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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Neurofibromatosis Type 1

Intervention / Treatment
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* Drug: Lovastatin ™
* Device: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 2<br>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<br>* Starting at 20mg for 2 weeks, then increasing to 40mg for 14 additional weeks for a total duration of treatment of 16 weeks.<br>|
| Experimental: 1<br>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 ™<br>* Lovastatin starting at 20mg for 2 weeks, increasing to 40mg for 14 weeks. Total duration of trial is 16 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Paired Associate Learning (Cambridge Neuropsychological Test Automated Battery). | 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. | Baseline and Post-treatment (16 weeks) | 
| Score! (Test of Everyday Attention for Children) | 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. | Baseline and Post-treatment (16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spatial Working Memory (Cambridge Neuropsychological Test Automated Battery) | 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. | Baseline and Post-treatment (16 weeks) | 
| Stockings of Cambridge (Cambridge Neuropsychological Test Automated Battery) Automated Battery). | 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). | Baseline and Post-treatment (16 weeks) | 
| Stop Signal Task (Cambridge Neuropsychological Test Automated Battery) | 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. | Baseline and Post-treatment (16 weeks) | 
| Sky Search (Test of Everyday Attention for Children) | 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. | Baseline and Post-treatment (16 weeks) | 
| Sky Search DT (Test of Everyday Attention for Children) | 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. | Baseline and Post-treatment (16 weeks) | 
| Creature Counting (Test of Everyday Attention for Children) | 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. | Baseline and Post-treatment (16 weeks) | 
| Commission Errors (Conners Continuous Performance Test, Second Edition; CPT-II) | 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. | Baseline and Post-treatment (16 weeks) | 
| Omission Errors (Conners Continuous Performance Test, Second Edition; CPT-II) | 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. | Baseline and Post-treatment (16 weeks) | 
| ADHD Inattentive Scale, Conners ADHD Scales | 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. | Baseline and Post-treatment (16 weeks) | 
| ADHD Hyperactive/Impulsive Scale, Conners ADHD Scales | 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. | Baseline and Post-treatment (16 weeks) | 
| Controlled Oral Word Association Test | 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. | Baseline and Post-treatment (week 16) | 
| Judgement of Line Orientation Test | 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. | Baseline and Post-treatment (week 16) | 
| Behavior Rating Inventory of Executive Function Global Executive Composite | 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. | Baseline and Post-treatment (week 16) | 
| Object Assembly (WISC-III) | 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. | Baseline and Post-treatment (week 16) | 
| Internalizing Behaviors, Behavior Assessment System for Children Second Edition | 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. | Baseline and Post-treatment (week 16) | 
| Internalizing Behaviors, Behavior Assessment System for Children Second Edition | 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. | Baseline and Post-treatment (week 16) | 
| Quality of Life Pediatric Quality of Life Inventory (PedsQL) | 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). | Baseline and Post-treatment (week 16) | 
| Psychosocial Quality of Life PedsQL | 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). | Baseline and Post-treatment (week 16) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurofibromatosis Type 1, Neurocognitive, Phase II