Neurofibromatosis 1
Conditions
Keywords
Neurofibromatosis 1, ADHD, Transcranial Magnetic Stimulation, Magnetic Resonance Imaging, N-acetylcysteine
Brief summary
Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments. At present, there is no specific treatment for this NF1 complication. In this project, the investigators will assess the safety and clinical benefit of N-acetylcysteine (NAC) as a pharmacological intervention in children with NF1. This drug choice is based on the recent findings from mouse models to study the central nervous system manifestations of NF1 at Cincinnati Children's Hospital Medical Center (CCHMC). These findings revealed a role for myelin-forming oligodendrocytes in the control of nitric oxide synthases (NOS) and their product, nitric oxide (NO), in maintenance of brain structure and function, including regulation of behavior and motor control. Treating these mice with NAC corrected cellular and behavioral abnormalities. This data from animal models of NF1 along with uncontrolled clinical observations in children with NF1 suggest that the antioxidant compound, NAC, may reduce these impairments. Therefore, the investigators propose performing a single center double-blind placebo controlled, prospective, Phase II study to explore safety, tolerability, and efficacy of NAC on motor behavior and/or learning in children with NF1 aged 8 through 16 years old. Participants will be carefully monitored for side effects. Primary and secondary outcome measures will be administered at baseline, follow-up, and post-treatment.
Detailed description
This is a phase II clinical trial with the goal to explore safety, tolerability, and efficacy of NAC on motor behavior in children with NF1 aged 8 through 16 years old. The investigators hypothesize that NAC therapy will improve motor function evaluated by the Physical and Neurological Examination for Soft Signs (PANESS) scale. This is based on studies demonstrating that NAC significantly improved impairments in the animal model of NF1. The investigators will also analyze NAC effects on attention deficit and impulsivity in children with NF1. This study will also help develop novel predictive biomarkers of response to neurocognitive therapies in patients with NF1 which are needed to evaluate treatment outcomes. The investigators will gain information in children with NF1 about possible clinical benefit of anti-oxidant treatment and to develop and evaluate quantitative brain-based and blood biomarkers relating to presence of NF1, symptom severity, and response to antioxidant therapy. Clinically, 50 percent of children with NF1 are underperforming or failing at school. This frequently leads to decreased educational attainment and fewer opportunities as adults. An important first step was preliminary work using the PANESS scale and Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (SICI) in children with NF1. The investigators propose to develop and extend understanding of NF1-related motor and learning behavior in response to antioxidant therapy with NAC. The purpose of the present study is to 1) evaluate tolerability, safety, and clinical benefit of NAC in this double-blind placebo controlled study using the motor function scale (PANESS); 2) to evaluate the effects of NAC on measures of NF1 neurocognitive symptomatology (ADHD/impulsive symptoms, executive function, working memory); and 3) to determine if TMS measurement (SICI) in children with NF1 will correlate with clinical effects of NAC treatment and evaluate utility of advanced brain imaging and spectroscopy measurements in children with NF1, and effects of NAC therapy. The investigators propose to study 58 children with NF1, ages 8-16 years, at baseline and after completion of 8 weeks of treatment with NAC, followed by a washout period of 4 weeks. The investigators believe this work has the potential to lay groundwork for future use of relevant biomarkers for treatment and outcomes research for NF1 as well as other biologically similar conditions, collectively designated the "RASopathies" (due to involvement of a protein first discovered in rat sarcomas (RAS), but not technically an acronym). RAS is family of proteins. This work may ultimately guide development of more effective treatments based on disease pathophysiology. STUDY OBJECTIVE: NAC Trial at Cincinnati Children's Hospital Medical Center (CCHMC) The investigators propose performing a single center randomized double-blind placebo controlled, prospective, Phase II study to explore safety, tolerability, and efficacy of NAC on motor behavior in children with NF1 aged 8 through 16 years old. Hypothesis: The investigators hypothesize that NAC therapy will improve motor function evaluated by the PANESS scale. This is based on studies demonstrating that NAC significantly improved impairments in the animal model of NF1. The investigators will also analyze NAC effects on attention deficit and impulsivity in children with NF1. Specific Aim: The primary outcome of this study is to characterize the effects of NAC treatment on motor function in children and adolescents with NF1 using the PANESS. The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. Secondary Aims: 1. To evaluate the effects of NAC on measures of NF1 neurocognitive symptomatology (ADHD/impulsive symptoms, executive function, working memory), the investigators will use Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) committee recommended assessments tools ADHD rating scale (ADHD-RS), Behavioral Rating Inventory of Executive Function second edition (BRIEF-2), Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) subtests, and Test of Variables of Attention (TOVA). 2. To determine if TMS measurement (SICI) in children with NF1 will correlate with clinical effects of NAC treatment. 3. To quantify microstructural properties of brain tissue based on water diffusion, glutathione (GSH) concentrations, and gamma-aminobutyric acid (GABA) concentration using brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in children with NF1. This will allow for regional correlation between imaging, spectroscopy and neuropsychometric outcomes. The investigators will also determine if these magnetic resonance based outcomes correlate with clinical effects of NAC treatment. 4. To evaluate safety and tolerability of NAC in children with NF1.
Interventions
DRUGN-Acetyl cysteine
Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
OTHERPlacebo
Eight (8) weeks of treatment with placebo.
Sponsors
Children's Hospital Medical Center, Cincinnati
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
In order to preserve the double-masking of the trial, only the investigation pharmacy will be unmasked. Both treatments (NAC and placebo) will be distributed from the investigational pharmacy. Except for the pharmacist, all staff will be blinded to the treatment sequence.
Intervention model description
This is a phase II, double blind, placebo-controlled clinical trial with the goal to explore safety, tolerability, and efficacy of N-acetylcysteine (NAC).
Eligibility
Sex/Gender
ALL
Age
8 Years to 16 Years
Healthy volunteers
Yes
Inclusion criteria
ѱ: You can be in this study if you have any of the following: 1. Males and females older than 8 years and younger than 16 years old 2. Has a diagnosis of NF1 (neurofibromatosis type 1) 3. Has an abnormal PANESS score 4. Has an intelligence quotient (IQ) at or above 70 5. Participants on stimulant or any other psychotropic medication should stay on a stable dose (no change in dose) for at least 30 days before entering the study and maintain that dose while in the study
Exclusion criteria
You cannot be in this study if you have any of the following: 1. Younger than 8 years or older than 16 years ѱ 2. Do not have a diagnosis of NF1 ѱ 3. IQ below 70 ѱ 4. Had a dose change of any stimulant or psychotropic medication in the last month (30 days) ѱ 5. Are being treated with chemotherapy or had chemotherapy in the last 6 months 6. Have epilepsy ѱ 7. High risk of upper gastrointestinal (GI, the stomach and the small and large intestine) hemorrhage (bleeding). Examples: presence of esophageal varices or peptic ulcers 8. Active intracranial lesions (abnormality found on brain imaging such as an MRI) (stable low-grade glioma is acceptable) or epilepsy diagnosis ѱ 9. Have Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other major Anxiety Disorders, or other developmental psychiatric diagnoses, based on history. ADHD is allowed. 10. For females, pregnancy 11. Is currently using antidepressants, dopamine blocking agents, or mood stabilizers 12. Have any of the following medical devices: implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal (VP) shunt, cardiac pacemaker, or implanted medication port ѱ 13. Asthma (bronchospasm has been reported as occurring infrequently and unpredictably when NAC is used as a mucolytic agent) 14. Current use of MEKINIST (MEK-inhibitor) or use within 30 days ѱ Indicates Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Soft Signs (PANESS) | Baseline vs. end of treatment, 8 weeks | Characterize effects of NAC treatment on motor function in kids with NF1 using the Physical and Neurological Examination for Soft Signs (PANESS). This is a validated scale that consistently demonstrates significant impairments in children with ADHD, and which preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC). The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. The range of this scale is 0-119, higher scores correlate with symptom severity (worse outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys | baseline vs. end of treatment, 8 weeks | Characterize effects of NAC treatment on ADHD symptoms in children with NF1. The investigators hypothesize that ADHD attention and hyperactive/impulsive symptoms, rated with the Diagnostic and Statistical Manual (DSM-5) based clinical rating scales, will improve after treatment with NAC. The range of this scale is 0-56, higher scores correlate with symptom severity (worse outcome). |
| Change From Baseline in Motor Cortex Inhibition/Excitation Measures, Expressed as Ratios of Single to Paired Pulse Transcranial Magnetic Stimulation (TMS) Motor Evoked Potential Amplitudes | baseline vs. end of treatment, 8 weeks | Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Output is quantified from surface EMG tracings after motor cortex stimulation with TMS. SICI, ICF, and LICI are standard paired pulse (condition/test-pulse) measures where the outcome is expressed as a ratio of motor evoked potential amplitudes. Ratios \< 1.0 represent inhibition, ratios \> 1.0 represent facilitation. CSP is a silent period in EMG activity, measure in milliseconds (ms). |
| Change From Baseline in Motor Cortex Inhibition/Excitation Measures, Expressed as Milliseconds of Single to Paired Pulse Transcranial Magnetic Stimulation (TMS) Motor Evoked Potential Amplitudes | baseline vs. end of treatment, 8 weeks | Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Output is quantified from surface EMG tracings after motor cortex stimulation with TMS. CSP is a silent period in EMG activity, measure in milliseconds (ms). |
| Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) | baseline vs. end of treatment, 8 weeks | To quantify microstructural properties of brain tissue based on water diffusion, glutathione (GSH) concentration, glutamate/glutamine (GLX) concentration, and gamma-aminobutyric acid (GABA) concentration using brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in children with NF1. This will allow for regional correlation between imaging, spectroscopy and neuropsychometric outcomes. We will also determine if these magnetic resonance based outcomes correlate with clinical effects of NAC treatment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDonald Gilbert, MD MS
Children's Hospital Medical Center, Cincinnati
Participant flow
Recruitment details
Recruitment occurred through clinic and IRB-approved study registry review. Determination of enrollment eligibility was a multi-step process. The study team screened and reviewed medical histories of 481 children and adolescents with NF1, of whom 203 (42%) were deemed eligible. From this eligible group, 25 (12%) agreed to participate. The first patient was enrolled and randomized February 23, 2021 and the last completed a final treatment visit November 13, 2023.
Pre-assignment details
After screening and baseline assessments, participants were randomized 1:1 to receive N-acetylcysteine (NAC) or matching placebo using permuted block randomization stratified by age, sex, and ADHD status. The study was double-blind; only the investigational pharmacy was unblinded. NAC was administered orally for 8 weeks at \ 70 mg/kg/day divided BID with weight-based dosing. Placebo was identical in appearance and schedule.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 13 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 12.4 years STANDARD_DEVIATION 3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 13 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 13 |
| other Total, other adverse events | 4 / 12 | 5 / 13 |
| serious Total, serious adverse events | 0 / 12 | 0 / 13 |
Outcome results
None listed