Shifting Perspectives: Enhancing Outcomes in Adolescent Anorexia Nervosa With Cognitive Remediation Therapy (CRT)
Phase: NA
Conditions: Anorexia Nervosa
Sponsor: Children's Hospital of Philadelphia

 
 
 
Title: 
Shifting Perspectives: Enhancing outcomes in adolescent anorexia 
nervosa with cognitive remediation therapy 
 
Short Title 
Shifting Perspectives 
Drug or Device 
Name(s): 
N/A 
FDA IND 
N/A 
Regulatory Sponsor: 
National Institutes of Health 
eIRB Number 
 
Protocol Date: 
February 24, 2021 
Amendment 1 Date: 10 July 2019 
Amendment 3 Date:  
Amendment 2 Date: 17 July 2019 
Amendment 4 Date: 
 
 
 
 
Study Principal Investigator  
C. Alix Timko, PhD 
The Children’s Hospital of Philadelphia 
Robert’s Center for Pediatric Research, 8-212 
Philadelphia, PA, 19104 
Phone 267-426-5467 
email: timkoc@chop.edu 
 

  
 
 
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms............................................................................. iv 
Abstract. ................................................................................................................................. v 
Table 1: Schedule of Study Procedures ............................................................................. vii 
Figure 1: Study Diagram ....................................................................................................... x 
1 
BACKGROUND INFORMATION AND RATIONALE ..................................................................... 11 
1.1 
INTRODUCTION ................................................................................................................................... 12 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ................................... 12 
1.2.1 
Family Based Treatment (FBT) ..................................................................................................... 12 
1.2.2 
Cognitive Remediation Therapy .................................................................................................... 12 
1.3 
RELEVANT LITERATURE AND DATA ................................................................................................... 13 
1.4 
COMPLIANCE STATEMENT .................................................................................................................. 14 
2 
STUDY OBJECTIVES ............................................................................................................................ 14 
2.1 
PRIMARY OBJECTIVE (OR AIM) .......................................................................................................... 14 
2.2 
SECONDARY OBJECTIVES (OR AIM) .................................................................................................... 15 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 15 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ............................................................................................... 15 
3.1.1 
Screening Phase ............................................................................................................................ 15 
3.1.2 
Study Intake ................................................................................................................................... 15 
3.1.3 
Study Treatment Phase (start of the study intervention) ............................................................... 16 
3.1.4 
Assessments ................................................................................................................................... 16 
3.1.5 
End of Treatment Evaluation ........................................................................................................ 16 
3.1.6 
Post Treatment Follow-up ............................................................................................................. 17 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ...................................................................... 17 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................. 17 
3.3.1 
Duration of Study Participation .................................................................................................... 17 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................................ 18 
3.4 
STUDY POPULATION ........................................................................................................................... 18 
3.4.1 
Inclusion Criteria (Adolescent) ..................................................................................................... 18 
3.4.2 
Inclusion Criteria (Parents) .......................................................................................................... 18 
3.4.3 
Exclusion Criteria (Adolescent) .................................................................................................... 18 
3.4.4 
Exclusion Criteria (Parents) ......................................................................................................... 19 
4 
STUDY PROCEDURES .......................................................................................................................... 19 
4.1 
STUDY INTAKE (VISIT 0) .................................................................................................................... 19 
4.2 
STUDY TREATMENT PHASE ................................................................................................................ 20 
4.2.1 
Visit 1-8, 10-12, 14-17................................................................................................................... 20 
4.2.2 
Visit 4 ............................................................................................................................................ 20 
4.2.3 
Visit 9 ............................................................................................................................................ 20 
4.2.4 
Visit 13 .......................................................................................................................................... 20 
4.2.5 
End of treatment evaluation (Visit 18) .......................................................................................... 20 
4.2.6 
Visits 19 and 20 ............................................................................................................................. 20 
4.3 
PERMISSION TO SPEAK WITH PHYSICIAN ............................................................................................ 21 
4.4 
UNSCHEDULED VISITS ........................................................................................................................ 21 
4.5 
CONCOMITANT MEDICATION ............................................................................................................. 21 
4.6 
HOSPITALIZATION DURING TREATMENT ............................................................................................ 21 
4.7 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 21 
4.8 
EARLY TERMINATION STUDY VISIT ................................................................................................... 21 
5 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 22 

 
 
 
 
 
 
 
 
iii
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 22 
5.1.1 
Medical Record Review ................................................................................................................. 22 
5.1.2 
Other Evaluations, Measures ........................................................................................................ 22 
5.2 
EFFICACY EVALUATIONS ................................................................................................................... 28 
5.3 
SAFETY EVALUATION ......................................................................................................................... 28 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 28 
6.1 
PRIMARY ENDPOINT ........................................................................................................................... 28 
6.2 
SECONDARY ENDPOINTS .................................................................................................................... 29 
6.3 
STATISTICAL METHODS...................................................................................................................... 29 
6.3.1 
Baseline Data ................................................................................................................................ 29 
6.3.2 
Safety Analysis .............................................................................................................................. 29 
6.4 
SAMPLE SIZE AND POWER .................................................................................................................. 29 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) .................... 31 
7.1 
DESCRIPTION ...................................................................................................................................... 31 
7.2 
FBT .................................................................................................................................................... 31 
7.3 
CRT ................................................................................................................................................... 31 
7.3.1 
Treatment Compliance and Adherence ......................................................................................... 31 
8 
SAFETY MANAGEMENT ..................................................................................................................... 32 
8.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 32 
8.2 
ADVERSE EVENT REPORTING ............................................................................................................. 32 
8.3 
MEDICAL EMERGENCIES .................................................................................................................... 32 
9 
STUDY ADMINISTRATION ................................................................................................................. 33 
9.1 
TREATMENT ASSIGNMENT METHODS................................................................................................. 33 
9.1.1 
Randomization............................................................................................................................... 33 
9.1.2 
Blinding ......................................................................................................................................... 33 
9.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 33 
9.2.1 
Data sharing.................................................................................................................................. 33 
9.3 
CONFIDENTIALITY .............................................................................................................................. 34 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 34 
9.4.1 
Data and Safety Monitoring Plan ................................................................................................. 34 
9.4.2 
Risk Assessment ............................................................................................................................. 35 
9.4.3 
Potential Benefits of Trial Participation ....................................................................................... 36 
9.4.4 
Risk-Benefit Assessment ................................................................................................................ 36 
9.5 
RECRUITMENT STRATEGY .................................................................................................................. 36 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 37 
9.6.1 
Waiver of Assent ............................................................................................................................ 38 
9.7 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 38 
9.7.1 
Reimbursement for travel, parking and meals .............................................................................. 38 
9.7.2 
Payments to parent for time and inconvenience (i.e. compensation) ............................................ 38 
9.7.3 Payments to subject for time, effort and inconvenience (i.e. compensation) ..................................... 39 
9.7.3 
Gifts ............................................................................................................................................... 39 
10 
PUBLICATION ............................................................................................................................... 39 
11 
REFERENCES ................................................................................................................................ 39 
 

  
 
 
 
 
 
 
 
iv
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
AN 
 
Anorexia Nervosa 
AE 
 
Adverse event 
CRT 
 
Cognitive Remediation Training 
FBT 
 
Family Behavioral Treatment 
TBI 
 
Traumatic Brain Injury 
ICH 
 
International Conference on Harmonization 
CHOP 
 
Children’s Hospital of Philadelphia 
PI 
 
Principal Investigator 
IQ 
 
Intelligence Quotient 
CRTP 
 
Parent-focused Cognitive Remediation Therapy 
CRTA 
 
Adolescent-focused Cognitive Remediation Therapy 
DSMB 
 
Data Safety and Monitoring Board 
EDATP 
 
Eating Disorder Assessment and Treatment Program 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
v
ABSTRACT. 
Context: (Background) 
Anorexia nervosa (AN) is a severe psychiatric condition; the hallmark features are low body 
weight and difficulties gaining weight. Family based treatment (FBT) is the most effective 
treatment; however, only 50% of adolescents improve. Cognitive Remediation Therapy 
(CRT) may augment treatment and improve outcome. The best way to add CRT to FBT 
remains understudied.  
 
Objectives: (primary and important secondary objectives) 
The primary objectives include determining whether or not Cognitive Remediation Therapy 
(CRT) can increase set-shifting in parents and/or adolescents with Anorexia Nervosa (AN). 
The second objective is to determine the appropriate dose of CRT needed to achieve positive 
change in set-shifting. 
 
Study Design:  
Randomized controlled trial with three groups. 
 
Setting/Participants: 
Participants will be 60 adolescents with AN and their families.  Treatment will occur on an 
outpatient basis at Children’s Hospital of Philadelphia.  
 
Study Interventions and Measures:  
All adolescents with AN enrolled in the trial will receive FBT.  Families will be randomized 
to FBT only, Family Based Treatment + Parent Focus Cognitive Remediation Therapy, or 
Family Based Treatment + Adolescent Focused Cognitive Remediation Therapy. 
Psychosocial, neurocognitive, and behavioral measures will be collected throughout the 
study.  

  
 
 
 
 
 
 
 
vi

 
vii  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Treatment/Intervention 
3- and 6-
month 
follow-
ups and 
12 
optional 
FBT 
sessions 
Visit Number 
 
0 
1 
2 
3 
4 
5 
6 
7  
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Assessment 
 
1 
 
 
 
2 
 
 
 
 
3 
 
 
 
4 
 
 
 
 
5 
6 
7 
Informed 
Consent/Assent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Chart 
Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
2D:4D 
measurement 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Questionnaire 
Battery 
 
 
 
BRIEF-2# 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
ABOS§ 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
AESED§ 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
EDE-Q* 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 

 
viii  
 
 
 
 
 
 
 
BIS/BAS# 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
BASC-3# 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
ECI§ 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
IUS# 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
OCI# 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
DFLEX# 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
FamQ§ 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
DASS# 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
EDFLIX* 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
SRQ* 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
AQ# 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
CEQ# 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WAI∞ 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
TEQ# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
PVA 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Neurocognitive 
Assessment 
 
 
 
WASI# 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
* 
 
 
RCFT# 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
DKEFS# 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
LBT* 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Buffet 
Challenge* 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Howe’s 
Grocery§ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
AAT#  
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
§Parent only completes this measure 
*Adolescent only 

 
ix  
 
 
 
 
 
 
 
# Parents and Adolescent complete this measure 
∞ Parent, adolescent, and therapist complete this measure 
 
.

 
page x 
  
 
 
 
FIGURE 1: STUDY DIAGRAM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 0/ Time point 1:  
Consent, Height & Weight, 
Baseline Questionnaires, 2D:4D, 
Neurocognitive Assessment, 
Buffet Challenge & How’s 
Grocery 
Randomization 
FBT alone 
FBT + CRTP 
FBT + CRTA 
Visit 1-3:  
Treatment  
Visit 4/ Time point 2:  
Treatment & Questionnaires  
Visit 5-8:  
Treatment 
Visit 9/ Time point 3:  
Questionnaires and Neurocognitive Assessment 
Visit 10-12:  
Treatment 
Visit 13/ Time point 4:  
Questionnaires and Neurocognitive Assessment, Buffet Challenge & Howe’s Grocery 
Visit 14-17:  
Treatment 
Visit 18/ Time point 5:  
Questionnaires, Neurocognitive Assessment, Buffet Challenge & Howe’s Grocery 
Visit 19& 20/Time points 6 & 7:  
Medical chart review & Questionnaires 
12 optional FBT sessions 

 
page 11 
  
 
 
 
1 
BACKGROUND INFORMATION AND RATIONALE 
Anorexia Nervosa (AN) is a serious eating disorder characterized by restriction of food intake 
and reduction of body weight below what is healthy or expected for someone of the same age 
and height.  AN has the highest mortality rate of all psychiatric disorders1,2 and is associated 
with significant morbidity.1 AN often begins during adolescence3 and early intervention is key 
in order to prevent a chronic, unremitting course of the disorder.4 To date, there is only one 
intervention with substantial empirical support for the treatment of AN in adolescents:  Family 
Based Treatment.5,6 In FBT, parents are essential to treatment and are charged with the task of 
re- nourishing their starving child. The effectiveness of FBT has established the importance of 
the family in treatment and empowered parents to play an active role in treatment.7,8  
 
Studies in adults9-12 and adolescents13-16 with AN indicate that they have reduced behavioral 
flexibility (e.g., extreme perfectionism, perseveration, difficulties in learning new behaviors)17 
that reflects underlying neurocognitive inefficiencies, specifically set shifting.18-20 Set-shifting is 
the ability to switch tasks, change mindsets, rapidly adapt to new situations, and respond to new 
environmental contingencies.21 The evidence of set-shifting difficulties in adults with AN is 
robust enough that it is considered a putative endophenotype.18,22 Endophenotypes are 
intermediate phenotypes that must be associated with an illness, be present within the individual 
regardless of the state of the illness, and are inherited. They are found in family members of the 
proband at a higher rate than in the population and within the family the illness and 
endophenotype are inherited together (co-segregate).23 Set-shifting inefficiencies in AN do not 
fully improve with re-nourishment.24 Similar inefficiencies are found in siblings and parents of 
individuals with AN.18,25-27 Executive functioning is heritable28 and there is preliminary evidence 
of co-segregation of cognitive inefficiencies in the context of AN.26 If set-shifting difficulties are 
an endophenotype - parents of adolescents with AN have a greater likelihood of having cognitive 
inefficiencies that may be exacerbated by the stress of caring for an ill child. Increased 
difficulties in set-shifting could lead to greater difficulty implementing FBT at home and poorer 
or less rapid gains for their child. Cognitive Remediation Therapy (CRT) is an adjunctive 
treatment that improves cognitive flexibility and can be used with the parents or child.   
  
Via structured input and repetition, CRT leverages the brain’s natural neuroplasticity and fosters 
changes in brain structure and connections. CRT can be restorative (focusing on decreasing 
cognitive inefficiencies), compensatory (maximize daily functioning without changing cognitive 
impairments), or metacognitive (monitoring one’s own thinking and subsequently adapting 
behavior to the environment).29 CRT for AN is metacognitive. The goal of CRT is to target a 
cognitive inefficiency using principles of learning in order to improve functional outcomes (i.e., 
improving memory in traumatic brain injury (TBI) significantly improves the probability of a 
return to work).30-32 CRT has a long history of improving aspects of executive functioning 
leading to positive impacts on behavior across a number of conditions (including, TBI33 
depression,31,34 schizophrenia,35,36 and eating disorders37,38). Recent work in AN indicates that 
CRT can improve eating disorder quality of life and may have a positive impact on weight 
gain.39,40 CRT addresses many characteristics of adolescents with AN that can make treatment 
more difficult.  
 
CRT for AN has an unambiguous target: cognitive flexibility. By improving this important 
aspect of a broader system, treatment gains can be maximized. Augmenting treatment with CRT 

 
page 12 
  
 
 
 
can potentially strengthen inherited inefficiencies and/or prevent the worsening of 
neurocognitive abilities due to prolonged malnourishment. Alternatively, as parents are the 
primary implementers of treatment, targeting their cognitive flexibility can increase their ability 
to (behaviorally) flexibly respond to contingencies in the environment and implement behavioral 
plans with their sick child. In turn, parents may be able restore their child’s weight more quickly 
and with a diet that is more macronutrient varied. Increasing flexibility in either the parent or 
child can impact a larger system of behaviors and lead to improved clinical outcome, including 
more a macronutrient varied diet and subsequent increase in rate of weight gain.  
 
1.1 
Introduction 
Augmenting FBT with CRT has the potential to impact the rate at which adolescents gain 
weight. While the vast majority of research has focused on CRT for adolescents, we propose that 
it may be more impactful to target the adolescent with AN’s parents as parents are the 
individuals carrying the burden of treatment and re-nourishment of their child. Parent only 
modifications of FBT are effective in increasing weight in adolescents with AN,41-43 thus a 
parent focused intervention can be effective.  
 
The purpose of this project is to establish that CRT can move the target of flexibility. The goal is 
to determine whether or not flexibility improves more in the parent or the adolescent and what 
dose of CRT is needed to achieve gains in flexibility.  
 
1.2 
Name and Description of Investigational Product or Intervention 
1.2.1 Family Based Treatment (FBT) 
FBT is a manualized family treatment for adolescents with AN. It is effective for children and 
adolescents aged 12-18. It is a conjoint family treatment with all family members attending all 
sessions. For this study, we will use a 15 session version of FBT used in prior research. The goal 
of treatment is weight restoration and reduction of eating disorder symptoms.  The primary focus 
of treatment sessions is to activate and empower the parents of the affected child to restore 
weight.  Secondary goals of FBT include aligning the parental and sibling subsystems and 
reestablishing healthy adolescent developmental trajectories.  Treatment will occur weekly at the 
beginning of treatment, move to bi-weekly, and then monthly for the last month of treatment. 
Families will have the option of receiving 12 additional FBT sessions after completing the first 
15 sessions. These 12 sessions will be scheduled as families see fit and will occur over the course 
of six months. 
 
The treatment takes place over 3 phases: 
1. Refeeding and Weight Restoration 
2. Returning Control of Eating to the Adolescent 
3. Addressing Adolescent Issues and Treatment Completion 
 
The PI has received training in the manual and has recently completed the necessary hours for 
certification in this treatment modality.  
 
1.2.2 Cognitive Remediation Therapy 
CRT is an adjunctive intervention focusing on the development of meta-cognition – teaching 
individuals to think about how they think.44 It involves presenting individuals with a variety of 

 
page 13 
  
 
 
 
tasks requiring increasingly complex mental abilities – these include geometric figures, illusions, 
reversing sequences of numbers and letters, completing sorting tasks wherein the rules change, 
and finding various routes on a map.45 Most importantly, CRT focuses on process instead of 
outcome. That is, instead of focusing on whether or not a task was accurately completed, 
individuals in CRT are asked to think about how they solved a puzzle, reflect on their thought 
processes, and identify steps in problem solving.  CRT has three goals: 
1.       Improve brain function by exercising and increasing connections in the brain 
2.       Encourage individuals to think about their thinking style 
3.       Encourage individuals and families to spend time away from thinking about the 
eating disorder. 
 
CRT can be delivered in individual, family, and group formats.46-48 For this study, we will 
administer CRT to either adolescents or their parents. CRT will be delivered for 45-60 minutes 
prior to FBT sessions for a total of 15 sessions. Participants in CRT will be given weekly 
homework.  
 
1.3 
Relevant Literature and Data 
Anorexia Nervosa (AN) is a life-threatening disorder with a significant impact on the quality 
of life of those afflicted.  Age of onset is typically during adolescence; it significantly alters 
patterns of healthy growth and development in adolescents and can impact the functioning of the 
entire family. Severe starvation during the critical period of adolescence affects all developing 
systems, especially brain development.  Results from longitudinal studies of brain function in 
adults with AN indicate that sufferers have long term difficulties with executive functioning and 
demonstrate behavioral rigidity (e.g., perseveration, extreme perfectionism, difficulties in 
learning new behaviors) that reflects underlying neuro-cognitive deficits.18,49 These underlying 
difficulties in executive functioning could be indicative of underlying traits that create of 
vulnerably to developing AN, they could be the result of starvation during a critical period, or 
they could be a marker for those who are likely to have a more chronic course of the 
disorder.  Regardless as to whether or not they are a cause or consequence of AN, it is likely that 
behaviors associated with neurocognitive deficits can maintain AN or interfere with 
treatment.  Thus, addressing executive functioning, specifically that related to flexibility may 
have a positive impact on treatment outcome.  Cognitive Remediation Therapy for AN was 
developed to do just that. 
  
Evidence for CRT in adolescents. CRT has been successfully developed for adolescents and 
for administration during a hospital stay.50 CRT has been proposed as a viable pre-intervention 
or adjunct to other forms of treatment.39 It increases cognitive flexibility in adult and adolescent 
patients with AN.38,51,52 For adolescents with AN, CRT is generally well received and can result 
in increased motivation to engage in treatment.52 Parents report feeling as if the rationale for 
CRT helps them understand their child’s behavioral difficulties.50 A family-based form of CRT 
for adolescents with AN facilitated parents’ ability to recognize their own and their child’s 
thinking style and helped the family to develop strategies to cope with these thinking styles.52 
CRT is generally well received by patients and parents, may increase treatment retention, and has 
a demonstrated impact on executive functioning.44 Despite preliminary positive findings, 
research on CRT in adolescents is limited.38 The dearth of research in this area is a significant 
gap in our knowledge regarding how best to apply CRT.   

 
page 14 
  
 
 
 
 
Augmenting FBT with CRT for parents may impact weight more. Inefficiencies in cognitive 
flexibility are likely inherited; thus, it is reasonable to assume that parents may also struggle 
with flexibility.  Prolonged stress (such as having a child with a potentially lethal illness) can 
decrease flexibility and narrow behavioral repertoires in face of threat.53-55 Parents who have 
cognitive inefficiencies in the area of set shifting and who are tasked with caring for an acutely 
ill child may struggle with being flexible in the moment. If parents of an adolescent with AN do 
not have cognitive inefficiencies, they likely experience a state-based reduction in flexibility. 
Whether state, trait, or combination of both – difficulties in cognitive and behavioral flexibility 
can translate into more difficulties implementing exposure to symptom specific stimuli and 
greater symptom accommodation which leads to less macronutrient variation and a slower rate 
of weight gain. Given that parental control of eating is a strong predictor of weight gain,56 
augmenting treatment with CRT to maximize their ability to do so has the potential to increase 
the number of adolescents who reach remission.  
 
The purpose of this study is to further investigate the role of CRT in the treatment of adolescent 
AN.  The goal of this study is to determine whether or CRT increases flexibility in adolescents or 
parents, if this increase is more than what is observed in FBT alone, and what the dose of CRT is 
needed to increase flexibility.  
 
1.4 
Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, and the Good Clinical Practice: Consolidated Guideline 
approved by the International Conference on Harmonization (ICH). All episodes of 
noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
assent, and will report unanticipated problems involving risks to subjects or others in accordance 
with The Children’s Hospital of Philadelphia IRB Policies and Procedures and all federal 
requirements. Collection, recording, and reporting of data will be accurate and will ensure the 
privacy, health, and welfare of research subjects during and after the study.  
 
2 
STUDY OBJECTIVES 
The purpose of the study is to determine whether or not augmenting FBT with CRT for parents 
or adolescents significantly improves cognitive flexibility and the dose required to do so.  
 
2.1 
Primary Objective (or Aim) 
Aim 1:  To identify whether or not it more impactful to add a parent or adolescent 
component of CRT to standard FBT. We hypothesize that both adolescents and parents who 
receive CRT will have greater increases in cognitive flexibility than those who receive FBT 
alone. We will examine magnitude of change in cognitive flexibility across groups.  
 
Aim 2: To determine the dose of CRT needed to lead to a medium effect size (increase in 
cognitive flexibility). We will examine the dose of CRT needed to obtain an increase in 
cognitive flexibility equal to a medium effect.  

 
page 15 
  
 
 
 
 
2.2 
Secondary Objectives (or Aim) 
• Collect preliminary data on outcome 
 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
3.1.1 Screening Phase 
Potential participants will be identified during presentation for treatment at CHOP for an eating 
disorder.  This includes during initial hospitalization for medical stabilization, during outpatient 
intake assessment, or during the initial medical visit and evaluation. Additionally, potential 
participants may respond to flyers and tearpads, and independently demonstrate interest in 
participating by getting in touch with the research coordinators. A member of the study staff will 
administer a verbal screening over the phone to determine adolescent and parent eligibility.  All 
potential participants who appear to meet inclusion will be provided with information about the 
clinical trial along with other treatment options. Families who are interested will meet with the 
study coordinator or research assistants, be provided with more information, and (if inclusion 
and exclusion criteria are met) scheduled for an intake.  
Parental/guardian permission (informed consent) will be obtained prior to any study procedures 
taking place.  
 
3.1.2 Study Intake 
The intake appointment is comprehensive and typically lasts an entire day.  The intake battery 
being used is comparable to one used in other studies by the PI with no ill effects. Families are 
informed of the length of the intake prior to arrival and it has been well tolerated in the past.   
 
The intake begins with informed consent.  Once consent is received, every effort will be made to 
ensure the family will complete all aspects of the baseline assessment (see Table 1).   
 
Parents and the adolescent will complete a standard questionnaire battery, neuro-psychological 
assessment, IQ assessment, and a number of behavioral tasks. In addition, the adolescents will 
complete a diagnostic interview to assess eating disorder symptoms. As part of the intake, the 
adolescent will be asked to serve and eat a meal. This will be videotaped.  
 
Video-taping will be done using a CHOP approved device.  Data will be uploaded to the CHOP 
server and deleted from the device. All videos will be retained for 6 years and destroyed at that 
time.   
 
At the end of the intake, the family will meet with their therapist, who will complete the clinical 
interview and provide information for and schedule the next session.  Randomization occurs after 
the clinical interview.  
 
Consent and assessments will ideally occur in-person; however, if this is not possible then 
remote consent and assessment will occur. Remote consent will take place on a CHOP-approved 
video conferencing platform, and study staff will review all sections of the informed consent 
form with families. Families will be sent a link to our REDCap project with the informed consent 
form. At the end of the informed consent discussion, families will be asked to e-sign and e-date 

 
page 16 
  
 
 
 
in the appropriate sections of the REDCap project. An electronic copy of the informed consent 
form will also be sent to the families for their records, and a signed version of the informed 
consent form will be available on REDCap for families to download. Remote assessments will 
also take place via CHOP-approved video conferencing platforms and will involve all tasks that 
do not involve physical manipulation of objects and will also not include the buffet challenge. If 
visits are done remotely, we may ask the parents to weigh their child and share this weight with 
the study therapist or assessor.  
 
 
3.1.3 Study Treatment Phase (start of the study intervention) 
After the baseline assessment/intake, the family will be randomized to one of three conditions: 
Family Based Treatment (FBT), Parent Focused Cognitive Remediation Therapy + FBT (CRTP), 
or Adolescent Focused Cognitive Remediation Therapy + FBT (CRTA). Families will have 15 
sessions of the assigned treatment and be assessed at 4 additional time points (baseline intake + 4 
more is a total of 5 time points). For treatment, all standard clinical procedures will be followed. 
 
In the event of an unforeseen circumstance whereby one’s presence at CHOP puts the patient, 
family, and/or CHOP staff at risk, treatment sessions can be done remotely. All treatment 
sessions done remotely will take place on a CHOP-approved video conferencing app, such as 
Vidyo or Skype Business. If treatment sessions are done remotely, we may ask the family to 
weigh their child and share this weight with the study therapist. A note to file is being made for 
every treatment session that occurs remotely and will be reported to the IRB and DSMB in a 
yearly report. 
 
3.1.4 Assessments 
Assessments will occur at baseline and then 4 additional times during treatment (total of 5) 
according to the schedule outlined in Table 1. Assessments will be scheduled within a week of 
the therapy appointment, ideally on the same day to minimize burden on the family. 
Questionnaires can be completed on line prior to coming in for the assessment.  
 
In the event of an unforeseen circumstance whereby one’s presence at CHOP puts the patient, 
family, and/or CHOP staff at risk, assessments can be done remotely. All assessment sessions 
done remotely will take place on a CHOP-approved video conferencing app, such as Vidyo or 
Skype Business. Remote assessments will involve all tasks that do not involve physical 
manipulation of objects and will also not include the buffet challenge. If assessments are done 
remotely, we may ask the family to weigh their child and share this weight with the assessor. A 
note to file is being made for every assessment that occurs remotely and will be reported to the 
IRB and DSMB in a yearly report. 
 
3.1.5 End of Treatment Evaluation 
The End of Treatment Evaluation will occur within 14 days of treatment end. It will mirror the 
intake and include the measures noted in Table 1.  
 

 
page 17 
  
 
 
 
3.1.6 Post Treatment Follow-up 
After finishing the study, participants will receive questionnaires via link in email (for RedCap) 
and/or paper versions mailed to them. These will be sent approximately 3- and 6-months after 
completing the study. Families will also have the option to receive an additional 12 FBT sessions 
during this time. The study team will also complete medical chart reviews during these two 
follow-up periods. Should an adolescent turn 18 years of age during post treatment follow-up, 
the study team will request that the adolescent makes an appointment for reconsenting after 
turning 18. This appointment can take place at any CHOP affiliated facility (e.g., Roberts Center 
for Pediatric Research, Adolescent Medicine Specialty Care Center, etc). If the adolescent is 
unable or unwilling to reconsent, they will not be sent questionnaires for completion. Parents, 
however, will be sent questionnaires. 
 
3.2 
Allocation to Treatment Groups and Blinding 
The study statistician will facilitate the sequential randomization of participants employing a 
covariate-adaptive randomization method (using open source free software; OxMaR)57 that 
ensures an equal distribution of males across the three conditions.58,59 Minimization works by re-
calculating the probability of allocation to the treatment and control groups after each new 
participant enters the cohort. The probability of assignment will depend on stratification by sex 
and age to assure that males have an equal probability of assignment to the different conditions, 
something that is not guaranteed with simple random assignment.  The algorithms for doing this 
will be programmed ahead of time, study team members will enter the sex and age of participant 
into the program in order randomize them to groups. The statistician will not have access to any 
PHI.  
Research assistants conducting assessments will be blinded to treatment condition at all time 
points.  
 
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
Total study duration for each participant is approximately 12-14 months. Participants will have 
6-12 months of active treatment. If there is a delay in treatment (brief hospitalization or 
cancelation of an appointment due to weather, illness, etc.) treatment duration may be slightly 
longer.  It is anticipated that all treatment will be complete within 12-14 months of enrollment.  
 
Adolescents and their families will be assessed at five time points: 
 
• T1: neuropsychological assessment, therapy session, questionnaires, Grocery store 
(parents), Buffet challenge (adolescent) 
• T2: therapy session, questionnaires 
• T3: neuropsychological assessment, questionnaires 
• T4: neuropsychological assessment, questionnaires, Grocery store (parents), Buffet 
challenge (adolescent) 
• T5: questionnaires, neuropsychological assessment, Grocery store (parents), Buffet 
challenge (adolescent) 

 
page 18 
  
 
 
 
• T6: Medical chart review and questionnaires (to be completed online/ mailed to the 
family, this will take place 3 months post end of primary treatment intervention) 
• T7: Medical chart review and questionnaires (to be completed online/ mailed to the 
family, this will take place 6 months post end of primary treatment intervention) 
 
 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will only be conducted at Children’s Hospital of Philadelphia. 
 
It is expected that approximately 60 subjects will be enrolled to produce at least 45 evaluable 
subjects.  
 
3.4 
Study Population 
3.4.1 Inclusion Criteria (Adolescent) 
1. Age 12-18 
2. Currently meets DSM-5 criteria for Anorexia Nervosa 
3. Medically stable for outpatient treatment 
4. Fluent in English 
5. No co-morbid condition that would exclude participation (diagnosis of a pervasive 
developmental disability or mental retardation, psychosis, bipolar disorder, substance abuse, or 
autism spectrum disorder) 
6. Medical clearance from primary care physician and permission to speak to PCP about clinical 
issues 
7. Biological parents or primary caregivers willing to engage in treatment and who live with the 
adolescent. 
 
3.4.2 Inclusion Criteria (Parents) 
1 Age >18 
2. Child with a diagnosis of AN 
3. Both parents willing to participate  
4. Fluent in English  
5. No co-morbid condition that would exclude participation 
 
3.4.3 Exclusion Criteria (Adolescent) 
1. Outside of age range 
2. Adopted 
3. No more than four sessions of prior CRT in any format 
4. Presence of: pervasive developmental disability, psychosis, bipolar disorder, substance abuse, 
autism spectrum disorder, or intellectual disability. 
5.  Presence of:  a brain disorder or injury (such as TBI) that could impact the ability to engage in 
treatment 
6. Use of anti-psychotic medication during first 15 FBT sessions. Use of this medication is 
permitted in the optional 12 FBT sessions in the 6-month follow-up period of this study. This 
medication can affect cognitive abilities, which may interact with assessments that measure 
cognitive flexibility. However, we do not measure cognitive flexibility in the 6-month follow-up 
period when the 12 additional FBT sessions can take place. 

 
page 19 
  
 
 
 
  
7. Concurrent psychosocial therapy 
 
3.4.4 Exclusion Criteria (Parents) 
1. Presence of: pervasive developmental disability, psychosis, bipolar disorder, substance abuse, 
autism spectrum disorder, or intellectual disability. 
2. Presence of: a brain disorder or injury (such as TBI) that could impact the ability to engage in 
treatment 
3. Use of anti-psychotic medication during first 15 FBT sessions. Use of this medication is 
permitted in the optional 12 FBT sessions in the 6-month follow-up period of this study. This 
medication can affect cognitive abilities, which may interact with assessments that measure 
cognitive flexibility. However, we do not measure cognitive flexibility in the 6-month follow-up 
period when the 12 additional FBT sessions can take place. 
4. No more than four sessions of prior CRT in any format 
 
Subjects who do not meet all of the enrollment criteria will not be enrolled. Any violations of 
these criteria will be reported in accordance with IRB Policies and Procedures.  
Patients with AN who receive psychosocial treatment at CHOP are typically followed by 
adolescent medicine at CHOP. Though it is possible that an adolescent will enter the trial and not 
be followed by CHOP’s adolescent medicine, this is extremely unlikely.  If it does happen, the 
adolescent will need to be followed by his or her pediatrician for the duration of the study and 
permission to speak to the pediatrician will be obtained (standard of care).  
 
Concurrent psychosocial therapy for the adolescent is an exclusionary criterion.  Given the life-
threatening nature of AN, treatment for it is primary.  It is standard of care for the outpatient 
program at CHOP to request that patients discontinue with outside therapy while receiving 
treatment for the eating disorder.  In addition to eliminating any confounding effects of outside 
treatment, this practice follows the current standard of care and will be used in this study. If 
medication is prescribed for the adolescent it is typically done by either adolescent medicine, the 
adolescent’s primary pediatrician, or by CHOP psychiatry.  Visits with psychiatry (either within 
or outside of CHOP) will be allowed for medication management only.  Any changes in 
medication will be confirmed with the prescribing physician or through the medical chart (if at 
CHOP) and noted.    
 
4 
STUDY PROCEDURES 
4.1 
Study Intake (Visit 0) 
• Informed Consent 
• Medical Record Review (without participants) 
• Height and weight 
• Questionnaires 
• Buffet Challenge 
• Howe’s Grocery 
• Neuropsychological and IQ testing 
• 2D:4D measurement  
• Clinical interview (video recorded) 
• Treatment sessions (audio or video recorded) 

 
page 20 
  
 
 
 
 
4.2 
Study Treatment Phase 
General overview of this phase.  
 
4.2.1 Visit 1-8, 10-12, 14-17 
Each visit the family will receive the treatment assigned during randomization (FBT, CRTP, or 
CRTA). The following will happen at each session: 
• Height and weight 
• Review of homework 
• Study intervention 
• Medical Record Review (without participants) 
 
4.2.2 Visit 4 
• Questionnaires (online or in-person) 
• Height and weight 
• Medical Record Review (without participants) 
4.2.3 Visit 9 
• Medical Record Review (without participants) 
• Height and weight  
• Questionnaires (online or in-person) 
• Neuropsychological testing 
4.2.4 Visit 13 
• Medical Record Review (without participants) 
• Height and weight  
• Questionnaires (online or in-person) 
• Buffet Challenge 
• Howe’s Grocery 
• Neuropsychological testing 
4.2.5 End of treatment evaluation (Visit 18) 
• Medical Record Review (without participants) 
• Questionnaires (online or in-person) 
• Height and Weight 
• Buffet Challenge 
• Howe’s Grocery 
• Neuropsychological and IQ testing 
• Clinical interview 
 
4.2.6 Optional continuation of FBT 
• 12 optional additional sessions of FBT 
 
4.2.7 Visits 19 and 20 
• Medical Chart Review (without participants) 
• Questionnaires (online or by mail) 
 

 
page 21 
  
 
 
 
4.3 
Permission to Speak with Physician 
Appropriate clinical management of AN requires that the treatment team be in communication. 
Participants must provide consent for the study therapist to speak with the medical provider to 
coordinate care (e.g., the therapist will need to know when the adolescent is medically able to 
return to school, exercise, or sports). In order for this clinical coordination to occur, the physician 
does not have to be informed of the participant’s participation in a clinical trial. Whether or not 
the physician is informed of study participation is at the participant’s participants’ discretion. As 
the primary treatment provided in this study is FBT and standard of care, there is no reason to 
expect the physician to think the adolescent is participating in a study.  
4.4 
Unscheduled Visits 
Unscheduled visits will not be permitted. Contact with families between sessions will be as 
needed or on an emergent basis.  Contact will be documented and must be in line with the 
appropriate treatment. 
 
4.5 
Concomitant Medication 
All prior and concomitant medications used within 30 days prior to the screening visit and 
through the end of the study will be recorded. The dates of administration, dosage, and reason for 
use will be included.  
 
4.6 
Hospitalization during Treatment 
Adolescents will be followed by their medical doctor during treatment; this is usually adolescent 
medicine at CHOP. Should the medical doctor determine that the adolescent needs to be 
hospitalized for medical stabilization, this recommendation will be followed. Adolescents will be 
allowed to return to the trial post-hospitalization.  Eating disorder symptomatology and weight 
will be assessed post-discharge from hospital.  Any medication changes/additions will be noted.  
If, however, the adolescent needs to be referred to a higher level of care (e.g., inpatient 
treatment), then the adolescent will be removed from treatment in the trial.  
 
4.7 
Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They may 
also be discontinued from the study at the discretion of the Investigator for lack of adherence to 
study treatment or visit schedules, AEs, or due to need to refer to a higher level of care (inpatient 
or residential treatment).  The Investigator may also withdraw subjects who violate the study 
plan, or to protect the subject for reasons of safety or for administrative reasons.  It will be 
documented whether or not each subject completes the clinical study. If the Investigator becomes 
aware of any serious, related adverse events after the subject completes or withdraws from the 
study, they will be recorded in the source documents and on the case report form. 
 
4.8 
Early Termination Study Visit 
Subjects who withdraw from the study will be asked complete the full questionnaire battery. 
Should the family not wish to complete these measures, data from their last visit will serve as the 
last data point.   

 
page 22 
  
 
 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 
Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Include a listing of the variables that will be abstracted from the medical chart (paper or 
electronic). 
• Date of birth 
• Height 
• Lowest weight 
• Highest weight 
• DSM-5 criteria for Anorexia Nervosa 
• Expected body weight (i.e., target goal weight for weight restoration) 
• Expected height (for those who have lost linear height) 
• Date of last menstrual period (if menarche has begun) 
• Parental date of birth (necessary for neuropsychological assessment) 
• Race (parental and adolescent) 
• Ethnicity (parental and adolescent) 
• Familial history of eating disorders 
• Parental height and weight 
• Mid-parental height 
• Hormonal levels 
• Vitals 
• Daily Weight 
• Caloric Intake 
• Medication 
5.1.2 Other Evaluations, Measures 
We will collect demographic information from the adolescent and parents. This includes age, 
date of birth, sex, race/ethnic.  
5.1.2.1 Cognitive flexibility 
Wechsler Abbreviated Scale of Intelligence (WASI;60): The WASI is a nationally 
standardized measure of general intellectual functioning used in clinical, educational, and 
research settings that scores individuals on four subtests: Vocabulary, Similarities, Block Design, 
and Matrix Reasoning.  We will administer the two subscale version of the WASI to calculate 
IQ.  This is necessary to provide a context in which to understand the results of the neuro-
psychological testing.    
 
Rey-Osterrieth Complex Figure Test (RCFT;61): The RCFT measures visual-spatial 
perception, construction, non-verbal memory, planning, problem solving, and motor function. 
This test is pen and paper based requiring participants to copy a complex figure. There are two 
important components to the recreation of the complex figure: recalling it after a brief period of 
time without priming and the copying it. It is valid to use in adolescents with AN.62 It is used as a 
measure of central coherence. Central coherence has been demonstrated to be impaired in some 
adolescents with AN.   
 

 
page 23 
  
 
 
 
Delis-Kaplan Executive Functioning Scales (DKEFS;63). The DKEFS is a comprehensive, 
standardized battery of assessments of executive functioning that can be used with children and 
adults, ages 8–89 years. It has also been validated for use with adolescents with AN.64 Selected 
subtests administered included: trail making test, verbal fluency test, color-word interference 
test, and sorting test.  
 
Behavior Rating Inventory of Executive Function-2 (BRIEF-2;65). The BRIEF-2 is an 86 
item questionnaire that assesses executive functioning in children and adolescents aged 5 to 18 
years of age. There is a global executive composite score as well as subordinate indices 
examining behavioral regulation and metacognition. The Behavioral Regulation index consists of 
subscales measuring inhibition, set-shifting, and emotional control. The Metacognition index 
consists of subscales looking at initiate, working memory, planning and organizing, organization 
of materials, and monitoring one’s own work. Internal reliability has been found to be good with 
an alpha of .96 for the Behavioral Regulation Index and an alpha of .96 for the Metacognition 
index. Adolescents will complete this about themselves and parents will complete it about the 
adolescent and themselves.  
5.1.2.2 Weight and Eating Disorder Symptoms 
Anorectic Behavior Observation Scale (ABOS;66). This 30-item self-report measure taps into 
parents’ observations of their child’s disordered eating behavior. This measure has good 
specificity (89.6%) and sensitivity (90%) in terms of parental report of ED symptoms; and it is 
correlated with other measures of disordered eating behavior. There are three subscales in this 
measure: eating behavior (ɑ=0.80), bulimic-like behavior (ɑ=0.69), and hyperactivity (ɑ=0.69). 
Good internal consistency has been found for each subscale. This measure is completed by 
parents and corroborates adolescent report of sympotms. 
 
Accommodation and Enabling Scale for Eating Disorders-Revised (AESED;67,68). This 41-
item measure gathers information about the enabling behaviors that family members with a child 
who has an eating disorder engage in. It is a revised version of a measure developed for use with 
adults. The origional measure contains three subscales: avoidance and modifying routine, meal 
ritual, and control of the family. The origional scale has internal consistency values ranging from 
0.77 to 0.92.  Only parents complete this measure.  
 
Eating Disorder Examination – Querstionnaire (EDE-Q;71, 72). The EDE-Q is a 29-item 
questionnaire that is a self-report version of the Eating Disorder Examination (EDE).  We use a 
self-report measure to reduce participant burden yet allow for assessment at specific time points.  
This measure assesses four symptom domains : restraint (ɑ=0.75), eating (ɑ=0.78), weight 
(ɑ=0.67), and shape concerns (ɑ=0.79) as well as the presence and severity of specific ED 
behaviors. This will be used to establish diagnosis and remission status. To track change over 
treatment and follow-up, the 28 item self-report version of the EDE will be used.  Finally, to 
track weekly change and assess any changes in eating disorder sympotmatology that might occur 
during medical hosptializaiton, a 12 item brief version of the EDE will be used.  The EDE and its 
variants are the gold-standard in symptom assessment for eating disorders. 
 

 
page 24 
  
 
 
 
5.1.2.3 Behavioral Flexibility 
Howe's grocery. Howe’s grocery is a website that mimics an online grocery store. The store 
contains 8000 products across various categories (e.g., breads, produce, beverages, snack foods). 
Each product is an actual product with the exception of store brand "Howe's" products. Product 
nutrition information and price are accurate as of February 2018. By clicking "check out" 
consumers indicate they have finished their shopping trip. Consumers are not charged for and 
they do not receive any groceries. Howe’s grocery has a logging framework that 
allows researchers have a granularity of understanding where users click, spend the most time, or 
the sequence of additions and removals from the user’s cart. In this study, parents’ food choices 
in their cart can be analyzed for macronutrient and caloric content. Parents will be asked to do 
three days of meal planning and then “shop” for those menu items on-line.  
 
Buffet Challenge. Adolescents with AN will be presented with a buffet of food options (See 
Table 2). Buffet options were created in collaboration with a nutritionist and generated from 
items in the Food Choice Task.73 We chose to present adolescents with actual food items instead 
of a computerized task as there may be a difference between being able to choose more varied 
food on a computer and actually choosing and consuming foods. Food options will include both 
“safe” foods (such as salad, lean protein) and common “fear” foods (pasta, pizza, desserts). 
Adolescents will approach the buffet, serve food, and consume the meal without coaching or 
support from parents. The meal will be videotaped and the following data collected: time to 
approach buffet, time spent serving food, time eating food, amount of food chosen (weight and 
calories), macronutrient profile of food chosen, and amount (calories and macronutrients) eaten. 
We will also code for meal time behaviors reported in Gianini74 (e.g., tearing, staring, 
dissecting). 
 
Approach-Avoidance Task (AAT): The AAT assesses approach-avoidance tendencies. Single 
stimuli are presented to participants on a computer screen. In response to the images, the 
participant presses a computer key.  One key represents a positive valence, or an “approach” 
response, and the other represents a negative valence, or an “avoidant” response. Unique 
deduction of stimuli valence, which, for this study, will display as food items. With a keyboard, 
participants will press one of two buttons for each stimulus presented to them. The images 
displayed in this AAT will be that of food items (e.g., pizza and cake) or personal care items 
(e.g., toothbrush or towel). 
 
Table 2. Buffet Challenge Foods 
(sample)  
grilled chicken  
tofu   
doughnuts/brownies 
French fries  
chicken fingers  
veggies  
peanut or almond 
butter 
yogurt and granola  
salad bar 
wrap/sandwich bar 
chocolate  
mac and cheese  
plain pasta with 
red sauce  
pizza 
      

 
page 25 
  
 
 
 
5.1.2.4 Comorbid symptoms and potential moderators 
Behavioral Inhibition System and Behavioral Activation System Scales (BIS/BAS;75). The 
behavioral inhibition system (BIS) and behavioral activation system (BAS) scales are self-report 
measures used to examine a patient’s inhibition and activation sensitivity. The scale is composed 
of four sub scales, one scale to measure BIS sensitivity, and three subscales related to BAS 
sensitivity (Drive, Fun Seeking, and Reward Responsiveness Scales). The BIS component 
measures patient sensitivity to signals of punishment, for example, patients high in BIS 
sensitivity are more responsive to punishment cues and experience greater negative affect 
(anxiety) in situations associated with punishment. The BAS component measures sensitivity to 
signals of reward, for example, patients with high BAS sensitivity are highly responsive to 
reward cues and experience positive affect. Internal consistency was high for the BIS (ɑ=0.74), 
BASS Reward Responsiveness (ɑ=0.73), BAS Drive (ɑ=0.76), and BAS Fun Seeking (ɑ=0.66).  
Recently, AN has been hypothesized to be related to abnormalities in reward processing.  
Adolescents will complete this about themselves; parents will complete it about themselves and 
their child. 
 
Behavior Assessment System for Children-3 Parent and Child Version (BASC-3;76). This is 
139 item self-report measure that assesses affective and behavioral functioning in adolescents. 
The BASC-3 is well validated and has reliability ranging from .88-.97 with test-retest reliability 
of .81-.89. Both parent and self-report versions are available, allowing for comparison of parent 
and self observations of behavior. The measure includes both adaptive scales (e.g. Daily Living, 
Social Skills, Functional Communication) and clinical scales (e.g. Depression, Anxiety, 
Withdrawal, Atypically). Given that mood disorders and interpersonal deficits often accompany 
AN, a full assessment of these domains will allow broader based evaluation of treatment. It 
might also provide information regarding the adolescent’s strengths and allow for tracking of 
improvement in adaptive areas.  
 
Experience of Caregiving Inventory (ECI;77). This 66-item self-report measure assesses 
caregivers’ perception of their experiences interacting with their child. It includes subscales with 
both negative (eight subscales) and positive items (two subscales). This measure is included to 
assess change in parental experience of having an ill child (i.e. greater hope for positive outcome, 
less judgmental of the adolescent). The ECI has demonstrated good construct validity 
(explaining 36% of the variance in scores on measures assessing general health and coping) and 
high internal consistency (Cronbach’s alphas ranging from 0.74 to 0.91) among caregivers for 
patients with AN.69 It is only completed by parents. 
 
Intolerance of Uncertainty (IUS;78). The IUS is a 27 item self-report measure that assesses six 
aspects of intolerance to uncertainity, 1) the emotional and behavioral consequences of being 
uncertain, 2) how being uncetain relects on an individuals character, 3) expectations that the 
future be predictable, 4) frusteration surrounding unpredictability of the future, 5) attempts to 
control the future, 6) and all or nothing situations when in unceratin situations. Items are 
measured on a 5 point Likert scale. The IUS showed strong internal consistency (α = .94) and 
good test-retest reliablity ( r =.74) over a 5 week period. The IUS is validated and considered to 
have good concurrent validity with measures of worry, anxiety, and depression. The IUS will be 
administered at all time points. 
 

 
page 26 
  
 
 
 
Obsessive Compulsive Inventory (OCI;79). There is an adult (OCI) and child (C-FOCI) version 
of this measure. The C-FOCI is a 17 item self-report questionnaire that assesses presence of 
common obsessions and compulsions. There are two parts to this scale – a symptom checklist 
and a severity scale. The adolescent checks yes or no for the checklist and for the scale endorse 
items according to a range from 0 (none) to 4 (extreme). The internal consistency was acceptable 
for both parts ranging from .76-.79. OCD is highly comorbid with AN and can appear as rigid 
behavior. Parents will complete the OCI about themselves. This is an 18 item scale using a 5 
point Likert type response that assesses distress associated with obsessions and compulsions. It 
has good internal consistency reliability (.81-.93). Parents will complete the OCI. 
Detail and Flexibility Questionnaire (DFlex;80). The DFlex is a 24-item self report measure 
assessing cognitive rigidity and attention to detail, both considered aspects of neurocognitive 
functioning. Both aspects have been measured in an Austistic sample using the Autism Spectrum 
Quotient (AQ), and thus the AQ was used to determine construct validity. A strong correlation 
for cognitive rigidity was shown (r = .72) and a moderate correlation for attention to detail (r = 
.26). The DFlex is a new measure developed to address both flexibility and central coherence. It 
will be completed by parents and adolescents.  
 
Line Bisection Task (LBT;81). The LBT has been widely used as a behavioral measure of visual 
neglect in patients with brain damage. More recently, neuroimaging research has confirmed it 
can also be used to measure approach motivation in non-clinical populations. In the task 
participants mark the perceived mid-point of staggered horizontal lines of the same length in 
millimeters (mm). When participants make errors in marking the midpoint left of the true 
midpoint these are scored as negative. Meanwhile, positive scores mean greater left to right 
hemisphere activation. The LBT is being piloted in this study as a behavioral measure of 
approach-based coping. It will be completed by both adolescent and parents.  
 
Family Questionnaire (FamQ;82). Expressed emotion (EE) has traditionally been assessed via 
clinical interview, however the interview can be laborious and time consuming. In order to 
address this issue, the FQ was developed. It is a 20 item self-report measure that includes two 
subscales: criticism and emotional over involvement. Scores on the FQ have high convergent 
validity with more traditional interview assessments of EE. Test-retest reliability over two weeks 
produced Pearsons correlations of r= 0.84 for the criticism (CC) and r=0.91 for the emotional 
overinvolvement (EOI) subscales. Similarly, internal consistency was good, ranging from 0.90-
0.92 for the CC and 0.79-0.82 for the EOI subscales. Only parents will complete this measure. 
 
Depression Anxiety Stress Scale (DASS;83): The DASS is a 42-item self-report instrument 
measuring current symptoms of depression, anxiety, and stress on three separate scales. Higher 
scores on each of the scales indicate higher levels of depression, anxiety, and stress. Among 
clinical and community populations high internal consistency was found for the depression 
(ɑ=0.94), anxiety (ɑ=0.87), and stress subscales (ɑ=0.91). The DASS-21 has also been found to 
have good convergent reliability with other well validated measures of depression and anxiety 
(e.g., Beck Depression Inventory, State-Trait Anxiety Inventory).  Parents and adolescents will 
complete this about themselves.  
 
Eating Disorder Flexibility Index (EDFLIX): The EDFLIX is a 51-item questionnaire where 
participants use a six-point Likert scale to respond to each question. The EDFLIX ranges in 

 
page 27 
  
 
 
 
questions, some asking specifically about their eating disorder (e.g., “I need my meals to be 
predictable (time, food, content)” and “I prefer eating the same foods as I usually do”) and others 
are more abstract (e.g., “I find it difficult to get used to new situations” and “When I am stuck on 
a task, I am unable to come up with new solutions.”)  
 
Autism Spectrum Quotient (AQ-10): The AQ is a 10-item questionnaire for parents to 
complete regarding the child’s behavior if their child is between 12 and 15 years old. If the child 
is 16-18 years old, the child will complete this questionnaire about themself. Additionally, 
parents will complete this questionnaire about their own behavior. The AQ contains a 4-point 
scale, ranging from “definitely agree” to “definitely disagree.” There are two versions of this 
questionnaire, one for participants aged 12-15 years old and another for participants aged 16 and 
older. Examples of questions are, “S/he notices patterns in things all the time” and “S/he is good 
at social chit-chat.”  
 
Social Reward Questionnaire (SRQ): There are two versions of the SRQ, one for adults and 
one for adolescents. We will administer the SRQ designed for adolescents (SRQ-A). This 20-
item questionnaire is scored on a 7-point scale, with responses ranging from “Strongly disagree” 
to “strongly agree.” The questionnaire asks participants to rate different statements such as, “I 
enjoy treating others fairly” and “I enjoy keeping promises I make to others.” 
 
Parent Versus Anorexia Scale (PVA):  The PVA is a 7-item questionnaire for parents to 
complete regarding their own self efficacy to feed their adolescent. They respond to each item on 
a 5 point Likert scale ranging from “strongly disagree” to “strongly agree”. It is aimed at 
measuring parental efficacy throughout family-based treatment to track changes over time.  
Treatment Credibility/Alliance 
Credibility/Expectancy Questionnaire (CEQ;84). This 6-item questionnaire measures both 
cognitive and affective elements regarding how much individuals believe in, and expect they will 
improve, due to treatment. The CEQ was designed to be used in clinical outcome trials and was 
validated on a mixed sample of patients. It has good internal consistency (.85) and test-retest 
reliability (.75-.82).  
 
Working Alliance Inventory (WAI;85). The WAI is a 36 item measure that assesses goals, 
tasks, and the bond present in therapy. It can be completed by the therapist, client, or an 
observer. Reliability ranges from .89-.93. Therapeutic alliance is recognized as an important 
contributor to outcome, however, adolescents with AN have been reported to demonstrate 
deficits in forming a strong therapeutic relationship and this may impact outcome.  
 
CRT Treatment Evaluation Questionnaire (TEQ;86) The TEQ is a 20-item measure that 
assesses how participant feel about CRT, including the perception of change, view of the 
therapist, treatment satisfaction. It is completed at the end of treatment and will only be 
completed by the individuals who receive CRT. It currently does not have published reliability 
statistics as it is a relatively new measure. 
 

 
page 28 
  
 
 
 
5.2 
Efficacy Evaluations 
There is no efficacy evaluation. The purpose of this study is to determine whether or not CRT 
can improve flexibility in the parents or the adolescent. We will gather data on efficacy in future 
work.   
 
5.3 
Safety Evaluation 
Subject safety will be monitored by adverse events, weight, parental report of behavior, and 
weekly checks on eating disorder symptoms (EDE short version). Regular contact with the 
adolescents’ pediatricians will also occur. When questions may arise about adolescent health, Dr. 
Peebles will review vital signs, weight gain, and eating disorder symptoms and make 
recommendations vis a vis hospitalization or referral to a higher level of care. 
 
6 
STATISTICAL CONSIDERATIONS 
6.1 
Primary Endpoint 
Aim 1:  To identify whether or not it more impactful to add a parent or adolescent 
component of CRT to standard FBT. To assess if CRT engages the target, we will use mixed 3 
(treatment) x 2 (time) Multivariate Analysis of Covariance (MANCOVA): one for adolescents, 
one for mothers, and one for fathers. The covariate for all analyses is total IQ on the WASI.  
Dependent variables are as follows: Trails Number-Letter Sequencing, Inhibtion, 
Inhibition/Switching, Correct Response Shifting, Category Switching, or Description 1 or 2 and 
Shift on the BRIEF-2. We will follow these steps:  
1. Conduct omnibus MANCOVA and evaluate significance. If not significant, stop and move to 
next analysis.  
2. If the omnibus test is significant, we will conduct individual 2 (treatment) X 2 (time) Analysis 
of Covariance (ANCOVA) to determine which dependent variable had significant change, with 
IQ again as the covariate.  
3. Each assessment of the target (DV) will be examined. Results will inform the Go/No-Go 
Decision as described in Table 6. 
These three steps will be repeated for adolescents, mothers, and fathers. We will include all 
three groups in the initial MANCOVA and follow-up with planned comparisons (ANCOVA) of 
FBT vs the appropriate CRT condition. In all analyses, we will focus on the within and between-
group effects, examining interaction effects are not necessary to evaluate the target. As we have 
chosen measures demonstrated to change with CRT,40,87-90 we will maintain α=0.15 for each 
analysis.91 We do not expect adolescents whose parents receive CRT or parents whose 
adolescents receive CRT to demonstrate increases in flexibility. However, should the planned 
ANCOVAs not be significant, we will be able to explore other possible group differences. 
Additionally, we will explore the relationship between dependent variables via discriminant 
analysis. These additional methods to examine the data will not factor into the Go/No-Go 
decision, but will enhance the depth of our understanding of the data and contribute to our 
understanding of neurocognition in AN.  
Aim 2: To determine the dose of CRT needed to lead to a medium effect size. Some research 
indicates that ≥8 sessions of CRT are necessary for improvement in cognitive flexibility with 
AN.92 It is unknown how many sessions will be needed for significant change in parents of 

 
page 29 
  
 
 
 
adolescents with AN. To determine optimal dose, we will model change across the 15 sessions 
using latent growth curve modeling (LGCM). LGCM will allow us to analyze individual and 
average trajectory and model linear and quadratic trend. We will visually assess for the point 
(dose) at which there is a significant decrease in the rate of improvement (quadratic). Parameter 
estimation will employ Maximum Likelihood (ML) estimation.93,94 We will evaluate model fit 
using chi-square (χ2), Comparative Fit Index (CFI), Standardized Root Mean Squared Residual 
(SRMR), and Root Mean Squared Error of Approximation (RMSEA).95 The following values are 
indicative of acceptable fit between the model and the observed data variance/covariance 
matrixes: CFI, SRMR, and RMSEA, < .95, < .80, and < .05, respectively.  We will assess and 
compare different models using BIC and novel criteria such as Scaled Unit Information Prior 
BIC.96,97 Examining standardized model residuals in addition to global fit indices (GFI) permits 
us to identify model misspecification even if GFI values suggest adequate fit.95  
6.2 
Secondary Endpoints 
Secondary endpoints include preliminary examination of symptom change (EDE, ABOS) and 
rate of weight gain.  
 
6.3 
Statistical Methods 
6.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive summaries 
(e.g. means and standard deviations for continuous variables such as age and percentages for 
categorical variables such as gender). 
 
6.3.2 Safety Analysis 
All participants enrolled will be included in the safety analysis.  Frequency of hospitalization and 
referral to a higher level of care will be summarized.  Differences between those who need 
hospitalization and those who do not over the course of the study will be explored and reported. 
 
6.4 
Sample Size and Power 
Power analysis Aim 1. In the initial phase of the proposed project (R61), our sample size 
estimation is based on a mixed MANCOVA design with two repeated measures from baseline to 
end-of-treatment (EOT; within subjects component) and three groups (CRTp, CRTA, and FBT; 
between subjects component). Based on a review of the literature, we are powering for a medium 
effect size. Our effect size estimate is Cohen’s f statistic.98 This effect size estimate is a ratio of 
variation explained to that unexplained by the model (treatment groups), and is expressed as 
follows: 𝑓𝑓= ට
𝜂𝜂2
(1−𝜂𝜂2), where 𝜂𝜂2 =
𝜎𝜎𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚
2
𝜎𝜎𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇
2
; proportion of variability due to the model.99,100 
Heuristics for small, medium, and large effect sizes are .1, .25, and .4, respectively. We selected 
an alpha of 0.15, given the nature of the study and the difficulty in recruiting participants from a 
low prevalence condition. Alpha of 0.15 is essential to provide adequate power for this study.91 
As any analysis powered for a medium effect will also be powered for a large effect, we only 
highlight the expected medium effect. For all analyses, we specified an α=0.15, two time points, 
and a correlation between measures of .3 (based on unpublished data). The anticipated N 
accounts for dropouts (i.e., number enrolled will be higher).  
Power analysis Aim 2. Using Mplus 7.2,94 we conducted a LGCM Monte Carlo simulation with 
1000 replications94,101-103 to determine power to identify CRTP/A dosage based on a half standard 

 
page 30 
  
 
 
 
deviation increase (rate of change; slope) from baseline (effect size) above FBT. With 15 
participants in 3 groups across 5 time points, parameter and standard error bias were ≤ 5%, 
confidence interval coverage ≥ 90%, and power = 0.59.   
 

 
page 31 
  
 
 
 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
7.1 
Description 
All treatment will be delivered by a doctoral- or Master’s-level psychologist. All therapists will 
be trained in FBT and CRT and will have their adherence to the manual supervised by the PI. 
These clinicians will be designated and added to section 1.02 of the eIRB once hired. Treatment 
will be delivered at the Robert’s Center for Pediatric Research.  
 
7.2 
FBT 
FBT was described in section 1.2.1.  15 sessions of FBT will be administered over the course of 
6-12 months, with the option to participate in an additional 12 follow-up FBT sessions. 
 
7.3 
CRT 
CRT was described in section 1.2.2. 15 sessions of CRT will be administered over the course of 
6 months for families in CRTA and CRTP.  
 
7.3.1 Treatment Compliance and Adherence 
Treatment Fidelity. Sessions will be conducted by doctoral- or Master’s-level therapists with 
training in FBT for AN. Prior to study start, therapists will attend a 3-day workshop with the PI. 
The first day reviews FBT; days 2-3 provide training in CRT. Dr. Timko will provide weekly 
supervision of FBT and CRT.  
Treatment sessions will be videotaped and a random selection of 20% tapes per patient will be 
reviewed for adherence to FBT and CRT. FBT fidelity will be assessed using published 
methods,104 CRT fidelity will be assessed by measures developed by the PI and used in a recent 
CRT pilot study. A trained master’s level research assistant will score tapes for adherence and 
review weekly with Dr. Timko. In the event that a participant receives care that is a significant 
deviation from protocol (lack of adequate adherence ratings on more than 20% of sessions), this 
participant’s data will be removed from analyses. If drift occurs, therapists will complete a 
refresher training session, the next three sessions will be reviewed and if improvement to 
criterion does not occur, the therapist will be withdrawn.  
Missed sessions. Should a therapist miss a session (due to illness or vacation) the session will 
be rescheduled, the other therapist will see the family to ensure that a week is not missed, or the 
family will be asked to schedule two sessions the following week.  Should the family need to 
cancel, all attempts will be made to reschedule within the week to ensure the family stays on 
schedule. If an appointment cannot be rescheduled within the week, the family will have two 
sessions scheduled the following week.  
 

 
page 32 
  
 
 
 
8 
SAFETY MANAGEMENT 
 
8.1 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
 
8.2 
Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen during 
the course of this study (including SAEs) they will be reported to the IRB in accordance with 
CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. AEs that are not 
serious but that are notable and could involve risks to subjects will be summarized in narrative or 
other format and submitted to the IRB at the time of continuing review.  
 
8.3 
Medical Emergencies 
As hospitalization for medical stabilization can occur during routine treatment, hospitalization 
will not be considered an SAE. A summary of all hospitalizations for medical stabilization will 
be provided at the time of continuing review. 

 
page 33 
  
 
 
 
9 
STUDY ADMINISTRATION 
9.1 
Treatment Assignment Methods 
9.1.1 Randomization 
Procedures for randomization were described in Section 3.2.  
 
9.1.2 Blinding 
Research assistants who assess adolescents at each time point will not be aware of their study 
condition.  
 
9.2 
Data Collection and Management 
All data (with the exception of DKEFS, WASI, BRIEF, and BASC as these have standardized 
forms) will be stored in RedCap.  Scores from these standardized forms will be entered into 
RedCap to ensure all data is in the same place.  
All participants will be given a unique study ID and all study information will be coded using 
this number (in RedCap and on standardized forms). The master list linking participants with 
their numbers will be stored in a separate RedCap file that only members of the research team 
will have access to.  
RedCap data will be downloaded weekly and stored in a password protected file on the secure 
research server. Only the CRC and PI will have the password. This is for backup.  
Audio/video files of treatment sessions will be stored on the research server and destroyed after 
study end. These are necessary to ensure treatment fidelity. Only study staff involved in the 
project will have access to these files.  
Data will remain coded until all study procedures are complete and initial findings have been 
published. After 6 years, the list linking study IDs to participants will be destroyed. Remaining 
data will be retained indefinitely. 
 
9.2.1 Data sharing  
Per NIH requirements, data will be shared via the National Database for Clinical Trials related to 
Mental Illness. Within 3-months of the award, the PI will complete a NIMH Data Repositories 
Data Submission Agreement. Per guidelines, data will be shared in two tiers: raw data while the 
study is on-going and analyzed data with publication of results/after the reward period. Once a 
manuscript is published, all analyzed data will be submitted.  Data will include descriptive/raw 
day from questionnaires, demographic data, and data abstracted from the medical chart. We will 
also include raw and standard scores for the neuropsychological assessments used in the course 
of this study. Per requirements, raw data will be submitted bi-annually, starting 6 months after 
project begin. Given the novel aspect of behavioral data (Howe’s Grocery and Buffet Challenge), 
we will work with staff in order to ensure appropriate and smooth submission of data.  Video 
recordings of the buffet challenge will not be submitted. Additionally, video recording of the 
clinical interviews will not be submitted.  We will ensure that all participants will have a Global 
Unique Identifier and each data set will be associated with the appropriate publications.  
 
The PI will encourage anyone who is interested in accessing the data to use the National 
Database. As some researchers may not have access to or wish to access the National Database, 

 
page 34 
  
 
 
 
we will make a cleaned, de-identified data set and codebook available for request 6 months after 
complete study end and the publication of initial manuscripts. The data will be made available to 
other researchers under a data sharing agreement that will provide for a commitment to using the 
data for research purposes and to destroying or returning the data after analysis are completed. 
Researchers can request the data from the PI via email. Requests are necessary given the nature 
of the data; although it will be de-identified, it will contain sensitive health information about the 
participants. 
 
9.3 
Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the study.  
 
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and any 
recipient researchers (including others at CHOP) before sharing a limited dataset (PHI limited to 
dates and zip codes).  
 
9.4 
Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
Data and safety will be monitored on multiple levels. The PI has primary responsibility of study 
oversight and will meet with study staff regularly to monitor study progress, safety issues, 
recruitment progress, attrition, and data quality. Dr. Timko will meet as needed with the Medical 
Safety Officer to review new patients or any concerns.   
 
We will monitor participants for the occurrence of any adverse events associated with data 
collection and participation and will report these events as directed by the institutional IRB and 
adverse event (AE) reporting policies. Events will be reported promptly to Dr. Timko (PI) and 
the study coordinator who will make provisions to respond appropriately, ensuring referral to 
medical/professional resources, as needed. 
 
9.4.1.1 Breach of Confidentiality.  
The PI will ensure that all members of the study team have completed all mandatory 
confidentiality statements and research ethics trainings and that data have been handled and 
stored properly. Annually, research staff will be required to sign a statement acknowledging their 
receipt and understanding of the confidentiality requirements and pledging to maintain 
confidentiality of the data to which they have access. If a breach of confidentiality is identified, 
the PI will immediately meet with IRB and data security leadership to review and identify how 
the breach occurred and to review and discuss steps to prevent future problems with ensuring 
participant confidentiality. 
 
9.4.1.2 Continuous Quality Assurance and Quality Control Procedures (QA/QC) 
QA/QC will be implemented to ensure compliance with study requirements in areas including 
recruitment and data collection. Quality control activities will be performed regularly on all 
electronic data and participant files to ensure that all data collected is complete and accurate. 
These will include the reconciliation of data forms, verification of codes and labels, and careful 

 
page 35 
  
 
 
 
review of each individual data field for omission and errors. All neuropsychological assessments 
will be scored twice for reliability and all data will be entered into the database twice to ensure 
accuracy.  
 
In terms of day-to-day safety monitoring, the therapist will track weight, eating disorder 
symptom information, and closely monitor suicidality, self-harm, and other concerns. If a 
therapist becomes aware of suicidal or homicidal ideation or serious self-harm behavior, the 
adolescent will undergo a comprehensive assessment of plan and intent and the necessary 
precautions will be taken to insure safety or medical attention as appropriate. Standard clinic 
practice is for therapists to make judgments about mental status, global symptom severity, and 
symptom improvement at each visit and this information becomes part of patients’ permanent 
clinical records. Participants in the study will have CHOP behavioral health emergency numbers. 
9.4.1.3 Data and Safety Monitoring Board 
This study will be conducted under the guidance of a Data Safety and Monitoring Board 
(DSMB). The DSMB will act in an advisory capacity to monitor participant safety, evaluate the 
progress of the study, and review procedures for maintaining the confidentiality of data and the 
quality of data collection, management, and analyses. The Board will be led by a chair and at 
least 3 additional members. Board members will have expertise in an area relevant to the study 
aims, examples are: adolescent health research, behavioral treatment, 
neuropsychology/neurocognition, treatment implementation, statistical analysis, adolescent 
development, and/or eating disorders. DSMB members will have no direct involvement with the 
study investigators or intervention. The board will meet 4 times during the study. Board 
members will review study progress, data quality, and participant safety. The first meeting will 
occur prior to initiation of study activities to review and approve the study protocol and safety 
monitoring and reporting plan. Subsequent meetings will occur 6 months after the start of study 
recruitment, 12 months after the start of study recruitment, and again after all treatment has 
ended and data analysis has begun. Ideally, all meetings will be in person, however, remote 
participation (i.e., via Skype or Zoom). A detailed DSMB Charter will be developed that 
provides a detailed list of DSMB responsibilities. 
 
The DSMB will receive a data and safety monitoring report at each scheduled meeting. This 
report will include the following sections: Overview of DSMB, Study Status, Study Recruitment, 
Study Enrollment, Study Randomization, Participant Characteristics, Study Data Collection, 
Regulatory Compliance, Adverse Events and Protocol Deviations, Quality Control and Data 
Management, Data Analysis, Sample Size and Power Analysis, Outcome Data, Recent 
Publications of Relevance, and Challenges and Resolutions. In these reports, data and discussion 
will be confidential and participant identities will not be revealed. 
9.4.2 Risk Assessment 
Risks are not greater than minimal. The treatments being used in this study are close to routine 
care and do not carry a great risk of harm. 
 
Completion of the measures can be burdensome, however, we have taken step to reduce the 
burden and any fatigue by breaking up questionnaire completing with neuropsychological 

 
page 36 
  
 
 
 
testing. Participants are allowed to take breaks as needed and are given time to eat snacks. A 
similar procedure has been used in prior research by the PI and was tolerated well by families.  
 
The buffet challenge may be difficult for adolescents at the beginning of treatment and 
videotaping may be stressful for the adolescent. Parents will be made aware of the challenge and 
will be able to provide the adolescent with snack after the buffet is complete.  As the initial 
clinical interview occurs at the end of intake, any concerns will be able to be addressed with the 
therapist.  
 
9.4.3 Potential Benefits of Trial Participation 
FBT is the gold standard of treatment. Families will receive guidance and support in refeeding 
their child.  Most adolescents should gain weight and experience a reduction in eating disorder 
symptoms. CRT is highly acceptable and has been shown to decrease drop out from treatment.  
 
9.4.3.1 Indirect benefit 
More treatments for anorexia are needed, particularly for those who do not fare well in FBT.   
This study investigates whether or not CRT can be a viable augmentation to treatment and for 
whom (parents or child) it has the most benefit.  
9.4.4 Risk-Benefit Assessment 
Risks are minimal. All adolescents will receive family-based treatment – the most recommended 
treatment for adolescents with AN.  Two groups will receive an additional session of CRT each 
week. Adolescents will be required to have medical care during the course of the study. If they 
are not improving, recommendations for a higher level of care will be given.  The benefits of 
finding a way to improve outcomes out-weighs the minimal risk. 
 
9.5 
Recruitment Strategy 
Eligible participants will be identified through the inpatient and outpatient programs of the 
Eating Disorder Assessment and Treatment Program (EDATP) at CHOP. We will also recruit 
through CHOP satellite primary care facilities and online.  
 
Adolescents enter our program through three primary pathways: through an outpatient nutrition 
and medical evaluation, through an outpatient multidisciplinary evaluation 
(psychology/psychiatry, nutrition, medical), or through hospitalization for medical stabilization 
of complications resulting from malnutrition. Screening for eligibility will occur either at an 
outpatient evaluation or during hospitalization for medical stabilization.  
 
Potentially eligible patients identified (those in hospital with a diagnosis of anorexia or those 
presenting for an evaluation) will be contacted in advance of their appointments and informed 
they may be eligible for participation in research. If the family is interested, study procedures 
will be described to the family, including a brief review of inclusion and exclusion criteria. If the 
family is interested, consent to participate will be coordinated with the clinical intake. Assuming 
the adolescent is stable for outpatient treatment, they can enter the research study after the intake. 
The study staff will only collect private health information as it pertains to determining eligibility 
before consent, per CHOP IRB guidelines. Study staff will not collect any additional private 
health information without obtaining consent and HIPAA authorization first. As the Eating 
Disorder Program also has an inpatient program, the list of patients being treated as part of the 

 
page 37 
  
 
 
 
adolescent service will be reviewed daily. Eligible families will be contacted during the hospital 
stay via direct communication with study team members or by handouts in the informational 
packet provided to families at the beginning of the hospital study. Families who are interested 
can receive information and undergo consent and parts of the assessment while in hospital, 
should they desire. The remainder of the assessment, randomization, and beginning of treatment 
in the study protocol will begin after discharge from hospital.  
 
In order to meet recruitment goals, we will augment the above procedures by advertising the 
study on the CHOP website as well as external websites such as FEAST. If a participant family 
reaches out to the study team based on internet announcements, tearpads, or fliers, general 
information about the study will be provided over the phone and, if interested, the family will 
have a limited phone screen to determine eligibility. If the adolescent and parents are eligible to 
participate, study staff will schedule the family for the baseline assessment.  If the family is not 
receiving medical care in the EDATP, medical records will be requested from the PCP. The 
medical safety officer (R. Peebles) will review the chart and make a recommendation regarding 
appropriateness for outpatient care.  
 
Additionally, this study will appear in “This Week @ CHOP,” a segment in an internal 
newsletter made available to all CHOP employees. Interested families will be instructed to call 
study staff to determine eligibility, as outlined above. 
 
Furthermore, the study team will be obtaining a list from CHOP’s Department of Biomedical 
Health Informatics (DBHI) of Medical Record Numbers (MRNs) of patients with an anorexia 
nervosa diagnosis within the last six months. Should they wish to, the DBHI could obtain this list 
of MRNs from the Recruitment Enhancement Core (REC), who has already pulled this data. 
Because we do not intend for the REC to act as an honest broker on our study team’s behalf, the 
REC will supply the DBHI with this information, which will then be supplied to our research 
team. When this list is obtained, the study team will communicate with eligible families to 
provide more information about this clinical trial if interested. We chose not to use the REC as 
an honest broker as we felt that it would potentially be overwhelming for families who have 
opted not to participate, are already involved in care, or otherwise not appropriate for the study. 
We will be able to compare the list of MRNs to those who have been screened and only approach 
those patients who have not been screened, if appropriate. With this approach, we hope to 
possibly identify adolescents who are being treated in primary care without behavioral health 
support. 
 
9.6 
Informed Consent/Assent and HIPAA Authorization 
Informed consent will be obtained by research assistants. Consent will take place prior to the 
intake and will occur at Robert’s Center for Pediatric Research prior to the intake. For 
adolescents who are hospitalized for medical stabilization and preparing for discharge to 
outpatient treatment, consent can occur while they are in hospital at CHOP.  
Participants will be able to take up to 48 hours to make a decision about participation in the 
study.  Should they ask to reschedule the intake after study procedures have been reviewed, this 
request will be accommodated.  Any and all questions will be answered by the study team 
member reviewing the consent form.  All risks and benefits will be explained. In prior research 
the consent procedure usually takes 30 minutes. 

 
page 38 
  
 
 
 
The consent form will be signed by parents, the adolescents, and a member of the study 
team.   HIPAA Authorization will be combined with the consent form. Parents will be given a 
copy of the consent form to take home with them. 
Consent and assent will be obtained from subjects who are 14+ years old and from parents. For 
all other adolescents, we will waive assent. This is in line with the Patient Care Manual Policy: 
Storage and Release of Mental Healthy Record stating that subjects who are 14 years old must 
provide their own consent for mental health treatment and for the review of their mental health 
records and must provide their own assent for participating in the research study. 
Consent will ideally occur in-person; however, if this is not possible then remote consent will 
occur. Remote consent will take place on a CHOP-approved video conferencing platform, and 
study staff will review all sections of the informed consent form with families. Families will be 
sent a link to our REDCap project with the informed consent form. At the end of the informed 
consent discussion, families will be asked to e-sign and e-date in the appropriate sections of the 
REDCap project. An electronic copy of the informed consent form will also be sent to the 
families for their records.  
 
9.6.1 Waiver of Assent 
We are requesting a waiver of assent for all subjects <14 years old. Adolescents with AN are 
in a state of acute malnutrition and starvation. This can impact their executive functioning and 
ability to understand what is being asked of them. In addition, anosognosia is common in AN 
and many adolescents do not recognize the fact that they are ill or understand the severity of 
their illnesses. Given the high morbidity and mortality rate in AN, requiring adolescent assent 
could delay treatment.  
 
9.7 
Payment to Subjects/Families 
9.7.1 Reimbursement for travel, parking and meals 
Families will be given a parking pass for each visit to Robert’s Center for Pediatric Research so 
that they do not have to pay for parking.  
 
9.7.2 Payments to parent for time and inconvenience (i.e. compensation) 
Time point 1: $50/parent for completing questionnaires, neuropsychological assessment, and 
Grocery challenge 
Time point 2: $10/parent for completing the questionnaires  
Time point 3: $25/parent for completing the questionnaires and neuropsychological assessment 
Time point 4: $35/parent for completing questionnaires, neuropsychological assessment, and 
Grocery challenge 
Time point 5: $50/parent for completing questionnaires, neuropsychological assessment, and 
Grocery challenge 
Time point 6: $5/parent and $5 for adolescent for completing questionnaires 
Time point 7: $5/parent and $5 for adolescent for completing questionnaires 

 
page 39 
  
 
 
 
 
9.7.3 Payments to subject for time, effort and inconvenience (i.e. compensation) 
 
Time point 1: $50/subject for completing questionnaires, neuropsychological assessment, and 
Grocery challenge 
Time point 2: $10/subject for completing the questionnaires  
Time point 3: $30/subject for completing the questionnaires and neuropsychological assessment 
Time point 4: $35/subject for completing questionnaires, neuropsychological assessment, and 
Buffet challenge 
Time point 5: $50/subject for completing questionnaires, neuropsychological assessment, and 
Buffet challenge 
 
9.7.3 Gifts 
The study team will send thank you cards after each assessment and give the family a refrigerator 
magnet as a reminder of participation.  
 
10 PUBLICATION 
This is the first phase of a two-phase study (R61/R33 mechanism). We must show improvement 
in the target and meet a-priori Go/No-Go criteria in order to move forward after year 2. Data 
gathered will initially be used to answer the Go/No-Go question. The publication time line would 
impacted by this funding decision. Data will be presented at conferences and published as 
appropriate.   
 
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Franko DL, Keshaviah A, Eddy KT, et al. A longitudinal investigation of mortality in anorexia nervosa and bulimia 
nervosa. American Journal of Psychiatry. 2013;170:917-925. 
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Swanson SA, Crow SJ, Le Grange D, Swendsen J, Merikangas KR. Prevalence and correlates of eating disorders in 
adolescents. Results from the national comorbidity survey replication adolescent supplement. Arch Gen Psychiatry. 
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Treasure J, Russell G. The case for early intervention in anorexia nervosa: theoretical exploration of maintaining 
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Lock J, Le Grange D, Agras WS, Moye A, Bryson SW, Jo B. Randomized clinical trial comparing family-based 
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Lock J, le Grange D. Treatment Manual for Anorexia Nervosa: A Family-Based Approach. 2nd ed. New York: 
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Loeb KL, le Grange D. Family-based treatment for adolescent eating disorders: Current status, new applications and 
future directions. International journal of child and adolescent health. 2009;2(2):243. 
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Nakazato M, Hashimoto K, Schmidt U, et al. Serum glutamine, set-shifting ability and anorexia nervosa. Ann Gen 
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Harper JA, Brodrick B, Van Enkevort E, McAdams CJ. Neuropsychological and cognitive correlates of recovery in 
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