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

Information source: University of Alabama at Birmingham
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Neurofibromatosis Type 1

Intervention: Lovastatin ™ (Drug); placebo (Device)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: University of Alabama at Birmingham

Official(s) and/or principal investigator(s):
Kathryn North, MD, Principal Investigator, Affiliation: University of Sydney - Westmead
Maria Acosta, MD, Study Director, Affiliation: Children's Research Institute
Jonathan Payne, MD, Study Director, Affiliation: University of Sydney - Westmead

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Visual Spatial Learning and Memory; Attention: *Score!; and TEA-Ch.

Secondary outcome: Conners' Continuous Performance Task - II (CPT-II: Conners, 2000)

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 10 and 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 10 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 10 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 10 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.

Eligibility

Minimum age: 10 Years. Maximum age: 15 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Males or females aged between 10 years and 15 years 11 months at time of enrollment

who meet NIH diagnostic criteria for NF1 (Appendix 1)

- Participants must have a full-scale IQ of 70 or above

- 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 with NF1 and a diagnosis of ADHD who are not taking stimulant or

non-stimulant medication

- Hepatic function:

- Participants must have a bilirubin within normal limits and AST and ALT ± 2 times the

upper limit of normal as determined by the standards at their institution

- Renal function:

- Participants must have an age-adjusted normal serum creatinine or a creatinine

clearance of greater than 70 ml/m/1. 73m2

- Hematologic function:

- Participants must have an absolute neutrophil count of greater than 1,500, a

hemoglobin of greater than 9 gms/dl, and a platelet count of greater than 100,000 on study entry

- Participants must sign all required documents, including informed assent and HIPAA

documents

- Female participants of childbearing age should not be pregnant, must have a negative

pregnancy test before initiation of treatment, and take appropriate birth control precautions to participate in this study. Exclusion Criteria:

- Full-scale IQ less than 70;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 stimulant medication or stratera will be excluded because it is

unclear whether Lovastatin ™ and ADHD medication utilize similar biological pathways, possibly leading to an interaction between the two medications

- Participants on psychotropic, behavioral, or antiepileptic medication

- 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 drugs of any type within 30 days of initiation of study

- Participants who participated in a Phase I trial of Lovastatin ™ or who have

previously taken Lovastatin ™

- 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 100mg/dl (2. 56mmol/L)

- Participants who have taken sirolimus within three months of enrollment. These

participants are eligible after a washout period of at least three months.

Locations and Contacts

The University of Alabama at Birmingham, Birmingham, Alabama 35294, United States

Children's Hospital Los Angeles, Los Angeles, California 90027, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

University of Chicago, Chicago, Illinois 60637, United States

Children' Hospital Boston, Boston, Massachusetts 02115, United States

Washington University - St. Louis, St. Louis, Missouri 63110, United States

The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19096, United States

Childrens Medical Center - Univ. of Texas SW Medical Center, Dallas, Texas 75235, United States

University of Utah, Salt Lake City, Utah 84132, United States

Additional Information

Starting date: July 2009
Last updated: July 3, 2015

Page last updated: August 23, 2015

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