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

Sponsor:	University of Alabama at Birmingham
Collaborators:	Children's Hospital Boston Children's Hospital Philadelphia Children's Research Institute Children's Hospital Medical Center, Cincinnati National Cancer Institute (NCI) University of Chicago University of Utah Washington University School of Medicine The Children's Hospital at Westmead
Information provided by:	University of Alabama at Birmingham
ClinicalTrials.gov Identifier:	NCT00853580

Purpose

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.

Condition	Intervention	Phase
Neurofibromatosis Type 1	Drug: Lovastatin ™ Device: placebo	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1

Resource links provided by NLM:

Genetics Home Reference related topics: neurofibromatosis type 1 neurofibromatosis type 2 Help Me Understand Genetics

MedlinePlus related topics: Memory Neurofibromatosis

Drug Information available for: Lovastatin

U.S. FDA Resources

Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:

Visual Spatial Learning and Memory; Attention: *Score!; and TEA-Ch. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Conners' Continuous Performance Task - II (CPT-II: Conners, 2000) [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment:	142
Study Start Date:	July 2009
Estimated Study Completion Date:	April 2012
Estimated Primary Completion Date:	April 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: 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 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.	Device: placebo Starting at 20mg for 2 weeks, then increasing to 40mg for 14 additional weeks for a total duration of treatment of 16 weeks.
Experimental: 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 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.	Drug: Lovastatin ™ Lovastatin starting at 20mg for 2 weeks, increasing to 40mg for 14 weeks. Total duration of trial is 16 weeks.

Arms

Assigned Interventions

Placebo Comparator: 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 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.

Device: placebo

Starting at 20mg for 2 weeks, then increasing to 40mg for 14 additional weeks for a total duration of treatment of 16 weeks.

Experimental: 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 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.

Drug: Lovastatin ™

Lovastatin starting at 20mg for 2 weeks, increasing to 40mg for 14 weeks. Total duration of trial is 16 weeks.

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

Ages Eligible for Study:	10 Years to 15 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

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 straterra 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00853580

Contacts

Contact: Bruce Korf, MD, PhD	205.934.9411	bkorf@uab.edu
Contact: Karen Cole-Plourde, BS	205.934.5140	kcole@uab.edu

Locations

United States, Alabama
The University of Alabama at Birmingham	Recruiting
Birmingham, Alabama, United States, 35294
Contact: Bruce Korf, MD 205-934-9411 bkorf@uab.edu
Contact: Christina Barger, MPH 205.934-9411 cbarger@genetics.uab.edu
Principal Investigator: Bruce Korf, MD, PhD
United States, District of Columbia
Children's National Medical Center	Recruiting
Washington, District of Columbia, United States, 20010
Contact: Roger Packer, MD 202-884-2120 rpacker@cnmc.org
Contact: Rochelle Kane 202.476.6485 RKanejac@cnmc.org
Principal Investigator: Roger Packer, MD
United States, Illinois
University of Chicago	Recruiting
Chicago, Illinois, United States, 60637
Contact: James Tonsgard, MD 773-702-6488 tonsgard@midway.uchicago.edu
Contact: Cynthia MacKenzie 773.702.6487 cmackenzie@peds.bsd.uchicago.edu
Principal Investigator: James Tonsgard, MD
United States, Maryland
National Cancer Institute (NCI)	Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: Brigitte Widemann, MD 301-496-7387 widemannb@mail.nih.gov
Contact: Andy Gillespie, RN 301.402.1848 gillesan@mail.nih.gov
United States, Massachusetts
Children' Hospital Boston	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Nicole Ullrich, MD 617-355-3193 nicole.ullrich@childrens.harvard.edu
Contact: Heather Spinney 617.355.2067 heather.spinney@childrens.harvard.edu
United States, Missouri
Washington University - St. Louis	Recruiting
St. Louis, Missouri, United States, 63110
Contact: David Gutmann, MD 314-362-7379 gutmann@neuro.wustl.edu
Contact: Linda Murray 314.454.4240 'Murray_KW@kids.wustl.edu
Principal Investigator: David Gutmann, MD
United States, Ohio
Cincinnati Children's Hospital Medical Center	Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Elizabeth Schorry, MD 513-636-4760 Elizabeth.Schorry@cchmc.org
Contact: Kristina Kruskamp 513.636.5336 Kristina.Kruskamp@cchmc.org
Principal Investigator: Elizabeth Schorry, MD
United States, Pennsylvania
Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19096
Contact: Michael Fisher, MD 215-590-5188 fisherm@email.chop.edu
Contact: Ratnakar Patti 215.590.5188 ratnakarp@email.chop.edu
Principal Investigator: Michael Fisher, MD
United States, Utah
University of Utah	Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Dave Viskochil, MD 801-581-8943 dave.viskochil@hsc.utah.edu
Contact: Heather Hanson 801.587.7689 Heather.Hanson@hsc.utah.edu
Principal Investigator: John Carey, MD
Australia, New South Wales
The Children's Hospital at Westmead	Recruiting
Westmead, New South Wales, Australia, 2145
Contact: Kathryn North, MD 61-9845-1906 kathryN@chw.edu.au
Contact: Jonathan Payne, MD 61.2.9845.3698 JonathaP@chw.edu.au
Principal Investigator: Kathyrn North, MD

Sponsors and Collaborators

University of Alabama at Birmingham

Children's Hospital Boston

Children's Hospital Philadelphia

Children's Research Institute

Children's Hospital Medical Center, Cincinnati

National Cancer Institute (NCI)

University of Chicago

University of Utah

Washington University School of Medicine

The Children's Hospital at Westmead

Investigators

Principal Investigator:	Kathryn North, MD	University of Sydney - Westmead
Study Director:	Maria Acosta, MD	Children's Research Institute
Study Director:	Jonathan Payne, MD	University of Sydney - Westmead

More Information

No publications provided

Responsible Party:	Dr. Bruce Korf, PI, The University of Alabama at Birmingham
ClinicalTrials.gov Identifier:	NCT00853580 History of Changes
Other Study ID Numbers:	X080929007, DOD: W81XWH-05-1 0615
Study First Received:	February 23, 2009
Last Updated:	July 27, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by University of Alabama at Birmingham:

Neurofibromatosis Type 1, Neurocognitive, Phase II

Additional relevant MeSH terms:

Neurofibromatosis 1
Osteitis Fibrosa Cystica
Neurofibromatoses
Neurofibroma
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases

Genetic Diseases, Inborn
Bone Diseases, Endocrine
Bone Diseases
Musculoskeletal Diseases
Lovastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 09, 2012