ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00853580
Recruitment Status : Completed
First Posted : March 2, 2009
Results First Posted : March 12, 2018
Last Update Posted : March 12, 2018
Sponsor:
Collaborators:
Boston Children’s Hospital
Children's Hospital of 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
Sydney Children's Hospitals Network
University of Texas Southwestern Medical Center
Information provided by (Responsible Party):
Bruce Korf, MD, University of Alabama at Birmingham

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.


Condition or disease Intervention/treatment Phase
Neurofibromatosis Type 1 Drug: Lovastatin ™ Device: placebo Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 146 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1
Study Start Date : July 2009
Actual Primary Completion Date : May 2014
Actual Study Completion Date : December 2016


Arm Intervention/treatment
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 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.
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 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.
Drug: Lovastatin ™
Lovastatin starting at 20mg for 2 weeks, increasing to 40mg for 14 weeks. Total duration of trial is 16 weeks.




Primary Outcome Measures :
  1. Paired Associate Learning (Cambridge Neuropsychological Test Automated Battery). [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    A computerized test of visuospatial learning. Participants had to remember patterns associated with different locations on the screen, and during the test phase, as each pattern is presented, point to the appropriate location. The test starts at a very simple level and gradually increases in difficulty. Higher number of errors indicates poorer performance. Scale does not have a maximum range.

  2. Score! (Test of Everyday Attention for Children) [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    Score! is a measure of sustained attention. Participants were required to silently count a series of aurally presented tones and say the total number of tones counted at the end of each trial. The number of tones ranged from 9 to 15, with a total of 10 trials (range 0-10). Higher values represent better performance.


Secondary Outcome Measures :
  1. Spatial Working Memory (Cambridge Neuropsychological Test Automated Battery) [ Time Frame: Baseline and Post-treatment (16 weeks) ]

    A computerized measure of spatial working memory. This task assessed the participant's ability to retain spatial information and to manipulate remembered items in working memory.

    In this test, participants were shown an array of boxes on a computer screen and they were required to search through the boxes for hidden tokens. One box at a time was touched until a blue token was found inside. Participants then commenced a new search for the next token. The key instruction was that, once a token had been located, that box would not be used again to hide another token.

    Unit of measure was between search errors, determined by the number of boxes a participant reopens in which a token had previously been found. Higher score indicated poorer performance. Scale does not have a maximum range.


  2. Stockings of Cambridge (Cambridge Neuropsychological Test Automated Battery) Automated Battery). [ Time Frame: Baseline and Post-treatment (16 weeks) ]

    A computerized measure of spatial planning based on the "Tower of London" test. It required participants to move balls in a lower display to match a pattern shown in the upper display in a certain number of moves.

    More specifically, the participant was shown two displays containing three coloured balls. The displays were presented in such a way that they could be perceived as stacks of coloured balls held in socks suspended from a beam. The test administrator first demonstrated to the participant how to move the balls in the lower display to copy the pattern in the upper display and completed one demonstration problem, where the solution required one move. The participant then completed problems that increased in difficulty, from one through to five move problems.

    The unit of measure was the mean number of moves taken to complete a problem that could not be completed in less than five moves. The higher the score, the poorer the performance (range 5-12).


  3. Stop Signal Task (Cambridge Neuropsychological Test Automated Battery) [ Time Frame: Baseline and Post-treatment (16 weeks) ]

    A computerized measure of inhibitory control. The participant quickly responded to an arrow stimulus by pressing one of two buttons (left or right), depending on the direction in which the arrow pointed on the screen. If an audio tone is present, the subject was supposed to withhold the response.

    The difficulty of the task was manipulated by altering the delay before a stop signal (auditory tone) was presented, known as the stop signal delay. The outcome from this measure was stop signal reaction time (last half of test), which was computed by subtracting the mean stop signal delay at which the participant was able to stop on 50% of trials from the mean reaction time on go trials. Poorer response inhibition was reflected by a larger stop signal reaction time. Scale does not have a maximum range.


  4. Sky Search (Test of Everyday Attention for Children) [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    Sky Search is a measure of selective visual attention. Participants were presented with a A3 sheet with target stimuli (spaceships in identical pairs) randomly distributed among many distractors (spaceships in non-identical pairs). They were required to circle as many of the targets as possible as quickly as possible. The outcome measure (attention score), was a timing score reflecting the average time taken per target found. Higher scores represent poorer performance. Raw data are reported. Scale does not have a maximum range.

  5. Sky Search DT (Test of Everyday Attention for Children) [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    Sky Search DT is a test of divided attention. Children completed a parallel version of the Sky Search subtest while at the same time, silently counted the number of tones in a similar way to the Score! subtest. Higher scores represent poorer performance. Raw data are reported. Scale does not have a maximum range.

  6. Creature Counting (Test of Everyday Attention for Children) [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    Creature Counting is a measure of attentional control. Participants were required to count "creatures" from top of the page to the bottom, using arrows as cues to switch from counting up to counting down (and vice versa). There were seven testing trials. The outcome variable was the total number of correct trials (range 0-7). Higher scores represent better performances.

  7. Commission Errors (Conners Continuous Performance Test, Second Edition; CPT-II) [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    A computerised measure of impulse control. Letters were presented serially on a screen in a random order. All letters were considered target stimuli, except for the letter 'X' which is a non-target stimulus. Participants responded to target stimuli by pressing the space bar of a computer keyboard (90% of the stimuli) while withholding responses to non-target stimuli (10% of the test). Commission errors represented the number of times a participant incorrectly responded to the non-target (letter 'X'). T-scores are reported, as generated by the test software. Higher scores indicate poorer performances.

  8. Omission Errors (Conners Continuous Performance Test, Second Edition; CPT-II) [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    A computerised measure of vigilance and concentration. Letters were presented serially on a screen in a random order. All letters were considered target stimuli, except for the letter 'X' which is a non-target stimulus. Participants responded to target stimuli by pressing the space bar of a computer keyboard (90% of the stimuli) while withholding responses to non-target stimuli (10% of the test). Omission errors represented the number of times a participant fails to respond to target letters (all other than 'X'). T-scores are reported, as generated by the test software. Higher scores indicate poorer performances.

  9. ADHD Inattentive Scale, Conners ADHD Scales [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    Parent rated inattentive ADHD symptoms, based on Diagnostic and Statistical Manual of Mental Disorders criteria, 4th edition. T-scores are reported. Higher scores indicate increased ADHD-related symptoms. A score below 60 is considered healthy, 61-65 a possible significant problem, and 66+ is considered a significant problem.

  10. ADHD Hyperactive/Impulsive Scale, Conners ADHD Scales [ Time Frame: Baseline and Post-treatment (16 weeks) ]
    Parent rated hyperactive/impulsive ADHD symptoms, based on Diagnostic and Statistical Manual of Mental Disorders criteria, 4th edition.T-scores are reported. Higher scores indicate increased ADHD-related symptoms. A score below 60 is considered healthy, 61-65 a possible significant problem, and 66+ is considered a significant problem.

  11. Controlled Oral Word Association Test [ Time Frame: Baseline and Post-treatment (week 16) ]
    A measure of verbal fluency. Participants were required to spontaneously produce as many words as they could, beginning with a designated letter in 60 seconds. Three letters were used. Higher scores represent better performances. Raw data are reported summing total words generated for all three letters. Scale does not have a maximum range.

  12. Judgement of Line Orientation Test [ Time Frame: Baseline and Post-treatment (week 16) ]
    A test of visuospatial judgement. The test measured the participant's ability to match the angle and orientation of lines in space. There were 30 trial in total. Correct response in a trial was awarded one point (range 0-30). Higher scores represent better performances. Raw data are reported.

  13. Behavior Rating Inventory of Executive Function Global Executive Composite [ Time Frame: Baseline and Post-treatment (week 16) ]
    A parent-rated questionnaire of executive behaviour assessing behavioral regulation (inhibit, shift, emotional control) and metacognition (initiate, working memory, plan/organize, organization of materials, self-monitoring). T-scores for the Global Executive Composite (overall summary score) are reported. Higher scores indicate poorer executive behaviors.

  14. Object Assembly (WISC-III) [ Time Frame: Baseline and Post-treatment (week 16) ]
    A measure of visuoperceptual organization. Participants were required to rebuild an item puzzle based on disassembled pieces. Age scaled scores are reported, which have a population mean of 10 and standard deviation of 3 (range 1-19). Higher scores indicate better performances.

  15. Internalizing Behaviors, Behavior Assessment System for Children Second Edition [ Time Frame: Baseline and Post-treatment (week 16) ]
    A parent-reported questionnaire assessing internalizing behaviors of anxiety, depression and somatization. T-scores are reported. Higher scores indicate increased internalizing behaviors. A score below 60 is considered healthy, 61-65 a possible significant problem, and 66+ is considered a significant problem.

  16. Internalizing Behaviors, Behavior Assessment System for Children Second Edition [ Time Frame: Baseline and Post-treatment (week 16) ]
    A self-reported questionnaire assessing internalizing behaviors such as anxiety and depression. T-scores are reported. Higher scores indicate increased internalizing behaviors. A score below 60 is considered healthy, 61-65 a possible significant problem, and 66+ is considered a significant problem.

  17. Quality of Life Pediatric Quality of Life Inventory (PedsQL) [ Time Frame: Baseline and Post-treatment (week 16) ]
    Parent-rated questionnaire of psychosocial Quality of Life (including emotional, social and school functioning). Summary scores are reported. Higher scores indicate increased increased quality of life (range 0-100).

  18. Psychosocial Quality of Life PedsQL [ Time Frame: Baseline and Post-treatment (week 16) ]
    Self-rated questionnaire of psychosocial Quality of Life (including emotional, social and school functioning). Summary scores are reported. Higher scores indicate higher quality of life (range 0-100).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   8 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Males or females aged between 8 years and 15 years 11 months at time of enrollment who meet NIH diagnostic criteria for NF1 (Appendix 1)
  • Participants must have a full-scale IQ of 70 or above. In cases where there is a statistically significant difference between verbal IQ and performance IQ (.05 level as determined by Table B3 in the WASI manual), participants will be eligible if at least one of these quotients is 70 or above
  • Participants must have a cognitive impairment defined as having a score of at least one standard deviation or more below the population mean on one or more of the primary objective outcome measures (i.e., impaired on a measure of visual spatial learning and/or sustained attention)
  • Participants must be medically stable
  • Participants who are on a stable dose of methylphenidate and/or dextroamphetamines for at least one month prior to screening and who will remain on the same dose for the duration of the study.
  • Hepatic function: Participants must have a bilirubin within normal limits and AST and ALT ± 2 times the upper limit of normal as determined by the standards at their institution
  • Renal function: Participants must have an age-adjusted normal serum creatinine or a creatinine clearance of greater than 70 ml/m/1.73m2
  • Hematologic function: Participants must have an absolute neutrophil count of greater than 1,500, a hemoglobin of greater than 9 gms/dl, and a platelet count of greater than 100,000 on study entry
  • Participants must sign all required documents, including informed assent and HIPAA documents
  • Female participants of childbearing age should not be pregnant, must have a negative pregnancy test before initiation of treatment, and take appropriate birth control precautions to participate in this study.

Exclusion Criteria:

  • Full-scale IQ less than 70; In cases where this is a statistically significant difference between performance IQ and verbal IQ (.05 level), patients will be excluded if both quotients fall below 70
  • Individuals that are not cognitively impaired on at least one of the primary objective outcome measures
  • Individuals with insufficient English to complete the assessments
  • Participants taking psychotropic medication other than methylphenidate and/or dextroamphetamines. These patients are eligible if, as clinically indicated, they cease medication for at least 30 days prior to screening and remain off these medication for the duration of the study
  • Participants with intracranial pathology such as epilepsy, diagnosed head injury, hydrocephalus or progressive intracranial tumors (children with asymptomatic or static lesions will be eligible)
  • Participants who are pregnant or breastfeeding; Participants who have received any investigational drug, other than sirolimus, within 30 days of initiation of study
  • Participants who have recently taken Lovastatin. These participants will be eligible after a washout period of at least three months.
  • Participants with significant hepatic, renal or hematologic function as previously defined
  • Participants with a history of neuromuscular disease, excluding hypotonias thought to be associated with NF1
  • Participants with a clinically significant unrelated illness, which in the judgment of the principal or associate investigator, would compromise the participant's ability to tolerate the medication or potentially interfere with the participant's ability to participate in the required testing
  • Low cholesterol (lower limit of a total cholesterol of 90mg/dl)
  • Participants who have recently taken sirolimus within three months of enrollment. These participants will be eligible after a washout period of at least three months.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00853580


Locations
United States, Alabama
The University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Maryland
NIH
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Children' Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University - St. Louis
Saint Louis, Missouri, United States, 63110
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19096
United States, Texas
Childrens Medical Center - Univ. of Texas SW Medical Center
Dallas, Texas, United States, 75235
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Australia, New South Wales
The Children's Hospital at Westmead
Westmead, New South Wales, Australia, 2145
Sponsors and Collaborators
University of Alabama at Birmingham
Boston Children’s Hospital
Children's Hospital of 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
Sydney Children's Hospitals Network
University of Texas Southwestern Medical Center
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
  Study Documents (Full-Text)

Documents provided by Bruce Korf, MD, University of Alabama at Birmingham:
Study Protocol  [PDF] May 11, 2011
Statistical Analysis Plan  [PDF] May 11, 2011
Informed Consent Form  [PDF] January 23, 2013


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bruce Korf, MD, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT00853580     History of Changes
Other Study ID Numbers: X080929007
DOD: W81XWH-05-1 0615 ( Other Identifier: Department of Defense )
First Posted: March 2, 2009    Key Record Dates
Results First Posted: March 12, 2018
Last Update Posted: March 12, 2018
Last Verified: March 2018

Keywords provided by Bruce Korf, MD, University of Alabama at Birmingham:
Neurofibromatosis Type 1, Neurocognitive, Phase II

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibromatosis 1
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
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Lovastatin
L 647318
Dihydromevinolin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors