Multimodal Intervention Trial for Cognitive Deficits in Neurofibromatosis Type 1: Efficacy of Computerized Cognitive Training and Stimulant Medication
Phase: NA
Conditions: Neurofibromatosis Type 1
Sponsor: Kristina Hardy

 
 
 
 
 
 
 
 
 
 
Multimodal Intervention Trial for Cognitive Deficits in Neurofibromatosis Type I: Efficacy 
of Computerized Cognitive Training and Stimulant Medication 
NCT02944032 
January 10, 2022 
 
 
 
 
 
 
 
 
 
 
 
 

COGTRAIN 
 
2  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Multimodal Intervention Trial for Cognitive Deficits in Neurofibromatosis Type I: 
Efficacy of Computerized Cognitive Training and Stimulant Medication 
Multicenter protocol Version 3: January 10, 2022 
STUDY CHAIR: 
 
Kristina Hardy, PhD 
Children’s National Health System, Washington, DC 
kkhardy@childrensnational.org, (202) 476-2514 
 
 
As a site principal investigator I will conduct, record, and report this study in compliance 
with the IRB/Ethics Committee, International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH), Good Clinical 
Practice Guidelines, and Declaration of Helsinki. No protocol deviation will be 
implemented without prior review and approval of the Sponsor and IRB/Ethics 
Committee except where necessary to prevent immediate hazard to research 
participants. In this case, the deviation will be immediately reported to the Sponsor and 
IRB/Ethics Committee. 
 
 
Signature of Investigator 
      Date 
 
 
Print Investigator Name 
Investigator Title 
 
 
Name of Clinical Site 
 
 
 
 
 
 
 
 
 
 
 
 
 

COGTRAIN 
 
3  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
1. PROTOCOL SYNOPSIS 
Full Title: Multimodal Intervention Trial for Cognitive Deficits in Neurofibromatosis Type 
1: Efficacy of Computerized Cognitive Training and Stimulant Medication 
Protocol Number: COGTRAIN 
Objective: To assess the efficacy of a home-based, computerized cognitive training 
(CT) program, called CogmedRM, targeted to improve working memory in children with 
NF1 and working memory difficulties. 
 
Study Design: This is a Phase II randomized parallel group controlled clinical trial 
comparing two interventions on cognitive outcomes. Participants will be stratified by 
stimulant medication use and randomized equally between the two interventions within 
stratum. Participants will be in the study for to 11 weeks. 
Number of Participants: 
Approximately 90 patients with Neurofibromatosis 1 (NF1) will be enrolled in the study.   
 
Study Centers and Coordinating Center:  Five study centers, 2 in the United States 
and 2 in Australia will participate in this clinical study. The Coordinating Center located 
at Children’s National Health System will manage the clinical study operations, data 
management, statistical management and study reporting. 
Eligibility Criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment: 
1. 8-16 years old at time of screening 
2. NF1 Diagnosis based on National Institute of Health (NIH) criteria 
3. Has an identified caregiver who is willing and able to oversee the training 
practice during the intervention period 
4. Has access to a telephone and phone number where they can be reached 
5. Both patient and caregiver have reading, speaking, and listening comprehension 
of English 
6. Treated with a stable dose of stimulant medication for at least the last 30 days 
and not planning to change the dose during study participation or receiving no 
stimulant medications for at least the last 30 days and not planning to initiate a 
trial of stimulant medications for the duration of the study. 
7. Score >1 SD below the mean on either the WISC-V-Integrated Spatial Span 
Forward or Backwards tasks or Digit Span Forward or Backwards tasks or score 
>1 SD below the participant’s estimated IQ on either Spatial Span Forward or 
Backwards or Digit Span Forward or Backwards. 
Patients will be excluded from enrollment in this study if they meet any of the following 
exclusion criteria: 

COGTRAIN 
 
4  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
1. Full scale IQ<70, as estimated by WASI-II (Block Design, Vocabulary, Matrix 
Reasoning, Similarities).  
▪ Note: In cases where there is a statistically significant difference 
between verbal IQ and performance IQ (.05 level as determined by 
the WASI-II manual), participants will be eligible if at least one of 
these quotients is 70 or above 
2. Current treatment for intracranial lesions, progressive tumors as per MRI 
evaluation or treatment with chemotherapy within the past 6 months 
3. A motor, visual, or auditory handicap that prevents computer use 
Study Intervention: Randomized participants will be trained on one of two home-based 
computer programs. The first, called CogmedRM targets working memory and is the 
targeted treatment of the study.  The second program is an active control condition 
called MobyMax, which targets academic skill development (i.e., reading 
comprehension).   
Study Duration: The length of time a participant is enrolled in this study will depend on 
how quickly each participant completes their at-home training.  The training phase of the 
study will last between 5-9 weeks, after which participants will be asked to return for 
post-intervention testing within two weeks of completion.  Therefore, participation could 
be as short as slightly over 5 weeks to a maximum of 11 weeks.  
Evaluations: 
Pre-study: Informed consent, inclusion/exclusion review, and demographics 
Study assessments: Physical exam, ADHD-Rating Scale, CogState, Wechsler 
Abbreviated Scale of Intelligence – Second Edition (WASI-II), Wechsler Intelligence 
Scale for Children – Fifth Edition (WISC-V-Integrated), Child Behavior Checklist (CBCL), 
and Behavior Rating Inventory of Executive Functioning (BRIEF), Test of Word Reading 
Efficiency- Second Edition (TOWRE-2) and the Test of Everyday Reading 
Comprehension (TERC). 
Statistical Methods:  
The primary objective to be addressed statistically is to determine whether CogmedRM 
improves scores on the CogState One-back subtest when compared to the control 
intervention MobyMax.   The primary analysis approach will be analysis of covariance 
(ANCOVA) with two factors. One factor is the intervention and the second factor is the 
stratum. The analysis is on the CogState one-back subtest result at Visit 2, with the 
baseline result as a covariate. 

COGTRAIN 
 
5  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
2. STUDY TEAM 
 
STUDY CHAIR: 
 
Kristina Hardy, PhD 
Children’s National Health System, Washington, DC 
kkhardy@childrensnational.org, (202) 476-2514 
PARTICIPATING SITE INVESTIGATORS 
CHILDREN’S HOSPITAL AT WESTMEAD, SYDNEY, AUSTRALIA 
PI: Belinda Barton, PhD; Belinda.barton@health.nsw.gov.au 
 
CHILDREN’S NATIONAL HEALTH SYSTEM, WASHINGTON, DC, USA 
PI: Kristina Hardy, PhD; kkhardy@childrensnational.org 
 
CHILDREN’S HOSPITAL OF LOS ANGELES, LOS ANGELES, CA, USA 
PI: Tena Rosser, MD; TRosser@chla.usc.edu 
 
ROYAL CHILDREN’S HOSPITAL, MELBOURNE, AUSTRALIA 
PI: Kathryn North, MD; Kathryn.north@Mcri.edu.au 
Co-I: Jonathan Payne, PhD; jonathan.payne@mcri.edu.au 
 
 
 
 
 
 
 
 
 
 
 
 

COGTRAIN 
 
6  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Table of Contents 
1. 
PROTOCOL SYNOPSIS ................................................................................................................... 3 
2. 
STUDY TEAM ..................................................................................................................................... 5 
3. 
ABBREVIATIONS .............................................................................................................................. 9 
4. 
BACKGROUND AND SIGNIFICANCE ......................................................................................... 11 
4.1. 
Overview of Disease ................................................................................................................ 11 
4.2. 
Research on Interventions to address Attention in NF1..................................................... 12 
4.3. 
Cognitive training (CT) Programs .......................................................................................... 14 
4.3.1. 
CogmedRM.......................................................................................................................... 15 
4.3.2. 
MobyMax ........................................................................................................................... 17 
5. 
STUDY OBJECTIVES ..................................................................................................................... 18 
5.1. 
Specific Aim 1 ........................................................................................................................... 18 
5.2. 
Exploratory Aim ........................................................................................................................ 18 
6. 
STUDY DESIGN AND METHODS ................................................................................................ 19 
6.1. 
Study Design ............................................................................................................................. 19 
6.2. 
Stratification and Randomization ........................................................................................... 19 
7. 
STUDY POPULATION AND SELECTION ................................................................................... 19 
7.1. 
Inclusion Criteria ....................................................................................................................... 20 
7.2. 
Exclusion Criteria ..................................................................................................................... 20 
7.3. 
Early Termination or Withdrawal ............................................................................................ 20 
7.4. 
Study Duration and Enrollment .............................................................................................. 21 
7.4.1. 
Study Enrollment – ........................................................................................................... 21 
7.4.2. 
Study Duration – ............................................................................................................... 21 
8. 
STUDY INTERVENTION ................................................................................................................ 22 
8.1. 
Product Details ......................................................................................................................... 22 
8.1.1. 
CogmedRM.......................................................................................................................... 22 
8.1.2. 
Control Program – MobyMax .......................................................................................... 23 
8.1.3 Ongoing communications with participants for both interventions.................................. 23 
9. 
STUDY ASSESSMENTS ................................................................................................................ 23 
9.1. 
Screening and Baseline Assessments (Visit 1) ................................................................... 25 
9.1.1. 
CogState ............................................................................................................................ 25 

COGTRAIN 
 
7  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
9.1.2. 
ADHD-RS .......................................................................................................................... 26 
9.1.3. 
Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II) ................ 26 
9.1.4. 
Child Behavior Checklist (CBCL) ................................................................................... 26 
9.1.5. 
Wechsler Intelligence Scale for Children – Fifth Edition (WISC-V) .......................... 26 
9.1.7. 
Test of Word Reading Efficiency – Second Edition (TOWRE-2) ................................ 27 
9.1.8. 
Test of Everyday Reading Comprehension (TERC) ................................................... 27 
9.1.9. 
Intervention training.......................................................................................................... 27 
9.2. 
Cognitive Training Follow-up (Visit 2) ................................................................................... 27 
9.3. 
Other Assessments .................................................................................................................. 29 
9.3.1. 
Demographics ................................................................................................................... 29 
9.3.2. 
Medical/Surgery History .................................................................................................. 29 
9.3.3. 
Weight/Height ................................................................................................................... 29 
9.3.4. 
Vitals ................................................................................................................................... 29 
9.3.5. 
Concomitant Medication .................................................................................................. 29 
10. 
SAFETY ......................................................................................................................................... 30 
10.1. 
Adverse Event and Serious Event Reporting................................................................... 30 
11. 
STATISTICAL PLAN .................................................................................................................... 30 
11.1 General ..................................................................................................................................... 30 
11.2 Baseline characteristics .......................................................................................................... 31 
11.3 Analyses of Specific Aim 1 ..................................................................................................... 31 
11.4 Sample size justification: ........................................................................................................ 32 
11.5 Other Summaries .................................................................................................................... 32 
12. 
DATA COLLECTION, QUALITY ASSURANCE AND MANAGEMENT ............................... 32 
12.1. 
Data Collection ..................................................................................................................... 32 
12.1.1. 
Electronic Data Capture (EDC) System .................................................................... 32 
12.3. 
Data Management ................................................................................................................ 34 
12.3.1. 
Source documents ....................................................................................................... 34 
12.2.3  
Data Processing ........................................................................................................... 34 
13. 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................................ 34 
13.1. 
Protocol Deviations .............................................................................................................. 34 
13.2. 
Access to Source Data/ Documents .................................................................................. 35 

COGTRAIN 
 
8  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
13.3. 
Investigator Responsibilities ............................................................................................... 35 
13.3.1. 
Institutional Review Board/Ethics committee ........................................................... 35 
13.3.3. 
Informed Consent and Assent .................................................................................... 35 
13.3.4. 
Participant Confidentiality............................................................................................ 36 
13.4. 
Participant Compliance and Compensation ..................................................................... 36 
 
 
 

COGTRAIN 
 
9  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
3. ABBREVIATIONS 
 
ADHD: Attention Deficit Hyperactive Disorder 
ADHD-RS: Attention Deficit Hyperactive Disorder- Rating Scale 
AE: Adverse Event 
ANCOVA: Analysis of Covariance 
BP: Binding Potential 
BRIEF: Behavior Rating Inventory of Executive Functioning 
CBCL: Child Behavior Checklist 
CI: Confidence Interval 
CNHS: Children’s National Health System 
CPT-II: Conners’ Continuous Performance Test, Version II 
CT: Cognitive Training 
DOD: Department of Defense  
DSM-5: Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
DSM-IV: Diagnostic and Statistical Manual of Mental Disorders Fourth Edition 
eCRF: electronic Case Report Form 
EDC: Electronic Data Capture 
GCP: Good Clinical Practice 
HIPAA: Health Insurance Portability and Accountability Act 
IRB: Institutional Review Board 
ICF: Informed Consent Form 
ICH: International Conference of Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IQ: Intelligence Quotient 
MPH: Methylphenidate 
MRI: Magnetic Resonance Imaging 
MTA: Multimodal Treatment of ADHD 
NF1: Neurofibromatosis Type 1 
NIH: National Institutes of Health 
OPG: Optic Pathway Glioma 
PET: Positron-Emission Tomography 
PI: Principal Investigator 

COGTRAIN 
 
10  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
rCBF: regional Cerebral Blood Flow 
REDCap: Research Electronic Data Capture 
SD: Standard Deviation 
SAE: Serious Adverse Event 
SWM: Spatial Working Memory 
TERC: Test of Everyday Reading Comprehension 
TOWRE-2: Test of Word Reading Efficiency—Second Edition 
VMAT2/DAT: Vesicular Monoamine Transporter Type 2; Dopamine Transporter 
WASI-II: Wechsler Abbreviated Scale of Intelligence—Second Edition 
WISC-V-Integrated: Wechsler Intelligence Scale for Children—Fifth Edition 
WM: Working Memory 
 
 

COGTRAIN 
 
11  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
4. BACKGROUND AND SIGNIFICANCE 
4.1. Overview of Disease 
NF1, cognitive dysfunction, and ADHD 
NF1 is a common autosomal dominant disorder with an incidence of 1 in 3,000 
characterized by diverse cutaneous, neurological, skeletal and neoplastic 
manifestations (Ferner, Huson et al. 2007). Improvements in the short and long term 
prognosis of patients with a diagnosis of NF1 have increased awareness that the most 
important factors in long term prognoses are cognitive deficits (North, Hyman et al. 
2002). Knowledge of the cognitive profile of patients with NF1 has dramatically 
increased over the past 15 years (Lehtonen, et al., 2012). While general intellectual 
functioning is only moderately affected, the impact of NF1 cognitive deficits is greatest 
on academic achievement, with up to 70% of school-aged children with NF1 
underachieving (Brewer, Moore et al. 1997) and learning disabilities estimated in 30-
65% of children with NF1 (North, Riccardi et al. 1997). In a recent Dutch study, 75% of 
the NF1 children performed more than one standard deviation below same-grade peers 
in at least one academic domain (Krab, Aarsen et al. 2008; Coude, Mignot et al. 2007). 
In addition, they had a four-fold increased risk for requiring special education and a six-
fold increased risk for receiving remedial teaching for learning, behavior, speech, or 
motor problems. Only 10% of children with NF1 did not show any school-functioning 
problems (Krab, Aarsen et al. 2008). Given that general intellectual deficiency is unlikely 
to sufficiently explain the pattern of observed academic failure, discovering specific 
neurocognitive deficits that contribute to the academic difficulties of children with NF1 is 
a high priority, as such deficits have potential negative consequences for daily living 
skills, employment opportunities and quality of life (Graf, Landolt et al. 2006). 
In terms of specific cognitive deficits, several studies report deficits in visual spatial 
function (Hyman, Shores et al. 2005; Levine, Materek et al. 2006) and attention 
difficulties including problems with sustained attention and divided attention (Gilboa et 
al., 2011; Isenberg et al., 2012; Hyman, Shores et al. 2005). In addition, children with 
NF1 exhibit extensive compromise in executive function in terms of reduced cognitive 
flexibility, working memory capacity, inhibition and planning; all functions thought to be 
mediated by the prefrontal cortex (Payne, Hyman, Shores et al., 2011;  Hyman, Shores 
et al. 2005).  Multiple research groups have noted the high incidence of attention deficit 
hyperactivity disorder (ADHD) in association with NF1 (Mautner, Kluwe et al. 2002). 
ADHD is defined as a neurodevelopmental disorder manifested by elevated levels of 
inattention and/or impulsivity and hyperactivity compared with other individuals of the 
same age (DSM-5, 2013).  In the NF1 population, ADHD diagnosis has been prevalent 
in several studies, with the incidence as high as 70%.  Beyond the implications on 
learning, the presence of ADHD has been found to be a major risk factor for poor social 

COGTRAIN 
 
12  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
functioning (Barton and North 2004), as well as general intellectual functioning (Lidzba 
et al., 2012; Koth, Cutting et al. 2000).  Although there is evidence that cognitive control 
deficits are not limited to NF1 patients with comorbid ADHD (Huijbregts, Swaab et al. 
2010; Roy, Roulin et al. 2010), children with both disorders are acknowledged to be 
among the most severely affected in terms of academic performance.  
Importantly, difficulties with working memory are also prevalent in both children with 
ADHD (Castellanos, Sonuga-Barke et al., 2006; Faraone and Biederman, 1998; 
Martinussen et al., 2005) and in children with NF1 (Payne, Arnold, et al., 2012).  
Specifically, children with developmental ADHD experience difficulties with verbal and 
visual working memory skills (Barnett, Maruff et al., 2001; Martinussen et al., 2005) of 
medium to large effect size. In a recent meta-analytic review, Kasper and colleagues 
(2012) analyzed the results of 45 trials with respect to differences in phonological and 
visuospatial working memory skills between children with ADHD and typically-
developing children.  Effects sizes (Hedges g) were reported of 0.69 (95% CI = 0.53-
0.84) for phonological working memory tasks and 0.74 (95% CI = 0.53-0.95) for 
visuospatial working memory tasks; moreover, these differences were larger for studies 
using tasks with higher cognitive “load”.  Similar difficulties in spatial working memory 
were recently reported by Payne and colleagues (2012) in a sample of children with 
NF1, both with and without comorbid ADHD.  
Working memory (WM) is a particularly compelling target for intervention, given its 
critical role in the development of other cognitive and academic outcomes. In healthy 
children, Fry and Hale (1996) found that almost half of developmental increases in IQ 
could be attributed to age-related improvements in WM and processing speed. Because 
WM capacity increases two- to three- fold from ages 4 to 16 (Gathercole et al., 1999), 
disruption to the development of these processes can significantly curtail a wide range 
of a child’s abilities over time. This may take the form of diminished IQ or difficulty with 
other aspects of executive functioning and academic performance. For example, 
children with reading difficulties frequently have deficits in WM which appear to 
contribute to problems with phonological memory (Swanson and Beebe-Frankenberger, 
2004).  Math skills are also strongly linked to WM capacity in typically-developing 
children, accounting for between 20 -57% of the variance in math performance 
(Swanson et al., 2004; Hutton and Towse, 2001). Thus, improving WM in children 
with NF1 may help to offset problems with IQ, executive functioning, and 
academic performance over time.  
4.2. Research on Interventions to address Attention in NF1  
Despite the significant negative impact of cognitive and behavioral deficits, few 
intervention studies have been conducted in patients with NF1 and attention problems.  
Given the observed similarities between patients with developmental ADHD and 

COGTRAIN 
 
13  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
children with NF1, interventions for ADHD are often employed clinically to treat the 
behavioral symptoms of children with NF1.  Yet, aside from a single study showing 
efficacy of stimulant medication in children with NF1, such interventions have not been 
evaluated empirically in the NF1 population, and we are unaware of any published 
studies using non-pharmacological approaches.  
In children with ADHD, the most-well-studied approach for remediating attention 
difficulties is the use of the stimulant medications, particularly methylphenidate (MPH). 
MPH is a piperidine derivative most commonly used to treat individuals with 
neurodevelopmental attention ADHD. It functions to increase the availability of 
dopamine in the prefrontal cortex and other subcortical connections considered critical 
for regulation of attentional processes (Volkow et al., 2005).   
In children with NF1, Mautner and colleagues (2002) published the only known study of 
stimulant medication in children with NF1 and ADHD. In this study, a small sample of 
children with NF1 and ADHD (n = 20) were compared with a group of non-NF1 ADHD 
participants (n = 26) in terms of response to stimulant medication. In an open label 
design, researchers used a daily titration of short acting MPH until patients reached a 
15 mg dose or test performance reached normal levels on a task of sustained visual 
attention and inhibition (i.e., Test of Variables of Attention).  Children in both groups 
showed statistically significant improvements in commission and omission errors on the 
Test of Variables of Attention, and the ADHD control group only showed statistically 
significant improvements in response time. In addition, at one-year follow-up, parent 
and teacher ratings of symptoms indicated significant improvements in the NF1+ADHD 
group for symptoms of inattention and impulse control. There were a number of notable 
limitations of the study, including the use of a short-acting MPH formula rather than a 
modern extended-release formula. In addition, there was no assessment of other 
relevant cognitive domains (e.g., executive functions including working memory), nor 
was efficacy determined over a range of performance-based and rating scale outcomes.  
There is biologically-based evidence that stimulant medications may impact 
dopaminergic alterations associated with deficits in neurofibromin (Brown et al 2010, 
Brown et al 2011). Recent studies using Nf1+/- mice with homozygous inactivation of 
the Nf1 gene in GFAP+ cells (known as Nf1 OPG mice) have established a mechanistic 
connection between Nf1 gene expression, attention system function, and dopaminergic 
pathway integrity (Brown, Emnett et al. 2010). These mice exhibit marked defects in 
non-selective and selective attention without an accompanying hyperactivity phenotype. 
Reverse-phase high performance liquid chromatography measurements demonstrated 
a marked reduction in dopamine levels in the striatum in Nf1 OPG mice (compared to 
control littermates).  Crucially, attention defects were rescued following treatment with 
MPH and levodopa. This was accompanied by normalization of dopamine levels in the 

COGTRAIN 
 
14  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
striatum (Brown, Emnett et al. 2010). Further extending these findings, the investigators 
found evidence of presynaptic dopamine deficits consisting of reduced striatal 
DARPP32 phosphorylation, reduced VMAT2/DAT (vesicular monoamine transporter 
type 2; dopamine transporter) expression in striatal tissue and reduced [11C]-raclopride 
positron-emission tomography (PET) binding in intact Nf1 OPG mice. They also showed 
that treatment with MPH or l-deprenyl, an irreversible MAO-B inhibitor that increases 
dopamine levels, reversed the cognitive and behavioral effects as well as the abnormal 
[11C]-raclopride binding (Brown, Emnett et al. 2010). These findings suggest that 
reduced dopamine levels underlie the inattention phenotype in Nf1 OPG mice. By 
extension, it is reasonable to hypothesize that MPH may improve cognitive deficits in 
children with NF1 by enhancing striatal dopamine levels. PET studies with adults have 
shown that treatment-naïve adults with ADHD have similar deficits in presynaptic striatal 
dopamine levels (Volkow, Wang et al. 2007). Based on these biological observations, it 
is possible to hypothesize that, if deficits in neurofibromin are related to alterations in 
dopaminergic pathways, clinical improvements or effects obtained using stimulant 
medications in NF1 patients may be similar to children with developmental ADHD.  
In children with ADHD, stimulants are most effective in reducing core symptoms of the 
disorder as delineated by the DSM-IV-TR (2000). Despite this, there is also evidence 
that stimulant treatment is less effective in reducing functional impairment related to 
symptoms, particularly with regard to problems related to executive dysfunction (Abikoff, 
Nissley-Tsiopinis et al. 2009).  Moreover, there is also data from the longitudinal 
Multimodal Treatment of ADHD (MTA) study that the effects of stimulant medication 
treatment may not persist over the long term (MTA Group 2004). Additionally, a sizable 
portion of children (i.e., 20-30%) either cannot tolerate or do not derive significant 
benefit from stimulant treatment.  For these reasons, a number of consensus groups 
have called for the continued examination of other treatment modalities, under the 
assumption that a multi-modal treatment approach is likely required for optimal 
functioning in many patients.  Towards this aim, the development of non-
pharmacological treatment methods has received increased attention in recent years, 
particularly for interventions aimed at reducing symptoms that are less well-targeted by 
psychostimulants (i.e., executive functioning). 
4.3. Cognitive training (CT) Programs 
Cognitive training (CT) programs have been used for decades to reduce or stabilize 
neurocognitive deficits in populations of individuals with accidental or disease-related 
brain injury. Most CT programs emphasize activities designed to improve specific 
cognitive deficits through repetitive practice of related skills, often with the aid of a 
trained therapist or “coach” who functions to guide and focus the activities, and to 
facilitate training with maximum effort and efficiency.  

COGTRAIN 
 
15  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
CT has been associated with improved functioning in several child and adult 
populations including those with traumatic brain-injury (Cicerone 2002; Cicerone 2002; 
Tiersky, Anselmi et al. 2005; Tiersky, Anselmi et al. 2005), dementia (Moore 2001; 
Cahn-Weiner, Malloy et al. 2003; Hofmann, Rosler et al. 2003; Cipriani, Bianchetti et al. 
2006), schizophrenia (Bell, Fiszdon et al. 2004; Fiszdon, Bryson et al. 2004), mild 
cognitive impairment (Cipriani, Bianchetti et al. 2006) and ADHD (Klingberg, Forssberg 
et al. 2002; Klingberg, Fernell et al. 2005).  A meta-analytic review of over 85 CT 
studies concluded that individuals receiving such treatment receive significantly more 
benefit than those in control/placebo conditions (Cicerone, Dahlberg et al. 2005). 
In the past several years, many computerized CT programs have been developed 
specifically to target attention and WM problems, primarily in children and adolescents 
diagnosed with Attention-Deficit Hyperactivity Disorder (ADHD).  Most consist of a 
series of attention/short-term memory tasks of increasing complexity, and there is 
emerging support for their efficacy with the ADHD population (Slate, Meyer et al. 1998; 
Kerns, Eso et al. 1999; Klingberg, Forssberg et al. 2002; Klingberg, Fernell et al. 2005).   
Several lines of research indicate that dopamine plays an important role not only in WM 
function but also for improving WM capacity. In addition, one of the mouse models of 
NF1 provides compelling evidence supporting dopaminergic modulation as a treatment 
of inattention in NF1. Pharmacological interventions acting on the dopaminergic 
system, such as methylphenidate, improve WM performance. Cognitive training 
programs for improving WM performance have also recently been associated 
with changes in dopamine receptor density. These two different means of improving 
WM performance--pharmacological and behavioral--are thus associated with similar 
biological mechanisms in the brain involving dopaminergic systems.  
4.3.1. CogmedRM 
Klingberg and colleagues developed a computerized CT program targeted at 
reducing deficits in working memory (Klingberg, Forssberg et al. 2002; Klingberg, 
Fernell et al. 2005).  The program, called CogmedRM, consists of game-like 
exercises that involve repeated practice of simple visual-spatial and verbal span 
tasks.  CogmedRM has been assessed in several studies in children with ADHD 
and other cognitive deficits associated with WM problems.  This program lends 
itself particularly well to randomized, controlled studies given the fixed training 
“dose” (i.e., 25 training sessions).  CogmedRM consists of exercises that are 
continuously adapted to the child’s skill level on a trial-by-trial basis.   
Participants who complete CogmedRM typically show immediate gains in 
objective and subjective attention and WM skills, and there is evidence to 
suggest that children maintain gains over time (Beck, Hansen et al., 2010; 

COGTRAIN 
 
16  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Bernards, Snijders et al. 1993; Klingberg, Forssberg et al. 2002; Klingberg, 
Fernell et al. 2005; Holmes, Gathercole et al. 2010) and also progress 
academically (Holmes, Gathercole et al. 2010). (Holmes, Gathercole et al. 2010). 
In controlled trials, effect sizes for parent-rated inattention and executive 
functioning have been moderate to large, averaging at approximately Cohen’s d 
= 0.80 (standardized mean difference; Cohen, 1988).   In terms of performance-
based measures, effect sizes are largest for near-transfer tasks, particularly 
visual-spatial tasks (d = .80 – 1.0).   Importantly, gains on near-transfer tasks 
have been largely maintained at 3-month (Klingberg, Fernell et al. 2005) and 6-
month (Holmes, Gathercole et al. 2009) follow-up assessments. Moreover, when 
Holmes and colleagues (2009) evaluated the academic achievement of children 
with low working memory scores (with or without comorbid ADHD) 6 months 
following CogmedRM training, math achievement scores were shown to have 
improved approximately 0.5 SD.  
Although it remains unclear both the extent to which training-related gains 
transfer to everyday functioning, and the exact mechanisms by which training-
related gains take place (Gibson, Gondoli et al. 2011; Gibson, Kronenberger et 
al. 2012), computerized CT is an emerging intervention approach with the 
potential to benefit children with NF1 and working memory difficulties.  Of 
importance, a recent trial comparing use of stimulant medication to participation 
in CogmedRM  training (Holmes, Gathercole et al. 2009) resulted in significant 
WM gains following both interventions.  However, children on stimulant 
medication made gains in visuo-spatial WM only, whereas those completing CT 
made broad gains in several types of WM.  Results thus suggest that WM 
training may  have complementary benefits to medication, especially for WM 
skills (Holmes, Gathercole et al. 2009). Thus, while stimulant medication is highly 
effective in improving core aspects of attention, WM training targets a broader 
range of skills related specifically to working memory. 
In addition, cognitive training may also impact the dopaminergic pathways and 
produce changes in neuronal plasticity.  McNab and colleagues (2009) showed 
changes in dopamine receptors using a WM training program. Thirteen 
volunteers (healthy males 20 to 28 years old) performed the 5-week WM training, 
resulting in significant gains on performance-based WM tasks. In addition, 
measurements of the binding potential (BP) of D1 and D2 receptors measured 
with PET using the radioligands [11C]SCH23390 and [11C] Raclopride, before and 
after training, showed that  increases in WM after training inversely correlated 
with the D1 dopamine receptor BP in the regions involved in WM performance. 
The present study shows that practice-induced changes in WM correlate with 
changes in the D1 receptor BP. 

COGTRAIN 
 
17  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
A potential synergistic effect may be observed combining MPH and WM 
training. Research in experimental animals strongly suggests that stimulation of 
dopamine receptors in the prefrontal cortex can ameliorate spatial working 
memory (SWM) related cognitive deficits, and may even enhance cognitive 
function in healthy animals. Research in humans has not been able to clearly 
replicate these findings, partly due to the lack of available agents that can safely 
be used. MPH can enhance cognitive performance in adults and children 
diagnosed with ADHD (Kempton et al., 1999; Riordan et al., 1999) and also in 
normal human volunteers on tasks sensitive to frontal lobe damage, including 
aspects of spatial working memory performance (Elliott et al., 1997). Mehta et al, 
2000, investigated changes in regional cerebral blood flow (rCBF) induced by 
MPH during performance of a SWM task to define the neuroanatomical loci of the 
beneficial effect of the drug. The results show that the MPH-induced 
improvements in WM performance occur with task-related reductions in rCBF in 
the dorsolateral prefrontal cortex and posterior parietal cortex. The beneficial 
effects of MPH on WM were greatest in the subjects with lower baseline WM 
capacity (Mehta, et all 2000).  Although a randomized clinical trial to investigate a 
synergistic effect of CogmedRM training and MPH use has not been conducted 
with any clinical population, Beck and colleagues (2010) conducted a 
randomized trial of children with ADHD (n = 52), many of whom were also 
receiving stimulant treatment during the study.  Although there were no 
differences in cognitive training outcomes between those receiving or not 
receiving stimulant treatment, it is important to note that the authors did not 
require that participants taking stimulant medication complete their cognitive 
training sessions during the therapeutic window of the drug.  Rather, they merely 
specified that children complete their training sessions at a consistent time of 
day; thus, any synergistic effect may have been obscured. 
4.3.2. MobyMax  
MobyMax (Willett & Willett, 2016) is an adaptive online educational program that 
targets academic skills across a range of subject areas (e.g., reading fluency, 
reading comprehension, math computation, etc.).  It is designed to be completed 
by children aged 5+ on a desktop or laptop computer or tablet device with 
minimal parental supervision.  The adaptive format is designed to keep a child 
practicing exercises within a range of difficulty appropriate to his or her level of 
performance.  MobyMax was selected as an active control for this study because 
it mirrors CogmedRM in its adaptive qualities; however, target content area in 
each program differs. CogmedRM is focused on training working memory skill 
whereas MobyMax is focused on reading comprehension. Although training 
sessions are defined by the number of trials, as with CogmedRM, participants 

COGTRAIN 
 
18  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
assigned to MobyMax will be asked to complete 25 training sessions, each 
between 30-45 minutes each, which will be automatically tracked by the 
MobyMax program.  Thus, the time spent on MobyMax activities and the time 
spent on CogmedRM training will be equivalent across groups.   
5. STUDY OBJECTIVES 
5.1. Specific Aim 1   
To assess the efficacy of CogmedRM, a home-based, computerized cognitive training 
(CT) program in children with NF1, ADHD, and working memory difficulties as 
compared to a control CT program. 
Hypothesis 1: Participants receiving the CogmedRM intervention will show a larger 
improvement in their CogState One-back scores from baseline than participants 
receiving the MobyMax intervention.   
Sub-Hypothesis 1a: Participants who are identified as ON Stimulants and 
receiving the CogmedRM intervention will perform better compared to those 
participants ON stimulants who completed MobyMax with respect to their scores on 
the CogState One-Back after completion of the intervention.  
5.2. Exploratory Aim 
To assess the efficacy of cognitive training on other outcomes of interest, including both 
performance-based and questionnaire measures of working memory. 
Exploratory Hypothesis:  
Participants who complete the adaptive version of CogmedRM will show significantly 
greater improvements than those who complete MobyMax on performance-based and 
questionnaire measures of WM and executive functioning. Participants who complete 
MobyMax are expected to show greater improvements on performance-based 
measures of reading than those who complete CogmedRM. 
 
 
 

COGTRAIN 
 
19  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
6. STUDY DESIGN AND METHODS 
6.1. Study Design 
Figure 1: Study design 
 
6.2. Stratification and Randomization 
All patients will be registered in a centralized participant registry system administered 
through the Children’s National Health System.  Eligible participants will subsequently 
be stratified by medication use and randomized equally between the two interventions 
using a HIPAA-compliant password-protected web site. This web site will incorporate 
randomization lists created by the study biostatisticians using a permuted block design 
with stratification according to stimulant medication status (ON vs. OFF). 
7. STUDY POPULATION AND SELECTION 
Approximately 90 patients with NF1 will be enrolled at 2 U.S. sites and 2 international 
sites. Potential participants will include children diagnosed with NF1 aged 8 to 16 who 
show signs of cognitive deficits related to NF1. No exclusions will be made based on 
gender, race, or ethnicity. To reach this goal, we anticipate needing to screen 
approximately 130 participants, though enrollment will end when, or continue until 90 
eligible participants are identified. Based on conservative estimates, approximately two-
thirds of those screened should meet all eligibility criteria for the intervention phase.  

COGTRAIN 
 
20  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Those who are enrolled in the intervention (n = 90) will be determined by the criteria 
listed in the inclusion and exclusion section of this document. 
7.1.  Inclusion Criteria 
• 8-16 years old at time of screening 
• NF1 Diagnosis based on NIH criteria 
• Has an identified caregiver who is willing and able to oversee the training 
practice during the intervention period 
• Has access to a telephone and phone number where they can be reached 
• Both patient and caregiver have speaking, and listening comprehension of 
English.  Caregivers must be able to read English with enough proficiency to 
complete study questionnaires (approximately 5th grade reading level). 
• Treated with a stable dose of stimulant medication for at least the last 30 days 
and not planning to change the dose during study participation or receiving no 
stimulant medications for at least the last 30 days and not planning to initiate 
a trial of stimulant medications for the duration of the study. 
• Score >1 SD below the mean on either the WISC-V-Integrated Spatial Span 
Forward or Backwards tasks or Digit Span Forward or Backwards tasks or 
score >1 SD below the participant’s estimated IQ on either Spatial Span 
Forward or Backwards or Digit Span Forward or Backwards. 
7.2.  Exclusion Criteria 
• Full scale IQ ≤ 70, as estimated by WASI-II (Block Design, Vocabulary, Matrix 
Reasoning, Similarities).  
o Note: In cases where there is a statistically significant difference 
between verbal IQ and performance IQ. (0.05 level as determined by 
the WASI-II manual), participants will be eligible if at least one of the 
these quotients is 70 or above 
• Current treatment for intracranial lesions, progressive tumors as per MRI 
evaluation or treatment with chemotherapy within the past 6 months 
• A motor, visual, or auditory handicap that prevents computer use 
7.3. Early Termination or Withdrawal 
A participant (or the legal guardian acting on behalf of the participant) is free to withdraw 
consent and discontinue participation in the study at any time, without prejudice to 
further treatment according to standard clinical practice. Study participation may be 
discontinued at any time at the discretion of the site PI. The following may be justifiable 
reasons for removing a participant: 

COGTRAIN 
 
21  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
• The participant is uncooperative/noncompliant and will not adhere to study 
responsibilities, including failure to appear at study visits. 
• The participant experiences an unmanageable AE. 
• The participant (or the legal guardian action on behalf of the participant) wishes 
to enroll in any other study which involves a different study intervention.  
For participants who discontinue early from the study or if the study is prematurely 
terminated, the site Principal Investigator (PI) or designee will contact the participant or 
the participant’s legal guardian within 30 days after withdrawal or termination to assess 
any AEs. The site PI will be asked to follow all Severe Adverse Events (SAEs) until the 
event returns to baseline or until the site PI determines that follow-up is no longer 
medically necessary. 
7.4. Study Duration and Enrollment 
7.4.1. Study Enrollment  
Children meeting the study eligibility criteria will be invited to participate at each 
participating site according to specific procedures that have been locally 
approved by the Institutional Review Board at each institution.  Study 
participation begins (i.e., as the participant is “enrolled”) once written informed 
consent form (ICF) is obtained from the potential participant and their 
guardian/legal representative before any study-specific procedures are 
performed.  The study will be explained and informed consent will be obtained 
from caregivers by a member of the study team at each institution.  Unique study 
IDs will be assigned to each participant. Each site principal investigator (PI) will 
keep a study number log relating the names of the participants to their study 
numbers to permit efficient verification of participant files, when required.   
7.4.2. Study Duration  
The length of time a participant is enrolled in this study will depend on how 
quickly each participant completes their at-home training.  At a minimum, 
participants will be enrolled for 5 weeks and may extend to 11 weeks. 

COGTRAIN 
 
22  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
8. STUDY INTERVENTION 
8.1. Product Details 
8.1.1. CogmedRM  
Cogmed RM is a computer program installable either as a direct download or from 
a CD-ROM, and compatible with any Windows-based or Apple personal 
computer. The program is commercially available to qualified practitioners 
through Cogmed, Inc., currently owned by Pearson. The program consists of 
twelve visually-engaging and interesting exercises that target skills involving 
visuo-spatial and verbal WM.  Difficulty of the tasks is automatically adjusted on a 
trial-by-trial basis throughout each training session to match a child’s current 
working memory span, such that as the child becomes more proficient, the 
exercises become more difficult.  Cogmed RM is designed for children aged 8 to 
16.  Exercises have space and robot themes with names such as “Decoder,” 
“Space Whack,” and “Visual Data Link.” For example, “Asteroids,” a visuo-spatial 
WM exercise, consists of a number of asteroids floating through space.  The 
asteroids light up in a random order, after which the child is asked to click on the 
asteroids in the order in which they just were highlighted.  When done correctly, 
the highlighted asteroids explode.  In “Stabilizer,” a verbal memory exercise, 
children hear a series of letters while lights illuminate with each letter.  Then, 
when the letter appears on the screen, the child must select the correct light that 
was originally paired with that letter.  Cogmed RM also contains a game, “Robo 
Racing,” that children can play as a reward for completing their session.  Children 
are encouraged to complete training tasks correctly to earn more “energy” that 
can later be used during the reward game.   
During the intervention, children complete 25 training sessions.  Children are 
asked to complete between 3 and 5 sessions per week, so the total treatment 
time to complete 25 sessions may range from 5 to 9 weeks.  For children 
completing CogmedRM, sessions typically last between 25 and 45 minutes, 
depending on the child’s working memory span.  Parents are asked to support 
their child’s training in developmentally appropriate ways. For younger children, 
this typically involves helping children to turn on the computer and launch the 
program, as well as providing frequent feedback and encouragement during 
sessions.  Older children usually require less supervision, though parents may be 
asked by coaches to help their children follow through with coaching suggestions 
(e.g., taking a break after challenging activities).  Prior to beginning training, all 
families are asked to identify specific days, times, and settings during which 
training sessions will take place (on average) so that a quiet, distraction-free 

COGTRAIN 
 
23  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
environment can be selected for training, at a time when the child has adequate 
energy and no competing demands. 
8.1.2. Control Program – MobyMax 
MobyMax’s “Reading Stories” program is an adaptive activity that mirrors 
CogmedRM on a learning level. The participant’s reading comprehension as 
determined by the baseline testing session, will determine the grade placement 
within the Reading Stories activity of the MobyMax program. Each grade 
contains 30 lessons, in which each lesson contains 3 stories that are tailored to 
the participant’s grade level. Participants are given questions to answer at the 
conclusion of each story. Depending on whether the participant passes or fails, 
the adaptive program will place the participant at the appropriate reading level. 
Participants randomized to this program, will be asked to spend the same 
amount of time as the participants randomized to CogmedRM (i.e., 30-45 minutes 
per session for 25 training sessions over a 5 to 8 week period), and, as with 
CogmedRM,  a training coach from the study team will be assigned to access and 
track each participant’s progress, as well as provide weekly, phone based 
coaching support.   
8.1.3 Ongoing communications with participants for both interventions 
For both intervention arms, families will have phone meetings at least once per 
week with an intervention coach to ensure compliance, record any adverse 
events (grade 3 or above), track progress, provide feedback and answer any 
questions that may have arisen during treatment. While the coaching structure is 
the same for all participants, the coach retains the flexibility to specifically 
address difficulties according to each child’s needs. There may be children who, 
despite coaching efforts, are not compliant with training. Every effort will be made 
to obtain follow up data from these participants, and their data will be analyzed 
on an intent-to-treat basis. 
9. STUDY ASSESSMENTS 
Table 1 Schedule of Assessments outlines the overall study schedule including clinic 
visits and at home follow-up. 
Table 1. Schedule of Assessments 
STUDY VISIT 
VISIT 1 
HOME 
TRAINING 
VISIT 2 

COGTRAIN 
 
24  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
STUDY INTERVAL 
BASELINE 
FOLLOW-
UP 
PHONE 
CALLS 
FOLLOW 
UP 
STUDY PROCEDURES 
DAY 
0 
WEEKS 
1-9 
DAY  
 
Informed Consent 
X 
 
 
Inclusion/Exclusion 
X 
 
 
NF1 Diagnosis Confirmed 
X 
 
 
Demographics 
X 
 
 
Medical/Surgery History 
X 
X 
X 
Weight/ Height 
X 
 
X 
Vital Signs 
X 
 
X 
Concomitant Medication 
X 
X 
X 
Physical Exam 
X 
 
X 
ADHD-RS 
X 
 
 
Wechsler Abbreviated Scale 
of Intelligence – Second 
Edition (WASI-II) 
X 
 
 
Wechsler Intelligence Scale 
for Children – Fifth Edition 
(WISC-V-Integrated)-select 
tests 
X 
 
X 
Child Behavior Checklist 
(CBCL) * 
X 
 
 
CogState 
X 
 
X 
Behavior Rating Inventory of 
Executive Functioning 
(BRIEF)* 
X 
 
X 

COGTRAIN 
 
25  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Test of Word Reading 
Efficiency Second Edition 
(TOWRE-2) 
X 
 
X 
Test of Everyday Reading 
Comprehension (TERC) 
X 
 
X 
Intervention Compliance 
Assessment 
 
X 
X 
Adverse Event 
 
X 
X 
*Parent completed measure 
9.1. Screening and Baseline Assessments (Visit 1) 
Below are the neuropsychological measures that will be administered at Visit 1 by a 
neuropsychologist or a Clinical Research Assistant supervised by the 
neuropsychologist. Of note, parents and members of the study team collecting outcome 
data will be blinded to participants’ treatment status throughout the study, such that they 
will not be given information on whether the child was randomized to CogmedRM or 
MobyMax (i.e., therapeutic intervention versus control condition). In addition, members 
of the research team collecting neurocognitive outcome data will also be blinded to each 
participant’s stimulant medication use. Training coaches, by definition, cannot be blind 
to the treatment arm, as they utilize feedback about the child’s daily training progress to 
make suggestions to the child and parents as to how training motivation and efficiency 
can be maximized. As such, at least three site-specific personnel are required at the 
screening/baseline assessment: a medical provider who will perform the medical 
examination (e.g., nurse practitioner, physician, nurse, etc.), a psychologist/ 
neuropsychologist who either performs the neurocognitive evaluation or supervises a 
mid-level provider or testing technician who does so, and a clinical research assistant 
who is able to provide the intervention training to the participants who qualify for 
randomization.    
9.1.1. CogState 
(Maruff, Thomas et al., 2009) CogState is a computerized package that offers a 
range of semi-automated assessment modules for individuals aged 6-90. We will 
use tasks of processing speed, visual attention, visual and verbal learning and 
memory, and working memory. Reliability is 0.77 with no practice effects after 
initial training (Falleti, Maruff, Collie, & Darby, 2006). Age-based standard scores 
(mean = 100, SD 10) are computed for each task based on a normative sample 
of several hundred individuals. CogState tasks have been used successfully in 

COGTRAIN 
 
26  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
trials of populations relevant to NF1.  Specifically, the battery has been used with 
children with ADHD, for which CogState tasks discriminate between those with 
and without the diagnosis, and those on and off medication, as well as typically-
developing children. Of importance, tasks in the CogState battery were also used 
in our pilot trial of CogmedRM with an NF1 sample. CogState will be administered 
at baseline (Visit 1) and follow-up (Visit 2) assessments. We will use the One-
back working memory task as the primary outcome measure of the study, and 
will also use the One-Card Learning and Groton Maze Learning tasks as 
supplemental working memory and executive functioning measures.  
9.1.2. ADHD-RS  
(DuPaul, Power, Anastopoulos, & Reid 1998). ADHD-RS consists of the 18 
DSM-IV ADHD symptoms. Each item is scored for frequency on a four-point 
Likert scale (0–3: 0 = never or rarely; 3 = very often). Summary T scores for 
Inattentive, Hyperactive-Impulsive, and Total symptoms are calculated based on 
norms for age and gender. This assessment will be completed by the parent or 
guardian of the participant during the baseline (Visit 1). 
9.1.3. Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II) 
(WASI-II; Wechsler 2011).  The WASI-II is an abbreviated measure of 
intelligence that can be administered to individuals aged 6 and older.  The WASI-
II will be used at the screening visit (Visit 1) to estimated IQ based on the scaled 
scores from four tasks: Block Design, Similarities, Vocabulary, and Matrix 
Reasoning. 
9.1.4. Child Behavior Checklist (CBCL) 
(Achenbach 1991) is a parent-completed measure of the emotional/behavioral 
functioning of children aged 4-18 across home and school domains. CBCL 
scores will be calculated during the baseline (Visit 1) in the assessment of 
participants’ psychological functioning. Population mean scores are 50 with an 
SD of 10. Values on any subscale or overall scale that are 70 or higher indicate a 
concern in that domain. 
9.1.5. Wechsler Intelligence Scale for Children – Fifth Edition (WISC-V-
Integrated) 
(Wechsler, 2015) Subtests from the WISC-V-Integrated will be administered at 
baseline and follow up, including verbal (Digit Span) and visual (Spatial Span) 
working memory subtests. This test will be administered at baseline (Visit 1) and 

COGTRAIN 
 
27  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
follow-up (Visit 2). For both subtests, scaled scores have a population mean of 
10 and SD of 3.  
9.1.6. Behavior Rating Inventory of Executive Functioning (BRIEF) 
(Gioia, Isquith et al. 2002) is a parent-completed measure of behavioral 
executive functioning. For this study, the Metacognition subscale will be used. 
The Working Memory score of the BRIEF will be administered at baseline and at 
follow-up as a secondary outcome measure for Exploratory Aim 1.  T-scores are 
calculated with a mean of 50 and a standard deviation of 10. 
9.1.7. Test of Word Reading Efficiency – Second Edition (TOWRE-2) 
(Torgesen, Wagner, & Rashotte 2012) The TOWRE-2 is a common test for 
children and young adults aged 6-24 that assesses fluency in word reading. This 
test will be administered at baseline (Visit 1) and follow-up (Visit 2).  Standard 
scores are calculated with a mean of 100 and a standard deviation of 15. 
9.1.8. Test of Everyday Reading Comprehension (TERC) 
(McArthur, Jones et al. 2013) The TERC is a screening test composed of 10 
items that is used to examine the reading comprehension of a child aged 6-12. 
This test will be administered at baseline (Visit 1) and follow-up (Visit 2). 
Standard scores are calculated with a mean of 100 and a standard deviation of 
15. 
9.1.9. Intervention training 
During Visit 1, a research participant will be randomized to receive one of two 
computer based training programs (either CogmedRM, or MobyMax).  During Visit 
1the neuropsychologist or designee will train the study participant on how to 
open the assigned computer program and use it.  
9.2. Cognitive Training Follow-up (Visit 2) 
Participants will return to clinic within two weeks of completing cognitive training for brief 
medical and neuropsychological assessment.  In addition to a medical exam recording 
participants’ weight, vital signs, and side effects, children will also undergo re-evaluation 
of neuropsychological outcomes of interest.  The entire visit is expected to last 1 to 1 ½ 
hours. 
Table 2. Timeline of Neurocognitive Measures 
Study Variable 
Measure 
Format/Subscales Respondent 
Time 
Required 
Time 
Points 

COGTRAIN 
 
28  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Attention 
Ratings 
ADHD-RS 
Symptom 
questionnaire of 
DSM-5 TR ADHD 
Symptoms 
Parent & 
Teacher 
(during the 
school 
year) 
5 
minutes 
Visit 1 
(Baseline 
Only) 
Intelligence 
WASI-II 
Block Design, 
Vocabulary, 
Matrix 
Reasoning, 
Similarities 
Child 
20-30 
minutes 
Visit 1 
(Baseline) 
only 
Psychological 
Functioning 
Achenbach 
Child 
Behavior 
Checklist 
(CBCL) 
Questionnaire of 
child’s emotional 
& behavioral 
functioning 
Parent  
10 
minutes 
Visit 1 
(Baseline) 
only 
Verbal Working 
Memory 
WISC-V- 
Integrated 
Digit Span 
(Backward)   
Child 
5 
minutes 
Visits 1,2 
Visual Working 
Memory 
WISC-V-
Integrated  
Spatial Span 
Child 
5 
minutes 
Visits 1,2 
Working 
Memory 
CogState 
CogState- One-
back 
Child 
5 
minutes 
Visits 1,2 
Short-term 
Memory 
CogState 
CogState One-
Card Learning 
Child 
5 
minutes 
Visits 1,2 
Executive 
Functioning 
CogState 
CogState- Groton 
Maze Learning 
Child 
10-12 
minutes 
Visits 1,2 
Executive 
Function 
BRIEF 
Questionnaire 
measure of 
everyday 
executive 
function 
Parent & 
Teacher 
(during the 
school 
year) 
10 
minutes 
Visits 1,2 
Reading 
fluency 
TOWRE -2 All 
Child 
5 
minutes 
Visit 1,2 

COGTRAIN 
 
29  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Reading 
comprehension 
TERC 
All 
Child 
5 
minutes 
Visit 1,2 
 
9.3. Other Assessments 
9.3.1. Demographics 
Demographics will be collected during the baseline assessments. The following 
information will be collected: date of birth, gender, race, and ethnicity and 
captured in the relevant eCRF (electronic Case Report Form). 
9.3.2. Medical/Surgery History 
Participant medical and surgical history will be collected during the baseline 
assessments. A qualified member of each participating clinical center will obtain 
detailed information regarding all past medical and surgical events. The dates 
and descriptions of past events will be captured in the relevant eCRF. 
9.3.3. Weight/Height 
Standing height in centimeters (cm) and weight in kilograms (kg) will be collected 
at both the baseline visits and the follow-up visit. Height and weight should take 
approximately 2 minutes and are not associated with any risks. These 
measurements are routinely performed during standard clinical examinations.  
9.3.4. Vitals 
The following vital signs will be collected: systolic and diastolic blood pressure 
(millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate 
(breaths/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit 
[°F]). Vitals will be captured in the relevant eCRF. 
9.3.5. Concomitant Medication  
All known prescribed medications, not including topical skin preparations, 
supplements, and other over the counter medications, used by the participant 
within 4 weeks before signing the ICF will be collected by a qualified member of 
each participating clinical center. The following information will be collected: the 
medication name, dose, unit, frequency, route, indication, start and stop dates. 
Prior medications will be captured in the relevant eCRF. 

COGTRAIN 
 
30  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
10. SAFETY 
10.1. 
Adverse Event and Serious Event Reporting 
There have not been any documented cases of an adverse event (AE) occurring with 
this intervention in any of the past published studies. However, we will define an AE as 
any unfavorable and unintended diagnosis, symptom, or disease temporarily associated 
with the study intervention, which may or may not be related to the intervention. AEs 
include any new events not present during the pre-intervention period or events that 
were present during the pre-intervention period, which have increased in severity. 
Because this is a minimal risk study for which no serious events are expected, we will 
only collect information on adverse events of at least moderate severity.  In addition, 
any pre-planned hospitalization will not be considered as a Serious Adverse Event, but 
any non-planned hospital admissions will be regarded as a Serious Adverse Event. 
Adverse Event and Serious Adverse events should be documented in the provided CRF 
with a full description including the nature, date and time of onset and resolution, 
determination of seriousness, severity, causality, corrective treatment, and outcome. 
Serious Adverse Events should be verbally notified to Project Manager and a Serious 
Adverse Event form should be fax within 24 hours to project manager. Follow-up 
information regarding the event must be reported to the Project Manager within 15 days 
of the initial event. SAEs will be followed by the site investigator until resolution. 
 
Additionally, the Ethical Committee must be notified in writing of any expedited SAEs. 
All unexpected SAEs associated with the use of the study treatment will be immediately 
reported to appropriate regulatory agencies by the sponsor. 
11. STATISTICAL PLAN 
     11.1 General 
The primary objective to be addressed statistically is to determine whether CogmedRM 
improves scores on the CogState One-back subtest when compared to the adaptive 
MobyMax control.  All analyses will be based on an intention to treat (ITT) approach, 
i.e., if a participant is randomized, they will be included in analyses, regardless of the 
number of sessions that they actually did in the assigned intervention. 
This is a Phase II study with two hypotheses within the primary aim. Each will be tested 
at a two-sided alpha=0.025. All other analyses will be considered exploratory. 

COGTRAIN 
 
31  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
11.2 Baseline characteristics 
We will use descriptive and summary statistics to detail the total number of patients 
screened, determine rates and reasons for non-eligibility and patient refusal for 
randomization. The baseline neuropsychological assessments will also be summarized 
descriptively by intervention group, within stratum, across both strata, and overall. 
11.3 Analyses of Specific Aim 1 
Specific Aim 1: To assess the efficacy of a home-based, computerized cognitive 
training (CT) program in children with NF1, ADHD, and working memory difficulties. 
Hypothesis 1: CogState One-back score errors in WM results will be lower in the 
CogmedRM group than in the MobyMax group. 
The primary analysis will be a two-way analysis of covariance (ANCOVA), analyzing the 
in post-intervention in the CogState One Back errors in WM. One factor in the analysis 
will be the intervention group (CogmedRM vs MobyMax), and the second factor will be 
the stratification group (on vs. off stimulant medication). The model will use baseline 
CogState errors as the covariate and the model will not include an interaction effect, in 
due to the moderate sample size. CogmedRM will be considered effective if the error rate 
is significantly lower than the error rate on MobyMax in this analysis.   
Sub-Hypothesis 1a: Participants who are identified as ON Stimulants and who have 
completed CogmedRM will perform better on the CogState One-Back subtest for working 
memory than those participants who completed the MobyMax training.  
In order to address this hypothesis, we will perform an ANCOVA within the ON 
Stimulants stratum. This analysis will have one factor for treatment group, and the 
baseline CogState result as a covariate. 
In addition, a linear regression model will be fit using the performance-based (CogState 
One-back) scores at Follow Up assessment as the outcome and intervention group, 
age, and CogState performance and ADHD-RS IV scores from the Baseline 
assessment included as covariates. In addition, we will also calculate standardized 
regression-based change (RBC) scores for each participant in order to determine 
whether or not any observed changes are clinically meaningful.  
Exploratory Aim: To assess the efficacy of working memory training on other outcomes 
of interest, including both performance-based and questionnaire measures of working 
memory and attention.   
Exploratory Hypothesis: We will again use linear regression models (with alpha set at 
.05) to analyze the change in performance-based and questionnaire ratings scores 

COGTRAIN 
 
32  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
between the Baseline (Visit 1) and Cognitive Training Follow-Up (Visit 2).  Specifically, the 
following performance-based measures will be included in the exploratory analyses: 
ADHD-RS,  WISC-V-Integrated Digit Span Backward, Letter-Number Sequencing, and 
Spatial Span, CogState One-card Learning and Groton Maze Learning.  In addition, the 
following questionnaire variables will be included in the exploratory analyses: BRIEF 
Working Memory Index, Behavioral Regulation Index, and Metacognition Index. Finally, in 
order to examine whether participants reading level is improved as a function of 
completing either the treatment or control conditions, we will examine the TOWRE-2 and 
TERC scores. Treatment group (i.e., CogmedRM vs. MobyMax) will be included as the 
independent variable.  These exploratory analyses will be used primarily to generate 
hypotheses for subsequent studies using these intervention approaches. 
11.4 Sample size justification:   
The target sample of 80 randomized subjects has 80% power to detect a mean 
difference of 5 in the CogState WM performance result between participants in the 
CogmedRM and the MobyMax interventions assuming a standard deviation of 10, and 
that the baseline CogState result will explain 50% of the variability in the results of the 
Visit 2 CogState. 
11.5 Other Summaries 
Other summaries for this study will include summaries of compliance with the 
interventions and comparison of compliance rates overall between the interventions and 
within each stratum. In addition, adverse events will be summarized as well as 
concomitant medications. Since this study is about behavioral interventions and not 
medications, these analyses are for completeness of review of the data in this clinical 
trial and are not expected to show any differences between the intervention groups, 
either overall or within stratum, nor to show any difference of adverse events from the 
background rates of children with NF1. 
12. DATA COLLECTION, QUALITY ASSURANCE AND MANAGEMENT 
12.1. 
Data Collection 
12.1.1. 
Electronic Data Capture (EDC) System  
Study data will be collected and managed using REDCap (Research Electronic 
Data Capture). REDCap is a secure web application designed to support data 
capture for research studies. REDCap provides user-friendly web-based case 
report forms, real-time data entry with branching logic and validation procedures 
for importing data from external sources, and advanced features such as a data 

COGTRAIN 
 
33  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
quality check module. It can export data to common statistical packages like 
SPSS, SAS, Stata, and R. The system was developed by a multi-institutional 
consortium initiated at Vanderbilt University (http://project-redcap.org/). 
Electronic CRFs and correction documentation will be maintained in the EDC 
system’s audit trail. System backups for data stored, and records retention for the 
study data will be consistent with standard operating procedures (SOPs). 
12.1.2. 
Data Entry 
All reported data from the enrolled treating-physician’s site will be entered via a 
secure web-based data entry screens and the data will be transferred via secure 
(SSL) connections to the study database. Access rights to the EDC system for 
the site team will need to be requested and every user of the system will be 
made aware of the fact that user names and passwords should never be shared 
and their electronic signature constitutes the legally binding equivalent of a 
handwritten signature.  All sites will be fully trained in using the EDC system, 
including eCRF screen completion guidelines and only trained personnel certified 
by the Coordinating Center will receive a username and password. All 
participating sites will only have access to view and enter the data for their own 
patients. 
All data will be directly entered or collected on a source document and then 
entered into REDCap. The Coordinating Center’s data management team will 
monitor the eCRFs for completeness and acceptability throughout the course of 
the study.  The Coordinating Center will be allowed access to all source 
documents in order to verify eCRF entries. 
12.2. 
Quality Assurance 
At its discretion, the Department of Defense (sponsor of this study) or its designee may 
conduct a quality assurance audit of this study.  Auditing procedures of the Sponsor 
and/or its designee will be followed in order to comply with GCP guidelines.  If such an 
audit occurs, the Investigator will give the auditor direct access to all relevant 
documents, and will allocate his/her time and the time of his/her staff to the auditor as 
may be required to discuss findings and any relevant issues. 
In addition, regulatory authorities and/or the IRB/IEC may conduct an inspection of this 
study.  If such an inspection occurs, the Investigator will allow the inspector direct 
access to all source documents, eCRFs, and other study documentation for source data 
check and/or on site audit inspection.  The Investigator must allocate his/her time and 
the time of his/her staff to the inspector to discuss findings of any relevant issues 

COGTRAIN 
 
34  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
12.3. 
Data Management 
12.3.1. 
Source documents  
Source documents are defined as original documents, data, and records. These 
documents may include hospital records, clinical and office charts, participant 
diaries or evaluation checklists, and other records. Data can be directly entered 
into REDCap however when data is collected on source documents the source 
documents must be filed with the participant study documents.. 
A participant screening/enrollment log is to be completed at each investigative 
site. Data recorded on the screening/enrollment log are to include a subject 
identifier, the date of screening, and the reason the participant was not entered (if 
applicable). All patients initially screened are to be recorded in this log. 
 
12.2.3  
Data Processing 
To ensure accuracy the data will go through validity checks (i.e. invalid values, 
outliers, missing data) at the time of entry. The Coordinating Center will also run 
monthly data query reports to check for higher level and longitudinal 
discrepancies. Clarification of data will be requested from the study site.  The 
database will be quality assured in accordance to the data management plan and 
will be available for statistical analysis according to the methods outlined in 11. 
Statistical Analysis and the Statistical Analysis Plan. 
13. SPECIAL REQUIREMENTS AND PROCEDURES 
13.1. 
Protocol Deviations 
A protocol deviation occurs when there is a variance between the procedures described 
in the protocol and the procedures performed. Protocol deviations may be minor or 
major. Minor protocol deviations, such as a site not recording a data point on a CRF, do 
not affect the participant’s rights, safety, and/or well-being. Major protocol deviations 
include any actions that jeopardize a participant’s rights, safety, and well-being, such as 
a breach of confidentiality.   
Major deviations must be reported to the site’s local ethics committee within the 
timelines defined by the site local ethics committee guideline or within 10 business 
days, whichever is first. All other minor deviations must be reported in writing to the 
local ethics committee as part of the annual report or when requested, whichever is first. 
The site PI must follow local regulations for reporting of protocol deviations and must 

COGTRAIN 
 
35  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
report deviations to the Coordinating Center as soon as possible or when reported to 
the site’s local ethics committee. 
13.2. 
Access to Source Data/ Documents 
Each participating site (both U.S. and international) will maintain appropriate medical 
and research records for this trial, in compliance with Section 4.9 of ICH E6 GCP, and 
regulatory and institutional requirements for the protection of confidentiality of 
participants.  Each site will permit authorized representatives of the Coordinating Center 
and regulatory agencies including the DOD to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, 
audits and evaluation of the study safety and progress. The investigator(s)/institution(s) 
will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s), providing direct access to source data documents 
13.3. 
Investigator Responsibilities 
13.3.1. 
Institutional Review Board/Ethics committee 
Each study site Principal investigator (PI) will be responsible for obtaining local 
ethics committee approval for the protocol and informed consent. Sites are 
responsible for providing the Coordinating Center with copies of the initial local 
ethics committee approval and any continuing review approvals. During the 
entire period of the study, each site will be responsible for providing their local 
ethics committee with any new protocol information and for submitting annual 
renewals. 
The investigator will notify the IRB of violations from the protocol and serious 
adverse events. 
13.3.2. 
Protocol Compliance 
Each site PI will also be responsible for conducting the study according to the 
procedures described in this protocol and any supplemental study-specific 
manuals or guidelines.  In addition, each site PI will be responsible for assuring 
that only qualified individuals perform each aspect of the study.   
13.3.3. 
Informed Consent and Assent 
All parent(s)/legal guardians acting on behalf of the participant in the study will be 
given the consent form that describes the study and provides sufficient 
information for the parent(s)/legal guardian to make an informed decision about 
whether to provide permission for the child to participate in this study. The formal 
consent, using the local ethics committee-approved consent form, will be 

COGTRAIN 
 
36  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
obtained before any study procedure. The consent form will describe the study 
intervention, the chance each participant has at receiving each intervention and 
any risk due to participation in the research study.  The participant and their 
family will have an opportunity to have all questions answered before signatures 
are added to the consent forms. This consent form must be signed by the 
participant and/or legal guardian, and the site investigator-designated research 
professional obtaining consent.  A copy of the consent form will be given to the 
participant’s parent/ legal guardian, and this will be documented in the 
participant’s record. A copy of the signed consent form will be retained in the 
participant’s medical record. The participants may withdraw consent at any time 
throughout the course of the study. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in this study. 
13.3.4. 
Participant Confidentiality 
The rights and privacy of participants who participate in this study will be 
protected at all times. The data obtained by the study will be kept confidential.  
All neuropsychological evaluation forms, and other data will contain only the 
participant’s identification number, respondent role (e.g., mother or father) and 
date of the study evaluation. The computerized information will be password 
protected and if printed, the records will be filed in a locked cabinet in the office 
of the site investigator or study coordinator. Participants will not be identified in 
any publicly released reports of this study. 
Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by an ethics committee, the study 
monitor, or other government agency. 
13.4. 
Participant Compliance and Compensation  
The CogmedRM program automatically tracks the number and length of children’s 
sessions, along with their progress through program levels.  Specifically, training data is 
uploaded into a secure server every time the child logs into the program. In the event 
that internet access is not available during a particular session, participants can still 
complete training, but will be required to upload training data at least every 3rd session.  
When CogmedRM is administered in typical clinical practice, coaches work with parents 
and children to identify external reinforcers to promote adherence to the training 
schedule.  In other words, caregivers typically provide tangible incentives (i.e., prizes) 
and/or enhanced privileges as their children complete CogmedRM sessions in order to 
help children maintain motivation and effort over the course of the training period.  
Accordingly, to provide a consistent incentive for participants in the proposed study, 

COGTRAIN 
 
37  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
children will earn gift cards following completion of each segment (session 8, session 
17, session 20, & session 25) of cognitive training.  As an additional reinforcer, each 
participant will be provided with a chart and stickers to visually track their progress 
through the program. 
The control condition, MobyMax, also automatically tracks the number and length of 
children’s sessions, along with their success with each training activity.  To be 
consistent with the incentives provided for participants training with CogmedRM, 
participants completing MobyMax will also be provided with gift cards following the 
completion of sessions 8, 17, 20, and 25, and will be provided with a chart and stickers 
to visually track their progress through the program. 
 
 

COGTRAIN 
 
38  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
 
REFERENCES 
Abikoff, H., Nissley-Tsiopinis, J. et al. (2009). Effects of MPH-OROS on the 
organizational, time management, and planning behaviors of children with ADHD. 
Journal of the American Academy of Child and Adolescent Psychiatry, 48(2), 166-175. 
 
 
Achenbach, T. M. (1991). Manual for the CBCL. Burlington, VT, University of Vermont. 
 
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental 
disorders (4th ed., text rev.). Washington, DC: American Psychiatric Publishing. 
 
American Psychiatric Association. (2013). Diagnostic ad statistical manual of mental 
health disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. 
 
Barnett, R., Maruff, P., Vance, A., Luk, E.S.L., Costin, J., Wood, C, Pantelis, C. (2001). 
Abnormal executive function in attention deficit hyperactivity disorder: the efect of 
stimulant medication and age on spatial working memory. Psychological Medicine, 
31(6), 1107-1115. 
 
Barton, B., & North, K. (2004). Social skills of children with neurofibromatosis type 1. 
Developmental Medicine & Child Neurology, 46, 553-563. 
 
 
Beck, S. J., Hanson, C. A. et al. (2010). A controlled trial of working memory training for 
children and adolescents with ADHD. J Clin Child Adolesc Psychol, 39(6), 825-836. 
 
 
Bell, M., Fiszdon, J. et al. (2004). Effects of neurocogntive enhancement therapy in 
schizophrenia: Normalisation of memory performance. Cognitive Neuropsychiatry, 9, 
199-211. 
 
Bernards, A., & Snijders, A. et al. (1993). Mouse neurofibromatosis type 1 cDNA 
sequence reveals high degree of conservation of both coding and non-coding mRNA 
segments. Human Molecular Genetics, 2, 645-650. 
 
 
Brewer, V., Moore, B., et al. (1997). Learning disability subtypes in children with 
neurofibromatosis. Journal of Learning Disabilities, 30, 521-533. 
 
 
Brown, J., Emnett, R., et al. (2010). Reduced striatal dopamine underlies the attention 
system dysfunction in neurofibromatosis-1 mutant mice. Human Molecular Genetics, 19, 
4515-4528. 

COGTRAIN 
 
39  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
 
Brown, J. A., Xu, J., Diggs-Andrews, K. A., Wozniak, D. F., Mach, R. H., Guttman, D. H. 
(2011). PET imagine for attention deficit preclinical drug testing in neurofibromatosis-1 
mice. Experimental Neurology, 232(2), 333-338. 
 
 
Cahn-Weiner, D., Malloy, P., et al. (2003). Results of a randomized placebo-controlled 
study of memory training for mildly impaired Alzheimer's disease patients. Applied 
Neuropsychology, 10, 215-223. 
 
Castellanos, F.X., Sonuga-Barke, E., et al. (2006). Characterizing cognition in ADHD: 
beyond executive dysfunction. Trends in Cognitive Sciences, 10(3), 117-123. 
 
 
Cicerone, K. (2002). Remediation of ‘working attention’ in mild traumatic brain injury. 
Brain Injury, 16, 185-195. 
 
 
Cicerone, K., Dahlberg, C., et al. (2005). Evidence-based cognitive rehabilitation: 
Updated review of the literature from 1998 through 2002. Archives of Physical Medicine 
and Rehabilitation, 86, 1681-1692. 
 
 
 
Cipriani, G., Bianchetti, A., et al. (2006). Outcomes of a computer-based cognitive 
rehabilitation program on Alzheimer's disease patients compared with those on patients 
affected by mild cognitive impairment. Archives of Gerontology and Geriatrics, 43, 327-
335. 
 
 
Conners, C. K. (2008). Conners Rating Scales - 3rd Edition. Toronto, ON, Multi-Health 
Systems, Inc. 
 
 
Conners, C. K., Epstein, J. N., et al. (2003). Continuous Performance Test Performance 
in a Normative Epidemiological Sample. Journal of Abnormal Child Psychology, 31(5), 
555-562. 
 
 
Coude, F., Mignot, C., et al. (2007). Early grade repetition and inattention associated 
with neurofibromatosis type 1. Journal of Attention Disorders, 11, 101-105. 
 
DuPaul, G.J., Power, T.J., Anastopoulous, A.D., Reid, R. (1998). ADHD Rating Scale -
IV: Checklist, norms, and clinical interpretation. New York, NY: Guilford Press. 
 
Elliott, R., Sahakian, B.J., Matthews, K., Bannerjea, A., Rimmer, J., Robbins, T.W. 
(1997). Effects of methylphenidate on spatial working memory and pkanning in healthy 
young adults. Psychopharmacology, 131, 196-206. 

COGTRAIN 
 
40  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
 
Falleti, M. G., Maruff, P., Collie, A., Darby, D. G. (2006) Practice effects associated with 
the repeated assessment of cognitive function using the CogState battery at 10-minute, 
one week and one month test-retest intervals. J Clin Exp Neuropsychol, 28, 1095-1112. 
 
Faraone, S. V., Biederman, J. (1998). Neurobiology of attention-deficit hyperactivity 
disorder. Biological Psychiatry, 44(10), 951-958. 
 
 
Ferner, R., Huson, S., et al. (2007). Guidelines for the diagnosis and management of 
individuals with neurofibromatosis 1. Journal of Medical Genetics, 44, 81-88. 
 
Fry, A. F., & Hale, S. (1996) Processing speed, working memory, and fluid intelligence: 
Evidence for a developmental cascade. Psychological Science, 7, 237-241. 
 
 
Fiszdon, J., Bryson, G., et al. (2004). Durability of cognitive remediation training in 
schizophrenia: Performance on two memory tasks at 6-month and 12-month follow-up. 
Journal of Psychiatric Research, 125, 1-7. 
 
 
Gathercole, S.E. (1999). Cognitive approaches to the development of short-term 
memory. Trends in Cognitive Science, 3, 410-419. 
 
Gibson, B., Gondoli, D., et al. (2011). Component analysis of verbal versus spatial 
working memory training in adolescents with ADHD: A randomized, controlled trial. 
Child Neuropsychology, 17, 546-563. 
 
 
Gibson, B., Kronenberger, W., et al. (2012). Component analysis of simple span vs. 
complex span adaptive working memory exercises: A randomized controlled trial. 
Journal of Applied Research in Memory and Cognition 1(3), 179-184. 
 
Gilboa, Y., Rosenblum, S., et al. (2011). Using a Virtual Vlassroom environment to 
describe the attention deficits profile of children with Nwurofibromatosis type 1. 
Research in Developmental Disabilities, 32(6), 2608-2613. 
 
 
Gioia, G. A., Isquith, P. K., et al. (2002). Confirmatory factor analysis of the Behavior 
Rating Inventory of Executive Function (BRIEF) in a clinical sample. Child 
Neuropsychology, 8(4), 249-257. 
 
 
Graf, A., Landolt, M., et al. (2006). Quality of life and psychological adjustment in 
children and adolescents with neurofibromatosis type 1. Journal of Pediatrics, 149, 348-
353. 

COGTRAIN 
 
41  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
 
 
Greenhill, L., Kollins, S., et al. (2006). Efficacy and safety of immediate-release 
methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc 
Psychiatry, 45(11), 1284-1293. 
 
 
Group, M. C. (2004). National Institute of Mental Health Multimodal Treatment Study of 
ADHD follow-up: 24-month outcomes of treatment strategies for attention-
defficit/hyperactivity disorder. Pediatrics, 113, 754-761. 
 
 
Hofmann, M., Rosler, A., et al. (2003). Interactive computer-training as a therapeutic 
tool in Alzheimer's disease. Comprehensive Psychiatry, 44, 213-219. 
 
 
Holmes, J., Gathercole, S., et al. (2009). Adaptive training leads to sustained 
enhancement of poor working memory in children. Dev Sci, 12, F9-F15. 
 
 
Holmes, J., Gathercole, S., et al. (2010). Working memory deficits can be overcome: 
Impacts of training and medication on working memory in children with ADHD. Applied 
Cognitive Psychology, 24, 827-836. 
 
 
Huijbregts, S., Swaab, H., et al. (2010). Cognitive and motor control in 
neurofibromatosis type I: Influence of maturation and hyperactivity-inattention. 
Developmental Neuropsychology, 35, 737-751. 
 
 
Hutton, U. M. Z., & Towse, J. N. (2001). Short-term memory and working memory as 
indices of children's cognitive skills. Memory, 9, 383-394. 
 
 
Hyman, S., Shores, E., et al. (2005). The nature and frequency of cognitive deficits in 
children with neurofibromatosis type 1. Neurology, 65, 1037-1044. 
 
 
Isenberg, J. C., Templer, A., Gao, F., Titus, J. B., Gutmann, D. H. (2012). Attention 
skills in children with Neurofibromatosis Type 1. Journal of Child Neurology, 28(1), 45-
49. 
 
Jacobson, N. S., & Truax, P. (1991). Clinical significance: a statistical approach to 
defining meaningful change in psychotherapy research. J Consult Clin Psychol, 59(1), 
12-19. 
 
Kempton, S., Vance, A., Luk, M. E., Costi, J., Pantelis, C. (1999). Executive function 
and attention deficit hyperactivity disorder: Stimulant medication and better executive 
function performance in children. Psychological Medicine, 29, 527-538. 
 

COGTRAIN 
 
42  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
 
Kerns, K., Eso, K., et al. (1999). Investigation of a direct intervention for improving 
attention in young children with ADHD. Developmental Neuropsychology, 16, 273-295. 
 
Karlson, C.W., Rapoff, M. A. (2009). Attrition in randomized controlled trials for pediatric 
chronic conditions. Journal of Pediatric Psychology, 34(7), 782-793. 
 
 
Klingberg, T., Fernell, E., et al. (2005). Computerized training of working memory in 
children with ADHD - A randomized, controlled trial. Journal of the American Academy 
of Child and Adolescent Psychiatry, 44, 177-186. 
 
 
Klingberg, T., Forssberg, H., et al. (2002). Training of working memory in children with 
ADHD. Journal of Clinical and Experimental Neuropsychology, 24, 781-791. 
 
 
Koth, C., Cutting, L., et al. (2000). The association of neurofibromatosis type 1 and 
attention deficit hyperactivity disorder. Child Neuropsychology, 6, 185-194. 
 
 
Krab, L., Aarsen, F., et al. (2008). Impact of neurofibromatosis type 1 on school 
performance. Journal of Child Neurology, 23, 1002-1010. 
 
 
Levine, T., Materek, A., et al. (2006). Cognitive profile of neurofibromatosis type 1. 
Seminars in Pediatric Neurology, 13, 8-20. 
 
 
Lehtonen, A., Howie, E., Trump, D., Huson, S. M. (2012). Behaviour in children with 
neurofibromatosis type 1: Cognition, executive function, attention, emotion, and social 
competence. Developmental Medicine and Child Neurology, 55(2), 111-125. 
 
Lidzba, K., Granström, S., Lindenau, J., Mautner, V. (2012). The adverse influence of 
attention-deficit disorder with or without hyperactivity on cognition in neurofibromatosis 
type 1. Developmental Medicine and Child Neurology, 54, 892-897. 
 
Martinussen, R., Hayden, J., et al. (2005). A meta-analysis of working memory 
impairments in children with Attention-Deficit/Hyperactivity Disorder. Journal of the 
American Academy of Child & Adolescent Psychiatry, 44(4), 377-384. 
 
Maruff, P., Thomas, E., et al. (2009). Validity of the CogState brief battery: relationship 
to standardized tests and sensitivity to cognitive impairment in mild traumatic brain 
injury, schizophrenia, and AIDS dementia complex. Arch Clin Neuropsychol, 24(2), 165-
178. 
 
 

COGTRAIN 
 
43  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
Mautner, V., Kluwe, L., et al. (2002). Treatment of ADHD in neurofibromatosis type 1. 
Developmental Medicine & Child Neurology, 44, 164-170. 
 
McArthur, G., Jones, K., et al. (2013). A Test of Everyday Reading Comprehension 
(TERC). Australian Journal of Learning Difficulties, 18(1), 35-85. 
 
McNab, F., Varrone, A., Farde, L., Jucaite, A., Bystritsky, P., Forssberg, H., Klingberg, 
T. (2009). Changes in cortical dopamine D1 receptor binding associated with cognitive 
training. Science, 323, 800-802. 
 
Mehta, M. A., Owen, A. M., Sahakia, B. J., Mavaddat, N., Pickard, J. D., Robbins, T. W. 
(2000). Methylphenidate enhances working memory by modulating discrete frontal and 
parietal lobe regions in the human brain. The Journal of Neuroscience, 20, 1-6. 
 
 
Moore, S. (2001). Memory training improves cognitive ability in patients with dementia. 
Neuropsychological Rahabilitation, 11, 245-261. 
 
 
North, K., Hyman, S., et al. (2002). Cognitive deficits in neurofibromatosis type 1. 
Journal of Child Neurology, 17(8), 605-612. 
 
 
North, K., Riccardi, V., et al. (1997). Cognitive function and academic performance in 
neurofibromatosis 1: Consensus statement from the NF1 Cognitive Disorders Task 
Force. Neurology, 48, 1121-1127. 
 
Payne, J. M., Arnold, S. S., Pride, K. A., North, K. N. (2012). Does attention-deficit-
hyperactivity disorder exacerbate dysfunction in children with neurofibromatosis type 1? 
Developmental Medicine & Child Neurology, 54(10), 898-904. 
 
 
Payne, J. M., Hyman, S. L., Shores, E. A., North, K. M. (2011). Assessment of 
executive function and attention in children with neurofibromatosis type 1: Relationships 
between cognitive measures and real world behavior.  Child Neuropsycholol, 17, 313-
329. 
 
Riordan, H. J., Flashman, L. A., Saykin, A. J., Frutiger, S. A., Carroll, K. E., Huey, L. 
(1999). Neuropsychological correlates of methylphenidate treatment in adult ADHD with 
and without depression. Archives of Clinical Neuropsychology, 14(2), 217-233. 
 
Roy, A., Roulin, J., et al. (2010). Executive dysfunction in children with 
neurofibromatosis type 1: A study of action planning. Journal of the International 
Neuropsychological Society, 16, 1056-1063. 

COGTRAIN 
 
44  
 
 
COGTRAIN – DOD 
Proprietary and Confidential  
 
Version 3.0: January 10, 2022 
 
 
Slate, S., Meyer, T., et al. (1998). Computerized cognitive training for severely 
emotionally disturbed children with ADHD. Behavior Modification, 22, 415-437. 
 
Swanson, H. L., & Beebe-Frankenberger, M. (2004). The relationship between working 
memory and mathematical problem solving in children at risk and not at risk for serious 
math difficulties. Journal of Educational Psychology, 96, 471-491. 
 
 
Thorell, L. B., Lindqvist, S., et al. (2009). Training and transfer effects of executive 
functions in preschool children. Dev Sci, 12(1), 106-113. 
 
 
Tiersky, L., Anselmi, V., et al. (2005). A trial of neuropsychologic rehabilitation in mild-
spectrum traumatic brain injury. Archives of Physical Medicine and Rehabilitation, 86, 
1565-1574. 
 
 
Tiersky, L. A., Anselmi, V, et al. (2005). A trial of neuropsychologic rehabilitation in mild-
spectrum traumatic brain injury. Archives of Physical Medicine and Rehabilitation, 86, 
1565-1574. 
 
Torgeson, J., Wagner, R., Rashotte, C. (2012). Test of Word Reading Efficiency – 
Second Edition. Auston, TX: ProED. 
 
Volkow, N., Wang, G., et al. (2007). Depressed dopamine activity in caudate and 
preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity 
disorder. Archives of General Psychiatry, 64, 932-940. 
 
 
            Volkow, N. D., Wang, G., Fowler J. S., Ding, Y. (2005). Imaging the effects of 
methylphenidate on brain dopamine: New model on its therapeutic actions for Attention 
Deficit/Hyperactivity Disorder. Biological Psychiatry, 57, 1410-1415. 
 
Wechsler, D., Wechsler Abbreviated Scale of Intelligence. 1999, San Antonio, TX: The 
Psychological Corporation. 
 
Wechsler, D. (2014). Wechsler Intelligence Scale for Children - 5th Edition. San 
Antonio, TX, The Psychological Corporation. 
 
Willett, W., Willett, G. (2016). MobyMax. Potomac, MD, MobyMax ,LLC.