Research, 2: 483-
491. 
Tucha O, Mecklinger L, Laufkotter R, Klein HE, Walitza S et al. (2006). Methylphenidate-induced 
improvements of various measures of attention in adults with attention deficit hyperactivity 
disorder. Journal of Neural Transmission, 113: 1575-1592. 
Varni JW, Seid M, and Kurtin PS (2001).  PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Medical Care, 
39: 800-12.  
Vickers AJ and Altman DG (2001). Analysing controlled trials with baseline and follow up 
measurements. British Medical Journal (BMJ), 323: 1123-1124. 
Vree TB, Dammers E, Ulc I, Horkovics-Kovats S, Ryska M et al. (2003). Differences between Lovastatin 
and simvastatin hydrolysis in healthy male and female volunteers: gut hydrolysis of Lovastatin is 
twice that of simvastatin. Scientific World Journal, 3: 1332-1343. 
Weeber EJ and Sweatt JD (2002). Molecular neurobiology of human cognition. Neuron, 33: 845-848. 
Wechsler, D. (1991). Wechsler Intelligence Scale for Children - Third Edition (WISC-III). San Antonio, 
TX: The Psychological Corporation. 
Wechsler D (1999). Wechsler Abbreviated Scale of Intelligence. San Antonio: The Psychological 
Corporation. 
Weiss B, Bollag G, and Shannon K. (1999). Hyperactive Ras as a therapeutic target in neurofibromatosis 
type 1. American Journal of Medical Genetics, 89: 14-22. 
Xu H and Gutmann DH (1997). Mutations in the GAP-related domain impair ability of neurofibromin to 
associate with microtubules. Brain Research, 759: 149-152. 
Xu GF, Lin B, Tanaka K, Dunn D, Wood D et al. (1990). The catalytic domain of the neurofibromatosis 
type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell, 
63: 835-841. 
Xu XQ, McGuire TF, Blaskovich MA, Sebti SM, and Romero G (1996). Lovastatin inhibits the 
stimulation of mitogen-activated protein kinase by insulin in HIRcB fibroblasts. Archives of 
Biochemistry & Biophysics, 326: 233-237. 


 
 
 
STARS April 13, 2011   
V 5.0 
45 
APPENDIX 1:  National Institute of Health Criteria for Neurofibromatosis 1 (1988) 
 
National Institute of Health Criteria Diagnostic for Neurofibromatosis 1  
Two or more of the following 7 clinical features (NIH, 1988): 
Six or more café au lait spots (>0.5 cm in prepubertal individuals and >1.5 cm in postpubertal 
individuals. 
Axillary or groin freckling. 
Optic glioma. 
Two or more Lisch nodules. 
A distinctive bony lesion. 
One plexiform neurofibroma or two or more neurofibromas of any type. 
A first degree relative with NF1 by the above criteria. 


 
 
 
STARS April 13, 2011   
V 5.0 
46 
APPENDIX 2: List of Common Psychotropic Medications 
 
Medication 
Generic Name 
Abilify 
Aripiprazole 
Clozaril 
Clozapine 
fluphenazine (generic only) 
Fluphenazine (Prolixin) 
Geodon 
Ziprasidone 
Orap (for Tourette's syndrome) 
Pimozide 
Risperdal 
Risperidone 
Seroquel 
Quetiapine 
Zyprexa 
Olanzapine 
Aventyl (tricyclic) 
Nortriptyline 
Celexa (SSRI) 
Citalopram 
Cymbalta (SNRI) 
Duloxetine 
Desyrel 
Trazodone 
Effexor (SNRI) 
Venlafaxine 
Elavil (tricyclic) 
Amitriptyline 
Lexapro (SSRI) 
Escitalopram 
Luvox (SSRI) 
Fluvoxamine 
Norpramin (tricyclic) 
Desipramine 
Pamelor (tricyclic) 
Nortriptyline 
Paxil (SSRI) 
Paroxetine 
Prozac (SSRI) 
Fluoxetine 
Remeron 
Mirtazapine 
Wellbutrin 
Bupropion 
Zoloft (SSRI) 
Sertraline 
Depakote 
Divalproex Sodium (Valproic Acid) 
Lamictal 
Lamotrigine 
Neurontin 
Gabapentin 
Tegretol 
Carbamazepine 
Topamax 
Topiramate 
Trileptal 
Oxcarbazepine 
Xanax 
Alprazolam 
Adderall 
Amphetamine 
Adderall XR 
Amphetamine (Extended Release) 
Concerta 
Methylphenidate (Long Acting) 
Daytrana 
Methylphenidate Patch 
Desoxyn 
Methamphetamine 
Dexedrine 
Dextroamphetamine 
Dextrostat 
Dextroamphetamine 
Focalin 
Dexmethylphenidate 


 
 
 
STARS April 13, 2011   
V 5.0 
47 
Focalin XR 
Dexmethylphenidate (Extended Release) 
Metadate ER 
Methylphenidate (Extended Release) 
Metadate CD 
Methylphenidate (Extended Release) 
Methylin 
Methylphenidate (Oral Solution And Chewable Tablets) 
Ritalin 
Methylphenidate 
Ritalin SR 
Methylphenidate (Extended Release) 
Ritalin LA 
Methylphenidate (Long Acting) 
Strattera 
Atomoxetine 
Vyvanse 
Lisdexamfetamine Dimesylate 
Catapress 
Clonidine 
 


 
 
 
STARS April 13, 2011   
V 5.0 
48 
APPENDIX 3:  Study Evaluation Before, During, Post Treatment and Follow-Up  
 
 
Observation 
Pre-
treatment 
2 
weeks* 
4 weeks 
(2 titrated 
& 2 weeks 
full dose) 
8 
weeks 
12 weeks 
Post-
treatment 
16 weeks 
 
Follow-up 
(8 weeks off 
medication) 
Phone Calls  
 
X 
 
 
 
 
 
Hx and Physical 
X 
 
X 
X 
X 
X 
X 
CBC  
X 
 
X 
X 
X 
X 
X 
Chemistries  
X 
 
X 
X 
X 
X 
X 
Neuropsychological 
measures  
X 
 
 
 
 
X 
X 
Pregnancy testing 
X 
 
 
X 
 
X 
 
Side-
Effects/Toxicity 
(Check List) 
 
X 
X 
X 
X 
X 
X 
Drug compliance 
 
X 
X 
X 
X 
X 
 
NB. Chemistries: Blood urea nitrogen (BUN), creatinine, glucose, alanine amino transferase 
(ALT), aspartate amino transferase (AST), total and direct bilirubin, CPK, Lipid profile (HDL, 
Cholesterol, LDL, Triglycerides). Indirect bilirubin will be computed from total and direct 
bilirubin serum measurements. 
*Use CRFs as a guide with questions for phone follow-up 


 
 
 
STARS April 13, 2011   
V 5.0 
49 
APPENDIX 4: Consent/Assent 
 
 
 
 
 
    [Blank intentionally – add your site specific approved consent/assents] 


 
 
 
STARS April 13, 2011   
V 5.0 
50 
 APPENDIX 5:  Outcome Measures: Neuropsychological Assessment 
 
Domain 
Measure 
Age range  
Time 
(mins) 
Memory 
*Paired Associate Learning 
(CANTAB) 
7 yrs - adult 
 
10 
 
 
 
 
Attention 
Test of Everyday Attention for 
Children 
*Score! 
Sky Search 
Creature Counting 
Sky Search DT 
6 yrs – 15 yrs 11 
mths 
25 
 
Continuous Performance Test –II 
6 yrs - adult 
15 
 
Conners‟ ADHD/DSM-IV scale 
(parent) 
3 yrs – 17 years 
10 
 
 
 
 
Executive Function 
Stop Signal Task (CANTAB) 
7 yrs – adult 
10 
 
Spatial Working Memory (CANTAB) 
7 yrs – adult 
15 
 
Stockings of Cambridge (CANTAB) 
7 yrs – adult 
10 
 
Controlled Oral Word Association Test 
7 yrs – adult 
5 
 
Behavior Rating Inventory of 
Executive Function (parent) 
5 – 18 yrs 
15 
 
 
 
 
Visual-spatial 
Judgment of Line Orientation 
7 yrs - adult 
10 
 
 
 
 
Visual-perceptual   
Object Assembly (WISC-III) 
6 yrs – 16yrs 
11mths 
13 
Motor 
Motor Screening (CANTAB) 
7 yrs – adult 
5 
 
 
 
 
Intelligence  
Wechsler Abbreviated Scale of 
Intelligence 
6 yrs – adult 
30 
 
 
 
 
Behavior 
Behavior Assessment Scale for 
Children – II (parent & child) 
2 – 25 yrs 
20 
 
 
 
 
Quality of Life 
 
Pediatric Quality of Life Inventory 
(parent & child) 
2 – 18 yrs 
10 
*Primary outcome measures.  
All tests of the comprehensive test battery are administered at baseline, post-treatment and 
follow-up except for the Wechsler Abbreviated Scale of Intelligence, which will only be 
administered at screening.   


 
 
 
STARS April 13, 2011   
V 5.0 
51 
APPENDIX 6:  Drugs & Other Components That Interact With Lovastatin 
 
AVOID WHILE TAKING LOVASTATIN 
CYP3A4/5 – Inducers 
Carbamazepine (Tegretol) 
Dexamethasone 
Ethosuximide (Zarontin) 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir (Viracept) 
Nevirapine (Viramune) 
Oxcarbazepine  (Trileptal) 
Phenobarbital 
Phenylbutazone 
Phenytoin  (Dilantin) 
Primidone  (Mysoline) 
Progesterone (all progestins) 
Rifabutin 
Rifampin 
Rofecoxib  
St John‟s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Rifapentine 
Modafinil 
CYP3A4/5 – Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin (Zithromax) 
Cannabinoids 
Cimetidine (Tagamet) 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine (Rescriptor) 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone  
Erythromycin 
Ethinyl estradiol 
Fluconazole (Diflucan) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
Indinavir (Crixivan) 
lsoniazid 
ltraconazole  
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole  
Nefazodone 
Norfloxacin 
Norfluoxetine 
Omeprazole  (Prilosec) 
Oxiconazole 
Paroxetine  
Propoxyphene 
Roxithromycin 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir (Norvir) 
Saquinavir (Invirase) 
Sertindole 
Sertraline 
Troleandomycin 
Valproic acid   (Depakote) 
Verapamil  
Voriconazole 
Zafirlukast (Accolate) 
Zileuton 
ADAPTED from Cytochrome P-450 Enzymes and Drug Metabolism: Lacy CF, Armstrong LL, Goldman MP, eds. Drug Information Handbook 
8th ed. Hudson, OH; LexiComp Inc. 2000: 1364-1371. 


 
 
 
STARS April 13, 2011   
V 5.0 
52 
APPENDIX 7:  Common Terminology, Criteria for Adverse Events (CTCAE) 
 
Items selected according to most common or serious side effects associated with Lovastatin 
Adverse Event  
 
0 
1 
2 
3 
4 
DERMATOLOGIC 
 
 
 
 
 
Allergic reaction/ 
hypersensitivity 
(including drug fever) 
 
 
none 
transient rash, 
drug 
fever 
<38°C 
(<100.4°F) 
 
 
urticaria, drug 
fever 
>38°C 
(>100.4°F), 
and/or 
asymptomatic 
bronchospasm 
 
symptomatic 
bronchospasm, 
requiring 
parenteral 
medication(s), with 
or 
without urticaria; 
allergy-related 
edema/angioedema 
 
Anaphylaxis 
 
Rash/desquamation  
 
none  
 
macular 
or 
papular 
eruption 
or 
erythema 
without 
associated 
symptoms 
 
macular 
or 
papular 
eruption 
or 
erythema 
with 
pruritus 
or other 
associated 
symptoms 
covering 
<50% of body 
surface 
or 
localized 
desquamation 
or other 
lesions 
covering 
<50% 
of 
body 
surface area 
 
symptomatic 
generalized 
erythroderma or 
macular, papular or 
vesicular eruption 
or 
desquamation 
covering 
>50% 
of 
body 
surface 
area 
 
generalized 
exfoliative 
dermatitis or 
ulcerative 
dermatitis 
 
HEMATOLOGIC 
 
 
 
 
 
Hemoglobin (Hgb)  
 
WNL 
<LLN - 10.0 
g/dL 
<LLN - 100 
g/L 
<LLN - 6.2 
mmol/L 
 
8.0 
- <10.0 
g/dL 
80 - <100 g/L 
4.9 
- 
<6.2 
mmol/L 
 
6.5 - <8.0 g/dL 
65 - <80 g/L 
4.0 - <4.9 mmol/L 
 
<6.5 g/dL 
<65 g/L 
<4.0 mmol/L 
 
Platelets  
 
WNL 
<LLN - 75.0 x 
109 /L 
<LLN 
- 
75,000/mm3 
 
>50.0 - <75.0 
x 109 /L 
>50,000 
- 
<75,000/mm3 
>10.0 - <50.0 x 
109 /L 
>10,000 
- 
<50,000/mm3 
<10.0 x 109 
/L 
<10,000/mm3 
 
CONSTITUTIONAL 
 
 
 
 
 
Fatigue 
(lethargy, malaise, asthenia) 
none  
 
increased 
fatigue over 
moderate 
(e.g., decrease 
severe 
(e.g., 
decrease in 
bedridden or 
disabling 


 
 
 
STARS April 13, 2011   
V 5.0 
53 
 
baseline, 
but 
not 
altering 
normal 
activities 
 
in 
performance 
status 
by 1 ECOG 
level or 
20% 
Karnofsky or 
Lansky) 
or 
causing 
difficulty 
performing 
some activities 
 
performance status 
by 
>2 ECOG levels or 
40% 
Karnofsky 
or 
Lansky) or 
loss of ability to 
perform 
some 
activities 
 
 
Dizziness/lightheadedness  
 
none 
not interfering 
with 
function 
interfering 
with 
function, 
but 
not 
interfering 
with 
activities 
of 
daily living 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
 
Insomnia  
Note: This adverse event is 
graded when insomnia is related 
to treatment. If pain or other 
symptoms interfere with sleep 
do NOT grade as insomnia. 
normal  
 
occasional 
difficulty 
sleeping 
not 
interfering 
with function 
 
difficulty 
sleeping 
interfering 
with 
function, 
but 
not 
interfering 
with 
activities 
of 
daily living 
 
 
frequent difficulty 
sleeping, 
interfering 
with activities of 
daily 
living 
 
- 
Headache 
 
 
none 
mild pain not 
interfering 
with function 
 
moderate pain: 
pain or 
analgesics 
interfering 
with function, 
but not 
interfering 
with 
activities 
of 
daily living 
severe pain: pain 
or 
analgesics severely 
interfering with 
activities of daily 
living 
disabling 
 
GASTRO-INTESTINAL 
 
 
 
 
 
Abdominal pain or cramping  
 
none 
 
mild pain not 
interfering 
with function 
moderate pain: 
pain or 
analgesics 
interfering 
with function, 
but not 
interfering 
with 
activities 
of 
severe pain: pain 
or 
analgesics severely 
interfering with 
activities of daily 
living 
disabling 
 


 
 
 
STARS April 13, 2011   
V 5.0 
54 
daily living 
Constipation  
 
none  
 
requiring stool 
softener 
or 
dietary 
modification 
requiring 
laxatives  
 
requiring 
manual evacuation 
or 
enema 
 
obstruction or 
toxic 
megacolon 
 
Diarrhea 
participants without colostomy: 
 
none 
increase of <4 
stools/day 
over 
pretreatment 
increase of 4-6 
stools/day, or 
nocturnal 
stools 
 
increase of >7 
stools/day or 
incontinence; 
or 
need 
for 
parenteral 
support 
for dehydration 
physiologic 
consequences 
requiring 
intensive care; 
or 
hemodynamic 
collapse 
Flatulence  
none  
mild  
moderate  
- 
 - 
HEPATIC 
 
 
 
 
 
AST 
 
WNL 
 
>ULN - 2.5 x 
ULN 
>2.5 - 5.0 x 
ULN 
>5.0 - 20.0 x ULN 
 
>20.0 x ULN 
 
ALT 
 
WNL 
>ULN - 2.5 x 
ULN 
>2.5 - 5.0 x 
ULN 
>5.0 - 20.0 x ULN  
 
>20.0 x ULN 
 
Bilirubin  
WNL 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
MUSCLE 
 
 
 
 
 
CPK 
(creatine phosphokinase) 
WNL 
 
>ULN - 2.5 x 
ULN 
>2.5 - 5 x 
ULN 
>5 - 10 x ULN  
 
>10 x ULN 
Muscle weakness 
(not due to neuropathy) 
 
 
normal  
 
asymptomatic 
with 
weakness 
on 
physical 
exam 
symptomatic 
and 
interfering 
with 
function, 
but 
not 
interfering 
with 
activities 
of 
daily living 
symptomatic and 
interfering with 
activities of daily 
living 
bedridden or 
disabling 
Myositis 
(inflammation/damage of 
muscle) 
 
Also consider CPK. 
Note: Myositis implies muscle 
damage (i.e., elevated CPK). 
none 
mild pain, not 
interfering 
with 
function 
pain 
interfering 
with 
function, 
but 
not 
interfering 
with 
activities 
of 
daily living 
pain 
interfering 
with 
function 
and 
interfering 
with activities of 
daily 
living 
bedridden or 
disabling 
Myalgia 
(muscle pain) 
 
none  
 
mild pain not 
interfering 
with function 
 
moderate pain: 
pain or 
analgesics 
interfering 
with function, 
but not 
interfering 
with 
activities 
of 
daily living 
severe pain: pain 
or 
analgesics severely 
interfering with 
activities of daily 
living 
Disabling 


 
 
 
STARS April 13, 2011   
V 5.0 
55 
 
B. TIMETABLE 
As outlined in the statement of work, the general timetable of this project is as follows: 
0 – 12 weeks:  Initiation of the study and subject recruitment 
12 – 24 weeks: Continue subject recruitment and initiation of treatment and evaluation 
24 - 36 weeks: Continue recruitment initiation and implementation of the clinical trial 
36 to 72 weeks: Continue study/follow-up participants 
72 to 96 weeks: Final data analysis and completion of the study  
Months 
0 - 3 
3 - 6 
6-9 
9-18 
18-24 
24-36 
Study Design/Ethics/Logistics 
X 
 
 
 
 
 
Subject Recruitment/Initiation /Evaluation 
 
X 
X 
X 
X 
 
Implementation of Trial 
 
 
X 
X 
X 
 
Follow-up Participants 
 
 
 
X 
X 
 
Begin and Complete Final Data Analysis 
 
 
 
 
 
X 


 
 
 
STARS April 13, 2011   
V 5.0 
56 
APPENDIX 8: List of Abbreviations 
 
ADHD 
Attention Deficit Hyperactivity Disorder  
ALT 
Alanine amino transferase 
ANCOVA 
Analysis of covariance 
Apo 
Apolipoprotein 
AST  
Aspartate amino transferase  
BASC-II 
Behavior Assessment System for Children, 2nd ed‟n 
BRIEF 
Behavior Rating Inventory of Executive Function 
BUN 
Blood urea nitrogen 
CADS 
Conners‟ ADHD/DSM-IV Scales 
CANTAB 
Cambridge Neuropsychological Testing Automated Battery 
CBC 
Complete blood count  
COWAT 
Controlled Oral Word Association Test 
CPK 
Creatine phosphokinase 
CPT 
Continuous Performance Task 
CTCAE 
Common Terminology Criteria for Adverse Events 
DoD 
Department of Defense 
DSMB 
Data and Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th ed‟n 
EAB 
External Advisory Board 
FDA 
Food and Drug Administration 
GABA 
Gamma-aminobutyric acid 
GDP 
Guanosine diphosphate 
GTP 
Guanosine-5'-triphosphate 
HDL 
High-density lipoproteins 
heFH  
Hypercholesterolemia  
HIPPA 
Health Insurance Portability and Accountability Act 
HMG CoA 
3-hydroxy-3-methyl-glutaryl-Coenzyme A 
IQ 
Intelligence quotient  
IRB 
Institutional Review Board 
JLO 
Judgment of Line Orientation 
LDL 
Low-density lipoprotein  
LTP  
Long-term potentiation 
MOT 
Motor Screening 
NF1 
Neurofibromatosis type 1 
NIH 
National Institutes of Health 
PAL 
Paired Associate Learning 
PedsQL 
The Pediatric Quality of Life Scale 
PPI  
Pre-pulse inhibition  
RBC 
Regression based change 
SD 
Standard deviation 
SGT 
Solanidine UDP-glucose glucosyltransferase  
SOC 
Stockings of Cambridge 
SST 
Stop Signal Task 
SWM 
Spatial Working Memory 
TEA-Ch 
Test of Everyday Attention for Children 
UDP-glucose 
Uridine diphosphate glucose 
VLDL 
Very low density lipoprotein 
WASI 
Wechsler Abbreviated Scale of Intelligence 
CGA 
Computer Generated Arena  


 
 
 
STARS April 13, 2011   
V 5.0 
57 
APPENDIX 9:  Protocol Roster 
 
Study Chair 
Gerard A. Gioia, Ph.D. 
Program Manager 
Kathryn North, M.D., F.R.A.C.P. 
George Washington U. School of Medicine 
Karen Cole-Plourde, B.S. 
The Children's Hospital at Westmead 
14801 Physician's Lane, Suite 173 
U. of Alabama at Birmingham 
Locked Bag 4001, Westmead 2145 
Rockville, Maryland  20850 
230 Kaul Bldg. 
Sydney, NSW, Australia 
301-738-8930 Phone 
Birmingham, AL  35294-0024 
61-2-9845-1906 Phone 
301-738-8932 Fax 
205-934-5140 Phone 
61-2-9845-3389 Fax 
ggioia@cnmc.org 
205-934-9488 Fax 
KathryN@chw.edu.au 
 
kcole@uab.edu 
 
Medical Monitor 
 
Study Co-Chairs 
Tena Rosser, M.D. 
Department of Defense 
Belinda Barton, Ph.D. 
Children‟s Hospital Los Angeles 
Naba Bora, Ph.D, MBA 
The Children's Hospital at Westmead 
Department of Neurology, MS# 82 
1077 Patchel St. Fort Detrick 
Locked Bag 4001, Westmead 2145 
4650 Sunset Boulevard 
Frederick, MD  21702-9218 
Sydney, Australia 
Los Angeles, CA 90027 
301-619-6881 Phone 
61-2-9845-0415 Phone 
323-361-2940 Phone 
301-619-7796 Fax 
61-2-9845-0421 Fax 
trosser@chla.usc.edu 
240-344-3786 Cell 
BelindaB@chw.edu.au 
 
Naba.Bora@amedd.army.mil 
 
Study Statistician 
 
Jonathan Payne, DPsych. 
Alan Cantor, Ph.D. 
Clinical Coordinator 
The Children's Hospital at Westmead 
University of Alabama at Birmingham 
Elizabeth Davis , RN, MPH, CCRC, 
Clinical Coordinator 
Locked Bag 4001, Westmead 2145 
1530 3rd Avenue South, MT 
U. of Alabama at Birmingham 
Sydney, Australia 
Birmingham, Alabama  35294-4410 
Dept. of Genetics, Kaul 202B 
61-2-9845-3698 Phone 
205-934-5165 Phone 
 
JonathaP@chw.edu.au 
205-975-7453 Fax 
Phone:  205-934-5376 
 
 acantor@uab.edu 
Fax:  205-934-9488 
Maria Acosta, M.D. 
 
lvdavis@uab.edu 
Children's National Medical Center 
 
 
111 Michigan Ave, N.W. 
 
 
Washington, D.C.  20010 
 
 
202-884-2120 Phone 
 
 
202-884-5226 Fax 
 
 
 
 
 
Pam Wolters, Ph.D. 
 
 
Center for Cancer Research-NCI 
 
 
9030 Old Georgetown Road 
 
 
Building 82, Room 109 
 
 
Bethesda, MD  20892-8200 
 
 
301-496-0562 Phone 
 
 
301-402-1734 Fax 
 
 
woltersp@mail.nih.gov 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
STARS April 13, 2011   
V 5.0 
58 
Participating Sites 
Bruce Korf, M.D., Ph.D. 
University of Alabama at Birmingham 
1530 3rd Avenue South - 230 KAUL 
Birmingham, Alabama  35294-0024 
Phone:  205-934-9411 
Fax: 205-934-9488 
bkorf@uab.edu 
 
Elizabeth Schorry, M.D.  
Cincinnati Children‟s Hospital Medical 
Center 
3333 Burnet Avenue - ML 4006 
Cincinnati, OH  45229 
Phone:  513-636-4760/Fax:  513-636-7297 
elizabeth.schorry@cchmc.org 
 
David Gutmann, M.D., Ph.D. 
Washington University School of Medicine 
660 South Euclid Avenue – Box 811 
St. Louis, MO  63110 
314-362-7379 Phone/314-362-2388 Fax 
gutmannd@neuro.wustl.edu 
Roger Packer, M.D. 
Children‟s National Medical Center 
111 Michigan Avenue, NW 
Washington, DC  20010 
Phone:  202-884-2120 
Fax:  202-884-2864 
rpacker@cnmc.org 
 
Michael Fisher, M.D. 
Children‟s Hospital of Philadelphia 
Abramson Research Center, Room 516B 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
Phone:  215-590-5188/Lab: 215-590-2107 
Fax:  215-590-9956 
fisherm@email.chop.edu 
 
James Tonsgard, M.D. 
University of Chicago 
5841 South Maryland Avenue, MC 3055 
Chicago, IL  60637 
Phone:  773-702-6488/Fax:  773-702-4786 
tonsgard@midway.uchicago.edu 
 
Nicole Ullrich, M.D., Ph.D. 
Children‟s Hospital Boston 
Department of Neurology 
300 Longwood Avenue 
Boston, MA 02115 
Phone:   617-355-3193 
Fax: 617-730-0282  
nicole.ullrich@childrens.harvard.edu 
 
David Viskochil, M.D., Ph.D. 
University of Utah 
50 North Medical Drive – 2C412 SOM 
Salt Lake City, UT  84132 
Phone:  801-581-8943/Fax: 801-585-7252 
dave.viskochil@hsc.utah.edu 
 
Kathryn North, M.D., F.R.A.C.P 
The Children‟s Hospital at Westmead 
Cnr Hawkesbury and Hainsworth St 
Westmead NSW 2145 Australia 
Ph: 61 2 9845 1906; Fax: 61-2-9845-3389 
kathryn@chw.edu.au  
 
Additional sites added in 2011: 
 
Susan Huson, MD 
Genetic Medicine Consultant 
Manchester Academic Univ. Hosp. 
NHS Foundation Trust 
Saint Mary‟s Hospital – Oxford Rd. 
Manchester, M13 9WL 
Ph: 0161 901 4924; Fax: 0161 276 6145 
Susan.huson@cmft.nhs.uk 
 
Laura Klesse‟, MD, PhD 
Dedman Family Scholar in Clinical Care 
Assistant Professor of Pediatrics 
Hematology/Oncology 
Childrens Medical Center of Dallas 
University of Texas SW Med Ctr 
Phone: 214-648-3896; Fax: 214-456-3727 
Laura.Klesse@utsouthwestern.edu 


 
 
 
STARS April 13, 2011   
V 5.0 
59 
Roles and Responsibility of Study Personnel 
 
Roger Packer, M.D.: Executive Director of NF Consortium, oversight of trial coordination  
Kathryn North, M.D., F.R.A.C.P.:   Principal Investigator & Protocol Chair 
Belinda Barton, Ph.D.: Protocol Co-Chair 
Jonathan Payne, DPsych: Protocol Co-Chair  
Maria Acosta, M.D.:  Protocol Co-Chair  
Gerard Gioia, Ph.D.: Protocol Co-Chair  
Bruce Korf, M.D., Ph. D:  Principal Investigator – NF Consortium Operations Center  
Alan Cantor, Ph.D.:  Study Statistician and Director,  NF Data Coordinating Center  
Tena Rosser, M.D., Medical Monitor 
Pam Wolters, Ph.D.: Quality of life and pain surveys 
Elizabeth Davis, RN, MPH, CCRC, Clinical Coordinator – NF Operations Center 
Karen A. Cole-Plourde, B.S.: Program Manager – NF Operations Center 


 
 
 
STARS April 13, 2011   
V 5.0 
60 
APPENDIX 10: Adverse Event Monitoring – UK Sites 
 
Participants will be monitored closely for medication side effects with a diary and with 
laboratory testing as indicated in the Study Procedures section (see of the protocol (see Section 
5). Adverse events will be addressed immediately.  Participants will also be closely followed 
clinically at least once per month while on the study medication by the site physician. The Side 
Effects Checklist and Adverse Event Monitoring Form will be used to assess participants at 
every visit or phone contact. 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after the study has commenced, even if not considered to be related to the 
investigational medicinal product.  Medical conditions/diseases present before starting the study 
will only be considered as adverse events if they worsen after the start of the study.  Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy, or as specified on CTCAE, 
version 4. 
 
The occurrence of adverse events will be sought by non-directive questioning of the patient 
during the study.  Adverse events also may be detected when they are volunteered by the patient 
or through physical examination, laboratory test, or other assessment.  As far as possible each 
adverse event will be evaluated to determine: 
 
1. 
The severity (mild, moderate, severe) 
2. 
Its relationship to the investigational medicinal product 
3. 
Its duration 
4. 
Action taken (no action taken; study drug dose adjusted/temporarily interrupted; study 
drug permanently discontinued; concomitant medication taken; non-drug therapy given; 
hospitalisation required) 
5. 
Whether it is serious, where a serious adverse event (SAE) is defined as one which: 
 
Is fatal or life-threatening 
 
Results in persistent or significant disability/incapacity 
 
Constitutes a congenital anomaly/birth defect 
 
Requires 
prolonged 
hospitalisation 
(except 
where 
it 
is 
for 
routine 
treatment/monitoring, elective or pre-planned treatment not related to study, for 
social or respite reasons) 
 
Is medically significant i.e. defined as an event that jeopardises the patient or may 
require medical or surgical intervention to prevent one of the above 
 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see below).   
 
All adverse events will be recorded in detail, reported to the sponosor and treated appropriately.  
Such treatment may include changes in study drug treatment including possible interruption or 
discontinuation, starting or stopping concomitant treatments, changes in the frequency or nature 


 
 
 
STARS April 13, 2011   
V 5.0 
61 
of assessments, hospitalisation, or any other medically required intervention.  Once an adverse 
event is detected it will be followed until its resolution, and assessments will be made at each 
visit (or more frequently if necessary) of any changes in severity, the suspected relationship to 
the investigational medicinal product, the interventions required to treat it, and the outcome. 
 
Evaluation of AEs and SAEs 
Seriousness, causality, severity and expectedness will be evaluated for each AE.  Cases that are 
considered serious, possibly, probably or definitely related to drug (i.e. serious adverse reactions, 
SARs) and unexpected (i.e. SUSARs) should be reported as described below. 
 
Assessment of Seriousness 
The Investigator should make an assessment of seriousness as defined above (see definitions). 
 
Assessment of Causality 
The Investigator must make an assessment of whether the AE/SAE is likely to be related to 
treatment according to the following definitions.  All AEs/SAEs judged as having a reasonable 
suspected causal relationship (e.g. possibly, probably, definitely) to the study drug will be 
considered as ARs/SARs.  If concomitant or rescue/escape drugs are given, the Investigator must 
also make an assessment of whether the AE/SAE is likely to be related to an interaction between 
the study drug and concomitant or rescue/escape drugs or whether the AE/SAE might be linked 
to either the study drug or concomitant or rescue/escape drugs but cannot be attributed to only 
one of these drugs.  All AEs/SAEs judged as being related (e.g. possibly, probably, definitely) to 
an interaction between the study drug and concomitant or rescue/escape drugs, or any AE/SAE 
that cannot be attributed to only the study drug or the concomitant or rescue/escape drugs  will 
also be considered to be ARs/SARs . 
 
Unrelated: where an event is not considered to be related to the study drug. 
Unlikely: the adverse event is doubtfully related to the study medication.  
Possibly: although a relationship to the study drug cannot be completely ruled out, the nature of 
the event, the underlying disease, concomitant medication or temporal relationship make other 
explanations possible. 
Probably: the temporal relationship and absence of a more likely explanation suggest the event 
could be related to the study drug. 
Definitely: The known effects of the study drug or its therapeutic class, or based on challenge 
testing, suggest that study drug is the most likely cause. 
 
Alternative causes such as natural history of the underlying disease, other risk factors and the 
temporal relationship of the event to the treatment should be considered and investigated. 
 
Assessment of Severity based on CTCAE (version 4) 
The Investigator will make an assessment of severity for each AE/SAE and record this on the 
Adverse Event (AE) Form according to one of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with every day activities. 


 
 
 
STARS April 13, 2011   
V 5.0 
62 
Moderate: an event that is sufficiently discomforting to interfere with normal everyday 
activities. 
Severe: an event that prevents normal everyday activities. 
 
Assessment of expectedness 
If an event is judged to be an AR/SAR, the evaluation of expectedness will be made based on 
knowledge of the reaction and the relevant product information documented in the Summary of 
Product Characteristics (SmPC). 
 
Serious Adverse Event (SAE) reporting 
Any SAE will be reported by the Principal Investigator (including a completed SAE form) 
within 24 hours of first knowledge to the Sponsor.  The Principal Investigator will ensure that the 
patient is appropriately treated.  They will also determine whether the SAE is a SUSAR 
(Suspected Unexpected Serious Adverse Reaction).  If it is deemed to be a SUSAR it will be 
reported immediately to the sponsor.  The Regulatory Competent Authority (MHRA) and 
Research Ethics Committee will also be informed in accordance with Trial regulations.  An 
annual safety report will be sent by the Chief Investigator to the MHRA, the Ethics Committee 
and sponsor.  Completed initial and follow-up Serious Adverse Event forms should be faxed to 
the sponsor on 0161 276 5766 and addressed „For the attention of the Quality Manager‟.  
Alternatively, scanned forms can be emailed to adverse.events@cmft.nhs.uk. 
 
Regulatory Reporting Requirements 
The sponsor, or their delegate, has a legal responsibility to notify the Regulatory Competent 
Authority and the Research Ethics Committee that approved the trial.  Fatal or life threatening 
SUSARs will be reported no later than 7 calendar days, with a further 8 days for follow up 
information.  All other SUSARs will be reported no later than 15 calendar days after the sponsor 
is first aware of the reaction.   
 
Follow up procedures 
After initially recording an AE or recording and reporting an SAE, the Principal Investigator is 
required to follow each participant until resolution.  Follow up information on an SAE should be 
reported to the sponsor.  AEs still present in participants at the last study visit should be 
monitored until resolution of the event or until no longer medically indicated. 
 
Criteria for premature termination of study 
These criteria include new safety data, or concerns from safety data (number and nature of 
SUSARs); or evidence from other studies. 
 
Pregnancy 
It the event that pregnancy does occur in a patient an any time between commencement of the 
study and 28 days after completion or termination of the study the pregnancy will be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.  Details of the pregnancy will be recorded on a Pregnancy Reporting Form.  After 


 
 
 
STARS April 13, 2011   
V 5.0 
63 
that the health of the baby will be followed up at 12 and 24 months old.  Any SAE experienced 
during pregnancy will be reported on the SAE Report form. 
 
All serious adverse events require immediate notification to the UK co-sponsor and US 
Operations Center. All adverse events, whether serious or otherwise, will be followed until 
resolution (the patients health has returned to his/her baseline status) or until the event has 
stabilized (investigator does not expect any further improvement or worsening of the adverse 
event). Participants withdrawn from the study due to adverse events will be followed by the 
investigator until resolution. All grade 3, 4 and 5 adverse events will be reviewed by the US 
Clinical Review Committee. 
 
All adverse events will be tabulated by treatment arm, severity grade and reported to the US NF1 
Data and Safety Monitoring Board (DSMB).  The occurrence of adverse events will be reviewed 
by the DSMB at 2-month intervals to monitor patient safety. Summary details of the occurrences 
and grade of adverse events will be distributed to each site at 2-monthly intervals. In addition, all 
unexpected and serious adverse events will be forwarded to the US medical monitor, Tena 
Rosser, M.D. She will serve as a patient advocate, will be independent of the clinical study team, 
and will report to the DSMB. She will oversee the progress of the protocol, especially issues of 
individual subject/patient management and safety. The monitor will provide an unbiased written 
report of each event. 
 
 

SAP_001.pdf: 
 
 
 
STARS April 13, 2011   
V 5.0 
34 
reassure the child that he/she is not expected to answer all the questions and it is only expected 
that he/she try his/her best on the task. All test administrators will have psychological training 
and experience with interacting and assessing children. If for some reason the child states that 
he/she does not want to continue, the assessment will cease. We will then consult with the parent 
and child to ascertain whether the testing will continue. 
 
There are an estimated six partial or whole days that a child could miss school while 
participating in this trial.  We will recommend to the parent (parents, legal guardians) that he/she 
should discuss school policies for excused absences and make necessary arrangements for make-
up work. 
 
 
 
7.0 
Statistics 
 
Determination of sample size: No data exist on the effects of Lovastatin in children with NF1. 
A clinical and meaningful difference for primary efficacy measures is defined as an effect size of 
one half of a standard deviation, which is classified as a treatment effect of medium magnitude 
(Cohen, 1988). A sample size of 64 participants per treatment group (128 total) will be sufficient 
to detect an effect size of half a standard deviation at the two-sided 0.05 significance level with 
power of 0.80 (Peat, Mellis, Williams & Xuan, 2001).  To allow for a 10% dropout rate prior to 
the 16-week point, a total of 142 participants will be enrolled.  
 
Interim analyses: Interim analyses will be done under the purview of the DSMB, which will set 
the content and frequency of analyses.  We will propose a Charter containing a data monitoring 
plan that will include stopping guidelines.  We expect these to be the Lan DeMets modifications 
of the O‟Brien Fleming boundaries (Lan & DeMets, 1983; O‟Brien & Fleming, 1979)).  It is 
expected that the DSMB will review this charter during its first meeting. 
         
Data analysis: Demographic and baseline characteristics will be summarized for each group 
using descriptive statistics. Intention-to-treat analyses will be conducted for the primary 
outcomes measures. An intention-to-treat analysis provides an unbiased, conservative and 
consistent estimate of a treatment effect (Heritier, Gebski & Keech, 2003).  
 
Analyzing change scores from baseline to post-treatment does not control for baseline imbalance 
because of the regression to the mean (Vickers & Altman, 2001). Also, with changes scores, if 
the treatment is effective, the statistical significance of the treatment effect will depend upon the 
correlation between baseline and follow-up scores. Therefore, to determine whether there has 
been a significant change from baseline to post-treatment, primary and secondary outcomes will 
be analyzed using ANCOVA, which is a better approach than analyzing change scores with 
independent t-tests (Vickers & Altman, 2001). 
 
In addition, at an individual case level to determine whether test-retest change scores from 
baseline to post-treatment are reliable and clinically meaningful, standardized regression based 


 
 
 
STARS April 13, 2011   
V 5.0 
35 
change scores (RBC) will be also be calculated. RBC can account for measurement error, 
differential practice effects and regression to the mean (Sherman et al., 2003). However, RBC 
scores do not necessarily indicate whether a significant change from baseline has occurred 
(Sherman et al., 2003).  Similar statistical analysis will be conducted for scores from post-
treatment to follow-up. Linear mixed models may also be conducted to examine changes over 
time. In addition, a number of sub-group analyses are planned to help identify individuals more 
likely to benefit from, or be harmed by, the treatment. In regard to treatment effects, definition of 
subgroups will rely on baseline data, not data measured after randomization. Such subgroups 
might include age (including comparison of 8-9 years to 10 years and older), gender, and 
presence of ADHD (on or off stimulant medication) (if there are sufficient cases). Exploratory 
data derived through subgroup analyses will serve primarily to generate new hypothesis for 
subsequent studies.  
 
8.0 
Data Management 
 
Data sets will follow all standards as per Data Coordinating Center‟s guidelines and 
recommendations. All paper charts, forms, and information associated with this study will be 
kept in a locked cabinet at the clinical sites. Access to this cabinet is available only to 
investigators on the study and research assistants. All participant information from this study will 
be strictly confidential. On entry to the study, participants will be assigned a unique PIN that will 
be used throughout the study. All data stored in computer systems will be password protected 
and stored using participant PINs only (see next section for more information regarding database 
security). Participant names will not be used in any computer databases associated with this 
project. A list of participant names and coordinating PINs will be kept separately on the 
password-protected principal investigator‟s computer. This information will be kept in 
accordance with the requirements of the Department of Defense. 
 
8.1 
Medical Monitor and Data Safety Monitoring Plan 
The Data Safety and Monitoring Plan for this study will follow the NIH guidelines. The External 
Advisory Board (EAB) will serve as external reviewers and advisors to DoD and the Governing 
Body.  The EAB will review and approve the protocol with respect to ethical and safety standards. 
Its primary responsibility will be to monitor the emerging results of the trial to assess treatment 
representatives are ex officio members of the EAB. The EAB will determine the content and 
frequency of safety reports it will review and will periodically review interim analyses of data 
collected for this study. 
 
In addition, the DSMB will protect the integrity of the study by ensuring that recruitment targets 
can be met within the study timelines. This will be achieved by comparing actual recruitment 
against planned and by monitoring participant drop-out rates. In the event that the number of 
accrued patients is less than 20% of the planned value, the DSMB will advise on appropriate 
remedial action. Possible remedial actions may include, but are not limited to, the extension of 
the recruitment period, review and amendment of inclusion criteria. 
 


 
 
 
STARS April 13, 2011   
V 5.0 
36 
Dr. Tena Rosser will be the medical monitor for this study. She is a qualified physician and is not 
associated with this protocol. She will work closely with the Principal Investigator to monitor the 
participants‟ treatment while on this study. The medical monitor is required to review all 
unanticipated problems involving risk to subjects or others, serious adverse events and all subject 
related deaths associated with the protocol, providing an unbiased written report of the event. At 
minimum, the medical monitor should comment on the outcomes of the event or problem, and in 
the case of a serious adverse event or death, comment on the relationship to participation in the 
study. The medical monitor should also indicate whether she concurs with the details of the 
report provided by the study investigator. Reports for events determined by either the 
investigator or the medical monitor to be possibly or definitely related to participation and 
reports of events resulting in death should be promptly forwarded to the USAMRMC ORP 
HRPO. 
 
It is expected that summaries of accrual, retention, and adverse events will be disseminated to the 
clinical centers periodically.  To maintain the blind, adverse events will be aggregated across 
treatment arms.  
 
8.2 
Confidentiality 
 
Data will be obtained and stored consistent with IRB and HIPAA guidelines. All participant 
charts, standardized study forms, and information associated with this study will be kept in a 
locked cabinet in the principal investigator‟s office. Access to this cabinet is available only to the 
principal investigator and the research team. All participant information from this study will be 
strictly confidential. On entry to the study, participants will be assigned a unique participant PIN 
that will be used throughout the study. All data stored in computer systems will be password 
protected and stored using PINS only. Participant names will not be used in any computer 
databases associated with this project. A list of participant  names and coordinating PINs will be 
kept separately on the password protected principal investigator‟s computer. This information 
will be kept in accordance with the requirements of the Department of Defense.  
 
9.0 
Ethical and Regulatory Consideration 
 
9.1 
Consent/Assent/HIPAA Process and Documentation 
 
The investigational nature and objectives of the study, procedures involved, treatments involved, 
medication side effects, risks, benefits and alternative therapies will be carefully explained to 
potential participants and their parents/legal guardians. Potential participants will be allowed to 
take their time in deciding whether to join the trial and will be given privacy to make their 
decision. They will also be encouraged to discuss their concerns or questions about joining the 
trial with their parents/guardian.  Consent will be obtained from parents/legal guardians and 
assent will be obtained from children aged 8 years to less than 16 years, with signatures obtained 
as appropriate.  This trial will be conducted in compliance with the Good Clinical Practice 
guidelines and the applicable regulatory requirements.