An Open-Label, Single- and Multi-Dose Study to Evaluate the Relationship Between the Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes of Atomoxetine in CYP2D6 Extensive, Intermediate and Poor Metabolizers in Children With Attention Deficit/Hyperactivity Disorder
Conditions: ADHD
Sponsor: Children's Mercy Hospital Kansas City

SHORT TITLE: ATX-PBPK-PD-Clinical Outcomes (U54) 
 
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PROTOCOL TITLE: 
An Open-Label, Single- and Multi-Dose Study to Evaluate the Relationship between the 
Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes of Atomoxetine in CYP2D6 
Extensive, Intermediate, and Poor Metabolizers in Children with Attention Deficit/Hyperactivity 
Disorder 
 
PRINCIPAL INVESTIGATORS: 
James Steven Leeder (Primary contact) 
Clinical Pharmacology, Toxicology, and Therapeutic Innovation 
816-302-3001 
sleeder@cmh.edu 
Sarah Soden 
Developmental and Behavioral Sciences 
816-302-8589 
ssoden@cmh.edu 
 
VERSION NUMBER/DATE: 
Version 19.0/April 1, 2023 
REVISION HISTORY 
 
Revision 
# 
Date of IRB 
Approval 
Consent 
Change? 
Describe 
plan/timeline 
Summary of Changes 
1.0 
11/29/2016 
N/A 
Initial submission  
2.0 
06/29/2017 
Y 
1) Expand enrollment to include ADHD Summer 
Treatment Program (STP) 
2) Med history, physical exam, Tanner staging 
added 
3) Typographical error fixed (Echo to EKG) 
4) Modified Vanderbilt form 
5) Drug manufacturer, NDC, lot # to be collected 
6) Urine to be collected 
7) Additional blood draws during PK visits 
8) Sweat patches to be collected 
9) Study booklet cosmetic changes 
10) Vitals to be obtained with PK visit blood draws 
11) Pupillometry/eye-tracking frequency changes 
3.0 
08/16/2017 
N 
1) Changing CDISC to KSADS instrument 
4.0 
12/18/2017 
Y 
1) Changes in recruitment pool and recruitment 
numbers 

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2) Add EKG to last PK visit 
3) Change to consent form regarding continuing 
care for ADHD after study completion 
5.0 
01/10/2018 
Y 
1) Changes to CRFs 
2) Tanner staging can be maxed out or does not 
need to be done if down in last 4 weeks 
3) Clarifications to P/A/C about physical exam, 
Tanner staging, pupillometry 
6.0 
07/05/2018 
Y – 
notification 
of DSQ  
1) Change inclusion/exclusion criteria to allow 
children who have taken other ADHD 
medications  
2) Addition of DSQ 
3) Distribute blood sample into 2 types of tubes 
for processing plasma and serum 
4) REDCap changes 
5) Allow physicians to titrate ATX slower 
6) Added SCARED questionnaire 
7.0 
11/12/2018 Y – reconsent 
at next 
available 
opportunity 
1) Allowance of a small snack to alleviate GI 
symptoms as needed during research visits 2-4 
2) Added side effects known to include GI upset, 
somnolence 
3) Add edited study booklet to accommodate 
participants recruited from the ADHD Clinic and 
the PCC (change in other docs) 
4) Addition of Sluggish Cognitive Tempo (SCT) 
scales 
5) A section for disposal of drug and situations 
when drug does not need to be returned to IDS 
Pharmacy  
6) Allowing omission of safety labs if prior safety 
labs were collected within the previous week  
8.0 
12/21/2018 
Y 
1) Adding Recruitment Flyer 
2) New washout period procedures 
3) Information on when a snack may be given 
9.0 
07/25/2019 
Y 
1) Modified inclusion/exclusion criteria 
2) Detailed pre-screening and recruitment 
methods 
3) Updated all CRFs and created checklists for 
each study visit 
4) Created CRFs for visits with study physicians 
5) Reformatted entire protocol to use new 
protocol template 
6) Creating of DSMP, DSMB, and CQMP 

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7) Clarified KSADS use 
8) Added 2-week follow-up after last study visit 
9) Added formal adherence and AE checks to 
study physician visits 
10) Added optional wean of study drug to avoid 
abrupt discontinuation 
11) Formalized templates for sharing research 
findings 
12) Changed subject reimbursement schedule 
13) Created CHADIS handouts, STP presentation, 
recruitment flyers, and washout handout 
Updated potential participant log and 
enrollment log 
10.0 
02/05/2020 Y – reconsent 
at next 
available 
opportunity 
1) Removed Jennifer Lowry from protocol. 
2) Added Wendy Wright to protocol. 
3) Added PCC ADHD Clinic on Broadway as a 
participant recruitment site. 
4) Modified Prescreening and Recruitment 
Methods to add PCC ADHD Clinic located on 
Broadway as a recruitment site. This is the 6th 
recruitment track. 
5) Clarified duration between Research Visit 2 and 
Research Visit 3. 
6) Updated Study Timeline for clarity and addition 
of a new 6th recruitment track. 
7) Updated Study Timeline to clarify timing of 
Study Physician Visits 
8) Added option for not repeating entire Intake 
Visit for participants referred to the research 
study by a Study Physician and if the participant 
had a clinical appointment with Study Physician 
within 6 weeks of enrollment. 
9) Clarified ADHD Care Following Conclusion of 
the Study and moved to section 11.5. 
10) Changed J-tip to “topical lidocaine,” to allow 
participants the option of requesting other 
topical lidocaine formulations. 
11) Expanded time frame to call families for 
adherence checks prior to Research Visit 3 and 
Research Visit 4. 
12) Updated Schedule of Events to be consistent 
with Study timeline. 
13) Described how to return genotyping results to 
families. Created letter to return research 

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genotyping results to participants and their 
families and explain the limitations of these 
research results. This is to be compliant with 
the following policy: Research Documentation 
in the Electronic Health Record, which was 
published on 9/26/2019 
14) Provided further details regarding genetic 
analysis, including future genetic analysis, and 
iGO-PK model refinement in protocol and 
permission/assent and consent forms. 
Additional formatting changes were included so 
that the permission/assent and consent forms 
are consistent with one another. 
15) Updated Study Setting to include ADHD Clinic 
on Broadway 
16) Updated Message Center Template to include 
provider at PCC ADHD Clinic as a Study 
Physician. 
17) Updated Study Coordinator/Research Assistant 
Recruitment Script for better comprehension 
and to better address participants recruited 
from different tracks. 
18) Updated permission/assent and consent forms 
for better clarity and comprehension. 
19) Updated permission/assent and consent forms 
to revise benefits of the study with regards to 
returning of genotyping information. 
20) Updated extra cost section in 
permission/assent and consent forms. 
21) Updated contact information on 
permission/assent and consent forms 
22) Revised formatting and wording of questions 
for contact about future research for better 
clarity on permission/assent and consent 
forms. 
23) Updated contact information and added ADHD 
Clinic on Broadway information in U54 Study 
Booklet. 
24) Modified Checklist for Research Visit 1 to 
include adding Certificate of Confidentiality for 
research. 
25) Checklists for Research Visit 2, Research Visit 3, 
and Research Visit 4 for both Study Design 1 
and Study Design 2 updated to include creation 

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of calendar invites, notes to describe if/when a 
study procedure does not need to be repeated, 
and ensuring accuracy of information on labels 
of biospecimens. 
26) Updated Research Visit 3 Study Design 1 and 
Study Design 2 checklists and Research Visit 4 – 
Study Design 1 and Study Design 2 checklists to 
reflect date range change for adherence checks 
27) Intake Visit CRF – updated to include “none” 
option for comorbidities 
28) Updated Research Visit 1 – Part 2 CRF to 
include Child Medical History. Correction made 
to respondents of Vanderbilt questionnaire. 
29) Updated page numbers on Serious Adverse 
Events CRF  
30) Updated Research Visit 4 – Study Design 1 and 
Study Design 2 CRFs to add EKG to procedures 
31) Research Visit 4 Adherence Check and Research 
Visit 3 Adherence Check CRFs updated to 
reflect changes in date range for adherence 
checks 
32) Updated Research Visit 1 – Part 1 CRF to add 
“N/A” option for creating CHADIS account and 
“N/A” for participant willingness to washout for 
those unable to provide assent. 
11.0 
3/19/2020 
N 
1) Removed Benjamin Black and Bridgette Jones 
from the protocol. 
2) Protocol modified to allow participants to take 
medication with a small amount of soft food to 
aid with capsule swallowing. 
3) Updated Date When Version 10.0 was 
approved in Revision History Table. 
4) Updated “topical lidocaine,” to specify that this 
refers to both J-tip and cream formulations.  
5) Updated protocol to allow topical lidocaine to 
be administered at either Research Visit 1 Part 
1 or Research Visit 1 Part 2 for venipuncture 
procedures. 
6) Updated permission/assent form with regards 
to Future Research section. This section now 
includes a yes/no box for data to be submitted 
to national database. 

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7) Uploaded most applicable version of NICHQ 
Vanderbilt Assessment questionnaires being 
used in the study (Version 2).  
8) Changed “Vanderbilt ADHD Rating Scales,” to 
official name, “NICHQ Vanderbilt Assessment 
Scales.” 
9) Uploaded NICHQ Vanderbilt Assessment Scales, 
both initial and follow-up, for parent and 
teacher informant. 
10) Uploaded School Intervention Questionnaire on 
myIRB. 
11) Updated CYP2D6 genotype-to-phenotype 
interpretation based on new Clinical 
Pharmacogenetic Implementation Consortium 
Guidelines (CPIC). 
12) Updated CYP2D6 Study Design Assignment 
based on new CPIC guidelines and data 
generated from participants who have 
completed ATX pharmacokinetic studies in Ped 
Develop Pharm U54 Study (IRB# 16010069) and 
this study. 
12.0 
3/26/2020 
N 
1) COVID-19 Addendum to Approved Study 
Protocol. This addendum was enacted as a part 
of the Children’s Mercy Hospital response to 
the global COVID-19 pandemic. 
2) Briefly, the addendum made the following 
changes to follow social distancing guidelines: 
a. Contacting all active participants and 
their families to alert them to upcoming 
changes and to ascertain interest in 
continuing the study. 
b. Prescreening, recruitment, and new 
enrollment in this study was paused. 
c. Participants who have not started on 
pharmacological intervention were 
advised to continue with their current 
ADHD therapy (if applicable) until it has 
been determined to be safe enough to 
progress with the remainder of the 
study. 
d. For participants who have started on 
pharmacological intervention (i.e. 
participants who have completed 
Research Visit 2 at a minimum), study 

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procedures were modified to allow 
social distancing. 
i. Full PK research visits are to be 
delayed or cancelled, based on 
the timing of the visit and the 
status of the pandemic. 
Research visits in full are only to 
be conducted if Children’s Mercy 
Hospital and Children’s Mercy 
Resesarch Institute have 
determined the COVID-19 
situtation has improved such 
that these visits may occur. 
Modified research visits are to 
occur in lieu in certain scenarios, 
and the procedures for these 
modified visits are limited to 
those which may be conducted 
remotely. 
ii. Study physician visits are to 
proceed according to schedule 
to provide continuity of ADHD 
care for study participants. 
However, the majority of these 
visits were conducted via 
telehealth. Study physicians are 
able to request in-person visits 
on a case-by-case basis. For 
telehealth visits, a physical exam 
and collection of vitals were not 
required to be collected. 
iii. Compensation was adjusted for 
participants completing modified 
research procedures. 
13.0 
7/6/2020 
N 
1) Modification to COVID-19 Addendum to 
Approved Study Protocol. This modification is 
part of Children’s Mercy Hospital plan to restart 
research during the global COVID-19 pandemic. 
2) In-person Study Physician visits are allowed at 
the discretion of the Study Physician and do not 
need to be deemed, “clinically necessary” for 
these to be scheduled. 
3) Research Visit 3 and Research Visit 4 may now 
occur at the PCRU. Participants will be asked 

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prior to scheduling Research Visit 3 and 
Research Visit 4 if the participant and/or 
parent/LAR would like to conduct these in 
person or cancel (pertains to Research Visit 3) 
or have a modified visit (pertains to Research 
Visit 4). 
4) Addition of COVID-19 symptom screening for 
in-person Research Visit 3. Updated 
“Adherence Check” CRF to “Research Visit 3 
(RV3) Screen” CRF which included adherence 
and COVID-19 Symptom Screen. 
5) Addition of COVID-19 symptom screening for 
in-person Research Visit 4. Updated 
“Adherence Check” CRF to “Research Visit 4 
(RV4) Screen” CRF which included adherence 
and COVID-19 Symptom Screen. 
6) An updated letter titled, “Temporary Study 
Changes in Response to COVID-19 Pandemic – 
Updated,” has been written to describe the 
changes to participants and families. 
7) Updated Research Visit 3 and Research Visit 4 
checklists to include COVID-19 symptom 
screening. 
8) Added “direct hand-off” as a method of 
transferring medication and study materials 
between the parent/LAR and study personnel. 
9) These changes will only be applicable to active 
participants who are currently taking 
atomoxetine (U54-035, U54-037, and U54-038). 
14.0 
9/8/2020 
Y 
1) Personnel changes: 
a. Added Jamie Neal-Lewis, RN, APRN, 
CPNP, CPN, to the protocol in the role of 
Study Physician. 
b. Removed Wendy Wright, MSN, RN and 
Madeline DeShazer, BS from the 
protocol. 
2) Permission/assent and consent forms changes:  
a. Added certificate of confidentiality 
language 
b. Modified injury language per IRB 
template 
c. Change in window for Research Visit 3 
d. Removed PCC ADHD Clinic as a site for 
Study Physician Visits. 

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e. Included option for telehealth Study 
Physician Visits. 
3) Protocol changes: 
a. Removed Track 6 for recruitment and 
the PCC ADHD Clinic on Broadway as a 
study site.  
b. Updated the Study 
Coordinator/Research Assistant 
Recruitment and Scheduling Scripts to 
remove Track 6. 
c. Inclusion/Exclusion criteria: 
i. Updated inclusion criteria to 
include “inferred” ADHD 
diagnosis. This is to account for 
the fact that obtaining typical 
diagnostic data for ADHD may 
not be feasible during the 
COVID-19 pandemic. 
ii. Updated exclusion criteria to 
include evidence of intellectual 
disability from review of EMR. 
d. Expanded window for Research Visit 3 
to make scheduling flexible. The 
timeframe for Research Visit 3 can now 
be scheduled anytime after the 
participant has been taking medication 
regularly for 2 weeks and up until the 
18-Week Visit with Study Physician. 
e. Amended Study Physician visits to occur 
in person or through telehealth. The 
type of visit will be at the Study 
Physician’s discretion. 
f. Updated Schedule of Events Table to 
reflect changes to RV3 and Study 
Physician visits. 
g. Drug handling and study drug timeline 
changed in to be compliant with IDS 
delivery policies developed to address 
specific scenarios, such as with the 
COVID-19 response.  
h. Methods of drug handling and the study 
drug timeline have been amended to 
include practices to reduce foot-traffic 
at CMH. 

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i. Pharmacy Policies cited updated to 
include latest revision date – Section 
5.2, pg. 34. 
j. CYP2D6 Phenotype, Activity Score, and 
example diplotype table headings 
updated. 
k. Updated Procedures to Reduce Risk 
section to include COVID-19 precautions 
and Certificate of Confidentiality 
changes in the permission/assent and 
consent forms. 
l. Removed “Appendix P,” “18-week Visit 
with Study Physician – Research 4 Delay 
Approval,” and the COVID-19 addendum 
because these documents were all 
associated with the COVID-19 response. 
These documents no longer needed 
with Version 14 of the protocol because 
this protocol has been updated to 
include COVID-19 precautions. 
Therefore, these document were 
removed from Smartform. These 
documents were never included in full 
version of the protocol because they 
were part of the COVID-19 addendum. 
4) Study Booklet Changes:  
a. New study timeline figure 
b. Removed PCC ADHD Clinic as Study 
Physician site. 
5) Updated checklists to include COVID-19 
instructions prior to research visits and 
changed “Madeline” to “RA/clinical 
psychologist,” where applicable: 
a. RV1 Part 1 and 2 Checklist No Washout 
Required (3.0) 
i. Changed “Madeline” to 
“RA/clinical psychologist” 
ii. Changed “Remind family to bring 
participant’s SSN” to “Call family 
1-2 days before and remind 
them of appointment time, to 
bring participant’s SSN, and go 
over COVID-19 instructions.” 

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b. RV1 Part 1 Checklist Washout Required 
(3.0) 
i. Changed “Remind family to bring 
participant’s SSN” to “Call family 
1-2 days before and remind 
them of appointment time, to 
bring participant’s SSN, and go 
over COVID-19 instructions.” 
c. RV1 Part 2 Checklist Washout Required 
(3.0) 
i. Changed “Madeline” to 
“RA/clinical psychologist” 
ii. Added “Call family 1-2 days 
before and remind them of 
appointment time and go over 
COVID-19 instructions.” 
d. RV2 – Study Design 1 Checklist (3.0) 
i. Changed “Call family 1-2 days 
before and remind to arrive at 
0700, fast after midnight, water 
is okay, bring study booklet” to 
“Call family 1-2 days before and 
remind to remind them of 
appointment time, go over 
COVID-19 instructions, fast after 
midnight (water is okay), and 
bring the study booklet.” 
e. RV2 – Study Design 2 Checklist (3.0) 
i. Changed “Call family 1-2 days 
before and remind to arrive at 
0700, fast after midnight, water 
is okay, bring study booklet” to 
“Call family 1-2 days before and 
remind to remind them of 
appointment time, go over 
COVID-19 instructions, fast after 
midnight (water is okay), and 
bring the study booklet.” 
f. RV3 – Study Design 1 Checklist (4.0) 
i. Changed, “Call patient 1-2 days 
prior to visit to check adherence, 
COVID-19 symptom screen, 
remind to bring study med and 
calendar, and fast after 

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midnight” to “Call patient 1-2 
days prior to visit to check 
adherence, go over COVID-19 
instructions, remind to bring 
study med and calendar, and 
fast after midnight” 
ii. Removed the “Log CMH COVID-
19 symptom screen for 
participant and family 
member(s) activity. 
g. RV3 – Study Design 2 Checklist (4.0) 
i. Changed, “Call patient 1-2 days 
prior to visit to check adherence, 
COVID-19 symptom screen, 
remind to bring study med and 
calendar, and fast after 
midnight” to “Call patient 1-2 
days prior to visit to check 
adherence, go over COVID-19 
instructions, remind to bring 
study med and calendar, and 
fast after midnight” 
ii. Removed the “Log CMH COVID-
19 symptom screen for 
participant and family 
member(s) activity. 
h. RV4 – Study Design 1 Checklist (4.0) 
i. Changed, “Call patient 1-2 days 
prior to visit to check adherence, 
COVID-19 symptom screen, 
remind to bring study med and 
calendar, and fast after 
midnight” to “Call patient 1-2 
days prior to visit to check 
adherence, go over COVID-19 
instructions, remind to bring 
study med and calendar, and 
fast after midnight” 
ii. Removed the “Log CMH COVID-
19 symptom screen for 
participant and family 
member(s) activity. 
i. RV4 – Study Design 2 Checklist (4.0) 

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i. Changed, “Call patient 1-2 days 
prior to visit to check adherence, 
COVID-19 symptom screen, 
remind to bring study med and 
calendar, and fast after 
midnight” to “Call patient 1-2 
days prior to visit to check 
adherence, go over COVID-19 
instructions, remind to bring 
study med and calendar, and 
fast after midnight” 
ii. Removed the “Log CMH COVID-
19 symptom screen for 
participant and family 
member(s) activity. 
6) Updated Research Visit 3 and 4 “Screens” to 
“Adherence Check”: 
a. RV3 – Adherence Check (6.0) 
i. Removed COVID-19 Symptom 
Phone Screen with 
parent/LAR/guardian section. 
ii. Removed Children’s Mercy 
Hospital COVID-19 Symptom 
Screen with participant, 
parent/LAR/guardian, and 
accompanying family members 
section. 
iii. Changed name of CRF from 
“Screen” to Adherence Check 
b. RV4 – Adherence Check (6.0) 
i. Removed COVID-19 Symptom 
Phone Screen with 
parent/LAR/guardian section. 
ii. Removed Children’s Mercy 
Hospital COVID-19 Symptom 
Screen with participant, 
parent/LAR/guardian, and 
accompanying family members 
section. 
iii. Changed name of CRF from 
“Screen” to Adherence Check 
7) Updated Study Physician checklists: 
a. Intake Visit – Checklist (2.0) 

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i. Changed “Ensure baseline 
CHADIS questionnaires are all 
completed” to “Ensure baseline 
CHADIS questionnaires have 
been sent out” 
ii. Changed “Collect physical exam 
data” to “Collect physical exam 
data if visit conducted in person. 
These measures are omitted for 
telehealth visits.” 
b. 6-week Study Physician Visit Checklist 
(2.0) 
i. Changed “Ensure baseline 
CHADIS questionnaires are all 
completed” to “Ensure baseline 
CHADIS questionnaires have 
been sent out” 
ii. Changed “Collect physical exam 
data” to “Collect physical exam 
data if visit conducted in person. 
These measures are omitted for 
telehealth visits.” 
iii. Added, “If needed, ask 
participant’s parents/LAR to 
send pictures of adherence 
calendar and remaining pills. 
Conduct pill count/adherence 
check.” 
c. 12-week Study Physician Visit Checklist 
(2.0) 
i. Changed “Ensure baseline 
CHADIS questionnaires are all 
completed” to “Ensure baseline 
CHADIS questionnaires have 
been sent out” 
ii. Changed “Collect physical exam 
data” to “Collect physical exam 
data if visit conducted in person. 
These measures are omitted for 
telehealth visits.” 
iii. Added, “If needed, ask 
participant’s parents/LAR to 
send pictures of adherence 
calendar and remaining pills. 

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Conduct pill count/adherence 
check.” 
d. 18-week Study Physician Visit Checklist 
(2.0) 
i. Changed “Ensure baseline 
CHADIS questionnaires are all 
completed” to “Ensure baseline 
CHADIS questionnaires have 
been sent out” 
ii. Changed “Collect physical exam 
data” to “Collect physical exam 
data if visit conducted in person. 
These measures are omitted for 
telehealth visits.” 
iii. Added, “If needed, ask 
participant’s parents/LAR to 
send pictures of adherence 
calendar and remaining pills. 
Conduct pill count/adherence 
check.” 
8) Updated Study Physician Visits CRFs to 
document telehealth visits and omit physical 
exam findings when these visits are telehealth. 
a. Intake Visit – CRF (3.0) 
i. Updated “Physical Exam Finding” 
section to include the following 
instructions: “Check box below if 
this is a telehealth visit. Physical 
exam findings are omitted for 
telehealth visits.” 
ii. Included a checkbox to indicate 
whether the visit was a 
telehealth visit. 
b. 6-week Study Physician Visit CRF (2.0) 
i. Updated “Physical Exam Finding” 
section to include the following 
instructions: “Check box below if 
this is a telehealth visit. Physical 
exam findings are omitted for 
telehealth visits.” 
ii. Included a checkbox to indicate 
whether the visit was a 
telehealth visit. 
c. 12-week Study Physician Visit CRF (2.0) 

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i. Updated “Physical Exam Finding” 
section to include the following 
instructions: “Check box below if 
this is a telehealth visit. Physical 
exam findings are omitted for 
telehealth visits.” 
ii. Included a checkbox to indicate 
whether the visit was a 
telehealth visit. 
d. 18-week Study Physician Visit CRF (2.0) 
i. Updated “Physical Exam Finding” 
section to include the following 
instructions: “Check box below if 
this is a telehealth visit. Physical 
exam findings are omitted for 
telehealth visits.” 
ii. Included a checkbox to indicate 
whether the visit was a 
telehealth visit. 
 
15.0 
03/16/2021 Y – reconsent 
at next 
available 
opportunity 
1) Personnel Changes (MOD00006449, approved 
12/28/2020): 
a. Added Sarah Beals-Erickson, Simone 
Moody, and Lynne Ray 
b. Removed Carla Allan 
2) Follow-up personnel changes: 
a. Removal of Sarah Beals-Erickson 
3) Changes to permission/assent and consent 
form: 
a. Update Krista Ladue-Wright’s phone 
number 
b. Update IRB’s phone number 
c. Update language on shipping 
medication to participants 
4) Changes to recruitment: 
a. Allow for advertising of study on CMH 
internal website and on CMRI public 
facing website. 
5) Update to shipping medications: 
a. Changed shipping protocol to reflect IDS 
Pharmacy’s primary role in shipping 
medications. 

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6) Updated KSADS questionnaire format to 
include use of KSADS-COMP, a computerized 
version of the KSADS questionnaire. 
16.0 
3/17/21 
Yes – 
Reconsent 
not needed; 
verbally 
notify 
currently 
enrolled 
participants 
at next study 
visit 
1. Personnel change – Jennifer Wagner, MD 
replacing Jean Dinh, PharmD, PhD as PI 
(primary contact); add James Steven Leeder 
to myIRB.  
2. Changes to P/A/C forms and recruitment 
flyer to reflect change in PI. 
3. Changes to CRFs to provide instruction 
clarity for study team members on 
completion of study procedures 
a. Adverse Events CRF, RV3 CRF (Study 
Designs 1 and 2), 6-Week, 12-Week, 
and 18-Week Visit with Study 
Physician CRFs, and RV4 CRF (Study 
Designs 1 and 2) 
17.0 
10/7/2021 
Y – This has 
been 
completed 
1) Intervention assignment to include Study 
Design 3 
2) Visit length by study design table (Figure 5) 
updated 
3) Research Visit 3 and 4 to describe possible 
switch to Study Design 3 
4) RV3 and RV4 confirmation of study design 
5) RV3 and RV4 addition of Study Design 3 dosing 
and collection time points 
6) RV3 and RV4 addition of Study design 3 urine 
collection instructions 
7) RV3 and RV4 addition of Study Design 3 sweat 
patch collection instructions 
8) RV3 and RV4 clarification on fasting for Study 
Design 3 
9) Procedures to reduce risk updated to include 
blood collection estimates and mitigation 
strategies for Study Design 3 
10) Payments addition of clarification for hours in 
the table 
11) Payments addition to maximum compensation 
for participants in Study Design 3 
12) Clarified number of doses needed from IDS 
pharmacy since option of Study Design 3 
13) Changes to P/A/C forms to reflect addition of 
Study Design 3 

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14) Changes to CRFs including checklists and data 
collection sheets for Study Design 3 
15) Changes to CRFs to include documentation of 
time of prior day before research visits 
16) Changes to Research visit Checklist forms to 
include securing participant binders and 
samples following the study 
17) Personnel Changes: Added Rachael Robertson 
to study 
 
18.0 
TBD 
No – Will 
verbally tell 
particpants at 
next 
Research 
Visit, but 
protocol 
change 
potentially 
confers less 
risk to the 
particpant 
1) Tanner staging changed to optional procedure 
per participant preference 
2) P/A/C forms updated to reflect that Tanner 
staging is now an optional procedure 
3) Personnel Changes: Remove Tamorah Lewis 
and Susan Abdel-Rahman from study 
4) P/A/C and protocol updated to remove 
verbiage listing Susan Abdel-Rahman as a PI. 
19 
TBD 
Yes 
1. Remove Jennifer Wagner from PIs. 
 
Table of Contents 
1.0 
Study Summary ......................................................................................................... 21 
2.0 Objectives ...................................................................................................................... 23 
2.1   Primary Objectives(s): ....................................................................................................... 23 
2.2   Hypotheses to be Tested: ................................................................................................. 23 
3.0 Background ................................................................................................................... 24 
3.1 Atomoxetine Background and Gaps in Knowledge ............................................................ 24 
3.2 Relevant Preliminary Data .................................................................................................. 25 
3.3 Study Significance ............................................................................................................... 26 
4.0 Study Endpoints and Rationale....................................................................................... 27 
4.1 Primary Study Endpoints ..................................................................................................... 27 
4.2 Primary Safety Endpoints .................................................................................................... 32 
5.0 Study Intervention/Investigational Agent ....................................................................... 33 
5.1  Description ......................................................................................................................... 33 
5.2  Drug Handling .................................................................................................................... 35 
6.0 
Inclusion and Exclusion Criteria ................................................................................. 36 
6.1  Inclusion Criteria ................................................................................................................ 36 

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6.2  Special Populations ............................................................................................................ 37 
7.0 
Vulnerable Populations ............................................................................................. 37 
7.1 Additional Safeguards ......................................................................................................... 38 
8.0 
Local Number of Subjects .......................................................................................... 38 
8.1 
Multiple Cohorts ............................................................................................................ 38 
8.2 
Target Participants ......................................................................................................... 38 
9.0 
Prescreening and Recruitment Methods .................................................................... 39 
9.1 Recruitment Overview ........................................................................................................ 39 
9.2 Chart Review ....................................................................................................................... 40 
9.3 Participant Notification of Study Opportunity .................................................................... 40 
9.4 PHI Documentation ............................................................................................................. 44 
10.0 Study Timelines ........................................................................................................... 45 
10.1   Study Duration ................................................................................................................ 45 
11.0 Procedures Involved .................................................................................................... 45 
11.1 Study Design Overview ..................................................................................................... 45 
11.2 
Description of Research Procedures .......................................................................... 50 
11.3 Procedures to Reduce Risks .............................................................................................. 83 
11.4  Source Records Used ....................................................................................................... 85 
11.5 Continuing Care ................................................................................................................ 87 
11.6 IBC ..................................................................................................................................... 87 
12.0 Data and Sample Banking ............................................................................................. 87 
13.0 Genetic Analysis Information ....................................................................................... 89 
14.0 Sharing of Results with Subjects ................................................................................... 90 
15.0 Reimbursement, Payment and Tangible Property provided to subjects ......................... 91 
15.1 Payments........................................................................................................................... 91 
16.0 Withdrawal of Subjects ................................................................................................ 92 
16.1 Anticipated circumstances in which subjects will be withdrawn from the research study
................................................................................................................................................... 92 
16.2 Procedures for orderly termination/subject withdrawal ................................................. 92 
17.0 Risks to Subjects .......................................................................................................... 93 
18.0 Potential Benefits to Subjects ....................................................................................... 94 
19.0 Investigator Assessment of Risk/Benefits Ratio ............................................................ 95 
20.0 Data Management ....................................................................................................... 96 
20.1 Data Analysis Plan ............................................................................................................. 96 
20.2 Sample Size Determination ............................................................................................. 103 
20.3 Confidentiality ................................................................................................................. 104 
20.4 Certificate of Confidentiality ........................................................................................... 104 

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20.5 Quality Control and Assurance ....................................................................................... 104 
20.6 Data and Sample Handling .............................................................................................. 104 
21.0  Provisions to Monitor the Data to Ensure the Safety of Subjects ................................ 105 
21.1 Data Safety Monitoring Board ........................................................................................ 105 
22.0  Provisions to Protect the Privacy Interests of Subjects ............................................... 106 
22.1 Privacy Interest ............................................................................................................... 106 
22.2 At Ease............................................................................................................................. 106 
22.3 Permission to Access Data .............................................................................................. 106 
22.4 PHI to be Accessed .......................................................................................................... 106 
22.5 HIPAA Authorization ....................................................................................................... 107 
23.0 Compensation for Research-Related Injury ................................................................. 107 
24.0 Economic Burden to Subjects ..................................................................................... 107 
25.0 Permission/Assent/Consent Process .......................................................................... 107 
26.0 Documentation of Permission/Assent/Consent .......................................................... 109 
27.0 Setting ....................................................................................................................... 109 
28.0 Resources Available ................................................................................................... 109 
29.0 Multi-Site Research .................................................................................................... 111 
30.0 International Research ............................................................................................... 111 
31.0 Appendices ................................................................................................................ 111 
Appendix A – ATX PBPK Model Validation Summary ............................................................. 112 
Appendix B – Message Center Template ................................................................................ 113 
Appendix C – ADHD Clinic RN ................................................................................................. 114 
Appendix D – Study Coordinator/Research Assistant Recruitment Script ............................. 115 
Appendix E – Recruitment Email or Letter ............................................................................. 118 
Appendix F – Study Coordinator/Research Assistant Scheduling Script ................................ 119 
Appendix G – U54 Study Booklet Questionnaire (please see PDF attachment for Study 
Booklet) ................................................................................................................................... 121 
Appendix H – Example of pupillometry and eye-tracking tasks ............................................. 122 
Appendix I – Example of neurotransmitters in metabolomics panel ..................................... 124 
Appendix J – Study Drug Timeline, a description of drug handling during the ATX PBPK-PD 
Clinical Outcomes Study ......................................................................................................... 125 
Appendix K – Sample Letter to Release Data and/or Specimens by PI .................................. 130 
Appendix L – Sample letters to Share Genetic Information ................................................... 131 
Appendix M – Sample letters to Release ADHD Results or Incidental Findings to Participants 
of this Study ............................................................................................................................ 136 
Appendix N – Sample letters for End of Study ADHD Care Transition ................................... 137 

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Appendix O – Literature Search and Documentation for Washout and Return to Baseline . 138 
32.0 List of Supplementary Documents .............................................................................. 140 
33.0 References ................................................................................................................. 140 
 
 
1.0 Study Summary 
 
Study Title 
An Open-Label, Single- and Multi-Dose Study to Evaluate 
the Relationship between the Pharmacokinetics, 
Pharmacodynamics, and Clinical Outcomes of Atomoxetine 
in CYP2D6 Extensive, Intermediate, and Poor Metabolizers 
in Children with Attention Deficit/Hyperactivity Disorder 
Study Design 
This is a non-randomized, un-blinded, exposure escalation 
efficacy trial of the effects of atomoxetine in children with 
attention deficit/hyperactivity disorder (ADHD). 
Primary Objective 
1. To investigate the effect of genetic variability on the 
pharmacodynamics of ATX by evaluating biomarkers of 
inhibition of the drug target, the norepinephrine re-
uptake transporter, following ATX exposure control. 
2. To explore how changes in pharmacodynamic markers 
correspond to clinical response to medication. 
Secondary Objective(s) 
1. To establish the relationship between ATX systemic 
exposure, inhibition of the norepinephrine uptake 
transporter, and therapeutic response 
2. To determine global baseline patient characteristics 
differences between ATX responders and non-
responders. 
3. To explore how baseline oral microbiome make-up 
influences clinical outcomes and to describe changes in 
the oral microbiome with ATX therapy. 
4. To refine the iGO-PK ATX dosing algorithm. 
5. To evaluate comprehension of the study procedures by 
study participants and their families when an illustrated 
study booklet is supplied with a consent form. 
6. To validate a urinary CYP2D6 phenotype biomarker.         
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
Atomoxetine – a norepinephrine reuptake transporter 
inhibitor which is FDA approved for the treatment of ADHD 
in children. 
iGO-PK dosing algorithm – a dosing algorithm to normalize 
atomoxetine exposure regardless of CYP2D6 genotype. 

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IND/IDE #  
NA 
Study Population 
Children, both males and females between the ages of 6-18 
with ADHD or a high likelihood of having ADHD, electing to 
receive care at Children’s Mercy Hospital and Clinics and 
children enrolling in the CMH&C ADHD Summer Treatment 
Program (STP). 
Sample Size 
Target enrollment of 160 research participants, in 
anticipation of 120 participants completing the research 
study. 
Study Duration for 
Individual Participants 
6-8 months 
Study Specific 
Abbreviations/ 
Definitions  
1. ADHD = attention deficit/hyperactivity disorder 
2. ATX = atomoxetine 
3. DHPG = dihydroxylphenol glycol 
4. iGO-PK = individualized genetic and ontogeny 
pharmacokinetic prediction 
5. PK = pharmacokinetic 
6. PD = pharmacodynamic 
7. Research Visit 1 = RV1 
8. Research Visit 2 = RV2, or may referred to as 
pharmacokinetic study 1 (PK1), or first dose PK 
9. Research Visit 3 = RV3, or may referred to as 
pharmacokinetic study 2 (PK2), or steady state PK 
10. Research Visit 4 = RV4, or may be referred to as 
pharmacokinetic study 3 (PK3), or end of study PK 

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2.0 Objectives  
2.1   Primary Objectives(s): 
 
• To investigate the effect of genetic variability on the pharmacodynamics of ATX 
by evaluating biomarkers of inhibition of the drug target, the norepinephrine re-
uptake transporter, following ATX exposure control. 
• To explore how changes in pharmacodynamic markers correspond to clinical 
response to medication. 
 
Secondary Objective(s): 
• To establish the relationship between ATX systemic exposure, inhibition of the 
norepinephrine uptake transporter, and therapeutic response 
• To determine global baseline patient characteristics differences between ATX 
responders and non-responders. 
• To explore how baseline oral microbiome make-up influences clinical outcomes 
and to describe changes in the oral microbiome with ATX therapy. 
• To refine the iGO-PK ATX dosing algorithm. 
• To evaluate comprehension of the study procedures by study participants and 
their families when an illustrated study booklet is supplied with a consent form 
(please see Supplementary Documents, “U54 Study Booklet” and “U54 Study 
Booklet Information Handout”). 
• To validate a urinary CYP2D6 phenotype biomarker. 
 
2.2   Hypotheses to be Tested: 
• Hypothesis 1: Genetic variability in the SLC6A2 gene is associated with 
variability in 1) concentration-time curves of DHPG and 2) pupil size 
changes, when evaluating tonic and phasic data. 
• Hypothesis 2: Variability in pharmacodynamics markers, i.e. plasma DHPG 
and pupil size changes, are associated with clinical response to 
atomoxetine. 
• Hypothesis 3: The atomoxetine response cohorts (i.e. response versus 
non-response and tolerant versus non-tolerant) will have differing global 
baseline characteristics, such as age, gender, ethnicity, ADHD subtype, 
genetic polymorphisms, etc. 

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3.0 Background 
3.1 Atomoxetine Background and Gaps in Knowledge 
Atomoxetine (ATX), Strattera®, is a norepinephrine re-uptake transporter inhibitor that 
is approved by the Food and Drug Administration (FDA) for the treatment of attention 
deficit/hyperactivity disorder (ADHD) (Seneca et al., 2006; Michelson et al., 2007). The 
drug is often considered a second- or third-line agent, due to the perception that the 
drug does not work very well.  In fact, in a review of studies submitted to the FDA, 
Newcorn et al reported that there appeared to be discrete classes of response to 
atomoxetine. After 6-9 weeks of treatment, 47% of the patients were considered 
“responders” based on changes in the rating scales used to measure ADHD symptoms 
whereas 40% of patients were considered non-responders (Newcorn et al., 2009).  
Statistically significant (p<0.001) differences in scores between responders and non-
responders were apparent after the first week of treatment (Fig. 1).   
 
At the relatively low starting doses of the titration scheme, this suggests that there may 
be a subgroup of patents who are particularly responsive to ATX.  We hypothesize that 
there could be two reasons for this: 1) variability in drug pharmacokinetics (i.e., 
inadequate drug concentrations in the blood over time could lead to poor response) and 
2) variability in drug pharmacodynamics (i.e. differences at the level of the target of 
drug action that limit the response to a drug, regardless of concentration of drug 
present in the blood). The interplay of pharmacokinetics and pharmacodynamics is 
presented in Figure 2 below:    

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Fig 2. Interplay of Pharmacokinetic and Pharmacodynamics 
The CYP2D6 gene, which encodes for the drug metabolizing enzyme CYP2D6 responsible 
for the clearance of ATX from the body, is highly polymorphic (Gaedigk et al., 2007; 
Gaedigk et al., 2010; Gaedigk et al., 2010; Gaedigk, 2013). ATX metabolism by CYP2D6 
protein is one of the major routes of clearance (i.e., removal) of this drug. Genetic 
variability in the CYP2D6 gene leads to wide inter-individual variability in the activity of 
the enzyme, ultimately resulting in differing amount of drug in the body (also referred to 
as “exposure,” and is a component of drug pharmacokinetics). Secondly, the SLC6A2 
gene which encodes for the norepinephrine reuptake transporter, the drug target for 
ATX, is also subject to genetic variation. Reported genetic variants of SLC6A2 have been 
associated with decreased abundance of the transporter (Kim et al., 2006). The 
consequences of SLC6A2 genetic variation with regards to ATX clinical response are 
currently unknown.  In the context of distinct “responder” and “non-responder” groups 
with a population of atomoxetine-treated patients, non-response could be due to 
definable differences at the level of the drug target (patients unlikely to respond 
regardless of the ATX concentrations achieved), or simply a consequence of inadequate 
exposure in a substantial proportion of population.  The goal of this study is to address 
this issue.  
 
3.2 Relevant Preliminary Data 
In a previous single-dose ATX pharmacokinetic study conducted at the Children’s 
Mercy Hospital, we investigated the impact of CYP2D6 genetic variability on drug 
pharmacokinetics as an initial step in better understanding the poor clinical 
response to the drug (Brown et al., 2016). The results from the single-dose ATX 
study found that ATX exposures varied greatly between children (30-50 fold) 
when administered the same weight-adjusted dose (0.5 mg/kg) with the highest 
concentrations/exposure in participants deficient in CYP2D6 activity (so-called 

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“poor metabolizers”) and the lowest exposure in participants who had two or 
more functional copies of the gene, and the highest CYP2D6 activity.  
Furthermore, simulations conducted to investigate the concentrations 
(exposure) achieved with chronic dosing indicated that a majority of patients 
with at least one functional copy of the CYP2D6 gene were unlikely to achieve 
the level of exposure associated with clinical response.   
A more important implication of these data is that it is impossible to investigate 
the effect of differences at the level of the drug target on variability in drug 
response unless we are able to minimize the variability in drug response that is a 
consequence of the normal variability in exposure when the same dose (0.5 
mg/kg) is given to patients who differ in their ability to eliminate the drug.  In 
other words, we need to develop models and systems by which we can 
individualize the dose of ATX so that every person has the same exposure. The 
data collected from this single-dose pharmacokinetic study were subsequently 
used to build a dosing algorithm to determine a dose that would lead to a 
desired exposure, defined initially as the peak concentration achieved (Cmax) with 
a priori knowledge of a child’s CYP2D6 genetic information, which can be used to 
predict activity, in addition to other patient characteristics such as weight and 
obesity status. The process for validation of this model, termed the 
individualized Genetic and Ontogenic Pharmacokinetics algorithm (iGO-PK), is 
described in the ATX PBPK Model Validation Study (Appendix A). The major 
strength of this dosing strategy is that it allows us to ensure that drug exposures 
do not greatly differ in children, and therefore allows us to describe 
quantitatively how genetic variability at the drug target alone affects ATX 
pharmacodynamics and clinical outcomes. 
 
3.3 Study Significance 
Prior studies evaluating variability in drug response are confounded by the highly 
variable ATX exposures between children, even when given the same weight-based 
dose, and hence are difficult to interpret (e.g., is a patient truly non-responsive to the 
medication, or is “non-response” simply due to having inadequate concentrations of the 
medication in the body).  In this investigation we propose to individualize ATX dosing in 
a cohort of children with ADHD to a standardized exposure goal (based on the maximum 
concentration achieved, or Cmax), initially using a iGO-PK model derived from our original 
genotype-stratified PK study, and assign responder or non-responder status according 
to response criteria established a priori by the clinical members of the study team.  
Subsequent analyses will investigate predictors of response (metabolomics analysis of 
pretreatment plasma samples; assessment of biomarkers of ATX inhibition of SLC6A2, 
such as dihydroxyphenylglycol (DHPG) concentrations and pupil diameter and eye-
tracking studies; SLC6A2 genotype; pharmacokinetic-pharmacodynamic (PK/PD) analysis 
of ATX and DHPG data, etc), as well as differences in exposure→response relationships 
for different DHPG strata or SLC6A2 genotypes.  In addition, the dosing algorithms (iGO-

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PK) will be updated and revised as the body of pharmacokinetic data increases through 
the duration of the study. 
4.0 Study Endpoints and Rationale 
 
4.1 Primary Study Endpoints 
 
The primary aims of this study focus on characterizing the relationship between changes 
in pharmacodynamic markers and clinical outcome measures, when inter-subject 
variability in ATX pharmacokinetics has been minimized (Fig. 3). ATX pharmacodynamics 
will be measured using plasma DHPG and metabolomic data, pupillometry during 
attention tasks, and changes in blood pressure and heart rate . Clinical outcomes will be 
assessed by standardized ADHD measures used in a clinical setting, of which include: 
NICHQ Vanderbilt Assessment Scale (ADHD symptom rating scale); Strengths and 
Difficulties Questionnaire; Child Behavior Checklist; the School Intervention 
Questionnaire; Medication Side Effects; and Clinical Global Impression. Some of these 
questionnaires will also capture comorbidity information, such as Oppositional Defiant 
Disorder (ODD). We will also use the Kiddie Schedule for Affective Disorders and 
Schizophrenia for School-Age Children – Present and Lifetime Version (K-SADS-PL) or K-
SADS-COMP (the computerized version of the K-SADS-PL) to diagnose ADHD and 
commonly associated comorbidities. The K-SADS-PL is a semi-structured interview that 
is extensively used in clinical psychology research to diagnose an extensive array of 
psychopathology based on the DSM-5. Given the length of this interview, common 
research practices are to select only the modules that are expected to be pertinent to 
the study participant (Black et al., 2012; Kariuki et al., 2018; Caudle et al., 2020). The K-
SADS-PL modules selected for this research study are as follows: agoraphobia, 
separation anxiety disorder, social anxiety disorder/selective mutism, specific phobias, 
generalized anxiety, obsessive compulsive disorder, and post-traumatic stress disorder.  
The other research comorbidities or impairments that we will assess for and associated 
psychometric tests we will use are as follows: impairment in executive function using 
the Behavior Rating Inventory of Executive Function (BRIEF); anxiety using the Screen for 
Child Anxiety and Related Disorders (SCARED); intelligence quotient using the Kaufman 
Brief IQ Test (KBIT); and sluggish cognitive tempo using the Barkley Sluggish Cognitive 
Tempo Scale (SCT). Pharmacodynamic data will be obtained: baseline (Research Visit 1); 
when ATX is first initiated in a participant with the first dose (Research Visit 2); when the 
participant has taken the medication chronically and thus, expected to be at steady-
state (Research Visit 3); and at the end of study when the dose has been optimized for 
the participant (Research Visit 4). Concurrent pharmacokinetic analysis will take place to 
ensure that ATX plasma and urine exposure variability has been minimized using 
methods described in a previous ATX pharmacokinetic study conducted at Children’s 
Mercy Hospital (Brown et al., 2016). Additionally, we will measure ATX and metabolites 
in sweat as surrogate for fraction of drug unbound (Marchei et al., 2012; Marchei et al., 
2013). The clinical ADHD questionnaires will be administered at the Intake Visit and at 
follow-up visits following initiation of atomoxetine treatment (6-weeks, 12-weeks, and 

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Page 28 of 143 
18 weeks). These questionnaires ask the participant’s parents and teachers to rate 
behaviors characteristic of ADHD. Changes in other comorbidities associated with ADHD, 
such as anxiety or sluggish cognitive tempo, will be evaluated at Research Visit 1 and at 
Research Visit 4. We will also simultaneously monitor side effects of ATX, another 
measure of clinical outcomes, and categorize study participants on their ability to 
tolerate ATX. Adverse events will be assessed at all encounters between the study 
personnel and study participant. At Research Visit 4, we will also administer the Dietary 
Survey Questionnaire, given that long-term dietary habits may affect both ATX 
pharmacokinetics and pharmacodynamics. 
 
 
Fig 3. - Analysis of Study Endpoints 
 
ATX is thought to exert its therapeutic effect in ADHD through inhibition of the 
presynaptic norepinephrine (NE) transporter (NET) encoded by the SLC6A2 gene.  NE is 
involved in several neuropsychological functions, including visual attention, general 
alertness, sustained attention, learning and memory and executive functions; 
dysregulation of NE homeostasis has been implicated in the development of ADHD.  
Consequently, there has been considerable interest in SLC6A2 as a candidate gene for 
ADHD, but the results of studies investigation associations between SLC6A2 allelic 
variants and ADHD and related phenotypes have been inconsistent and discordant.  Of 

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Page 29 of 143 
interest is rs28386840, also known as SLC6A2 -3081 A>T, in the regulatory region of the 
SLC6A2 gene.  The minor -3081 T allele has been associated with a reduction in 
promoter activity, which would result in lower expression of the NET transporter. 
 
In vitro, as well as in vivo animal and human studies have provided evidence that plasma 
concentrations of 3,4-dihydroxyphenylglycol (DHPG) are derived predominantly from NE 
inside nerve cells.  As a consequence, inhibition of NE reuptake by ATX is accompanied 
by decreases in NE inside presynaptic nerve cells, and subsequently, decreases in 
plasma DHPG concentrations.  Published studies in adults indicate that DHPG 
concentrations in plasma progressively decrease for the first four hours following ATX 
administration and gradually recover in 24 hours; comparable data in children with 
ADHD receiving ATX have not been reported.  In contrast, single doses of a structurally 
related norepinephrine reuptake inhibitor, edivoxetine to adolescents produced an 
average reduction in baseline DHPG of 28% across all tested doses.  With chronic dosing, 
the reduction in DHPG concentration persisted for at least 12 hours.  Of particular 
interest is the observation that no reduction from baseline was observed in two 
subjects, both of whom had relatively low baseline concentrations of 431 pg/ml and 657 
pg/ml and for whom the lack of response could not be attributed to low drug exposure; 
no information regarding clinical response was provided.  These considerations provide 
the basis for assessing DHPG as a potential biomarker of clinical response to ATX, and 
specifically for investigating the relationship between the magnitude of reduction in 
plasma DHPG concentration as a function of ATX concentration, and how it translates 
into clinical response in children with ADHD.  As ATX selectively binds to NET in the 
prefrontal cortex and modulates the reuptake of not only norepinephrine, but also 
dopamine, we propose to conduct a comprehensive analysis of neurotransmitters, 
including norepinephrine, dopamine, DHPG and several of the breakdown products (see 
Secondary Aims). (Kielbasa et al., 2009; Kielbasa and Lobo, 2015; Kielbasa et al., 2015). A 
similar approach has been applied to serotonin selective reuptake inhibitors for adults 
with major depressive disorder. Responders and non-responders 
citalopram/escitalopram displayed significantly different baseline metabolomics 
signatures (Kaddurah-Daouk et al., 2011). 
 
In addition to DHPG as a pharmacodynamics marker, we also propose to investigate a 
biomarker of SLC6A2/NET inhibition in the brain. The SLC6A2/NET transporter is 
expressed both in the central nervous system (i.e., the brain) and peripheral nervous 
systems (i.e, the rest of the body), the measurement of change in plasma DHPG likely 
represents a combination of drug binding at both sites. To differentiate between 
SLC6A2/NET peripherally and in the brain, we will collect additional data.  To assess 
peripheral inhibition we will also monitor heart rate and blood pressure as measures of 
ATX drug action in the peripheral nervous system. Current information suggests that 
controlled release of norepinephrine by a region of the brain called the locus coeruleus 
is responsible for optimal attention and alertness during cognitive tasks.  Functional MRI 
data collected in 20 healthy male adults administered with a single dose of 40 mg 

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atomoxetine found activation in the right inferior frontal gyrus, a region that is 
associated with inhibitory control (Chamberlain et al., 2009). Furthermore, there is a U-
shaped relationship between norepinephrine release and task performance insofar that 
too little or too much norepinephrine leads to decreased attention and problematic task 
performance, while low-to-moderate levels of norepinephrine are considered optimal 
for maintaining alertness and attention during cognitive tasks. Moreover, pupil diameter 
changes mirror norepinephrine release in the locus coeruleus in non-human primates 
(Gilzenrat et al., 2010).  In a carefully controlled experiment, where light levels were 
held constant during a well-established test of attention, one research group 
demonstrated that more difficult cognitive tasks were associated with decreases in pupil 
diameter. In contrast, larger pupil diameters were associated with exploratory behavior, 
poorer task performance and disengagement.  Thus, the magnitude of increase in pupil 
size in response to standardized tasks during ATX treatment offers potential as a 
biomarker of central inhibition of NET activity. See the section below for further details 
regarding this test of attention.  
 
Attentional Orienting and Pupil Size Measurement 
Eye movement and dilation in response to attentional-shift requiring tasks will be used 
to measure ATX drug action in the CNS. The tasks are based on a modified Posner Cuing 
Task, which measures both endogenous and exogenous orientation of attention, which 
correspond to tonic and phasic locus coeruleus activation. This is an established non-
invasive method to measure norepinephrine signaling in the brain. Assessment will take 
place at both the ADHD Specialty clinic and at the PCRU. Participants will be asked to sit 
57 cm from a computer monitor, which is housed in a light dome to maintain a 
consistent level of illumination. Volunteers will be asked to place their chin in a 
mounted chin rest to stabilize the facial area. Each study participant will be asked to 
complete target localization and target discrimination tasks. Both tasks begin with the 
participants looking at two white squares on black background. In between these two 
boxes will be a white fixation cross. Participants will be asked to begin each trial by 
focusing on the fixation cross. Next, a cue is given. In this case, one of two boxes 
brightening will serve as the cue. Following the cue, a target will appear in one of the 
two boxes by presentation of an “O” or a “Q” in one of the two boxes. Participants will 
be asked to push colored buttons on the game controller that correspond with the 
correct answer when presented with the target. If the target appears in the box that 
was brightened, this is defined as a valid trial. When this does not occur, this is 
considered an invalid trial. Half of the trials will be designed to be invalid. The valid and 
invalid cues serve to measure directing of attention by study participants. Volunteers 
will be measured for their ability to localize the target (e.g. did the target appear on the 
left or right box?) and discriminate the target (e.g. is the target a “Q” or an “O”?) 
following the cue. In localization tasks, if the target appears on the left side, volunteers 
will be asked to push the blue button. When the target is on the right side, a successful 
trial would mean the volunteer pushed the red button. In discrimination tasks, if the 
target presented is a “Q” the volunteer will be asked to push the red button, while an 
“O” target means the volunteer should press the blue button. Volunteers will be given 

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the opportunity to practice the tasks (3 trials). Measurements will be recorded for 162 
trials which for both localization and discrimination tasks. Eye-moment, dilation, and 
reaction time will be measured during all tasks. Please see Figures 1 and 2 in the 
Appendix H of this document. Figure 1 illustrates an example of a valid and invalid trial 
for successful completion of the localization task, while Figure 2 illustrates an example 
of a valid and invalid trial for successful completion of the discrimination task.(Aston-
Jones and Cohen, 2005; Alnaes et al., 2014) 
 
Secondary Study Endpoints: 
 
The secondary aims focus on: exploring baseline patient characteristics that may 
predispose an individual to have beneficial clinical response from ATX therapy; 
refinement of the iGO-PK dosing algorithm; exploration of the role of the microbiome in 
impacting ATX pharmacokinetics and pharmacodynamics; validation of a urinary CYP2D6 
biomarker; and exploring ways improve study participant understanding of research 
procedures. A previous study with an anti-depressant, citalopram, suggests that the 
ability to respond positively to a medication may be predicted given an understanding of 
the individuals’ composite of signaling molecules, i.e. the global neurotransmitter 
profile. We are interested in comparing the baseline global neurotransmitter profile 
between children who do and do not respond. We are also interested in understanding 
how the neurotransmitter profile changes with chronic ATX use and correlating these 
changes with clinical benefit of toxicity. To do this, we will evaluate a panel of 
approximately 30 neurotransmitters (Gupta et al., 2016)(refer to Appendix I for example 
list) prior to treatment and during treatment with ATX.  
 
Because there is evidence that the gut microbiome can to influence host 
neurotransmitter concentrations (Petra et al., 2015), we would like to evaluate this as a 
possible confounder to the global neurotransmitter profile. Given that the oral and gut 
microbiome landscape correlate well with one another (Zhang et al., 2015) we will also 
sample saliva to account for factors that could contribute to an individual’s 
neurotransmitter make-up. 
 
The pharmacokinetic data that we collect on each individual participant allows us to 
provide more information for modeling, and for further refinement. We recognized in 
our previous pharmacokinetic study that CYP2D6 activity, as measured using a 
phenotypic marker (urinary dextromethorphan/dextrorphan ratio), was the best 
predictor of ATX exposure. This urinary ratio was associated with ~75% of variability 
observed in ATX exposure in the study. We would like to explore a urinary biomarker 
that is reflective of CYP2D6 activity that has previously been studied (Tay-Sontheimer et 
al., 2014) for possible inclusion in the iGO-PK model. Validation of this biomarker with 
ATX exposure is necessary prior to consideration as a variable in the iGO-PK algorithm. 
 
Lastly, we recognize that our patient population will include young children and that 
lengthy consent forms may not be optimal for conveying information. We plan to 

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distribute a supplemental illustrated booklet (please refer to Supplementary 
Documents, “U54 Study Booklet”) explaining study procedures along with a standard 
consent form to all participants approached for the study. A short questionnaire will 
accompany the booklet, asking study participants and their families to evaluate the 
study booklet (please refer to Appendix G) in helping with their clarity and 
comprehension of the study. 
 
4.2 Primary Safety Endpoints 
 
Participant baseline health, including behaviors, will be recorded at Research Visit 
1 with a physical exam, baseline electrocardiogram, medical history, and 
concomitant medication history. Additionally, baseline health and behavior data will be 
captured at the Intake Visit with the Study Physician. Adverse events will also be closely 
monitored. These are defined by Children’s Mercy Hospital Reportable Events Research 
Policy and Procedures as “untoward or unfavorable occurrences in a human subject, 
including an abnormal sign [e.g., abnormal physical exam or laboratory finding], 
symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the 
research.” Additionally, an adverse event is also defined as behaviors or symptoms that 
occur with increased frequency or severity as consequence of the subject’s participation 
in the research study.   
 
Both types of adverse events will be documented in this study. Adverse events are 
reported in many ways in this study. These include but are not limited to: emails to 
study coordinators/clinical trial manager, phone calls on study cell phone, phone calls to 
ADHD Clinic or Developmental and Behavioral Clinic, reported to study physician at 
clinic visit, reported on Medication Side Effects questionnaires, reported at research 
visits when asked, or via a Cerner notification of admission to the hospital to the study 
physician. Additionally, adverse events will be assessed and documented at Research 
Visit 2, Research Visit 3, Research Visit 4, 6-week Visit, 12-week Visit, and 18-week Visit.  
 
Adverse events will be categorized and reported to the IRB as outlined in CM Policy 
regarding adverse events.  These events will be documented consistently, regardless of 
how they were reported. This includes the delegation of an individual member of the 
study personnel to handle all adverse event reporting. All adverse events will be 
recorded at all research visits and in between visits as needed on the Adverse Event CRF 
kept in the subject’s study binder.   
  
In addition, subjects will be classified based on their tolerance of ATX.  A participant is 
considered tolerant of ATX if the side effects did not lead to discontinuation of ATX 
therapy. A participant is considered intolerant of ATX if the side effects lead to the 
discontinuation of medication and withdrawal of a subject from the study. 
 

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5.0 Study Intervention/Investigational Agent 
5.1  Description 
ATX is a norepinephrine reuptake transporter inhibitor which is approved by the 
FDA for use in children with ADHD. The medication displays high inter-individual 
pharmacokinetic variability, which has been associated with CYP2D6 genotype. 
An individual’s predicted CYP2D6 phenotype can be estimated from their 
genotype. This estimation is quantified as a CYP2D6 activity score (AS). The 
CYP2D6 predicted phenotype and the participant’s height, weight, habitus, and 
gender are used to inform the ATX dosing tool, the individualized genetic and 
ontogeny pharmacokinetic model (iGO-PK). Both the CYP2D6 genotype-
predicted phenotype activity score and iGO-PK are described below. Doses that 
are expected to result in Cmax,ss values of 400 ng/mL, 600 ng/mL, and 800 ng/mL 
will be calculated for each participant. Study physicians will start with a dosing 
regimen that is predicted to achieve a Cmax,ss of 400 ng/mL and will titrate the 
dose to reach Cmax,ss values of 600 ng/mL or 800 ng/mL according to participant 
response. Study physicians may choose to titrate slowly to Cmax,ss of 400 ng/mL 
when initiating ATX therapy to avoid side effects. 
 
CYP2D6 Genotype-Predicted Phenotype Activity Score 
Participants will be assigned a CYP2D6 phenotype based on the CYP2D6 activity score, 
which is calculated using CYP2D6 genotype information. These data are used to 
determine the design and length of stay of the PK studies. Calculation of an activity 
score is done first by determining the functional score for each copy of CYP2D6 present 
in a patient.  
 
When this study was first submitted, a CYP2D6 allelic variant is given a score of 1 if it is 
considered fully functional when compared to the wild-type reference sequence. If an 
allelic variant is reported to result in decreased activity, the functional score assigned is 
0.5. It is important to note that a functional score of 0.5 does mean the allelic variant 
exhibted 50% reduction in activity; rather this designation is meant to convey that a 
variant had less activity compared to wild-type, while at the same time not being devoid 
of catalytic capability. An allelic variant that results in complete loss of CYP2D6 activity 
was given a functional score of 0. The activity score is a summation of the functional 
score for all CYP2D6 gene copies. An activity score of 0 or 0.5 would have originally 
placed an individual in the poor metabolizer (PM) or intermediate metabolizer (IM) 
study design (i.e. Study Design 1), and a score ≥ 1 would assign an individual to an 
extensive metabolizer (EM) study design (i.e. Study Design 2). It should be noted that 
individuals in the latter study design were comprised of EM1s, EM1.5s, EM2s, and ultra-
rapid metabolizers (UM). (Gaedigk et al., 2008; Hicks et al., 2013; Twist et al., 2013). 
 
New standardized guidelines for CYP2D6 genotype-to-phenotype interpretation were 
recently published in 2020 by the Clinical Pharmacogenetic Implementation Consortium 

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(CPIC) (Caudle et al., 2020), which recommended a different functional score for the 
CYP2D6*10 allelic variant (reduced score to 0.25) and also different phenotype 
assignments based on activity score. The different phenotype designations are listed in 
the table below.  
 
Inferred CYP2D6 Phenotype 
Consensus contiguous 
CYP2D6 Activity Score 
Definition 
Examples of CYP2D6 
diplotypes for consensus 
translation method1 
Ultra-rapid Metabolizer (UM) 
> 2.25 
*1/*1xN, *1/*2xN 
Normal Metabolizer (NM) 
1.25 ≤ x ≤ 2.25 
*1/*10, *1/*1, *1/*2 
Intermediate Metabolizer (IM) 
0 < x < 1.25 
*4/*10, *41/*41, *1/*4 
Poor Metabolizer (PM) 
0 
*4/*6, *3/*5 
Table is edited from (Caudle et al., 2020). 
1Functional scores for the reference: *1 = 1, *2 = 1, *3 = 0, *4 = 0, *5 = 0, *6 =0, *10 = 
0.25, *41 = 0.5. 
 
Additionally, data generated from studies conducted at Children’s Mercy Hospital has 
suggested that changes in study design assignment are warranted, particularly for 
children with an activity score of 1, which could be a result of having two reduced 
function CYP2D6 alleles (0.5/0.5) or one functional copy and one non-functional copy of 
CYP2D6 (1/0). The studies mentioned above are: Ped Develop Pharm U54 (IRB# 
16010069) and this study, ATX-PBPK-PD-Clinical Outcomes (U54) (IRB# 16100728). Initial 
analysis suggests that 0.5/0.5 children have higher ATX exposure compared to 1/0 
children, suggesting slower ATX apparent oral clearance. Additionally, 1/0 children more 
closely resembled children with two fully functional copies of CYP2D6 in their 
pharmacokinetics. 
 
This preliminary data generated from previous ATX studies and the revised CPIC 
guidelines have prompted the study team to revise study design assignment. Therefore, 
to ensure that each participant’s ATX pharmacokinetics are accurately characterized, all 
children with an activity < 1 and those who have a two reduced function alleles will be 
assigned to Study Design 1. All other participants will be initially assigned to Study 
Design 2. 
 
Additional genotype testing may be conducted if the participant’s pharmacokinetic 
profile and genotype are inconsistent with one another. The additional genotype 
testing, if needed, will be documented on the provided CRF. 
 
iGO-PK Model 
This method was developed using data generated from a previous ATX single-dose PK 
study conducted at Children’s Mercy Hospital (Brown et al., 2016). This model stratifies 
participants into two distinct populations: individuals who are CYP2D6 PM and those 
who non-PMs, i.e. IM, EM1, EM2, and UM (read above for more details on CYP2D6 
genotype and phenotype prediction). With the new changes to CYP2D6 genotype-to-

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phenotype interpretation and study design, the only major change is that children with 
two reduced function alleles will be modeled as an IM. Analysis of the previous PK study 
found that in non-PM participants, the dose-exposure relationship was best described 
using a two-compartment model with first order absorption and first order clearance. In 
PM participants, dose-exposure was best described using a one compartment model 
with first order absorption, first order clearance, and a secondary peaking component. 
Additionally, lean body weight (LBW) and obesity status (positive or negative) variables 
were found to significantly impact variability in ATX exposure in both models. 
Retrograde extrapolation of an initial dose of ATX for PK Study 1 will be determined by 
setting the desired Cmax goal at steady-state (Cmax,ss) to 400 ng/mL, and incorporating 
patient specific parameters CYP2D6 AS, LBW, and obesity status. The actual dose 
dispensed will be as close as possible to the model generated dose, given the available 
atomoxetine capsule formulations. Additionally, we will also consider the most 
convenient combination of capsules for a child to take and how a prescriber would dose 
this medication in a naturalistic setting. During the course of the study, we will also be 
monitoring clinical response and toxicity. The exposure (Cmax,ss) may be titrated down to 
below 400 ng/mL to reduce toxicity or up to 800 ng/mL to increase response as 
tolerated. 
 
5.2  Drug Handling 
 
The study drug, ATX, will be stored, prepared, labeled, and dispensed by the CMH 
Investigational Drug Service (IDS) pharmacy. Study file documentation, accountability, 
and records for dispensing of atomoxetine will be maintained by IDS pharmacy 
personnel.  
 
The study physician will submit a signed and dated prescription for ATX to IDS 
Pharmacy. Alternately, designated study personnel will deliver a prescription that has 
been signed and dated prescription by the study physician to IDS Pharmacy. A copy of all 
prescriptions will be retained in the participant’s study binder. IDS Pharmacy will deliver 
the ATX prescription to the PCRU for Research Visit 2. Subsequent prescriptions for ATX 
will be filled as needed and will typically occur in conjunction with 6-week, 12-week, and 
18-week visits. Medication refills may also occur outside of the 6-week, 12-week, and 
18-week visits. Medication refills may be handed off or delivered to the participant to 
reduce foot traffic at Children’s Mercy Hospital, as needed. Dose adjustments may also 
occur outside of the 6-week, 12-week, and 18-week visits.  
 
All investigational drug will be returned to the study team at the end of the study for 
disposal by the IDS pharmacy, unless the child and their family would like to continue 
using ATX. In addition, if the participant would like to discontinue the study drug, but he 
or she will require an ATX wean to reduce risk of side effects from abrupt 
discontinuation as directed by his or her study physician, the participant may keep the 
remaining drug to complete this wean. 
 

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Refer to the Investigational Drug Service Policy and Procedure (Last Revision 04/2020) 
for the standard operating procedure (SOP) outlining details regarding the control of the 
study drug used in this protocol. Transportation of study drug will be handled by 
both IDS pharmacy and study personnel. Refer to the Investigational Drug 
Product Transport Policy (Last Revision 12/2019.) The locations of 
drug transportation and how this will be conducted are summarized below. Further 
details for drug handling may be found in Appendix J, “Study Drug Timeline.”  
 
• IDS to participant at CMH Adele Hall – IDS personnel or designated study 
team members, as specified on the Delegation of Authority, may transfer 
investigation drug from IDS pharmacy to clinics located in CMH Adele Hall. 
Direct hand-off of medication to the participant or their LAR may also occur 
outside of CMH Adele Hall, such as at the front entrance of the hospital, to 
reduce foot traffic. Lastly, IDS personnel may transfer the investigational 
drug to the CMH Adele Hall outpatient pharmacy for the study 
participant/family to pick up.   
 
• IDS to PCRU – IDS personnel or designated study team members may 
transfer investigation drug from IDS pharmacy to the PCRU.  
 
• IDS to Children’s Mercy Hospital Kansas (CMK) – IDS personnel may use a 
courier service to deliver a filled prescription to the outpatient pharmacy at 
CMK for study participants to pick up at their convenience. 
 
• 
IDS to participant’s residence – IDS Pharmacy may ship medication to the 
participant’s residence. The party responsible for shipping medication will be 
determined by applicable IDS policies at the time of shipment. During the 
consent process, the participant and/or guardian providing consent will 
provide written authorization for IDS Pharmacy to ship study medication to 
the participant’s home, if needed.  
6.0  Inclusion and Exclusion Criteria 
6.1  Inclusion Criteria 
• Males and females 6-18 years of age at the time of enrollment 
• Diagnosis of ADHD, as confirmed or inferred by a Study Physician at Intake visit.  
• Intention of the Study Physician to begin therapy with ATX at intake visit 
• Willing to provide written permission/assent to participate 
• ADHD Medication Status is one of the following: 
• ADHD medication naïve or not currently taking ADHD medication 
including stimulants, α2-agonists, and ATX, or 
• Currently taking a stimulant for ADHD and is willing to wash out of 
stimulants prior to starting ATX. This washout is also approved by a Study 

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Physician, or other qualified study personnel (see Section 11.0 for 
Procedures Involved). 
 
Exclusion Criteria 
• An IQ < 70 or evidence of intellectual disability from review of EMR 
• A diagnosis of Autism Spectrum Disorder 
• Inability or unwillingness to have blood drawn as described in the protocol 
schedule of events and consent 
• Underlying risk for cardiotoxicity, such as presentation of structural cardiac 
abnormalities, cardiomyopathy, or arrhythmias 
• Clinically significant abnormal safety laboratory values as determined by treating 
physician 
• Diagnosis that may cause abnormal absorption or gastric emptying, such as 
reflux, inflammatory bowel disease, or Crohn’s disease 
• For females, a positive urine pregnancy test 
• Previous history of adverse drug reaction to ATX  
• Use of drugs known to inhibit CYP2D6: 
• Concurrent therapy with sertraline, venlafaxine, imipramine, nortriptyline, 
quinidine, propafenone, cimetidine, tamoxifen, bupropion, over-the-counter 
medications containing diphenhydramine, codeine, tramadol, hydrocodone, 
or oxycodone 
• Concurrent or previous therapy with fluoxetine or paroxetine in the last 2 
months 
• Concurrent or previous therapy with terbinafine in the last 6 months  
• Unwillingness or inability to washout of stimulant ADHD medications 
• Concurrent or recent use of other psychiatric/behavioral health drugs including 
SSRIs, SNRIs, antipsychotics, anxiolytics, anti-epileptics, and α2-agonists that 
would impact the participant’s pharmacokinetic and/or pharmacodynamic 
baseline 
• Subject is considered by PI to be unsuitable for participation in the study for any 
reason 
6.2  Special Populations 
We will include individuals who are not yet adults (children and teenagers who up to 18 
years of age). We will exclude adults unable to consent, pregnant women, prisoners, 
and wards of the state.  
7.0  Vulnerable Populations 
 

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7.1 Additional Safeguards 
 
This research study aims to enroll children and teenagers with ADHD between the ages 
of 6-18 years of age. Because children are vulnerable to coercion or undue influence, 
appropriate provisions will made to obtain and document:  
• Permission to participate in the study from the participant’s legally authorized 
representative.  
• Assent to participate in the study from the participant. An illustrated study 
booklet, see supplemental document, “U54 Study Booklet,” that complements 
the permission/assent form will be provided for children to better understand 
study procedures.  
• For children age 7 and older, a signature is required to document assent to study 
procedures. Signatures may be waived if the child is capable of assenting but 
unable to sign. Documentation of the reason is required. 
• For children under age 7, only the permission of the legally authorized 
representative is required for study participation. A study participant under age 7 
who wishes to revoke assent and withdraw from the study may do so at any 
time.  
• The PI may also remove a child under the age of 7 without the assent of the 
legally authorized representative for reasons that include, but are not limited to, 
safety, participant not responding well to medication, or issues with participant 
non-compliance, etc. 
8.0  Local Number of Subjects 
 
8.1 Multiple Cohorts 
A total of 160 subjects will be accrued locally. The study does not contain multiple 
cohorts.  
 
8.2 Target Participants 
The research proposal targets 160 participants who are expected to be enrolled and 
screened. The target number of subjects needed to complete research procedures is 
120.  Participants who complete at least Research Visits 1-3, the Intake Visit, and the 
6-Week Visit with the Study Physician will be considered to have “partially 
completed” the study.  Completion of these visits will include obtaining baseline 
measurements, confirmation of eligibility, single and steady-state PK and PD 
measurements, and at least one post-treatment clinical response assessment.  Since 
data from these participants will meet the study aims, those who partially complete 
the study will be counted toward the 120.  
 

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9.0  Prescreening and Recruitment Methods 
9.1 Recruitment Overview 
 
Participants will be recruited over four years from patients and families seeking care for 
ADHD at Children’s Mercy Hospital and Clinics.  These participants may be recruited 
from six different tracks: 
 
Track 1: Patients referred to ADHD Clinic on College Boulevard 
Track 2: Patients at Pediatric Care Clinic (PCC) at the Broadway and West 
locations 
Track 3: All other patients seeking ADHD care from Children’s Mercy Hospital 
and Clinics providers 
Track 4: External provider referral to Children’s Mercy Hospital and Clinics and 
patient self-referral 
Track 5: Children’s Mercy Summer Treatment Program (STP) participants 
 
Active Recruitment: Participants will be actively recruited from Track 1 and Track 2. 
Active recruitment entails study personnel performing regular chart review of patients 
seen through Track 1 and Track 2 (see section 9.2). These two clinics were selected for 
active recruitment because patients and families generally seek care for ADHD at these 
Children’s Mercy Hospital and Clinics locations. As such, these clinics represent the 
largest population of potentially eligible participant population.   
 
Passive Recruitment: Participants will be passively recruited from Track 3, Track 4 and 
Track 5.  With passive recruitment, potential participants or their healthcare providers 
self-identify or refer, respectively, potential research participants to the study.  
Potential participants may learn about this study from information posted on the 
internal Children’s Mercy Hospital website and on the Children’s Mercy Research 
Institute (CMRI) public facing website. Social media platforms, such as Twitter and 
Facebook, may be used to disseminate study information. The social media platforms 
will reference or link to study information available on the CMRI website. Use of social 
media to share study information will be compliant with any existing CMH policies. The 
use of social media to share study information will not begin until these policies have 
been developed. Presentation of study information and content posted on the CMRI 
website will be at the discretion of the Digital Team, Research Administration, and the 
research team. Modification of images may be applied by the Digital Team and Research 
Administration to in be consistent with the aesthetic of the CMRI webpage. All study 
information will be approved by the IRB (Supplementary document, “CMRI Website 
Information”) 
 
Track 3 allows a mechanism for potential participants within the Children’s Mercy 
Hospital and Clinic systems to participate in this research study, who are not actively 
being recruited. Track 4 allows a mechanism for potential participants outside of the 

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Children’s Mercy Hospital and Clinic systems to participate in this research study. The 
STP is a summer program for children with ADHD where both behavioral and medical 
therapies are provided.  Track 5 provides a mechanism for STP participants to enroll in 
this study.  
 
 
9.2 Chart Review 
 
The following prescreening information will be identified from chart review when 
possible for Tracks 1-5: 
 
• 6-18 years of age 
• Diagnosis or indication of intellectual disability (IQ <70) 
• Diagnosis or indication of Autism Spectrum Disorder (ASD) 
• Diagnosis or indication of underlying risk for cardiotoxicity, such as 
presentation of structural cardiac abnormalities, cardiomyopathy, or 
arrhythmias 
• Diagnosis or indication of disease that may cause abnormal absorption or 
gastric emptying 
• Previous history or indication of prior adverse drug reaction to ATX 
• Current or previous therapy with drugs used to treat ADHD 
• Concurrent or previous therapy with drugs known to inhibit CYP2D6 
• Concurrent therapy with other psychiatric/behavioral drugs 
• Presence of any of the following questionnaires: 
• Child Medical History 
• NICHQ Vanderbilt Assessment Scale Initial Assessment 
• Child Behavior Checklist 
• Strengths and Difficulties Questionnaire 
• School Intervention Questionnaire 
• Please note: any version of the above questionnaires are permissible for 
chart review, screening, and recruitment given that these only inform the 
research team of the likeliness of participant suitability for the study. 
 
9.3 Participant Notification of Study Opportunity 
 
Participants may be informed of the study opportunity in multiple ways, depending 
upon the recruitment track.   
 
Active Recruitment: Track 1 and Track 2 
1. The potential participant’s assigned provider will be contacted regarding 
eligibility for potential participants meeting eligibility criteria upon initial 
chart review. For message center template, please see Appendix B. If the 
provider approves, the family will be contacted by phone and the study 

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opportunity will be presented (for the phone script, please refer to Appendix 
C or D).   
2. If the family is interested in learning more, study personnel will either email 
or mail a copy of the study consent or permission/assent form (whichever is 
applicable) and a recruitment flyer with FAQs (see Supplementary 
Documents, “Recruitment Flyer”) to the family based on their preferred 
communication method.   
a. Study personnel will specify that the family/potential participant are 
not to sign the form to provide consent, but rather, the form is used 
for information purposes at this juncture and study personnel will 
review this formally with the family/participant if he or she choose to 
enroll. (See Appendix E for the email/letter sent with the consent or 
permission/assent form and recruitment flyer.) 
b. This conversation will be documented in an electronic Potential 
Participant Log located on the Hospital Share Drive in the Clin Pharm 
folder, U54 sub-folder.  
c. Study personnel will include contact information for the 
family/participant for any questions, concerns, etc with the email or 
mailing.   
d. Study personnel will ask permission to make a follow-up call one 
week after the email/mailing is sent out.   
3. A follow-up call will be made one week later.   
a. If families/potential participants are interested, study personnel will 
proceed to enrollment (section 11.1). 
b. If families/potential participants are not interested, no further 
contact attempts will be made. 
c. Up to three follow-up calls will be made until the family/participant is 
reached. All potential participant contact will be documented in the 
“Potential Participant Log” (see subsection 9.4 below; see 
Supplementary Documents “U54 Potential Participant Log”).  
 
Passive Recruitment: Track 3 
1. CMH provider notifies study personnel of the potential participant; 
2. OR an individual self-identifies themselves or their child, as a potential 
participant to study personnel and the potential participant is patient of 
provider at CMH. 
3. Study personnel perform a chart review. If upon chart review,  
a. The potential participant meets prescreening criteria, study personnel 
will contact the family by phone and the study opportunity will be 
presented (for the phone script, please refer to Appendix 
D).  Subsequent steps are the same as steps 2 and 3 in “Active 
Recruitment” above. 

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b. The potential participant does not meet prescreening criteria, study 
personnel will notify the referring provider or the individual and/or 
family. If the family would like the results from the prescreen for 
follow-up care, the study team will write a letter to be given to the 
participant’s primary care provider. (See Appendix M). 
 
Passive Recruitment: Track 4  
1. An external provider refers their patient OR an individual self-identifies 
themselves or their child as a potential participant to study personnel and 
the potential participant is not currently being seen by a provider at CMH. 
Potential participants and families will be made aware of the study through 
listing on ClinicalTrials.gov, posting of the study on the CMRI externally facing 
website, the CMRI website, or social media referencing the CMRI website.  
2. Study personnel will contact the participant by phone to introduce the study. 
a. Study personnel will either email or mail a copy of the study consent 
or permission/assent form (whichever is applicable) and a 
recruitment flyer with FAQs (see Supplementary Documents, 
“Recruitment Flyer”) to the family based on their preferred 
communication method along with the Recruitment Letter or Email 
(Appendix E).   
i. This conversation will be documented in an electronic 
Potential Participant Log located on the Hospital Share Drive 
in the Clin Pharm folder, U54 sub-folder.  
ii. Study personnel will include contact information for the 
family/participant for any questions, concerns, etc with the 
email or mailing.   
iii. Study personnel will ask permission to make a follow-up call 
one week after the email/mailing is sent out.   
b. Study personnel will specify that the family/potential participant are 
not to sign the form to provide consent, but rather, the form is used 
for information purposes at this juncture and study personnel will 
review this formally with the family/participant if he or she choose to 
enroll.     
c. A follow-up call will be made one week later.   
i. If families/potential participants are interested, study 
personnel will conduct a phone consent or via telehealth 
appointment. 
1. Families may fax signed and document 
permission/assent or consent forms. Study personnel 
must instruct families to bring original signed and 
dated forms at Research Visit 1. 

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2. Families may also mail signed and document 
permission/assent or consent forms to designated 
study personnel. 
3. Once a faxed copy or a mailed original version of the 
consent has been received, the study team will 
proceed with research procedures. 
ii. If families/potential participants are not interested, no further 
attempts to contact will be made.  
3. After enrollment and receipt of faxed or mailed signed and dated 
permission/assent form or consent form, study personnel will send out 
questionnaires to gather preliminary information. 
a. The following questionnaires will be sent via CHADIS. These 
questionnaires are administered as part of the standard-of-care 
intake process at ADHD Clinic on College Boulevard.  Information 
collected on these questionnaires provides necessary information for 
prescreening to guage the likelihood these children meet the 
eligibility criteria that would be identified from chart review in other 
tracks. The questionnaires are: 
i. Child Medical History (parent informant) 
ii. NICHQ Vanderbilt Assessment Scale – Initial Assessment 
(parent and teacher informant) 
iii. Child Behavior Checklist (parent and teacher informant) 
iv. Strengths and Difficulties Questionnaire (parent and teach 
informant) 
v. School Intervention Questionnaire (teacher informant) 
vi. Please note that all questionnaires (and other versions of 
these questionnaires) are validated clinical measures that aid 
in the diagnosis. However, these data are used in conjunction 
with Study Physician clinical impressions and do not directly 
determine a diagnosis. Because this, any version of the  
questionnaires listed are permissible in aiding diagnosis 
determination. 
b. After these questionnaires are submitted and returned, study 
personnel will review and determine if prescreening criteria are met.  
i. If initial prescreening criteria are met, study personnel will 
proceed to schedule Research Visit 1 (section 11.1). 
ii. If initial prescreening criteria are not met, study personnel will 
notify the family. If the family would like the results from the 
prescreen for follow-up care, the study team will write a letter 
to be given to the participant’s primary care provider. (See 
Appendix M). 
 
Passive Recruitment: Track 5 

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1. All participants and their families at STP will be provided the study 
information handout (please see Supplementary Documents, “Recruitment 
Flyer”). 
2. A study team member will present study information briefly at the end of a 
weekly behavioral parent training meeting and answer any 
parent/participant questions.  See Supplementary Documents, “STP 
presentation” for presentation content.   
3. Interested participants may call the study cell phone listed on the handout. 
a. Subsequent steps are the same as steps 2 and 3 in “Active 
Recruitment” above. 
b. Baseline results from psychometric questionnaires administered prior 
to beginning STP (as a requirement of participation in the STP 
program) will be obtained from the participant’s electronic medical 
record and/or STP research records 
 
9.4 PHI Documentation 
 
PHI will be recorded for potential participants prior to obtaining informed 
permission/assent/consent during pre-screening procedures outlined above.  This 
information will be stored securely on the Hospital Share Drive under the file name 
“Potential Participant Log.” (see Supplementary Documents, under “U54 Potential 
Participant Log.”)The PHI collected will consist of: 
 
• Patient first and last name 
• Appointment date and appointment location (PCC or ADHD Clinic) 
• Parent Name 
• Parent Phone Number 
 
Other non-PHI collected on this spreadsheet will include attempts to call the family 
including date, time, notes from the conversation, interest, if consent form was 
sent, follow-up call attempts after consent form was sent, and enrollment status.  
This spreadsheet of potential participants will only be kept until completion of 
enrollment to avoid duplicate recruitment.  
 
A partial waiver of HIPAA Authorization (waiver for recruitment purposes only) 
was approved at the time of the initial protocol approval (see Notification of Initial 
Approval, 11/29/2016).  
 
Data for participants who are determined to be ineligible for the study after 
enrollment/upon screening will be stored in the “U54 Master Enrollment Log” and 
will be documented as “screen fails.” (see Supplementary Documents, under “U54 

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Master Enrollment Log”). The reason for screen fail will also be documented in the 
participant’s study binder.  
10.0 Study Timelines 
 
10.1   Study Duration 
 
• The duration of an individual subject’s participation in the study will be 
approximately 6-8 months. 
• The duration anticipated to enroll all subjects and complete participant study 
procedures is approximately 5 years (June 2022) 
• The estimated date for the investigators to complete this study (complete primary 
analysis) is approximately 5 years from when enrollment began (December 2022). 
11.0 Procedures Involved 
 
11.1 Study Design Overview 
 
This is a longitudinal exposure escalation study of atomoxetine in children with ADHD. 
This study simultaneously measures participants’ pharmacokinetic and 
pharmacodynamic profiles after administration of a single-dose of ATX, approximately 
2-8 weeks, and approximately 18 weeks of chronic use as well as the therapeutic 
efficacy/clinical response after chronic use. The study design is best illustrated by 
categorizing the chronological visits by phase as illustrated in Figure 4. The phases occur 
in the following order: 
 
1) Prescreen 
2) Enrollment 
3) Screen 
4) Intervention  

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Fig. 4 – Study Design Overview 

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1. Prescreen 
This phase consists of identifying and contacting eligible study participants and 
presenting the study opportunity. See section 9.0 for details. 
 
After a family expresses interest in enrolling, study personnel will contact the 
participant/family to review key parts of the study in preparation for the first research 
visit. See Appendix F “Study Coordinator/Research Assistant Scheduling Script” for 
details. This discussion with review: 
 
a. Frequency and duration of study visits 
b. If a medication washout is required, explanation about washout safety and 
instruction to not begin the washout until written permission/assent or consent 
has been obtained 
c. The study drug is only available in capsule form, so the child will need to be able 
to swallow pills 
d. The study will require multiple blood draws and an IV 
 
2. Enrollment 
Enrollment typically takes place during Research Visit 1 Part 1. Enrollment can occur 
prior to Research Visit 1 Part 1 when a diagnosis of ADHD has not been established or 
the diagnosis cannot be verified by review of EMR.  Additionally, enrollment may occur 
prior to Research Visit 1 Part 1 by phone or telehealth to minimize in-person procedures 
to prevent SARS-CoV-2 viral transmission. Research Visit 1 Part 1 visit takes place in the 
PCRU and includes obtaining informed consent or permission/assent, gathering 
information about a participant’s comfort with needlesticks and pill swallowing, 
obtaining a blood sample to determine the participant’s genotype, collecting medical 
history, demographics, medication history, and initiating an ADHD medication washout 
if needed.   
 
3. Screen 
After enrollment at Research Visit 1 Part 1, the remaining screening procedures will 
occur during Research Visit 1 Part 2 and the Intake Visit with Study Physician.  
 
If study personnel determine no washout will be required, Research Visit 1 Parts 1 and 2 
may occur in tandem.  However, if a washout will be required, the 2 parts of Research 
Visit 1 will occur separately.  After the participant has completed the washout, he or she 
will return for Part 2 to initiate screening procedures.  
 
Research Visit 1 Part 2 takes place in the PCRU and includes obtaining baseline research 
psychometric measures and baseline safety and research measures to assess for 
inclusion/exclusion criteria. Psychometric measures will be administered via paper 
questionnaires, electronically (as with K-SADS-COMP), or obtained using the 
Comprehensive Health and Decision Information System (CHADIS). K-SADS-COMP was 

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developed using Microsoft ASP.NET 4.0 framework and  Microsoft SQL Server 2016 
database. These platforms are stable, reliable and secure. CHADIS is a secure web-based 
patient questionnaire tool to assist healthcare professionals with their patient clinical 
care decisions. Parents and caregivers of the study participant are able to complete 
certain questionnaires online. These results are then imported into the participant’s 
electronic medical record. 
 
The Intake Visit with Study Physician takes place in the Developmental and Behavioral 
Health Sciences Clinic at the Adele Hall campus, the ADHD Clinic on College Boulevard, 
or via telehealth. During this visit, the participant and family undergo a routine standard 
of care visit with a study physician to confirm/infer a diagnosis of ADHD, determine an 
ADHD subtype, assess for co-morbidities, perform a physical exam, and determine if ATX 
is an appropriate therapy for the participant. If the Intake Visit occurs via telehealth, all 
in-person procedures may be omitted. Further details are described in section 11.2. The 
results from questionnaires will be reviewed. For participants without a formal diagnosis 
(i.e. documented on participant’s electronic medical record), questionnaires must be 
received from both parent and teacher.   
 
If the subject was seen by a study physician within 6 weeks prior to enrollment and at 
baseline (meaning not taking any ADHD medication), the visit does not need to be 
repeated in its entirety.  The study physician may amend his or her visit note in the EMR 
to document the following for research purposes:  
 
a. Confirm/infer ADHD diagnosis 
b. Assess and confirm/infer diagnosis of other comorbidities 
c. Assess and confirm appropriateness of atomoxetine therapy for 
participant 
d. Complete Clinical Global Impression (CGI). 
 
After this, the Principle Investigator(s) (PI) will review information from these visits to 
determine if the participant meets all eligibility criteria. 
 
4. Intervention assignment 
Once all inclusion and exclusion criteria have been assessed during screening 
procedures, the PI will document that the subject meets all eligibility criteria to qualify 
for study participation.  The PI will then assign the participant to one of three study 
designs based on his or her CYP2D6 activity score (see section 5.1).  The length and data 
collection procedures of Research Visit 2, Research Visit 3, and Research Visit 4 will vary 
based on the participant’s CYP2D6 activity score, genotype, and frequency of dosing.  
During the course of the study following Research Visit 2, some study particpants may 
be changed from the usual once daily dosing to twice a day (bid) dosing per their study 
physician.  These participants initially assigned to Study Design 2 may require switching 
to Study Design 3 as determined by the research team to capture pharmacokinetic data 

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of non-Q12-hour bid dosing.  Additionally, Study Design 3 participants taking twice daily 
dosing may be switched back to daily dosing over the course of the study, thus 
necesaitating assignment back to Study Design 2.  Given the decreased drug clearance 
of poor metabolizers, particpants in Study Design 1 are not anticipated to be prescribed 
bid dosing and thus would not require switching to Study Design 3.  These length 
variations are illustrated in Figure 5 below. Data collection procedure variations are 
illustrated in the specific visit descriptions in section 11.2. 
 
 
Visit Length by Study Design 
 
Study Design 1 
Activity Score < 1 
or participants 
have 2 reduced 
function alleles 
Study Design 2 
Activity Score > 
1 (i.e. all other 
scores) 
Study Design 3 
Partcipant previously in Study 
Design 2, on non-Q12-hour bid 
dosing 
Research 
Visit 2 
72 Hours 
12 Hours 
Non applicable 
Research 
Visit 3 
24 Hours 
12 Hours 
Up to 24 Hours 
Research 
Visit 4 
24 Hours 
12 Hours 
Up to 24 Hours 
Figure 5 – Please note, visit length is expressed in hours post-drug administration. 
 
After study design assignment, the participant will begin the study intervention 
procedures, starting with Research Visit 2. See below for a brief description of each visit.  
 
Research Visit 2 – This visit is also referred to as pharmacokinetic study 1 (PK1), or first 
dose PK. This visit takes place in the PCRU and also includes procedures occurring in 
preparation of this visit, in addition to procedures occurring after administration 
of the first dose of ATX.  
 
Research Visit 3 – This visit is also referred to as pharmacokinetic study 2 (PK2) or steady 
state PK.  This visit takes place in the PCRU and also includes procedures occurring in 
preparation of this visit, in addition to procedures after administration of medication 
when the participant is at steady-state. Steady-state is assumed to have been achieved 
once the participant has been taking atomoxetine routinely for two weeks.  This visit 
may occur any time after the participant has been taking study drug routinely for 2 
weeks and prior to the 18-Week Visit with Study Physician.  If the participant is 
prescribed non-Q12-hour twice daily dosing at this time, the study team will notify 
paritipant and/or family prior to visit, and the participant will be switched to Study 
Design 3 for this research visit.  Compliance will be documented by checking the capsule 
count against the medication calendar and documented in corresponding CRFs. 
Additionally, study personnel will reach out participants and/or their families ~1 week 

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prior to remind them that all medications need to be taken in the week prior to 
Research Visit 3. Study personnel will call prior to Research Visit 3 to ensure that 
participants have been compliant for a week.  
  
6-Week Visit with Study Physician – The participant and family meet with a study 
physician approximately 6 weeks after ATX therapy was initiated. A ± 2-week window is 
allowed for ease of scheduling and to ensure Research Visit 3 occurs prior to the 
visit.  Prior to this visit, questionnaires will be sent out via CHADIS to parents and 
teachers to assess participant’s behavior. During this visit, safety, efficacy, and side 
effects will al be assessed and dose adjustments will be made accordingly. Dose 
adjustments may be outside research and visits with study physicians as needed.  
 
12-Week Visit with Study Physician – The participant and family meet with a study 
physician approximately 6 weeks after the 6-Week Visit with Study Physician. A ± 2-
week window is allowed for ease of scheduling.  Prior to this visit, questionnaires will be 
sent out via CHADIS to parents and teachers to assess participant’s behavior. During this 
visit, safety, efficacy, and side effects will be assessed and dose adjustments will be 
made accordingly. Dose adjustments may be outside research and visits with study 
physicians as needed.     
 
18-Week Visit with Study Physician – The participant and family meet with a study 
physician approximately 6 weeks after the 12-Week Visit with Study Physician. A ± 2-
week window is allowed for ease of scheduling. Prior to this visit, questionnaires will be 
sent out via CHADIS to parents and teachers to assess participant’s behavior. During this 
visit, safety, efficacy, and side effects will be assessed and dose adjustments will be 
made accordingly. In addition, baseline questionnaires will be re-administered to gauge 
symptom and impairment changes post-treatment initiation. Dose adjustments may be 
outside research and visits with study physicians as needed. 
 
Research Visit 4 – This visit is also referred to as pharmacokinetic study 3 (PK3) or end of 
study PK.  This vist occurs after the 18-Week Visit with Study Physician. This visit takes 
place in the PCRU and consists of the same procedures as Research Visit 3. 
Determination of Study Design will be confirmed prior to visit, as some participants may 
require switching to a different study design if frequency of dosing has changed.  During 
this visit, baseline psychometric measures will be re-administered to measure change 
post-treatment initiation. An end of study EKG will be obtained, and a Dietary Survey 
Questionnaire will be administered. 
 
o 
Description of Research Procedures 
 
1. Research Visit 1 – Part 1 
a. When scheduling this visit, the research team will ensure that the 
participant and their family are aware of the safety measures at 

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Children’s Mercy Hospital to prevent transmission of the SARS-CoV-2 
virus. These resources and information to be shared will be detailed 
on the Children’s Mercy Hospital homepage and any PCRU guidance 
in response to the COVID-19 pandemic. The research team will 
discuss with the participant and their family that safety procedures to 
reduce SARS-CoV-2 transmission will be in place for all in-person visits 
for the foreseeable future.  
b. Conduct permission/assent with participant and legally authorized 
representative (LAR), respectively. Obtain a signed and dated, written 
informed permission/assent form. 
i. If permission/assent conducted via phone or virtually prior to 
Research Visit 1 – Part 1, ensure that original copy with 
participant and LAR is received prior to beginning research 
procedures. 
ii. Make a copy of all permission/assent forms for the participant 
and LAR. 
c. Obtain demographic data: age, gender, race.  
d. Obtain medical history, including prior surgeries.  
e. Obtain history of prior and concomitant medication. Add to 
Concomitant and Prior Medications Log. 
f. Provide participants and their families the illustrated U54 Study 
Booklet that will be used to:   
i. Supplement the information about the study procedures given 
in the permission/assent form;  
ii. Record medication administration, and;  
iii. Detail answers to any questions they have about the study. 
iv. A questionnaire will be included with the booklet asking 
families to evaluate how helpful the U54 Study Booklet was in 
their understanding of the research study. The participant and 
their parents may also provide feedback for the U54 Study 
Booklet as well; 
v. Because this questionnaire and survey are a nested study 
within the longitidunal study, participants and their families 
will also be given a handout,  (please see supplemental 
document, “U54 Study Booklet Information Handout,”) to 
explain the purpose of the U54 Study Booklet, the purpose of 
the questionnaire, and it describes that the responses to the 
booklet will be anonymous. 
vi. The U54 Study Booklet Information Handout serves as a 
permission/assent or consent document and the voluntary 
return of the questionnaire and survey serves as assumed 
permission/assent or consent. 
g. Provide handout explaining CHADIS. 

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h. Collect information regarding the participant’s comfort with 
needlesticks and ability to swallow pills.  Questions include: 
i. Parent impression about child’s anticipated comfort with 
needlestick 
ii. History of needlesticks 
iii. General fears about healthcare settings 
iv. Fears about unfamiliar situations 
v. Ability to swallow pills 
i. Collect blood sample for genotyping (~1 mL).  
i. The study team may order topical lidocaine (which for this 
study refers to either a J-tip or cream) if the study participant 
requests this for procedures requiring a needlestick. 
j. For enrolled participants where a washout is needed prior to 
beginning atomoxetine:  
i. A washout will only be considered for participants currently 
taking stimulant medication for ADHD. Examples of this 
include methylphenidate or amphetamine salts. 
ii. A study physician or qualified study personnel will determine 
if the washout may be conducted safely. If so, he or she will 
document approval of the washout on associated CRF. If this 
conversation occurs via telehealth, the study physician or 
qualified study personnel may document the conversation 
electronically and send an approval via email. The CRF and 
email will be printed and stored in the participant’s binder. 
Persons who are able to approve a washout will be identified 
in the Delegation of Authority/Roles. 
iii. Once the washout has been approved, study personnel will 
review the washout plan with the participant. Study personnel 
will: 
1. Document any questions or concerns that the 
participant and family have regarding washout.  
2. Document participant and family’s understanding and 
willingness to complete washout.  
3. Educate families on who to call if issues arise during 
washout. See “Washout Handout” in Supplementary 
Documents. 
4. Educate families to restart on medications (particularly 
if participant was on stimulants) if behaviors while off 
medication could cause risk to the participant.  
iv. A 1-week washout period of at least one week is sufficient for 
children taking stimulants. 
v. If the child is unable to washout of medication or the study 
physician does not approve the washout’s safety, they will be 
removed from the study.   

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vi. Schedule Research Visit 1 – Part 2 after washout period is 
anticipated to be completed. 
k. If it is determined that the participant was previously taking and 
subsequently discontinued any of the following medications (see 
below) prior to notification of study opportunity, an appropriate time 
to administer baseline questionnaires and to begin ATX intervention 
must be determined. 
i. ADHD medication other than a stimulant, e.g. ATX or α2-
agonists 
ii. Selective Serotonin Reuptake Transporter Inhibitor (SSRI) 
iii. Selective Serotonin/Norepinhephrine Reuptake Transporter 
Inhibitor (SNRI) 
iv. Any medication that could reasonably be expected to affect 
neurotransmitter concentrations, such as anxiolytics, 
antiepileptics, antipsychotics. 
v. A CYP2D6 inhibitor 
vi. The following table will be used as guidance for when to 
administer baseline questionnaires (i.e. return to baseline 
neurotransmitter levels and/or behavior) and when to begin 
ATX therapy (i.e. drug and/or active metabolites excreted 
from participant). However, this only addresses the most 
common medications that children with ADHD or behaviorial 
concerns are likely to be trialed on.  
1. The time indicated in “Medication Washout Interval,” 
is the minimum amount of time needed for medication 
to be removed and thus, the amount of time needed 
before beginning ATX intervention.  
2. Administering baseline questionnaires relates to 
estimating when the participant is likely to return to 
baseline behavior, which could be longer than the time 
needed for drug to be removed from systemic 
circulation. When it is noted that the, “length of 
pharmacodynamic effects can be variable,” the 
research team must rely on parent, teacher, and or 
participant report of symptoms and function. 
Evaluation of the participant’s medication chart may 
be also assessed for this information. 
vii. A detailed literature search must be conducted for 
medications not listed here. The process by which this occurs 
will be described in more detail in Appendix O. 
 
 

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Medication 
Class/Group 
Examples        
*also CYP2D6 
inhibitor 
(indication) 
When to Administer Baseline 
Questionnaires 
Medication Washout Interval (time 
expected for drug to be removed 
from systemic circulation) 
ADHD 
Medications     
(non-
stimulants) 
atomoxetine 
2-4 weeks 
CYP2D6 genotype dependent (2- 4 
weeks) 
clonidine 
(sleep) 
1-2 weeks 
CYP2D6 genotype dependent  (1-2 
weeks) 
clonidine 
(ADHD) 
2-4 weeks 
CYP2D6 genotype dependent  (2-4 
weeks) 
guanfacine 
(sleep) 
1-2 weeks 
May be CYP2D6 genotype dependent 
(1-2 weeks) 
guanfacine 
(ADHD) 
2-4 weeks 
May be CYP2D6 genotype dependent 
(2-4 weeks) 
SSRIs 
fluoxetine* 
Length of PD effects can be variable 
2 months, (inhibits 2D6, 3A4, 2C19) 
sertraline* 
Length of PD effects can be variable 
1 week, weak inhibitor of CYP2D6 
SNRI 
bupropion* 
Length of PD effects can be variable 
2 – 4 weeks (metabolites primary 
inhibitors) 
venlafaxine* 
Length of PD effects can be variable 
1 week, weak inhibitor of CYP2D6 
Antipyschotics 
aripiprazole 
Length of PD effects can be variable 
CYP2D6 genotype dependent (1-2 
months) 
risperidone 
Length of PD effects can be variable 
CYP2D6 genotype dependent (1 -2 
weeks) 
Antiepileptics 
levetiracetam 
Length of PD effects can be variable 
1 week 
valproic acid 
Length of PD effects can be variable 
1 week (2-4 years, t1/2 3.5 – 20 
hours) 
Anxiolytics 
buspirone 
Length of PD effects can be variable 
1 week 
CYP2D6 
Inhibitors 
imipramine 
Length of PD effects can be variable 
2 weeks 
nortriptyline 
Length of PD effects can be variable 
2 weeks (t1/2 14 -51 hours) 
quinidine 
immediately after washout 
1 week 
propafenone 
immediately after washout 
2 weeks 
cimetidine 
immediately after washout 
1 week (weak inhibitor of CYP2D6) 
tamoxifen 
immediately after washout 
2 months (may inhibit through 
competition at active site) 
terbinafine 
immediately after washout 
6 months 
cetirizine 
most likely immediately after 
washout, however histamine can 
affect neurotransmitter profile 
1 week 
loratidine 
most likely immediately after 
washout, however histamine can 
affect neurotransmitter profile 
1 week 
 
 
 

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2. Research Visit 1 – Part 2 
a. If Research Visit 1 – Part 1 and Research Visit 1 – Part 2 are scheduled on 
different dates, the research team will ensure that the participant and 
their family are aware of the safety measures at Children’s Mercy 
Hospital to prevent transmission of the SARS-CoV-2 virus. These 
resources and information to be shared will be detailed on the Children’s 
Mercy Hospital homepage and any PCRU guidance in response to COVID-
19. 
b. For participants where washout was needed: ensure that medication 
washout (with or without taper) has been completed. Ask about any 
changes to medical history, including if surgeries occurred between 
Research Visit 1 – Part 1 and this visit. Add this data to the CRF for 
Research Visit 1. Ask about any changes to history of prior and 
concomitant medication. Add to Concomitant and Prior Medications Log. 
c. Measure vital signs: height, weight, blood pressure, heart rate, 
respiration rate, and temperature.  
d. Perform physical exam.  
e. Perform Tanner Staging.  This procedure is optional according to 
participant preference.  
f. Obtain electrocardiogram reading. Send to cardiologist for interpretation. 
Sign off that participant has no underlying cardiac disease.  
g. Collect blood samples for safety laboratory tests (processed immediately 
at Children’s Mercy Hospital): CBC with differential, basic metabolic 
panel, and liver function test.  
i. 
The study team may order topical lidocaine (either J-tip or cream) 
if the study participant requests this for procedures requiring a 
needlestick. 
h. Collect blood samples for global neurotransmitter metabolomics analysis 
(pharmacodynamic sample) (2 mL).  
i. Perform urinary pregnancy test for female subjects age 10 and above.  
j. Collect urinary sample for safety laboratory tests (processed immediately 
at Children’s Mercy Hospital): urinalysis with microbiology.   
k. Collect urinary sample for CYP2D6 biomarker measurement (~10 mL).  
l. Collect baseline saliva for microbiome analysis (~2 mL).  
m. Perform assessment of attention tasks (Pupillometry during Posner’s 
Cuing Task). Further details can be found in Appendix H. 
n. Perform psychometric measures to confirm ADHD diagnosis and possible 
comorbidities:  
i. 
Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) 
(either paper or K-SADS-COMP). The following sections from the 
screen interview will be used: agoraphobia, separation anxiety 
disorder, social anxiety disorder/selective mutism, specific 

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phobias, generalized anxiety, obsessive compulsive disorder, and 
post-traumatic stress disorder. Supplemental sections will be 
filled for the above selected psychopathology as needed (parent 
and participant informant). 
ii. 
Kaufman Brief Intelligence Test (KBIT) (participant informant).  
iii. 
Behavior Rating Inventory of Executive Function (BRIEF) (parent 
informant. Teacher informant is optional).  
iv. 
Screen for Child Anxiety Related Disorders (SCARED) (parent and if 
participant ≥ 8 years of age) 
v. 
Barkley’s Sluggish Cognitive Tempo (SCT) (parent informant) 
o. Administer the following questionnaires:  
i. 
Medication Side Effects (parent and teacher informant) 
ii. 
NICHQ Vanderbilt Assessment Scale – Initial Assessment (parent 
and teacher informant) 
iii. 
Strengths and Difficulties Questionnaire (parent and teacher 
informant) 
iv. 
Child Behavior Checklist (parent and teacher informant) 
v. 
School Intervention Questionnaire (teacher informant) 
vi. 
Child Medical History$ (parent informant) 
vii. 
Of note, if these questionnaires were obtained within one year of 
this visit date AND were completed while the participant was not 
taking ADHD medication, these do not need to be readministered. 
Additionally, these are clinically validated questionnaires for 
ADHD. Different versions of these questiononaires are permissible 
to use to aid the Stuey Physician in a determination a diagnosis.  
p. Record adverse events. Document in Adverse Events log.  
q. Create Greenphire account. 
r. Add compensation to participant’s Greenphire account. 
s. Update Prior Medical History from data collected on questionnaire 
marked with $ above.  
 
3. Intake Visit with Study Physician 
a. This visit may occur in-person or via telehealth, at the Study Physician’s 
discretion. 
b. If this visit occurs in-person: 
i. Conduct physical exam. Documentation will be in EMR.   
ii. Assess and confirm/infer ADHD diagnosis.  
1. For participants without a formal diagnosis of ADHD (e.g. 
documentation of ADHD in participant’s electronic medical 
record), responses to questionnaires from parent and 
teacher will be sought prior to diagnosis. During the 
COVID-19 pandemic, teacher response are will not always 
available. In the event that teacher responses are not 

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Page 57 of 143 
available, the Study Physician may infer a diagnosis with 
the information that is available to the Study Physician, 
(e.g. school reports, previous teacher’s feedback) at their 
clinical discretion. Follow-up for a formal diagnosis is at 
the discretion of the Study Physician and is dependent on 
the pandemic situation and the available tools for 
diagnosis available while the participant is active in the 
study. 
2. For participants with a pre-existing diagnosis of ADHD, 
data from participant EHRs may be used to support 
confirmation of a diagnosis. EHRs from clinics outside of 
Children’s Mercy Hospital may be requested in the course 
of clinical practice. 
iii. Assess and confirm diagnosis of other comorbidities.  
iv. Assess and confirm appropriateness of atomoxetine therapy for 
participant.  
v. Assess for adverse events. Document in Adverse Events log.  
vi. Complete Clinical Global Impression (CGI). 
c. If this visit occurs via telehealth, the physical exam will be omitted. 
d. This visit may occur before enrollment if participant is referred from a 
Study Physician. This visit can occur within 6 weeks enrollment. 
e. If Children’s Mercy Hospital develops procedures for drive-up collection 
of vital signs (e.g. heart rate, blood pressure), the Study Physician may 
ask the participant to use this service to supplement their evaluation. 
 
4. Research Visit 2 
Prior to Visit 
a. Obtain CYP2D6 genotyping results for participant to 
calculate CYP2D6 activity score and determine a CYP2D6 predicted 
phenotype.  
b. Determine whether the First Dose Pharmacokinetic Study of 
atomoxetine for participant will be Study Design 1 or Study Design 2.   
c. Determine an atomoxetine dose using participant CYP2D6 predicted 
phenotype, height, weight, obesity status, and gender obtained from 
Research Visit 1. This dose will be simulated to target a 
plasma Cmax,ss of 400 ng/mL. This will be determined using the iGO-PK 
model (see section 5.1 above) . 
d. Obtain a signed and dated prescription from a Study Physician for a 
dose of atomoxetine that is expected to result in a plasma Cmax,ss of 
400 ng/mL.   
e. Optional: Obtain a signed and dated prescription for topical lidocaine 
(either J-tip or cream) to alleviate pain with needlestick for 
participant.  

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f. Submit signed and dated prescription to Children’s Mercy Hospital 
Investigation Drug Services (IDS) pharmacy.  
g. Confirm placement in Study Design 1 or Study Design 2. 
h. Contact participant and participant’s family  prior to the visit to:  
a. Remind them of their scheduled Research Visit 2.  
b. Inform as to which Study Design the participant will be under 
for Research Visit 2 and all remaining research visits.   
c. Instruct participant to begin fasting at midnight prior to 
coming in for Research Visit 2. Water is permissible while 
fasting.  
d. The research team will ensure that the participant and their 
family are aware of the safety measures at Children’s Mercy 
Hospital to prevent transmission of the SARS-CoV-2 virus. 
These resources and information to be shared will be detailed 
on the Children’s Mercy Hospital homepage and any PCRU 
guidance in response to COVID-19. 
 
On Day of Visit  
a. Confirm participant’s willingness to continue in the research study.  
b. Obtain medication history and concomitant medications. Add to 
Concomitant and Prior Medications Log. 
c. Measure vital signs: height, weight, blood pressure, heart rate, 
respiration rate, and temperature.  
d. Perform physical exam.  
e. Place indwelling venous catheter to obtain blood samples for safety 
labs and for atomoxetine pharmacokinetic and pharmacodynamic 
analysis.  
f. Collect blood samples for the following safety laboratory tests (to be 
processed immediately at Children’s Mercy Hospital): CBC with 
differential, basic metabolic panel, and liver function test.   
i. 
These tests may be omitted if these data were collected in the 
week prior, at the discretion of the study coordinator, the 
physician performing the physical exam, or any person 
designated in the delegation of authority log.  
g. Collect urine for urinalysis with microbiology.  
h. Perform urinary pregnancy test on female subjects.  
i. Collect baseline urine sample (~10 mL) for predose urine sample and 
CYP2D6 biomarker analysis.  
j. Confirm prior to dosing that participant is:  
i. 
Healthy enough to continue Research Visit 2 (sign off on safety 
labs and physical exam sheet by physician).  
ii. 
Not pregnant, females only (urine pregnancy test).  
k. Place two sweat patches on the participants back. The sweat patch is 
15.4 cm2 in size and consists of a cellulose blotter paper collection pad 

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(PharmChek®, PharmaChem Laboratories, Menlo Park, CA). Prior to 
patch placement, clean the area of skin to which the patch will be 
applied with rubbing alcohol.  
l. Collect pre-dose blood, blood pressure, and heart rate prior to dosing 
medication.  
m. Administer dose of atomoxetine according to prescription.  
n. Collect  3 mL of blood, blood pressure, and heart rate at the following 
time points after dose administration:  
i. 
Timeframe:  
i. Study Design 1: 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 
20, 24, 48, and 72 hours.  
ii. Study Design 2: 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 
hours.  
iii. A window of ± 5 minutes is acceptable for blood draws 
at time points 0.5 – 2 hours.  
iv. A window of ± 15 minutes is acceptable for blood 
draws at all other time points.  
ii. 
Collection Instructions: 2 mL of blood will be collected in a 
EDTA tube and 1 mL of blood will be collected in a serum gel 
separator tube.  
iii. 
Processing: Within an hour of collecting sample, plasma and 
serum will be separated by centrifugation at 4°C (1000 – 
2000 g x 10 min), aspirated manually, and transferred to 
polypropylene cryovials for storage at -70°C until analysis.   
o. Collect and pool urine starting after dose administration.  
i. 
Study Design 1: collect all urine for the first 24 hours in the 
PCRU. Discharge participant with urine jug at 24 hour and 48 
hour time point and instruct participants to return urine jug 24 
hours later to PCRU. Record volume of urine excreted for the 
intervals of 0-24 hrs, 24-48 hrs, and 48-72 hours post drug 
administration. Collect a ~10 mL sample from each urine 
interval. NB: The study team will instruct the participant that 
every attempt should be made to collect all urine, however 
the team recognizes that collecting urine while at school or at 
work may not be feasible. 
ii. 
Study Design 2: collect all urine 12 hours post drug 
administration. Record the volume of urine excreted. Collect a 
~10 mL sample.  
p. Collect ~ 2 mL of saliva. Instruct participant not to eat or drink for 30 
minutes prior to beginning to spit.  
q. Remove sweat patches  
i. 
For Study Design 1, remove one sweat patch 12 and 24 hours 
post drug administration. Place sweat patch in 
labeled ziplock bag for storage at -70°C until analysis.   

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ii. 
For Study Design 2, remove one sweat patch 8 and 12 hours 
post drug administration. Place sweat patch in 
labeled ziplock bag for storage at -70°C until analysis.  
r. The research team will ask the participant to fast for 2 hours after 
drug administration. After this 2-hour mark, the participant is free to 
eat and drink as desired. Document all meal times and content. 
Collect food receipts when available. The following are scenarios 
where the research team may deviate from fasting for 2 hours post-
administration: 
i. 
A participant may request to take atomoxetine with a small 
amount of soft food (e.g., pudding, applesauce, etc.) to aid 
with capsule swallowing. Document the food and approximate 
volume the participant used to aid with capsule swallowing 
(e.g., participant took capsule with ~1 teaspoon of chocolate 
pudding). 
ii. 
If participant reports GI upset, a small snack may be given to 
alleviate symptoms, even in the event that the fasting time 
has not been completed. Document GI upset as an adverse 
event in the adverse events log. If snack is given, document 
the snack time and content. 
s. Perform assessment of attention tasks (Pupillometry during Posner’s 
Cuing Task). Further details can be found in Appendix H. 
t. Perform Tanner Staging exam. This procedure is optional according to 
participant preference. The participant does not need to have Tanner 
Staging if this was performed previously within 4 weeks prior of 
Research Visit 2 or if the participant has already reached maximum 
stage in a prior Tanner staging exam.  
u. Dispense medication to participant and discuss instructions on 
atomoxetine prescription and for medication calendar.   
v. Assess for adverse events. Document in Adverse Events log.  
w. Add compensation to participant’s Greenphire account. 
 
5. Research Visit 3 
Prior to Visit  
a. Optional: Obtain a signed and dated prescription from a Study 
Physician for topical lidocaine (either J-tip or cream) to alleviate pain 
with needlestick for participant.  
b. Submit signed and dated prescription to Children’s Mercy Hospital 
Investigation Drug Services (IDS) pharmacy.  
c. Confirm participation in Study Design 1, Study Design 2, or need to 
switch to Study Design 3. 
d. If participant will be changing to Study Design 3, discuss with 
participant and/or family changes from Study Design 2. 

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e. Contact participant and participant’s family between 8-10 days prior 
to Research Visit 3 to remind participant to take all prescribed doses 
the week prior to Research Visit 3.  
f. Contact participant and participant’s family 1 -2 days prior to the 
visit to:  
i. 
Remind them of their scheduled visit.  
ii. 
Ensure that participant has been compliant on medication for 
1 week prior to scheduled Research Visit 3.  
i. If the participant has not been compliant, the visit will 
need to rescheduled. 
iii. 
Instruct participant to begin fasting at midnight prior to the 
visit. Water is permissible while fasting.  
iv. 
Remind participant to bring their home atomoxetine 
medication to the PCRU, but to not take the medication in the 
morning.  
v. 
Remind participant to bring U54 Study Booklet, which contains 
the participant’s medication calendar.  
vi. 
If participant has been switched to evening dosing of ATX, 
schedule Research Visit 3 to mirror how the participant 
typically takes their medication. (i.e. if the participant takes 
their medication in the evening, the beginning of their 
pharmacokinetic study should also be in the evening). 
vii. 
The research team will ensure that the participant and their 
family are aware of the safety measures at Children’s Mercy 
Hospital to prevent transmission of the SARS-CoV-2 virus. 
These resources and information to be shared will be detailed 
on the Children’s Mercy Hospital homepage and any PCRU 
guidance in response to COVID-19. 
 
On Day of Visit  
a. Confirm participant’s willingness to continue in the research 
study.  
b. Obtain medication history and concomitant medications. Add to 
Concomitant and Prior Medications Log. 
c. Verify medication calendar with remaining capsules count.  
d. Make copies of pages in medication calendar. 
e. Measure vital signs: height, weight, blood pressure, heart rate, 
respiration rate, and temperature.  
f. Perform physical exam.  
g. Place indwelling venous catheter to obtain blood samples for 
safety labs and for atomoxetine pharmacokinetic and 
pharmacodynamic analysis.  
h. Collect blood samples for the following safety laboratory tests (to 
be processed immediately at Children’s Mercy Hospital): CBC with 

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differential, basic metabolic panel, and liver function test. These 
tests may be omitted if these data were collected in the week 
prior, at the discretion of the study coordinator, the physician 
performing the physical exam or any person designated in the 
delegation of authority log.  
i. Collect urine for urinalysis with microbiology.  
j. Perform urinary pregnancy test on female subjects 10 years of age 
or older.  
k. Collect baseline urine sample (~10 mL) for predose urine sample 
and CYP2D6 biomarker analysis.  
l. Confirm prior to dosing that participant is:  
i. 
Healthy enough to continue Research Visit 3 (sign off on 
safety labs and physical exam sheet by physician).  
ii. 
Not pregnant, females only (urine pregnancy test).  
iii. 
Has been compliant with medication (medication calendar 
check).  If the participant has not been compliant, the visit 
will need to rescheduled. 
m. Place two sweat patches on the participant’s back. The sweat 
patch is 15.4 cm2 in size and consists of a cellulose blotter paper 
collection pad (PharmChek®, PharmaChem Laboratories, Menlo 
Park, CA). Prior to patch placement, clean the area of skin to 
which the patch will be applied with rubbing alcohol.  
n. Collect pre-dose blood, blood pressure, and heart rate prior to 
dosing medication.  
o. Administer dose of atomoxetine according to prescription.  
p. Collect 3 mL of blood, blood pressure, and heart rate at the 
following time points after dose administration:  
i. 
Timeframe:  
i. Study Design 1: 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 
16, 20, and 24 hours.  
ii. Study Design 2: 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 
hours.  
iii. Study Design 3:  
1. Following first dose: Collect at 0.5, 0.75, 1, 
1.5, 2, 3, 4, 6, 8, 10, and 12 hours as 
applicable following first dose and will 
continue only until the second dose is given.   
2. Second dose will be given at the same time 
increment between when participant 
routinely takes their first and second dose ± 
5 minutes (eg. If 6 hours are between 
routine dosing for participant, the second 
study dose will be given 6 hours ± 5 minutes 
after the first dose).   

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3. Collect predose blood, blood pressure, 
heart rate prior to dosing 2nd dose 
4. Once the second dose is given, continued 
blood draws, blood pressure, and heart rate 
collection based on the timing of the first 
dose will stop.   
5. Timing of blood, blood pressure, and heart 
rate will now be timed according to second 
dose only.   
6. Timing of collections will restart, with 
timepoints 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 
and 16 hours after the second dose. 
iv. A window of ± 5 minutes is acceptable for blood 
draws at time points 0.5 – 2 hours.  
v. A window of ± 15 minutes is acceptable for blood 
draws at all other time points.  
ii. 
Collection Instructions: 2 mL of blood will be collected in 
an EDTA tube and 1 mL of blood will be collected in a 
serum gel separator tube.  
iii. 
Processing: Within an hour of collecting sample, plasma 
and serum will be separated by centrifugation at 4°C (1000 
– 2000 g x 10 min), aspirated manually, and transferred to 
polypropylene cryovials for storage at -70°C until analysis.   
q. Collect and pool urine starting after dose administration.  
i. 
Study Design 1: collect all urine for the first 24 hours in the 
PCRU. Record the volume of urine excreted. Collect a ~10 
mL sample and store in 15 mL polypropylene falcon tubes 
for storage at -70°C until analysis.  
ii. 
Study Design 2: collect all urine 12 hours post drug 
administration. Record the volume of urine excreted. 
Collect a ~10 mL sample and store in 15 mL polypropylene 
falcon tubes for storage at -70°C until analysis.  
iii. 
Study Design 3: collect all urine starting after the first dose 
and continuing through 16 hours post second dose 
administration. Record the volume of urine excreted. 
Collect a ~10 mL sample and store in 15 mL polypropylene 
falcon tubes for storage at -70°C until analysis.  
r. Collect ~ 2 mL of saliva. Instruct participant not to eat or drink for 
30 minutes prior to beginning to spit.  
s. Remove sweat patches  
i. 
For Study Design 1, remove one sweat patch 12 and 24 
hours post drug administration. Place sweat patch in 
labeled ziplock bag for storage at -70°C until analysis.   

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ii. 
For Study Design 2, remove one sweat patch 8 and 12 
hours post drug administration. Place sweat patch in 
labeled ziplock bag for storage at -70°C until analysis.  
iii. 
For Study Design 3, remove one sweat patch 8 and 16 
hours post second drug dose administration. Place sweat 
patch in labeled ziplock bag for storage at -70°C until 
analysis.  
t. The research team will ask the participant to fast for 2 hours after 
drug administration. After this 2 hour mark, the participant is free 
to eat and drink as desired. Document all meal times and content. 
Collect food receipts when available. The following are scenarios 
where the research team may deviate from fasting for 2 hours 
post-administration 
i. A participant may request to take atomoxetine with a 
small amount of soft food (e.g., pudding, applesauce, etc.) 
to aid with capsule swallowing. Document the food and 
approximate volume the participant used to aid with 
capsule swallowing (e.g., participant took capsule with ~1 
teaspoon of chocolate pudding). 
ii. If participant reports GI upset, a small snack may be given 
to alleviate symptoms, even in the event that the fasting 
time has not been completed. Document GI upset as an 
adverse event in the adverse events log. If snack is given, 
document the snack time and content 
iii. Fasting will not be required for participants taking 
medication in the evening who are participating in an 
overnight pharmacokinetic study. The research team does 
not believe it is feasible to expect a child to fast for 8-12 
hours while awake. 
iv. If participant is assigned Study Design 3, fasting prior to 
and/or after the second dose of medication will not be 
required.  The research team does not believe it is feasible 
to expect a child to fast prior to both the first dose and 
second dose. 
u. Perform assessment of attention tasks (Pupillometry during 
Posner’s Cuing Task). Further details can be found in Appendix H. 
v. Perform Tanner Staging. This procedure is optional according to 
participant preference. The participant does not need to have 
Tanner Staging if this was performed previously within 4 weeks 
prior of Research Visit 3 or if the participant has already reached 
maximum stage in a prior Tanner staging exam.  
w. Assess for adverse events. Document in Adverse Events log.  
x. Add compensation to participant’s Greenphire account. 
 

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6. 6-Week Visit with Study Physician 
Prior to Visit  
a. Dose adjustment may be required before this visit, particularly if 
there are reports of severe adverse events (e.g. unremitting GI 
issues) or lack of efficacy. When this occurs, the study physician 
may adjust the ATX regimen as needed. Documentation of 
changes will be recorded in the participants electronic medical 
record. If a new prescription is required, the study physician will 
follow the procedures outlined in “Other visit related activities,” 
(see below). 
b. Send out the following psychometric questionnaires 1-2 weeks 
prior to 6-Week Visit with Study Physician:  
i. 
Medication Side Effects (parent and teacher informant) 
ii. 
NICHQ Vanderbilt Assessment Scales follow-up 
assessment (parent and teacher informant) 
iii. 
Please note: Responses will always be sought, but the 
study team recognizes the potential difficulties with 
returning results, particularly during the summer break or 
the pandemic for teachers. The study team will remind the 
parent to complete his or her questionnaires a maximum 
of 3 times if applicable to the participant’s school 
situation. Additionally, the study team will encourage 
parents to reach out to their child’s teacher(s) to return 
questionnaires as well. A reminder for parents to reach 
out to teachers will occur a maximum of 3 times. 
iv. 
Questionnaires should be returned ± 2 weeks of study visit 
with physician. 
v. 
If questionnaires are late or are not received, this will be 
noted on CRFs and are considered “missing data.”  
vi. 
Both the Medication Side Effects and NICHQ Vanderbilt 
Assessment scales are validated questionnaires that are 
used to aid Study Physician in determining treatment 
response. Use of different versions of these questionnaires 
are permissible to aid the Study Physician, in additional to 
clinical impression, with medication management and 
determination of response. 
c. Contact participant and participant’s family 1 -2 days prior to 6-
Week Visit with Study Physician to:  
i. 
Remind them of their scheduled 6-Week Visit with Study 
Physician.  
ii. 
Remind participant to bring their home atomoxetine 
medication to 6-Week Visit with Study Physician (in-person 
visit only). 

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iii. 
Remind participant to bring U54 Study Booklet, which 
contains the participant’s medication calendar (in-person 
visit only).  
Day of Visit  
a. This visit may occur in-person or via telehealth, at the Study 
Physician’s discretion. 
b. If this visit occurs in-person: 
i. The research team will ensure that the participant and 
their family are aware of the safety measures at Children’s 
Mercy Hospital to prevent transmission of the SARS-CoV-2 
virus. These resources and information to be shared will 
be detailed on the Children’s Mercy Hospital homepage. 
ii. Conduct physical exam. Documentation will be in EMR. 
iii. Assess ADHD symptoms/review questionnaires.  
iv. Assess other comorbidities and concurrent medications. 
Add to Concomitant and Prior Medications Log. 
v. Assess for atomoxetine side effects.  
vi. Make atomoxetine dose changes as necessary, with 
guidance from study team if necessary and document 
reason for changes.  
vii. Document prescription change (if made) in CRF.  
viii. Assess for adverse events. Document in Adverse Events 
log.  
ix. Verify medication calendar with remaining capsules 
count.  
x. Make copies of pages in medication calendar. 
xi. Complete Clinical Global Impression (CGI) 
c. If this visit occurs via telehealth proceed with all procedures 
stated above with the following exceptions: 
i. The physical exam will be omitted. 
ii. Ask the participant to email pictures of the pertinent 
adherence calendar pages and a picture of the remaining 
medication. 
 
Other Visit Related Activities 
a. Obtain a signed and dated prescription for atomoxetine from 
Study Physician. This may occur prior, during, or after this visit. 
b. Submit signed and dated prescription to Children’s Mercy Hospital 
Investigation Drug Services (IDS) pharmacy.  
c. Deliver medication to patient, or leave medication at Children’s 
Mercy Outpatient Pharmacy for family to pick up medication at 
their convenience. Medication may be mailed (see section 5.2) at 
the request of the participant’s family. 

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d. Add compensation to participant’s Greenphire account if calendar 
and medication bottle brought to visit. 
e. If Children’s Mercy Hospital develops procedures for drive-up 
collection of vital signs (e.g. heart rate, blood pressure), the Study 
Physician may ask the participant to use this service to 
supplement their evaluation. 
 
7. 12-Week Visit with Study Physician 
Prior to Visit 
a. Dose adjustment may be required before this visit, particularly if 
there are reports of severe adverse events (e.g. unremitting GI 
issues) or lack of efficacy. When this occurs, the study physician 
may adjust the ATX regimen as needed. Documentation of 
changes will be recorded in the participants electronic medical 
record. If a new prescription is required, the study physician will 
follow the procedures outlined in “Other visit related activities,” 
(see below). 
b. Send out the following psychometric questionnaires 1-2 weeks 
prior to  12-Week Visit with Study Physician:  
i. 
Medication Side Effects (parent and teacher informant) 
ii. 
NICHQ Vanderbilt Assessment Scales follow-up assessment 
(parent and teacher informant) 
iii. 
Please note: Responses will always be sought, but the 
study team recognizes the potential difficulties with 
returning results, particularly during the summer break or 
the pandemic for teachers. The study team will remind the 
parent to complete his or her questionnaires a maximum 
of 3 times if applicable to the participant’s school 
situation. Additionally, the study team will encourage 
parents to reach out to their child’s teacher(s) to return 
questionnaires as well. A reminder for parents to reach 
out to teachers will occur a maximum of 3 times. 
iv. 
Questionnaires should be returned ± 2 weeks of study visit 
with physician. 
v. 
If questionnaires are late or are not received, this will be 
noted on CRFs and are considered “missing data.”  
vi. 
Both the Medication Side Effects and NICHQ Vanderbilt 
Assessment scales are validated questionnaires that are 
used to aid Study Physician in determining treatment 
response. Use of different versions of these questionnaires 
are permissible to aid the Study Physician, in additional to 
clinical impression, with medication management and 
determination of response. 

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c. Contact participant and participant’s family 1 -2 days prior to 12-
Week Visit with Study Physician to:  
i. 
Remind them of their scheduled 12-Week Visit with Study 
Physician.  
ii. 
Remind participant to bring their home atomoxetine 
medication to 12-Week Visit with Study Physician (in-
person visit only). 
iii. 
Remind participant to bring U54 Study Booklet, which 
contains the participant’s medication calendar (in-person 
visit only).  
Day of Visit 
a. This visit may occur in-person or via telehealth, at the Study 
Physician’s discretion. 
b. If this visit occurs in-person: 
i. Conduct physical exam. Documentation will be in EMR. 
ii. Assess ADHD symptoms/review questionnaires.  
iii. Assess other comorbidities and concurrent medications. 
Add to Concomitant and Prior Medications Log. 
iv. Assess for atomoxetine side effects.  
v. Make atomoxetine dose changes as necessary, with 
guidance from study team if necessary and document 
reason for changes.  
vi. Document prescription change (if made) in CRF.  
vii. Assess for adverse events. Document in Adverse Events 
log.  
viii. Verify medication calendar with remaining capsules 
count.  
ix. Make copies of pages in medication calendar. 
x. Complete Clinical Global Impression (CGI) 
c. If this visit occurs via telehealth, proceed with all procedures 
stated above with the following exceptions: 
i. The physical exam will be omitted. 
ii. Ask the participant to email pictures of the pertinent 
adherence calendar pages and a picture of the remaining 
medication. 
 
Other Visit Related Activities 
a. Obtain a signed and dated prescription for atomoxetine from 
Study Physician. This may occur prior, during, or after this visit. 
b. Submit signed and dated prescription to Children’s Mercy Hospital 
Investigation Drug Services (IDS) pharmacy.  
c. Deliver medication to patient, or leave medication at Children’s 
Mercy Outpatient Pharmacy for family to pick up medication at 

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their convenience. Medication may be mailed (see section 5.2) at 
the request of the participant’s family. 
Add compensation to participant’s Greenphire account if calendar 
and medication bottle brought to visit. 
d. If Children’s Mercy Hospital develops procedures for drive-up 
collection of vital signs (e.g. heart rate, blood pressure), the Study 
Physician may ask the participant to use this service to 
supplement their evaluation. 
 
8. 18-Week Visit with Study Physician 
Prior to Visit  
a. Dose adjustment may be required before this visit, 
particularly if there are reports of severe adverse events 
(e.g. unremitting GI issues) or lack of efficacy. When this 
occurs, the study physician may adjust the ATX regimen as 
needed. Documentation of changes will be recorded in the 
participants electronic medical record. If a new 
prescription is required, the study physician will follow the 
procedures outlined in “Other visit related activities,” (see 
below). 
b. Send out the following psychometric questionnaires 1-2 
weeks prior to  18-Week Visit with Study Physician:  
i. 
Medication Side Effects (parent and teacher informant) 
ii. 
NICHQ Vanderbilt Assessment Scales follow-
up assessment (parent and teacher) 
iii. 
Strengths and Difficulties Questionnaire (parent and 
teacher informant) 
iv. 
Child Behavior Checklist (parent and teacher 
informant) 
v. 
School Intervention Questionnaire (teacher informant) 
vi. 
Please note: Responses will always be sought, but the 
study team recognizes the potential difficulties with 
returning results, particularly during the summer break 
or the pandemic for teachers. The study team will 
remind the parent to complete his or her 
questionnaires a maximum of 3 times if applicable to 
the participant’s school situation. Additionally, the 
study team will encourage parents to reach out to their 
child’s teacher(s) to return questionnaires as well. A 
reminder for parents to reach out to teachers will 
occur a maximum of 3 times. 
vii. 
Questionnaires should be returned ± 2 weeks of study 
visit with physician. 

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viii. 
If questionnaires are late or are not received, this will 
be noted on CRFs and are considered “missing data.”  
vii. 
All clinical questonnaires are validated tools that are 
used to aid the Study Physician in determining 
treatment response. Use of different versions of these 
questionnaires are permissible to aid the Study 
Physician, in additional to clinical impression, with 
medication management and determination of 
response. 
 
b. Contact participant and participant’s family 1 -2 days prior to 18-
Week Visit with Study Physician to:  
i. 
Remind them of their scheduled 18-Week Visit with Study 
Physician.  
ii. 
Remind participant to bring their home atomoxetine 
medication to 18-Week Visit with Study Physician (in-
person visit only). 
iii. 
Remind participant to bring U54 Study Booklet, which 
contains the participant’s medication calendar (in-person 
visit only).  
Day of Visit  
a. This visit may occur in-person or via telehealth, at the Study 
Physician’s discretion. 
b. If this visit occurs in-person: 
i. Conduct physical exam. Documentation will be in EMR. 
ii. Assess ADHD symptoms/review questionnaires.  
iii. Assess other comorbidities and concurrent medications. 
Add to Concomitant and Prior Medications Log. 
iv. Assess for atomoxetine side effects.  
v. Make atomoxetine dose changes as necessary, with 
guidance from study team if necessary and document 
reason for changes.  
vi. Document prescription change (if made) in CRF.  
vii. Assess for adverse events. Document in Adverse Events 
log.  
viii. Verify medication calendar with remaining capsules 
count.  
ix. Make copies of pages in medication calendar. 
x. Complete Clinical Global Impression (CGI) 
c. If this visit occurs via telehealth, proceed with all procedures 
stated above with the following exceptions: 
i. The physical exam will be omitted. 

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Page 71 of 143 
ii. Ask the participant to email pictures of the pertinent 
adherence calendar pages and a picture of the remaining 
medication. 
 
Other Visit Related Activities 
a. Obtain a signed and dated prescription for atomoxetine from 
Study Physician. This may occur prior, during, or after this visit. 
b. Submit signed and dated prescription to Children’s Mercy Hospital 
Investigation Drug Services (IDS) pharmacy.  
c. Deliver medication to patient, or leave medication at Children’s 
Mercy Outpatient Pharmacy for family to pick up medication at 
their convenience. Medication may be mailed (see section 5.2) at 
the request of the participant’s family. 
d. Add compensation to participant’s Greenphire account if calendar 
and medication bottle brought to visit. 
e. If Children’s Mercy Hospital develops procedures for drive-up 
collection of vital signs (e.g. heart rate, blood pressure), the Study 
Physician may ask the participant to use this service to 
supplement their evaluation. 
 
9. Research Visit 4   
 Prior to Visit  
a. Optional: Obtain a signed and dated prescription by a Study 
Physician for topical lidocaine (either J-tip or cream) to alleviate 
pain with needlestick for participant.  
b. Submit signed and dated prescription to Children’s Mercy Hospital 
Investigation Drug Services (IDS) pharmacy.  
c. Confirm participation in Study Design 1, Study Design 2, or need 
to switch to Study Design 3. 
d. If participant will be changing to Study Design 3 or back to Study 
Design 2, discuss with participant and/or family changes from 
prior study design. 
e. Contact participant and participant’s family 8-10 days prior to 
Research Visit 4 to remind participant to take all prescribed doses 
of medication in the week prior to Research Visit 4.  
f. If participant has been switched to evening dosing of ATX, 
schedule Research Visit 4 to mirror how the participant typically 
takes their medication (i.e. if the participant takes their 
medication in the evening, the beginning of their pharmacokinetic 
study should also be in the evening). 
g. Contact participant and participant’s family 1 -2 days prior to 
Research Visit 4 to:  
i. 
Remind them of their scheduled visit.  

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ii. 
Ensure that participant has been compliant on medication 
for 1 week prior to scheduled Research Visit 3.  
i. If the participant has not been compliant, the visit will 
need to rescheduled. 
iii. 
Instruct participant to begin fasting at midnight prior 
to visit. Water is permissible while fasting.  
iv. 
Remind participant to bring their home atomoxetine 
medication to the PCRU, but to not take the medication in 
the morning.  
v. 
Remind participant to bring U54 Study Booklet, which 
contains the participant’s medication calendar.  
vi. 
The research team will ensure that the participant and 
their family are aware of the safety measures at the 
Children’s Mercy Hospital to prevent transmission of the 
SARS-CoV-2 virus. These resources and information to be 
shared will be detailed on the Children’s Mercy Hospital 
homepage and any PCRU guidance in response to COVID-
19. 
 
On Day of Visit  
a. Confirm participant’s willingness to continue in the research 
study.  
b. Obtain medication history and concomitant medications. Add 
to Concomitant and Prior Medications Log. 
c. Verify medication calendar with number of remaining 
capsules.   
d. Take back medication calendar.   
e. Measure vital signs: height, weight, blood pressure, heart rate, 
respiration rate, and temperature.  
f. Perform physical exam.  
g. Place indwelling venous catheter to obtain blood samples for 
safety labs and for atomoxetine pharmacokinetic and 
pharmacodynamic analysis.  
h. Collect blood samples for the following safety laboratory tests 
(to be processed immediately at Children’s Mercy Hospital): 
CBC with differential, basic metabolic panel, and liver function 
test.  These tests may be omitted if these data were collected 
in the week prior, at the discretion of the study coordinator, 
the physician performing the physical exam or any person 
designated in the delegation of authority log.  
i. Collect urine for urinalysis with microbiology.  
j. Perform urinary pregnancy test on female subjects 10 years of 
age or older.  

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k. Collect baseline urine sample (~10 mL) for predose urine 
sample and CYP2D6 biomarker analysis.  
l. Confirm prior to dosing that participant is:  
i. 
Healthy enough to continue Research Visit 4 (sign off on 
safety labs and physical exam sheet by physician).  
ii. 
Not pregnant, females only (urine pregnancy test).  
iii. 
Has been compliant with medication (medication calendar 
check).  If the participant has not been compliant, the visit 
will need to rescheduled. 
m. Place two sweat patches on the participant’s back. The sweat 
patch is 15.4 cm2 in size and consists of a cellulose blotter 
paper collection pad (PharmChek®, PharmaChem 
Laboratories, Menlo Park, CA). Prior to patch placement, clean 
the area of skin to which the patch will be applied with 
rubbing alcohol.  
n. Collect pre-dose blood, blood pressure, and heart rate prior to 
dosing medication.  
o. Administer dose of atomoxetine according to prescription.  
p. Collect 3 mL of blood, blood pressure, and heart rate at the 
following time points after dose administration:  
i. 
Timeframe:  
i. 
Study Design 1: 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 
12, 16, 20, and 24 hours.  
ii. 
Study Design 2: 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 
10, and 12 hours.  
iii. 
Study Design 3:  
1. Following first dose: Collect at 0.5, 
0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 
hours as applicable following first 
dose and will continue only until the 
second dose is given.   
2. Second dose will be given at the 
same time increment between when 
participant routinely takes their first 
and second dose (eg. If 6 hours are 
between routine dosing for 
participant, the second study dose 
will be given 6 hours after the first 
dose).   
3. Collect predose blood, blood 
pressure, heart rate prior to dosing 
2nd dose 
4. Once the second dose is given, 
continued blood draws, blood 

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pressure, and heart rate collection 
based on the timing of the first dose 
will stop.   
5. Timing of blood, blood pressure, and 
heart rate will now be timed 
according to second dose only.   
6. Timing of collections will restart, 
with timepoints 0.5, 0.75, 1, 1.5, 2, 
3, 4, 6, 8, 12, and 16 hours after the 
second dose. 
iv. 
A window of ± 5 minutes is acceptable for blood 
draws at time points 0.5 – 2 hours.  
v. 
A window of ± 15 minutes is acceptable for blood 
draws at all other time points.  
ii. 
Collection Instructions: 2 mL of blood will be collected in 
an EDTA tube and 1 mL of blood will be collected in a 
serum gel separator tube.  
iii. 
Processing: Within an hour of collecting sample, plasma 
and serum will be separated by centrifugation at 4°C (1000 
– 2000 g x 10 min), aspirated manually, and transferred to 
polypropylene cryovials for storage at -70°C until analysis.   
q. Collect and pool urine starting after dose administration.  
i. 
Study Design 1: collect all urine for the first 24 hours in the 
PCRU. Record the volume of urine excreted. Collect a ~10 
mL sample and store in 15 mL polypropylene falcon tubes 
for storage at -70°C until analysis.  
ii. 
Study Design 2: collect all urine 12 hours post drug 
administration. Record the volume of urine excreted. 
Collect a ~10 mL sample and store in 15 mL polypropylene 
falcon tubes for storage at -70°C until analysis.  
iii. 
Study Design 3: collect all urine starting after the first dose 
and continuing through 16 hours post second dose 
administration. Record the volume of urine excreted. 
Collect a ~10 mL sample and store in 15 mL polypropylene 
falcon tubes for storage at -70°C until analysis.  
r. Collect ~ 2 mL of saliva. Instruct participant not to eat or drink 
for 30 minutes prior to beginning to spit.  
s. Remove sweat patches  
i. 
For Study Design 1, remove one sweat patch 12 and 24 
hours post drug administration. Place sweat patch in 
labeled ziplock bag for storage at -70°C until analysis.   
ii. 
For Study Design 2, remove one sweat patch 8 and 12 
hours post drug administration. Place sweat patch in 
labeled ziplock bag for storage at -70°C until analysis.  

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iii. 
For Study Design 3, remove one sweat patch 8 and 16 
hours post second drug dose administration. Place sweat 
patch in labeled ziplock bag for storage at -70°C until 
analysis.  
t. Obtain end of study electrocardiogram reading. Send to 
cardiologist for interpretation.  
u. The research team will ask the participant to fast for 2 hours 
after drug administration. After this 2-hour mark, the 
participant is free to eat and drink as desired. Document all 
meal times and content. Collect food receipts when available. 
The following are scenarios where the research team may 
deviate from fasting for 2 hours post-administration:  
i. 
A participant may request to take atomoxetine with a 
small amount of soft food (e.g. pudding, applesauce, etc.) 
to aid with capsule swallowing. Document the food and 
approximate volume the participant used to aid with 
capsule swallowing (e.g. participant took capsule with ~1 
teaspoon of chocolate pudding). 
ii. 
If participant reports GI upset, a small snack may be given 
to alleviate symptoms, even in the event that the fasting 
time has not been completed. Document GI upset as an 
adverse event in the adverse events log. If snack is given, 
document the snack time and content. 
iii. 
Fasting will not be required for participants taking 
medication in the evening who are participating in an 
overnight pharmacokinetic study. The research team does 
not believe it is feasible ot expect a child to fast for 8-12 
hours while awake. 
iv. 
If participant is assigned Study Design 3, fasting prior to 
and/or after the second dose of medication will not be 
required.  The research team does not believe it is feasible 
to expect a child to fast prior to both the first dose and 
second dose. 
v. Perform assessment of attention tasks (Pupillometry during 
Posner’s Cuing Task). Further details can be found in Appendix 
H. 
w. Perform Tanner Staging. The participant does not need to 
have Tanner Staging if this was performed previously within 4 
weeks prior of Research Visit 3 or if the participant has already 
reached maximum stage in a prior Tanner staging exam.  
x. Administer end of study psychometric questionnaires:  
i. 
Screen for Child Anxiety Related Disorders (SCARED parent 
and participants ≥ 8 years old informant).  

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ii. 
Barkley’s Sluggish Cognitive Tempo (SCT) (parent 
informant).  
iii. 
Behavior Rating Inventory of Executive Function (BRIEF) 
(parent informant. Teacher informant is optional).  
y. Administer Dietary Survey Questionnaire (participant 
informant).  
z. Please note that the SCARED and the BRIEF are validated tools 
that are used to aid the Study Physician in determining 
treatment response. Use of different versions of these 
questionnaires are permissible to aid the Study Physician, in 
additional to clinical impression, with medication 
management and determination of response. 
aa. Assess for adverse events. Document in Adverse Events log.  
bb. Determine and document participant’s adherence to ATX 
medication regimen.  
i. 
High adherence is defined as the participant taking ≥ 
80% of their scheduled doses  
ii. 
Medium adherence is defined as the participant taking 
between 40 – 79% of their scheduled doses.  
iii. 
Low adherence is defined as a participant taking < 40% of 
their scheduled doses.  
11.1.1.1 
Add compensation to participant’s Greenphire account. 
 
 
10. ADHD Care Following Conclusion of the Study 
Research personnel will call research participants and/or their parents two 
weeks (± 1 week) following study conclusion or withdrawal from the study to 
check if any adverse events occurred in the interim. The research team will 
also take the opportunity to re-educate the family if a taper of medication 
was needed. This information will be documented on the 2-week Post-Study 
Completion Check CRF. 
 
 
See the Schedule of Events (SOE) table below outlining all of the above 
procedures by visit.  

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Schedule of 
Events 
Prescreen 
Research 
Visit 1*ϴ 
Intake 
with Study 
Physicianψ 
Research 
Visit 2* 
Research 
Visit 3* 
6-Week 
Visit with 
Study 
Physicanψ 
12-Week 
Visit with 
Study 
Physicianψ 
18-Week 
Visit with 
Study 
Physicianψ 
Research 
Visit 4* 
2-week 
Post-
Study 
Check 
Time point 
N/A 
N/A 
N/A 
Start 
Med/Day 
0 
Day 0 +  
at least 2 
weeks€  
Day 0 + 6 
weeks and 
after RV3 
6-Week 
Visit with 
Study 
Physican + 
6 weeks 
12-Week 
Visit with 
Study 
Physican + 
6 weeks 
After 18-
Week Visit 
After 
Research 
Visit 4 
Visit Window 
N/A 
N/A 
N/A 
N/A 
See note€ 
± 2 weeks 
± 2 weeks 
± 2 weeks 
N/A 
± 1 weeks 
Type of Visit/Event 
Phone 
Phone/In 
Person 
In person/ 
telehealth 
In Person 
In Person 
In person/ 
telehealth 
In person/ 
telehealth 
In person/ 
telehealth 
In Person 
Phone 
Potential Participant 
Identified 
X 
 
 
 
 
 
 
 
 
 
Introduce the Study 
X 
 
 
 
 
 
 
 
 
 
Schedule Research 
Visit 1 
X 
 
 
 
 
 
 
 
 
 
Obtain Consent or 
Permission/Assent 
 
X1 
 
 
 
 
 
 
 
 
Obtain participant 
continued assent 
(verbal) 
 
 
 
X 
X 
 
 
 
X 
 
Document 
continued assent in 
research note 
 
 
 
X 
X 
 
 
 
X 
 
Provide U54 Study 
Booklet 
 
X 
 
 
 
 
 
 
 
 

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Schedule of 
Events 
Prescreen 
Research 
Visit 1*ϴ 
Intake 
with Study 
Physicianψ 
Research 
Visit 2* 
Research 
Visit 3* 
6-Week 
Visit with 
Study 
Physicanψ 
12-Week 
Visit with 
Study 
Physicanψ 
18-Week 
Visit with 
Study 
Physicanψ 
Research 
Visit 4* 
2-week 
Post-
Study 
Check 
Needlestick/Pill 
Swallowing 
Questions 
 
X 
 
 
 
 
 
 
 
 
Explain and Begin 
Washout (if needed) 
 
X 
 
 
 
 
 
 
 
 
Demographic Data 
 
X 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Meds 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Prior Medical 
History 
 
X 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
 
X2 
X2 
 
 
 
X2 
 
Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram 
 
X 
 
 
 
 
 
 
X 
 
Tanner Staging 
(optional) 
 
X 
 
X 
X 
 
 
 
X 
 
Pregnancy Test 
 
X 
 
X 
X 
 
 
 
X 
 
Safety Laboratory 
Tests (CBC w/diff; 
Base Met; LFTs; UA 
w/micro) 
 
X 
 
X 
X 
 
 
 
X 
 
Confirm ADHD 
Diagnosis 
 
 
X 
 
 
 
 
 
 
 
Assess for 
Comorbidities 
 
 
X 
 
 
X 
X 
X 
 
 

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Confirm ATX 
appropriateness for 
participant 
 
 
X 
 
 
 
 
 
 
 
Schedule of 
Events 
Prescreen 
Research 
Visit 1*ϴ 
Intake 
with Study 
Physicianψ 
Research 
Visit 2* 
Research 
Visit 3* 
6-Week 
Visit with 
Study 
Physicanψ 
12-Week 
Visit with 
Study 
Physicanψ 
18-Week 
Visit with 
Study 
Physicanψ 
Research 
Visit 4* 
2-week 
Post-
Study 
Check 
Interpret 
genotyping results 
 
 
 
X3 
 
 
 
 
 
 
Assign study design 
 
 
 
X3 
 
 
 
 
 
 
Determine 
medication dose 
 
 
 
X3 
 
 
 
 
 
 
Pre-Visit Reminder 
Call 
 
 
 
X3 
X3,4 
X3 
X3 
X3 
X3,4 
 
Administer 
medication 
 
 
 
X 
X 
 
 
 
X 
 
Dispense 
medication 
 
 
 
X 
 
X 
X 
X 
 
 
Dispense topical 
lidocaine (optional) 
 
 
 
X 
X 
 
 
 
X 
 
Place IV 
 
 
 
X 
X 
 
 
 
X 
 
Genotyping sample 
(blood) 
 
X 
 
 
 
 
 
 
 
 
Pharmacokinetic 
sample (blood) 
 
 
 
X 
X 
 
 
 
X 
 
Pharmacodynamic 
sample (blood) 
 
X 
 
X 
X 
 
 
 
X 
 
CYP2D6 Biomarker 
(urine) 
 
X 
 
X 
X 
 
 
 
X 
 

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Pharmacokinetic 
sample (urine) 
 
 
 
X 
X 
 
 
 
X 
 
Microbiome sample 
(saliva) 
 
X 
 
X 
X 
 
 
 
X 
 
Schedule of 
Events 
Prescreen 
Research 
Visit 1*ϴ 
Intake 
with Study 
Physicianψ 
Research 
Visit 2* 
Research 
Visit 3* 
6-Week 
Visit with 
Study 
Physicanψ 
12-Week 
Visit with 
Study 
Physicanψ 
18-Week 
Visit with 
Study 
Physicanψ 
Research 
Visit 4* 
2-week 
Post-
Study 
Check 
Sweat patches 
(sweat) 
 
 
 
X 
X 
 
 
 
X 
 
Pupillometry during 
Posner’s Cuing Task 
 
X 
 
X 
X 
 
 
 
X 
 
Dietary Survey 
Questionnaire 
 
 
 
 
 
 
 
 
X 
 
Kiddie Schedule for 
Affective Disorders 
and Schizophrenia 
(KSADS) 
 
X 
 
 
 
 
 
 
 
 
Kaufman Brief IQ 
Test (KBIT) 
 
X 
 
 
 
 
 
 
 
 
Behavior Rating 
Inventory of 
Executive Function 
(BRIEF) 
 
X 
 
 
 
 
 
 
X 
 
Barkley Sluggish 
Cognitive Tempo 
Scale (SCT) 
 
X 
 
 
 
 
 
 
X 
 
Screen for Child 
Anxiety and Related 
Disorders (SCARED) 
– parent 
 
X 
 
 
 
 
 
 
X 
 

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Screen for Child 
Anxiety and Related 
Disorders (SCARED) 
– child (≥ 8) 
 
X 
 
 
 
 
 
 
X 
 
Schedule of 
Events 
Prescreen 
Research 
Visit 1*ϴ 
Intake 
with Study 
Physicianψ 
Research 
Visit 2* 
Research 
Visit 3* 
6-Week 
Visit with 
Study 
Physicianψ 
12-Week 
Visit with 
Study 
Physicianψ 
18-Week 
Visitwith 
Study 
Physicianψ 
Research 
Visit 4* 
2-week 
Post-
Study 
Check 
NICHQ Vanderbilt 
Assessment Scales – 
parent 
 
 
X5,6 
 
 
X 
X 
X 
 
 
NICHQ Vanderbilt 
Assessment Scales – 
teacher 
 
 
X5,6 
 
 
X 
X 
X 
 
 
Child Behavior 
Checklist – parent 
 
 
X5,6 
 
 
 
 
X 
 
 
Child Behavior 
Checklist – teacher 
 
 
X5,6 
 
 
 
 
X 
 
 
Strengths and 
Difficulties 
Questionnaire – 
parent 
 
 
X5,6 
 
 
 
 
X 
 
 
Strengths and 
Difficulties 
Questionnaire – 
teacher 
 
 
X5,6 
 
 
 
 
X 
 
 
Medication Side 
Effects – parent 
 
 
X5,6 
 
 
X 
X 
X 
 
 
Medication Side 
Effects – teacher 
 
 
X5,6 
 
 
X 
X 
X 
 
 

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School Intervention 
Questionnaire 
 
 
X5,6 
 
 
 
 
X 
 
 
Child Medical 
History 
Questionnaire 
 
 
X5,6 
 
 
 
 
 
 
 
Schedule of 
Events 
Prescreen 
Research 
Visit 1*ϴ 
Intake 
with Study 
Physicianψ 
Research 
Visit 2* 
Research 
Visit 3* 
6-Week 
Visit with 
Study 
Physicianψ 
12-Week 
Visit with 
Study 
Physicianψ 
18-Week 
Visit with 
Study 
Physicianψ 
Research 
Visit 4* 
2-week 
Post-
Study 
Check 
Clinical Global 
Impression 
 
 
X 
 
 
X 
X 
X 
 
 
Adherence Check 
 
 
 
 
X 
X 
X 
X 
X 
X7 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Take Back U54 
Study 
Booklet/Survey 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1 Execution of permission/assent may occur via phone to allow participants to fill out psychometric questionnaires. 
2 Heart and blood pressure to take with each blood draw.  
3 These events occur prior to the visit for preparation. 
4 These phone calls occur in 2 parts. 
5 These questionnaires must be completed by the Intake Visit; however, they may be assigned at Research Visit 1 to allow participants ample  
time to complete.   
6 For participants recruited from Track 4, these questionnaires are assigned immediately after consent has been obtained. 
7 For participants who require a taper off medication.  
*These visits will occur in the Pediatric Clinical Research Unit (PCRU). 
ψThese visits will occur at either the ADHD Clinic on College Boulevard or in the Developmental and Behavioral Sciences Clinic. If these visits are 
telehealth visits, all in-person procedures, such as obtaining vitals or a physical exam, may be omitted. 
ϴThis visit can occur in two parts to minimize time of washout. 
€The window for this visit is flexible and has been expanded from the previous versions of this protocol. This visit can occur anytime after the 
participant has been taking medication regularly for 2 weeks and up until prior to the 18-Week Visit with Study Physician. 

ATX PBPK-PD Clinical Study 
IRB # 16100728 
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o 
Procedures to Reduce Risks  
1. Medical Chart Review during Prescreen will be used to determine if a 
potential participant has any of the following: 
a. Diagnosis or indication of underlying risk for cardiotoxicity, 
such as presentation of structural cardiac abnormalities, 
cardiomyopathy, or arrhythmias.  
b. Diagnosis or indication of disease that may cause abnormal 
absorption or gastric emptying.  
c. Previous history or indication of prior adverse drug reaction to 
atomoxetine  
d. Concurrent therapy with drugs known to inhibit CYP2D6 or 
previous treatment with strong CYP2D6 inhibitors. 
e. Concurrent therapy with other psychiatric/behavioral drugs 
2. The two parts of Research Visit 1 may occur at separate times for 
participants who require a washout prior to beginning atomoxetine 
therapy. Research Visit 1 Part 1 includes a blood stick for genotyping 
purposes. Genotyping analysis, which takes approximately one week 
to complete and interpret, will be conducted while the participant is 
washing out. Were we to collect genotyping sample when the 
participant is at baseline, the participant could potentially be off of 
medication for ~ 2 weeks, while waiting for genotyping results such 
that ATX can be dosed in the participant using the iGO-PK model.  
3. Needlestick comfort and pill-swallowing ability questions will be 
asked to reduce discomfort and anxiety associated with needlesticks 
and taking the study drug. 
4. Baseline electrocardiogram during Research Visit 1 to assess presence 
of any underlying risks for cardiotoxicity prior to starting participant 
on ATX.   
5. End of study electrocardiogram during Research Visit 4 to assess for 
any cardiac injury that may have occurred while the participant was 
taking ATX chronically.  
6. Safety Labs – CBC with differential, hepatic function test, basic 
metabolic panel, and urinary analysis with microbiology will be 
conducted at Research Visit 1, Research Visit 2, Research Visit 3, and 
Research Visit 4. 
7. Pregnancy Test will be conducted at Research Visit 1, Research Visit 2, 
Research Visit 3, and Research Visit 4 to ensure the subject is not 
pregnant. 
8. Assessment of adverse events  
9. For blood collection:  

ATX PBPK-PD Clinical Study 
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a. Blood will be obtained either through needle stick (Research 
Visit 1) or through an indwelling venous catheter (Research 
Visit 2, Research Visit 3, and Research Visit 4).  
b. With our study design, the maximal amount of blood drawn 
from any participant for clinical and research purposes for a 
research visit assigned Study Design 1 or 2 is 54 mL in a 72 
hour period. This would mean that the lower limit for weight 
to complete study procedures is 11 – 15 kg. Our study 
population typically exceeds this weight range. However, 
given that there are multiple research visits where blood is 
drawn, for younger child and for those who are approximately 
11- 15 kg, we will schedule research visits such that they are 
greater than 30 days a part.  
c. For subjects who are less than 16.5 kg, the total amount of 
blood drawn from the subjects may exceed the 3 ml/kg/day 
limit, particularly if the individual is a CYP2D6 intermediate or 
poor metabolizer. The maximum amount of blood drawn 
within a 24 hour period is 48 mL.  
d. With our study design, the maximal amount of blood drawn 
for a participant for clinical and research purposes for a 
research visit assigned Study Design 3 is 75ml in a 24 hour 
period.  The majority of patients will not be enrolled under 
Study Design 3. The lower limit of weight to complete all 
possible blood draws for Study Design 3 is 15kg – 25kg (3-
5ml/kg = 75ml).  Our study population typically exceeds this 
weight range.  Additionally, participants in Study Design 3 may 
not be required to have all blood draws adding up to 75ml, as 
the number of draws depends on the timing of their dosing.   
e. For Study Design 3 subjects who are less than 25 kg, research 
visits will be scheduled to not exceed predicted blood draw 
totals of 9.5ml/kg or more over an 8 week period.  
10. Incidental findings which are discovered during the course of this 
study may be released to families in a letter at their request for the 
purposes of seeking further care (please refer to Appendix M). 
11. During the COVID-19 pandemic, the research team will make every 
attempt to reduce the number of in-person procedures while 
providing ADHD care to the participant and achieving the aims of this 
research study. 
12. The research team will adhere to all Children’s Mercy Hospital and 
Children’s Mercy Research Institute guidelines for reducing 
transmission of SARS-CoV-2 virus. 
13. The research team will ensure that participants and their LARs have 
resources for reducing SARS-CoV-2 virus tranmission from Children’s 
Mercy Hospital and Children’s Mercy Research Institute. 

ATX PBPK-PD Clinical Study 
IRB # 16100728 
Page 85 of 143 
 
14. A Certificate of Confidentiality has been issued for this study by the 
National Institutes of Health which protects the privacy of research 
participants by prohiting disclosure of identifiable and sensitive 
information. However, disclosure is permitted for the following 
scenarios: 
a. Required by Federal, State, or local laws (e.g., as required by 
the Federal Food, Drug, and Cosmetic Act, or state laws 
requiring the reporting of communicable diseases to State and 
local health departments), excluding instances of disclosure in 
any Federal, State, or local civil, criminal, administrative, 
legislative, or other proceeding; 
b. Necessary for the medical treatment of the individual to 
whom the information, document, or biospecimen pertains 
and made with the consent of such individual; 
c. Made with the consent of the individual to whom the 
information, document, or biospecimen pertains; or 
d. Made for the purposes of other scientific research that is in 
compliance with applicable Federal regulations governing the 
protection of human subjects in research. 
11.4  Source Records Used  
a. Permission/Assent or Consent Forms (Research Visit 1 or 
Phone Consent) 
b. Demographics (Research Visit 1 CRF)  
c. Prior/Concomitant Medications (Research Visit 1, Research 
Visit 2, Research Visit 3 and Research Visit 4 CRFs)  
d. Prior Medical History (Research Visit 1 CRF, Child Medical 
History Questionnaire) 
e. Needlestick and Pill Swallowing Questions (Research Visit 1 
CRF)  
f. Vital Signs (Research Visit 1, Research Visit 2, Research Visit 3 
and Research Visit 4 CRFs)  
g. Data from physical exam (Research Visit 1, Research Visit 2, 
Research Visit 3 and Research Visit 4 CRFs)  
h. Pregnancy status (Research Visit 1, Research Visit 2, Research 
Visit 3 and Research Visit 4 CRFs)  
i. Baseline and end of study electrocardiogram (Research Visit 1 
and Research Visit 4 CRFs)  
j. Tanner Staging (Optional) (Research Visit 1, Research Visit 2, 
Research Visit 3 and Research Visit 4 CRFs)  
k. Genotyping data (Research Visit 2 and Research Visit 3 CRFs)  
l. Atomoxetine dose (IDS pharmacy prescriptions)  

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m. Pharmacokinetic Samples – plasma, urine, and sweat 
(Research Visit 1, Research Visit 2, Research Visit 3 and 
Research Visit 4 CRFs)  
n. Pharmacodynamic Samples – plasma and serum (Research 
Visit 1, Research Visit 2, Research Visit 3 and Research Visit 4 
CRFs)  
o. Microbiome Samples – saliva (Research Visit 1, Research Visit 
2, Research Visit 3 and Research Visit 4 CRFs)  
p. CYP2D6 biomarker analysis – urine (Research Visit 1, Research 
Visit 2, Research Visit 3 and Research Visit 4 CRFs)  
q. Attention Tasks – Pupillometry during Posner’s Cuing Task 
data (data stored on computer hard drive, documentation in 
Research Visit 1, Research Visit 2, Research Visit 3 and 
Research Visit 4 CRFs)  
r. Long-term dietary patterns – Dietary Survey Questionnaire 
(paper questionnaire)  
s. Intelligence Quotient – Kaufman Brief IQ Test (KBIT) (paper 
questionnaire)  
t. ADHD and comorbidities –  
i. Kiddie Schedule for Affective Disorders and 
Schizophrenia Present and Lifetime (K-SADS-PL) (paper 
questionnaire or KSADS-COMP);  
1. Subject Information (pages 1-3) 
2. Attention Deficit/Hyperactivity Disorder (pages 
4-12) 
3. Generalized Anxiety Disorder (pages 13-17) 
4. Social Anxiety/Selective Mutism Disorder 
(pages 18-21) 
5. If KSADS-COMP is used, the above data are 
available electronically. These data will be 
downloaded and added to the participant 
binder. 
ii. Behavior Rating Inventory of Executive Function 
(BRIEF) (paper questionnaire);  
iii. Bradley Sluggish Cognitive Tempo Scale (paper 
questionnaire);  
iv. Screen for Child Anxiety and Related Disorders (CHADIS 
questionnaire);  
v. NICHQ Vanderbilt Assessment Scales for parent and 
teacher (CHADIS questionnaire);  
vi. Child Behavior Checklist (CHADIS questionnaire);  
vii. School Intervention Questionnaire (CHADIS 
questionnaire);  
viii. Clinical Global Improvement (Study Physician Note)  

ATX PBPK-PD Clinical Study 
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u. Medication side effects –  
i. Medication Side Effects (CHADIS questionnaire);  
ii. In-person assessment (study CRFs and participant 
EMR);  
iii. Parental reports (study CRFs and participant EMR if 
parent calls in and reports to a RN or physician on-call)  
v. Adverse events –  
i. in person assessment (study CRFs and participant 
EMR);  
ii. parental reports (study CRFs and participant EMR if 
parent calls in and reports to a RN or physician on-call)  
w. Study medication adherence – in person assessment 
(Research Visit 3, 6-Week Visit with Study Physician, 12-Week 
Visit with Study Physician, 18-Week Visit with Study Physician, 
and Research Visit 4 CRFs, Drug Adherence Calculator Excel 
Workbook) 
11.5 Continuing Care  
Additional clinical ADHD care will be at the discretion of the study physician, 
participant, and participant’s family. This may include, but is not limited to, the 
following: 1) immediate transition of atomoxetine prescribing to the primary 
care physician or other specialist identified by the family, 2) continuation of 
atomoxetine prescribing and follow-up care by the study physician, 3) 
discontinuation or weaning of atomoxetine when deemed clinically 
appropriate.   If the participant’s ADHD care will be transitioned to their primary 
care provider or another community provider. A letter describing the course of 
the participant’s care in the research trial will be provided to the family and the 
care provider. (See “End of Study ADHD Care Transition Letter” in the Appendix 
N) 
 
11.6 IBC 
 
The following IBC protocols will be used in this study:  
• IBC Protocol #18-27  “Processing of Blood, Urine, Saliva, and 
Cerebral Spinal Fluid Samples from Clinical/Research Studies in 
the Clinical Pharmacology Research Laboratories” 
• IBC Protocol #18-10  “Processing of Blood, Saliva, and Urine 
Samples from Clinical/Research Studies in the Pediatric Clinical 
Research Unit” 
12.0 Data and Sample Banking 
• Data Banking Procedures: All data collected on study related CRFs and 
participant data on the EMR assessing participant outcomes (in 

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particular, participant safety, efficacy, and toxicity) will serve as source 
documents for this study. For ease of analysis and logistics of sharing data 
with the study team members, a subset of the complete dataset that are 
pertinent to assessing the research aims will be entered in a REDCap 
database. This is currently being developed and is tentatively titled, “U54 
Longitudinal Atomoxetine – Clinical Outcomes 2.0.” All study personnel, 
research associates,  and U54 collaborators may have access to the data, 
however on a need to know basis. 
 
• Sample Storing Procedures:  Samples will be stored in –80 
degree C freezers housed within the department of Clinical 
Pharmacology, Toxicology, and Therapeutic Innovation. These samples 
will be kept and stored here until all data analysis is complete and 
all findings from this research study have either been finalized or 
published. All study personnel, research associates, 
and U54 collaborators may have access to the samples.  Following 
completion of this study and processing of all samples, these samples will 
be moved to the Pharmacokinetics/Pharmacodynamics (PK/PD) 
Repository (see the corresponding bullet point below) 
 
 
• Procedures to release data or samples: Researchers within Children’s 
Mercy Hospital, or their collaborators, who may find these data and/or 
specimens useful to answering future research questions may submit a 
written request to the PI of this study (in the event that data analysis and 
collection are still occurring) or the PI of the PK/PD Repository (following 
study completion). Permission will be granted by written letter by the 
respective principal investigator(s) (AppendixK). The distribution of data 
and/or samples will be facilitated by the PI and study personnel in the 
event that data and samples are shared prior to the conclusion of this 
study. Following the conclusion of this study and transfer to the PK/PD 
repository, release of data and specimens are the responsibility of the 
PK/PD Repository PI and Manger and will follow the protocol 
Pharmacokinetics/Pharmacodynamics Repository (IRB# TBD).  
 
 
• Transfer to the Pharmacokinetics/Pharmacodynamics (PK/PD) 
Repository:  Following conclusion of this study, samples will be 
transferred to the Pharmacokinetics/Pharmacodynamics Repository 
which will be maintained by the Children’s Research Institute 
Biorepository (CRIB). The Pharmacokinetics/Pharmacodynamics 
Repository will be an identified repository which is comprised of clinical 
data, research data, and biological samples (e.g. blood, urine, tissue 

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samples, etc.) that may be used prospectively to answer research 
questions relating to pediatric clinical pharmacology. The data distributed 
for prospective future research will be de-identifed by CRIB personnel as 
is described in the  PK/PD Repository protocol (IRB # TBD). 
 
 
• Samples from minors, plan for re-contacting and obtaining consent: The 
study population will include minors whose samples will be retained for 
long term research. The permission/assent and consent forms for this 
study will provide participants with the option of allowing retention of 
their samples and data in the PK/PD Repository for prospective future 
studies. If the participant turns 18 at the time of data collection, the 
participant will be reconsented. If the participant turns 18 after data 
collection has taken place, no attempt shall be made to recontact the 
participant (see section 25.0). 
 
 
13.0 Genetic Analysis Information 
• Genome-wide analysis and single nucleotide polymorphism (SNP) analysis 
will be conducted on participant samples.  
 
• We do not expect to discover paternity findings, as we are not enrolling 
trios in this study. However, given that we are assaying for genetic 
variants in biochemical pathways that affect neurotransmitter levels and 
activity, it is possible that findings may be made regarding 
other diseases. In particular, findings may be made where there is 
significant overlap between ADHD and the disease in question, such as 
autism or anxiety.    
 
 
• Genetic testing (microarray SNP analysis, PCR sequencing, etc.) to 
determine ATX dose and study design will not be conducted in a CLIA-
certified lab. Genome-wide testing will be conducted at the Children’s 
Mercy Hospital Genome Center, which is CLIA-certified. Additional testing 
may be conducted should more information regarding genes associated 
with  ATX pharmacokinetic, pharmacodynamic, and clinical outcomes 
become available. The assays may be conducted in either the Clinical 
Pharmacology laboraties or at the Genome Center, depending on assay 
availability. 
 
 

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14.0 Sharing of Results with Subjects  
• Sharing Results with Participants: Results from genetic testing 
of pharmacogenes, such as, CYP2D6, CYP2C19, CYP2B6, etc. will be 
shared with participants and their families. In particular, CYP2D6  genetic 
information will be pertinent to research participants as 
this result determines the duration of Research Visit 2, Research Visit 3, 
and Research Visit 4. CYP2C19 data will also be shared given the number 
of available medication guidelines written for this pharmacogene. Should 
additional actionable pharmacogene information become available 
during the course of this study, further information may be shared with 
the family. Genetic information will be explained in a letter (Appendix L) 
to the participant/family. The letter will state that the genotyping 
information obtained from this study are research results that are used 
to achieve the research goals of this study. These results were obtained 
from our research lab which does not adhere to CAP/CLIA guidelines. 
Because of this, these results cannot be included in the participant’s 
medical record and should not be used to make medical decisions. The 
research team will inform participants/families that the Genotype- and 
Ontogeny Linked Dose Individualization and Clinical Optimization for Kids 
(GOLDILOKs) Clinic can facilitate obtaining genetic testing that is 
CAP/CLIA certified at the expense of the participant. Additonally, the 
GOLDILOKs Clinic can interpret the genetic results obtained from 
CAP/CLIA labs for the participant and their families. The results obtained 
by the GOLDILOKs clinic can be documented in the participant’s medical 
record for future medical decision-making.  This practice complies with 
the CRI Policy and Procedure, “Research Documentation in the Electronic 
Health Record” approved on 09/26/2019.  
 
• Sharing Incidental Findings with Participants: Incidental findings that a 
discovered during the course of this study may be released to 
participants and their families for the purposes of seeking further care 
(Appendix M). 
 
 
• Sharing Results with Providers: Participant results from genetic testing 
of pharmacogenes will be documented in the EMR if the family requests 
a referral to the GOLDILOKs Clinic for further interpretation of genetic 
results. However, this note will include a statement that these data were 
not obtained from a CLIA-certified lab. At the end of the study, or when 
the study participant withdraws or is lost to follow-up, a final research 
note will be included to describe the atomoxetine regimen for the 
participant while in the study. This note will be forwarded to 

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the Study Physician to aid in the transition of care of the participant from 
the study to a healthcare provider.  
 
 
15.0 Reimbursement, Payment and Tangible Property provided to 
subjects 
 
15.1 Payments  
 
Below is the payment schedule for activities related to participation in this study. 
Payments to subjects will be made via Greenphire. Families will be asked to 
provide a social security number for their child so that their child may be 
reimbursed.  
 
Activity 
Compensation 
Completion of Research Visit 1 
$50.00   
Completion of Research Visit 2, 0 –12 hours 
$200.00 
Completion of Research Visit 2, 12 – 24 hours 
$60.00 
Completion of Research Visit 2, return 48 hours 
$30.00 
Completion of Research Visit 2, return 72 hours 
$30.00 
Completion of Research Visit 3, 0 –12 hours 
$200.00 
Completion of Research Visit 3, 12 – 24 hours 
$60.00 
Completion of Research Visit 4, 0 –12 hours 
$200.00 
Completion of Research Visit 4, 12 – 24 hours 
$60.00 
Completion, return of drug taking calendar, and drug bottle 
at Research Visit 3 
$15.00 
Completion, return of drug taking calendar, and drug bottle 
at Research Visit 4 
$15.00 
Return of drug taking calendar and drug bottle at 6-Week 
Visit with Study Physician 
$10.00 
Return of drug taking calendar and drug bottle at 12-Week 
Visit with Study Physician 
$10.00 
Return of drug taking calendar and drug bottle at 18-Week 
Visit with Study Physician 
$10.00 
Please note, visit length is expressed in hours post-drug administration. 
 
The maximum compensation for participants in Study Design 1 is: $950.00 
The maximum compensation for participants in Study Design 2 is: $710.00 
The maximum compensation for particpants in Study Design 3 is: $830.00 
 

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16.0 Withdrawal of Subjects 
 
16.1 Anticipated circumstances in which subjects will be withdrawn from the 
research study  
• Participant experiences a serious adverse event and there 
is a probable association between the serious adverse 
event and study drug and/or research procedures. 
• Participant experiences an adverse event, and there is a 
high probability of an association between the adverse 
event and study drug and/or research procedures and the 
adverse event interferes significantly with the participant’s 
well-being (e.g. daily stomach aches). 
• Participant requires care beyond what the research study 
team can provide while still meeting eligibility criteria (e.g. 
participant requires medication for tics that interferes will 
study drug). 
• Participant is lost to follow-up. 
• Participant is not compliant with study procedures. 
• Participant revokes consent/assent. 
• Participant no longer meets inclusion/exclusion criteria 
(e.g. abnormal safety labs). 
• Participant does not have adequate response from ATX at 
12-week visit and 18 week visit (<10% reduction in 
symptoms). 
The PI may remove the participant from the study without the LAR’s 
permission or participant’s consent/assent if the above circumstances 
occur. 
 
16.2 Procedures for orderly termination/subject withdrawal 
1. PI, Study Physician, or individual designated in the Delegation 
of Authority will contact the study participant and their family. 
a. If the participant initiates the withdrawal, reasons will 
be documented and if applicable, intervention or plans 
for follow-up will made.   
b. If the study team terminates the subject’s participation 
in the study, study personnel will clearly explain the 
reasons for removal from the study and if applicable, 

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discuss next steps for necessary interventions or plan 
for follow-up care (e.g titration schedule for 
discontinuing study drug, etc). 
2. If applicable, adverse events related to withdrawal will be 
promptly reported to the IRB per CM Policy 5.11 “Reportable 
Events”. Adverse events will continue to be followed until 
resolution. 
3. Study personnel will complete end-of-study and withdrawal 
documentation in the subject binder. 
4. All previously collected samples and data, regardless of 
whether participant completed the research study in its 
entirety, will be saved for data analysis. 
5. Transfer of care procedures from the study physician to the 
participant’s primary care provider will take place in 
accordance with those outlined in section 11.6 for participants 
completing the study in its entirety.  
 
 17.0 Risks to Subjects 
• Confidentiality Risk:  There is a risk of loss of 
confidentiality. Confidentiality will be protected to the 
greatest extent possible. There is also a risk of loss of 
confidentiality when using the internet. This is especially 
pertinent when filling out questionnaires using a web 
interface. The study team will make every effort to protect 
the participant’s confidentiality such that this risk is 
minimal. 
 
• Blood Draw: Risks of drawing blood include discomfort and/or 
bruising. A needlestick can be greater than minimal risk. However, 
numbing spray and topical lidocaine can be provided to minimize 
pain associated with needle sticks.  In addition, the study team 
will inquire about needlestick fears and comfort techniques prior 
to the first needlestick. 
 
 
• Allergic reaction:  It is possible to have an allergic reaction to 
atomoxetine. Currently, there is no way to predict whether an 
individual will have an allergic reaction to atomoxetine a priori. 
However, the percentage of individuals experiencing allergic 
reaction is low. The first dose of atomoxetine will be administered 

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to the participant in the PCRU. Medications and procedures are in 
place should a participant have an allergic anaphylactic reaction 
to atomoxetine. 
 
 
• Genetic Risks: The unauthorized disclosure of genetic information 
may have an impact on a participant’s employability, insurability, 
immigration status, paternity suits, or social reputation. These 
risks include the chance of discrimination. The study team will 
make every effort to protect the participant’s genetic such that 
this risk is minimal. Additionally, the genes investigated in the 
study have thus far only been associated with drug 
pharmacokinetics and pharmacodynamics. The risk of 
discrimination with this type of genetic information is lower 
compared to genes linked to predisposition of disease. 
 
 
• Side Effects Risks: Participants may experience side effects of 
atomoxetine related to the way the medication is dosed. Typical 
side effects include increased heart rate, headache, stomach 
upset, nausea, sleepiness, and emotional lability. In addition, 
there are reports of suicidal ideation with atomoxetine use. The 
level of risk is variable given that the severity of side effects can 
be different among participants.  
 
 
• Psychological Risks: There may be psychological risks associated 
with answering questions about the participant’s mood and 
behaviors at home and at school. The level of risk in answering 
psychological questionnaires would be equal to an individual 
seeing care for ADHD and comorbidities associated with ADHD, as 
many of these questionnaires are used to assess symptoms and 
improvement. We therefore expect the psychological risks to pose 
no increase in psychological risks over baseline. 
 
 
18.0 Potential Benefits to Subjects 
 
• Personalized Medication Dosing: Participants will receive more personalized 
dosing of atomoxetine therapy through participation in study. 
 

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• Genetic Information: Participants will have genetic information returned to 
them (as it is related to duration of study visits) and will be given information 
about the GOLDILOKs Clinic at Children Mercy’s Hospital where they can learn 
about the impact that their unique genetic information has on the way their 
body processes ATX and numerous other medications.  As mentioned 
previously in section 14.0, it will be explained to families that genetic testing 
results obtained as part of the study cannot be used by GOLDILOKs Clinic for 
interpretation, but rather, that the testing will need to be repeated in a CLIA-
certified lab.  If the participant and/or family would like to be seen in 
GOLDILOKs Clinic and repeat genetic testing, these services will not be paid for 
by the study and will be the responsibility of the participant/family.  
 
 
 
 
 
19.0 Investigator Assessment of Risk/Benefits Ratio 
 
Select as applicable: 
Pediatric Risk Category: 
 
Category 
1  
Research not involving greater than minimal risk  
(45 CFR §46.404 and 21 CFR §50.51)   
 
x 
Category 
2 
Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the 
individual 
subjects. (45 CFR §46.405 and 21 CFR §50.52) 
 
Category 
3 
Research involving greater than minimal risk and 
no prospect of direct benefit to individual 
subjects, but 
likely to yield generalizable knowledge about the 
subject’s disorder or condition.  
(45 CFR §46.406 and 21 CFR §50.53) 
 
Category 
4 
Research not otherwise approvable which 
presents an opportunity to understand, prevent, 
or alleviate a serious problem affecting the 
health or welfare of children. (45 CFR §46.407 
and 21 CFR §50.54) 
Select if applicable: 
Adult Risk Category: 
 
Not Greater than Minimal Risk 
x 
Greater than Minimal Risk 
 
 

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20.0 Data Management  
 
20.1 Data Analysis Plan 
Population to be Analyzed: 
• The pharmacokinetic population will consist of all participants with 
sufficient plasma concentrations for calculation of all pharmacokinetic 
parameters.  
• The pharmacodynamic population will comprise of all patients with 
sufficient DHPG plasma concentrations, adequate data from pupil dilation 
and eye-tracking measurements, and cardiovascular measures (heart rate 
and blood pressure). Additional metabolites analyzed via metabolomics 
platform will also be analyzed (as discussed below). 
• All participants who meet criteria for determination of both 
pharmacokinetic and pharmacodynamic parameters and have at least 
partially completed the study will be evaluated for pharmacodynamic 
linked clinical outcomes analysis. A partial completion is any participant 
where at least Research Visit 1, Research Vist 2, Research Visit 3, Intake 
Visit with Physician, and 6-week Visit with Study Physician have been 
completed. Clinical outcomes will be analyzed in four ways: 
o Response: responder vs. non-responder  
o Toxicity: tolerant vs. non-tolerant 
o Adherence: low, medium, and high 
o Adverse event reporting   
• In addition, all participants for which demographic and background 
characteristics and concomitant medication history were collected will be 
analyzed.  
• All completed and returned U54 Study Booklet questionnaires and 
surveys will be used to assess the effectiveness of the U54 Study Booklet 
in study comprehension. Feedback from the survey will be compiled for 
analysis. 
Pharmacokinetics: 
Estimation of the pharmacokinetic parameters and generation of the statistical 
analyses on the PK parameters will be performed by The Division of Clinical 
Pharmacology Toxicology & Therapeutic Innovation at the Children’s Mercy 
Hospital, Kansas City, MO. Pharmacokinetic analyses will be conducted using 
KineticaTM version 5.0 (ThermeElectron, Philadelphia, PA). Plasma ATX 
concentration versus time data will be curve fit using a peeling algorithm to 
generate initial polyexponential parameter estimates. Final parameter estimates 
will be determined from an iterative, nonlinear weighted least squares 
regression algorithm with reciprocal (1/y2calc) weighting. Model-dependent 
pharmacokinetic parameters will be calculated from final polyexponential 
parameter estimates. Final model selection will be performed by evaluating the 

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goodness-of-fit criteria including; the objective function, Akaike & Schwartz 
criteria, standard deviations and coefficients of variation for the polyexponential 
parameters estimates and the correlation matrix detailing the degree of 
interdependence between the parameter estimates for each model. In the event 
that an insufficient number of post-peak ATX plasma concentration time points 
are available, a model-independent approach will be used and parameters of 
interest calculated using standard techniques.  Specifically, Cmax and Tmax will be 
obtained by direct examination of the plasma concentration versus time profile.  
The area under the plasma concentration versus time curve during the sampling 
period (AUC0-n) will be calculated using the mixed log-linear rule and 
extrapolation of the AUC to infinity (AUC0-∞) calculated by summation of AUC0-n 
+ Cpn/λz, where Cpn represents the final plasma concentration predicted from 
the fitted apparent terminal elimination phase and λz is the apparent terminal 
elimination rate constant. Model-independent pharmacokinetic parameters will 
then be calculated using standard (i.e., statistical moment theory) techniques. 
ATX metabolites N-desmethylatomoxetine (NDM-ATX), 4-hydroxyatomoxetine 
(4-OH-ATX) and hydroxyl-2-carboxylatomoxetine (OH-2-COOH-ATX) 
pharmacokinetics will be evaluated in a fashion analogous to that described for 
the parent compound.  
 
The following PK parameters will be derived by non-compartmental analysis 
from plasma concentration data following a single dose study drug 
administration: 
 
Cmax  
Peak plasma concentration determined from the observed data 
Tmax 
Time to observed maximum drug concentration 
AUC0-τ 
Area under the plasma concentration versus time curve, 
determined by log-linear trapezoidal estimation, to the 12 or 24 
hour time point (depending on CYP2D6 AS designated study 
design). 
AUC0-∞  
Area under the concentration versus time curve to infinity, 
determined by log-linear trapezoidal estimation AUC0‑τ + CT/k 
Where k is the elimination rate constant defined as the negative 
slope following maximum concentration determined by least 
squares regression from terminal phase data. 
T½  
Terminal half-life determined by quotient 0.693/k 
CL/F  
Oral clearance determined by quotient dose/ AUC0-∞ 
Vd/F 
Terminal phase volume of distribution determined by Dose/k· 
AUC0-∞ 

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fm 
Fraction of drug metabolized through different pathways of 
biotransformation 
 
        
The following PK parameters will be derived by non-compartmental analysis 
from plasma concentration data following chronic dosing to steady-state of 
study drug: 
 
Cmax,ss 
Peak plasma concentration determined from the observed data 
at steady-state 
Tmax, ss 
Time to observed maximum drug concentration at steady-state 
AUC0-τ,ss 
Area under the plasma concentration versus time curve, 
determined by log-linear trapezoidal estimation, to the 12 or 
24 hour time point (depending on CYP2D6 AS designated study 
design). 
T½  
Terminal half-life determined by quotient 0.693/k 
CL/Fss  
Oral clearance determined by quotient dose/ AUC0-¥ 
Vd/Fss 
Terminal phase volume of distribution determined by Dose/k· 
AUC0-¥ 
 
iGO-PK Model Update: The current iGO-PK Model (Version 1.0) uses ATX 
pharmacokinetic data from 24 pediatric participants (Brown et al., 2016). Since 
the building of Version 1.0, more ATX pharmacokinetic data has been collected 
from studies conducted at Children’s Mercy Hospital (IRB# 16010069) and this 
current study. The data will be used to update and refine the iGO-PK model 
when it has been determined that sufficient new data has been collected. This 
determinination will be made by the Principal Investigators and other Co-
Investigators. 
 
Pharmacodynamics: 
Estimation of the pharmacodynamics parameters and generation of statistical 
analyses will be performed by The Division of Clinical Pharmacology, Toxicology 
& Therapeutic Innovation at the Children’s Mercy Hospital, Kansas City, MO. An 
indirect model of pharmacodynamic changes, using change in plasma DHPG as a 
function of systemic plasma ATX concentration will be evaluated using Phoenix 
NLME (Certara, Princeton, NJ, USA), NONMEM (Icon, Dublin, Ireland), MATLAB 
(Natick, MA, USA), SAS version 9.4 (SAS, Cary, NC, USA), and R (The R 
Foundation). Concentration changes in DHPG as a function of change in systemic 
ATX levels will be fit to an indirect model (Equation A). Pharmacodynamic 
parameters kin, kout, Imax, and IC50 will be estimated for each metabolite studied 
using a nonlinear mixed effects model to take into account variability of 
pharmacodynamic marker change within the study population. Statistical 
regression models will be constructed to determine which patient covariates are 

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predictive of pharmacodynamic response. A maximal effect (Emax) model 
describing the relationship between ATX concentration and pharmacodynamic 
effect will also be assessed in this study (Equations B and C). Models will be 
compared using statistical tests (Sum of Squares, Loglikelihood, AIC, standard 
error of estimates, and distribution of residuals). Changes in ATX Cmax and AUC0-¥ 
will also be plotted against pupillometry and eye-tracking data gathered when 
testing participants with localization and discrimination tasks. To describe the 
relationship between attentional orientating as function of ATX exposure, the 
data will be regressed both linearly and non-linearly and best of fit statistics 
(Akaike Information Criteria and Bayesian Information Criteria) will be employed 
to determine the most appropriate model. 
 
Global Neurotransmitter Analysis 
kin, DHPG  
Rate at which DHPG is created endogenously 
kout, DHPG 
Rate at which DHPG is catabolized endogenously 
Imax, DHPG 
Maximal fractional inhibition produced by ATX 
IC50, DHPG  
Concentration of ATX that results in 50% of maximal inhibition 
Emax, DHPG 
Maximum response through interaction of drug and drug target  
EC50, DHPG 
Concentration of ATX that results in 50% of maximal response 
 
Rates of formation and elimination (kin and kout), maximal inhibition (Imax), 
concentration at which 50% maximal inhibition is achieved (IC50), maximal 
response (Emax), and concentration at which 50% maximal response is achieved 
(EC50) will be determined for all neurotransmitters assessed in the in the global 
neurotransmitter panel (see Appendix I for metabolite list). The Dietary Survey 
Questionnaire and microbiome information from saliva samples will be analyzed 
as possible covariates of the neurotransmitter profiles. 
 
Genetic Analysis: Genome-wide analysis and single nucleotide polymorphism 
(SNP) analysis will be conducted on participant samples. Genetic testing 
(microarray SNP analysis, PCR sequencing, etc.) will be conducted to characterize 
variants in genes involved in disposition and response of ATX. Some examples of 
genes that may affect drug disposition and response include, but are not limited 
to, CYP2D6, CYP2C19, ABCB1, and SLC6A2. Genes associated with ADHD 
phenotype may also be analyzed, especially if ATX response (or lack thereof), is 
associated with a particular sub-population of individuals with ADHD. Additional 
testing may be conducted should more information become available regarding 
genes that may affect the prescribed drug’s pharmacokinetic profile, 
pharmacodynamic characteristics, or clinical outcomes (i.e. safety, efficacy, or 
toxicity). Information on variants will be analyzed to determine impact on ATX 
safety, efficacy, or toxicity. 
Pupillometry Analysis: 

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Changes in performance during Posner Cuing Task will be measured as a function 
ATX exposure and Cmax concentrations. Pupil size will be measured during two 
types of activities: localization and discrimination tasks. Pupil size differences 
during localization tasks report on the individuals’ baseline (tonic) release of 
norepinephrine. This corresponds to endogenous, or volitional attention. Pupil 
size differences during discrimination tasks is a composite of the individuals’ 
baseline (tonic) and situational (phasic) release of norepinephrine. Currently it is 
unclear whether tonic, phasic, or both are impaired in individuals with ADHD. 
  
Cardiovascular Marker Analysis: 
Changes in heart rate will also be measured as a function ATX exposure and Cmax 
concentrations. One side effect of ATX that is directly related to the 
pharmacodynamics of the drug is an increased heart rate due to increased 
concentration of norepinephrine in blood. We would like to understand the 
extent of this side effect as a function of increased systemic ATX exposure and 
Cmax. By studying these two components, we will be able to distinguish ATX drug 
action in central and peripheral nervous systems. 
 
Pharmacodynamic Changes Correlated with change in NICHQ Vanderbilt 
Assessment Scales: 
All changes markers of pharmacodynamic action will be correlated with whether 
a child is classified as a responder or non-responder; and tolerant or intolerant 
(see Clinical Outcomes below for details). Extent of adherence will be used as a 
confounding factor in both of these analyses. 
  
Clinical Outcomes: 
Determine and document participant response to ATX therapy: 
• Responders will be defined as:  
• 
Participants, who after approximately 18 weeks of continuous 
treatment with ATX, demonstrate ≥ 40% reduction of baseline 
ADHD symptom score; 
• 
OR the Clinical Global Improvement rating is 1 or 2 (Very Much 
Improved or Much Improved). 
• Non-responders will be defined as: 
• 
Participants, who after approximately 18 weeks of continuous 
treatment with ATX, demonstrate < 40% reduction of baseline 
ADHD symptom score, AND the Clinical Global Improvement score 
≥ 3. 
• 
Participants who discontinue ATX prior to the planned end of study 
(18 weeks) due to perceived lack of efficacy despite dose 
escalation. 

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Determine and document participant tolerance of ATX therapy: 
• ATX intolerant participants are: 
• Participants who present with side-effects that significantly 
interfere with daily functioning or outweigh therapeutic benefit 
(CGI Efficacy Scale categorization) 
• Participants who must discontinue ATX for any of the following 
reasons: AST or ALT three times the upper limit of normal (ULN) 
for age, alkaline phosphatase five times the ULN, total bilirubin 
two times ULN, QT prolongation or dysrhythmia, hypertension 
(systolic or diastolic BP above 95% for age), tachycardia (HR above 
95% for age) 
 
Parent and teacher responses for the NICHQ Vanderbilt Assessment Scales will 
be obtained at baseline and ± 2 weeks of 6-week Visit with Study Physician, 12-
week Visit with Study Physician, and 18-week Visit with Study Physician. If 
questionnaires are returned outside of this window, or are unreturned, these 
will be considered, “missing data.” Determination of response, i.e. responder vs. 
non-responder, will be done using parent responses to questionnaires. Teacher 
response to questionnaires will also be analyzed to evaluate symptom reduction 
in a secondary setting. Partial return of teacher questionnaires are still useful in 
that these data may be used to correct for bias in parental response. 
 
Questoinnaires conducted at baseline and at either 18-week visit with Study 
Physician or a Research Visit will be analyzed for change pre- and post- 
intervention. These include: BRIEF – parent, SCT, SCARED, CBCL, and School 
Intervention Questionnaire. 
 
Statistical analyses of clinical response in the population studied will be 
performed by The Division of Health Services and Outcomes Research at the 
Children’s Mercy Hospital, Kansas City, MO. SAS version 9.4 (SAS, Cary, NC, USA) 
and R (The R Foundation) will be used to determine if ATX responders and non-
responders can be differentiated by a subset of patient specific covariates. 
Variables that will be included in this analysis are data collected at the patient’s 
initial clinic visit: DHPG, SLC6A2 genotype, ADHD subtype, ADHD severity, co-
morbid anxiety or oppositional defiant disorder, age, and gender. Predictive 
power of classification models will be assessed by computing the area under the 
receiver operating characteristic curve and/or by k-fold cross-validation. Two-
sample t-tests or non-parametric alternatives will be utilized to test for group 
differences in percent decrease in DHPG and a differences in proportions test 
will be used to assess the association between response and SLC6A2 genotype. 
In additional, global metabolomic analyses will be conducted to determine 
whether non-responders and responders are intrinsically different in their 
biochemical make-up. This will further understanding of how differences in 

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response phenotype could be a result of different biological pathway 
involvement in ADHD.  Digital maps will be constructed for partial least square-
discriminant analysis (PLS-DA) models with prior knowledge of which volunteers 
were categorized as responders and non-responders. The variable influence on 
the projection (VIP) parameter will be used to identify which metabolites (i.e. 
pathways) are the most predictive of differentiating between the responder and 
non-responder populations. Analyses will also be conducted to determine 
mechanistic reasons for why certain individuals are non-responders or 
responders. Changes in pharmacodynamic endpoints will be compared between 
responders and non-responders. Specifically pharmacodynamic parameters such 
as Imax, IC50, differences in pupil diameter changes in localizations and 
discrimination tasks, and overall change in DHPG will be compared between the 
two populations using MANOVA and/or appropriate two-sample test. 
 
ATX pharmacodynamic data for each SLC6A2 activity group will be examined 
using standard descriptive statistics. Analysis of variance will be used to compare 
parameters between pre-defined genotype populations followed by application 
of the appropriate parametric or non-parametric post-hoc test to determine 
where inter-group differences occur. Linear and non-linear least squares 
regression analysis will be used to examine the correlation between DHPG fitted 
parameters and changes in eye-tracking and pupillometry differences in SLC6A2 
genotype groups. Univariate analysis of variance, nonlinear regression and 
analysis of covariance will be used to evaluate the relationship between 
demographic variables (alone or in combination) with corresponding 
pharmacodynamic parameter estimates.  All analyses will be performed in SPSS 
version 11.5 (SPSS, Chicago, IL) with the significance limit set at α=0.05. A sample 
size of 120 was deemed reasonable with the volume of patients being referred 
to the ADHD sub-specialty over a four year period. Powering of statistical tests 
was done assuming 20% attrition and data simulated for 96 patients. Assuming 
that 30% of the participants completing the study are categorized as responders, 
an α = 0.05, and power = 80%, a mean difference in covariates assessed of 0.6 
standard deviations is detectable with a one-sided t-test. With zero attrition, the 
mean detectable difference in covariates of interest drops to 0.5 standard 
deviations. 
 
Study Comprehension: 
Responses to the U54 Study Booklet questionnaire will be summarized by 
frequency counts and percentages to each question asked. Improvement to the 
study booklet will be categorized by type of improvement suggested and 
summarized by frequency counts and percentages.  
  
Background and Demographic Characteristics: Background and demographic 
characteristics will be listed by participant. Continuous variables will be 
summarized by sample size (n), mean, median, standard deviation (SD), 

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minimum, and maximum.  Discrete variables will be summarized by frequencies 
and percentages.  
 
Concomitant Therapy: Descriptive statistics such as frequency counts and 
percentages of participants who use concomitant medications will be provided 
by therapeutic classification and specific therapy.  
 
20.2 Sample Size Determination 
We hypothesize that there are at least two discrete ATX response phenotypes 
groups and additionally that these groups may be distinguished by differences in 
pharmacodynamic markers, and/or baseline patient characteristics. We will use 
two-sample t-tests (if transformed data are approximately Gaussian) or 
appropriate non-parametric alternatives to test for group differences in baseline 
and maximal change in DHPG, and a difference in proportions test to assess 
association between response group and SLC6A2 genotype. To estimate power 
for these tests we assumed 20% attrition and simulated data for 96 patients.  For 
a 30% response rate among study completers (a conservative estimate), α = 
0.05, and power = 80%, a mean difference of 0.6 SDs between responders and 
non-responders (eg, on DHPG) was detectable using a one-sided t-test.  With 120 
patients (zero attrition) a 0.5 SD difference was detectable.  Depending on the 
rate and nature of attrition and missing data we will consider non-response 
weighting or data imputation to reduce estimation bias and improve power. We 
assessed power for the difference in proportions test based on a 45% probability 
of a given patient having at least one SLC6A2 lower expression “T” allele (i.e., 
frequency of SLC6A2 -3081 AT and TT genotypes ~45% based on a minor T allele 
frequency of 0.061 
(http://useast.ensembl.org/Homo_sapiens/Variation/Population?db=core;g=ENS
G00000103546;r=16:55655604-
55706192;v=rs28386840;vdb=variation;vf=109832868)).    
 Assuming attrition of 20% and a response rate of 30%, power was 81% to detect 
a 0.23 difference in allele frequency between responders and non-responders 
using a one-sided test.  With 120 patients a 0.20 difference was detectable with 
80% power.    
  
 While these analyses are central to our hypothesis, we recognize that other 
plasma metabolites or genetic differences may contribute to varying drug 
response. A target metabolite panel will be assayed in each participant and 
statistical analyses of these will be analogous to DHPG. A panel of genetic 
variants will also be analyzed for contribution to variable drug pharmacokinetics, 
pharmacodynamics, and clinical response in the same manner as the SLC6A2 
variant described above.  
 

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20.3 Confidentiality 
 
Research records which include, but are not limited to: participant study binders, 
financial binders, regulatory binders, study logs, etc. These records will be stored 
in a locked cabinet in the study coordinators’ office or will be stored on 
Children’s Mercy Hospital secure server. Any electronic files containing PHI will 
be password protected. Access to research records and data will be restricted to 
study personnel and project collaborators. Information shared with project 
collaborators will be on a need to know basis and will be limited to the 
information needed to perform thorough data analysis. Study personnel who will 
be in contact with PHI will be trained on PHI practices in accordance to Children’s 
Mercy Hospital standards and will regularly be certified per institution policy.   
 
20.4 Certificate of Confidentiality 
 
A Certificate of Confidentiality has not been issued for this investigation. The 
original notice of award for this grant (Funding ID: 1-U54-HD090258-01) was 
issued on 09/23/2016, which is prior to the date when Certificates of 
Confidentiality were automatically supplied by the National Institutes of Health.  
 
20.5 Quality Control and Assurance 
 
Quality Control (QC) and Quality Assurance (QA) of data collected as a part of 
this investigation will be described in a Clinical Quality Management Plan 
(CQMP) (Supplementary Documents, “Clinical Quality Mangement Plan.”).  
Under this plan, QA and QC procedures will take place at each subject study visit 
and on a quarterly and annual schedule, and as needed in response to staff or 
process changes.  Key components reviewed in these processes will include: 
consent and permission/assent processes and documentation, review of 
participant-related CRFs, review of study drug accountability logs, review and 
update of the delegation of authority, review and update of the training log, and 
review and update of the regulatory binder.  Documentation of all QC and QA 
processes outlined in the CQMP except for visit checklists will be maintained in 
the Quality Management Binder alongside the study regulatory binders. Visit 
checklists will be maintained in the study subject binder. 
 
20.6 Data and Sample Handling 
 
All samples will be stored within the Clinical Pharmacology laboratories under 
appropriate storage conditions. Access to the laboratory is secured by card 
access only. Samples will be associated with a study identification number: U54-
XYZ (where XYZ denotes a number assigned by study personnel). Samples will be 
stored and kept until such time that all samples have been processed, data are 

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finalized, and manuscripts/publications detailing study findings have been 
completed. All research personnel, research associates, and laboratory staff will 
have access to samples and research data. Sample information may be shared 
with associates of study personnel (e.g. grant collaboraters) for the purposes of 
data analysis that are relevant to achieving study objectives and aims detailed in 
the grant funding this project (1-U54-HD090258-01).  
  
Receipt and transmission of data and/or samples will be conducted by study 
personnel designated in the Delegation of Authority Log. Samples that need to 
be transported or transferred to a facility outside of Children’s Mercy Hospital 
will be shipped overnight on dry ice, following the Children’s Mercy Hospital’s 
Policy, 1200.RLSM Transport of Research Materials Ver1.2.  
 
21.0  Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
21.1 Data Safety Monitoring Board 
  
The PI and study personnel will be responsible for monitoring the safety of 
participants. Additionally, a Data and Safety Monitoring Board (DSMB) will be 
organized to review the progress of the study and ensure the safety of study 
participants per Children’s Mercy Hospital Policy 11.01 Data Safety Monitoring. 
The board will consist of faculty from both the Children’s Mercy Hospital, 
national experts on clinical pharmacology, and physicians who have previously or 
are actively involved in the care of children with ADHD. The board will consist of:  
 
• James McCracken, MD, PhD 
• Erika Nurmi, MD, PhD 
• Bridget Clark, DO 
• Jennifer Goldman, MD, MS 
 
Dr. McCracken and Dr. Nurmi are child psychiatrists at UCLA Mattel Children’s 
Hospital and Resnick Neuropsychiatric Hospital at UCLA. Bridget Clark is a child 
psychiatrist at Children’s Mercy Hospital. Jennifer Goldman is an infectious 
disease physician with expertise in adverse drug reactions. 
 
The board will meet on a bi-annual basis and after all participants have been 
enrolled and completed study procedures. Further ad-hoc meetings will be 
determined by the PI and DSMB, particularly in the event of new or significant 
findings.  Documentation of the meetings will be recorded and stored in the 
Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation at 
Children’s Mercy Hospital and Clinics and will be submitted to myIRB. The DSMB 
will be responsible for monitoring adverse events, serious adverse events, 

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enrollment numbers, protocol violations/deviations, participant 
withdrawal(s)/termination(s), and efficacy data.   
  
Collection of Safety Information:  
Safety information will include source documents that record measures to 
reduce risk for participants (section 11.3), QC/QA findings reports (section 20.5), 
and adverse events (section 4.2).  
 
Please Supplementary Documents, “DSMB Charter,” and “DSMB Protocol” for 
further details. 
 
22.0  Provisions to Protect the Privacy Interests of Subjects 
22.1 Privacy Interest 
The study will follow standards established by the following Children’s 
Mercy Hospital policy: Request Restrictions to Protected Health 
Information.  
 
22.2 At Ease 
The study team will allow the participant and their families time to decide 
whether he/she wants to both participate and continue in the study. 
Families are given at least a week to review the permission/assent forms 
before deciding whether to participate in this study. During enrollment, 
families are encouraged to ask questions and additionally, a 
supplemental illustrated booklet detailing study procedures is provided 
to the family. The study team will review the type of information that is 
being collected with the participant and their family. The participant and 
their family will also be asked at each research visit whether they would 
like to continue to participate in the study. 
 
22.3 Permission to Access Data 
The study will follow standards established by the following Children’s 
Mercy Hospital policies: Confidentiality; HIPAA & Privacy Manual 
Standard. 
 
22.4 PHI to be Accessed 
The electronic medical record will be accessed for the purposes of 
recruitment and prescreening (see section 9.0). Data related to ADHD 
and comorbidity symptoms will be collected from the participant EMR for 
the purposes of data analysis. 
 

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22.5 HIPAA Authorization 
The study has a partial HIPAA waiver for the purposes of recruitment and 
prescreening (see section 9.0). 
23.0 Compensation for Research-Related Injury 
 
There is no compensation for research-related injury. Should illness or 
injury occur during participation in this study, treatment is available and 
will be provided at the usual charge. Payment for this treatment will be 
the responsibility of the participant. 
24.0 Economic Burden to Subjects 
 
Participation in Research Visit 1, Research Visit 2, Research Visit 3, and 
Research Visit 4 will not result in any extra cost to the participant or their 
parents aside from personal time and travel costs to come to these visits.  
 
Intake Visit with Study Physician, 6-Week Visit with Study Physician Visit, 
12-Week Visit with Study Physician, and 18-Week with Study Physician 
may incur extra costs to the participant or their families depending on 
their insurance plan. This is because the Study Physicians involved in the 
care of the participants are considered consultants and these visits with 
the Study Physician may be considered as referrals to secondary care. 
25.0 Permission/Assent/Consent Process 
 
The research team will be obtaining permission and assent if the potential 
participant is younger than 18 years of age. Consent will be obtained if the 
potential participant is over 18 years of age and if the participant turns 18 during 
the study.  
 
• Permission/assent or consent may be conducted in person with the study 
team at the PCRU or this may take place over the phone.  
• The research team will wait at least for at least a period of one week 
between informing the prospective subject and obtaining either 
permission/assent or consent.  
• Permission and assent will be reaffirmed prior to any research 
procedures take place at Research Visit 1, Research Visit 2, Research Visit 
3, and Research Visit 4.  
• This research study will be following the CM research policies regarding 
informed permission/assent/consent.  
• This research team will be obtaining permission/assent/consent via 
telephone, and we will be following CM research policy 10.05 Telephone 
Process regarding telephone consent. 

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• The permission/assent and consent forms will contain a section for 
participants to allow their data and samples to be stored in the PK/PD 
Repository for use in prospective research. 
 
Subjects Who Are Not Yet Adults 
 
Prospective subjects under the age of 18 are considered minors and have 
not attained the legal age for consent to treatments or procedures 
involved in the research under the applicable law of the jurisdiction (the 
state of Missouri) in which the research will be conducted.    
 
• Parental permission need only be obtained from one parent even 
if the other parent is alive, known, competent, reasonably 
available, and shares legal responsibility for the care and custody 
of the child. Permission to participate in the research study is 
done so by the potential participant’s legally authorized 
representative (LAR). LARs who are not the potential participant’s 
biological parents must provide documentation (e.g. adoption 
paperwork) prior to or at the time of the permission/assent 
process. The study team will maintain a copy of these records as a 
part of the participant’s study binder. Assent will be obtained for 
all children greater than or equal to 7 years of age. For children 
under the age of 7, assent is not required, but may be obtained at 
the discretion of the study team.  
 
• Documentation of both permission and assent will be recorded on 
study specific permission/assent forms and will be signed and 
dated by the parent or LAR and potential participant (if 
applicable). If potential participant is unable to sign, the study 
team will document the reason for this. If assent is not obtained 
for a child under 7, this will also be documented on the 
permission and assent form.  
 
  
Subjects Who Become Adults at 18 Years of Age At the Time of Data 
Collection 
 
Participants who turn 18 years old while actively participating in this 
study procedures will be consented at age 18 using a full Adult Consent 
form.  
 
Subjects Who Become Adults at 18 Years of Age After Data Collection is 
Completed 
 

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The study is seeking a waiver of consent for participants who turn 18 
after data collection has been completed due to: the amount of time 
needed to complete enrollment for this study, study procedures, data 
processing, and data analysis (~ 5 years) and the potential of not 
completing study procedures by the time many of the participants turn 
18; the fact that participants may move; or may not follow up; and the 
high number of participants. This study could not be reasonably 
completed without a Waiver of Consent for children reaching the age of 
majority after study procedures have been completed. 
 
26.0 Documentation of Permission/Assent/Consent 
 
This research study will be following the CM Research Policy 10.04 Obtaining 
Permission/Assent/Consent.   
27.0 Setting 
 
The following are the main sites where the research team will identify and recruit 
potential participants:  
• ADHD Clinic, Children’s Mercy College Boulevard Clinics, 5520 College 
Boulevard, Ste 365, Overland Park, KS, 66211 
• Children’s Mercy, Broadway Clinics, 3101 Broadway Boulevard, Kansas 
City, MO 64111  
• Children’s Mercy West Clinic, 4313 State Avenue, Kansas City, KS 66102  
 
Research data collection will be performed at the following sites:  
• Pediatric Clinical Research Unit, Adele Hall Campus, Children’s Mercy 
Hospital, 2401 Gillham Road, MO 64108  
• ADHD Clinic, Children’s Mercy College Boulevard Clinics, 5520 College 
Boulevard, Ste 365, Overland Park, KS, 66211  
• Developmental and Behavioral Sciences, Adele Hall Campus, Children’s 
Mercy Hospital, 2401 Gillham Road, MO 64108  
28.0 Resources Available 
 
Facilities 
• PCRU: The Clinical Research Unit is a six-bed inpatient facility designed 
for the conduct of pediatric clinical research.  The unit is located on the 
ground floor of the Hall Tower (0460.900).  The unit has three private 
patient rooms and one room containing three patient beds with basic 
furniture.  All rooms are equipped with emergency equipment and 
supplies, bathroom facilities and couches for parents to stay with 

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children.  The unit has an exam room, two sample processing 
laboratories, medication room, kitchen, clean utility, dirty utility, a 
nurses’ station with four workstations, photocopying and fax machine, 
and a Translogic tube system.  The unit also has secured storage for 
medications and supplies.  
 
• Drug Biotransformation/Analytical Laboratory: The analytical facilities of 
the Division of Clinical Pharmacology, Toxicology, and Therapeutic 
Innovation occupy approximately 1280 square feet in the CMH Pediatric 
Research Center and contains several analytical instruments, including 
three triple quadrupole mass spectrometers (a Waters Xevo TQD, a 
Waters Xevo TQS, and a Waters Xevo TQ-XS), a Waters Xevo G2-XS QtoF 
mass spectrometer, each with Acquity UPLC front end systems. 
Additionally, the lab has access to a Waters Ion key source coupled to an 
M-class Acquity that can be used for nanoflow type of experiments on all 
Waters systems. The laboratory also has three Agilent HPLC systems, two 
of which are equipped with fluorescence and UV/vis detectors and the 
third with a diode array detector, and two POC-One infrared 
spectrometers for analyzing [13C]O2 breath test samples. Cold rooms, 
centrifuges, electrophoresis and blotting systems, and -20°C and -80°C 
storage are available to conduct experiments and store samples. 
 
 
• Pharmacogenetics/Pharmacogenomics Laboratory: The Pharmacogenetic 
and Pharmacogenomics Core Laboratories has access to a variety of 
platforms to conduct genotype analysis: TaqMan analysis; High-
Resolution Melt Curve analysis (HRM); traditional PCR-RFLP for SNP 
detection and long-range PCR to detect major gene arrangements. 
Genotyping panels have been established for many CYP genes, including: 
CYP2D6 (the panel established by this group represents one of the most 
comprehensive genotyping panels for this highly polymorphic gene, 
which is notoriously difficult to genotype); CYP2C9; CYP2C19; CYP2B6; 
and the CYP3A gene locus. Quantitative PCR procedures have been 
established to determine copy number variation for CYP2D6, SULT1A1, 
and UGT2B17. Additional genotyping platforms, such as the Affymetrix 
DMET chip, are available through the Cytogenetics and Molecular 
Genetics Laboratory. The Pharmacogenetics/Pharmacogenomics 
Laboratory is equipped with standard and real-time PCR instruments, a 
3730x DNA sequencer (Applied Biosystems), and a Kodak DS Image 
Station 440 CF (PC-controlled) for photodcumentation, data analysis, and 
storage. Centrifuges, electrophoresis and blotting systems, and -20°C and 
-80°C storage are available to conduct and store samples. The unit has 
nine 96-well PCR instruments, three quantitative real-time PCR cyclers 
(ABI 7900HT real time thermocycler; an Eppendorf realpex epgradient S 

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Mastercycler and an MJ Research Opticon 2 Q-PCR instrument) as well as 
two EcoRealTime PCR instruments (Illumina) to facilitate HRM analysis. 
The laboratory also has a dedicated MiSeq platform that is housed in the 
Center for Pediatric Genomic Medicine. 
 
 
29.0 Multi-Site Research 
 
This section is not applicable to this study.  
30.0 International Research 
This section is not applicable to this study.  
31.0 Appendices 
 
Title 
Appendix 
Title 
Section Referenced 
Within Protocol 
ATX PBPK Model Validation Study Summary 
Appendix A 
3.2 
Message Center Template 
Appendix B 
9.3 
Phone Message from ADHD Clinic Nurses 
Appendix C 
9.3 
Study Coordinator/RA Recruitment Script 
Appendix D 
9.3 
Recruitment Email or Letter 
Appendix E 
9.3 
Study Coordinator/RA Scheduling Script 
Appendix F 
11.1 
U54 Study Booklet Questionnaire 
Appendix G 
4.1, 11.2 
Pupillometry Example 
Appendix H 
11.2 
Neurotransmitters in metabolomic panel 
Appendix I 
20.1 
Study Drug Timeline 
Appendix J 
5.2 
Sample Letter to Release Data and/or Specimens by PI 
Appendix K 
12.0 
Sample Letter to Share Genetic Results 
Appendix L 
14.0 
Sample Letters to Release ADHD Results or Incidental 
Findings to Participants of this Study 
Appendix M 
9.3, 11.3, 14.0 
Sample Letters for End of Study ADHD Care Transition 
Appendix N 
11.2 
Literature Search and Documentation for Washout and 
Return to Baseline 
Appendix O 
11.2 
 
 
 
 
 

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Appendix A – ATX PBPK Model Validation Summary 
 
The primary aim of this study is to validate a method to individualize ATX dosing to 
achieve a desired level of ATX exposure, referred to as the individualized Genetic and 
Ontogenic Pharmacokinetic (iGO-PK) algorithm. This dosing algorithm relies on two 
separate models, one that is used to dose CYP2D6 PMs and a model for the rest of the 
population (i.e., the non-PM model). This dosing algorithm has been designed to 
calculate a dose of ATX for individual patients that is expected to result in ATX Cmax 
concentrations at steady-state associated with a reduction in ADHD symptoms 
(Michelson et al, 2007) The model takes into account CYP2D6 genotype, which is 
converted into an activity score, weight, and obesity status. Validation and refinement 
of this dose prediction model is required to ensure that a Cmax goal can be achieved 
reliably with the patient information that is provided. Additionally, we are interested in 
obtaining more data for CYP2D6 Ims and PMs because of the small sample size in these 
phenotype groups in the initial pharmacokinetic study conducted by Brown et al (2016). 
The data collected from this study will also be used to refine the model, given that the 
initial model only utilized data from 23 children who represent a wide range of CYP2D6 
activity.  
 
 
 

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Appendix B – Message Center Template 
 
I am recruiting patients ages 6-18 with suspected or diagnosed ADHD for a study with 
the medication Atomoxetine (Strattera) through Clinical Pharmacology/GOLDILOKs. 
Atomoxetine is an FDA-approved medication for ADHD, but its use has been 2nd or even 
3rd line for ADHD due to lack of efficacy. In our study, we are interested in using 
personalized medicine to tailor a dose to each patient to improve how this medication 
works for each child. In this longitudinal study, patients interested in non-stimulant 
medication will receive personalized Atomoxetine dosing based on their CYP2D6 
genotype (the enzyme that breaks down the medication). Patients referred for this 
study will receive their ADHD care from a study physician for the next 6-8 months and 
have intermittent research visits in the Pediatric Clinical Research Unit (PCRU) at the 
Adele Hall campus to monitor how they are responding to and breaking down the 
medication. From this study, we hope to learn how to better use this medication for 
children with ADHD. 
 
After reviewing this patient’s chart, he/she is eligible for the study, and I see he/she has 
an appointment with you [timeframe]. If you, your patient, and his/her family are 
interested in starting this medication, please feel free to mention there is an ADHD 
medication study available. If he/she and his/her parents are interested, please feel free 
to either give them my contact information below to call or email me, provide the study 
handout available in each provider workroom, or simply reply back and I will reach out 
to the family. 
 
If your patient is currently on an alpha agonist or atomoxetine for ADHD, unfortunately, 
he/she cannot enroll in our study. However, if your patient is currently taking a 
stimulant for ADHD, he/she will need to undergo a 1 week washout period prior to 
starting the study medicaiton. Please note, the study team must first obtain 
permission/assent or consent prior to any study procedures, including initiating a 
medication washout.  
 
There is a slide regarding this study on the workroom monitors for you to refer to, but if 
you have any further questions, please feel free to reach out.  
 
Thank you, 
 
(signature + contact information) 
 
 
 

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Appendix C – ADHD Clinic RN 
 
Hi, my name is ____________ and I am a nurse/care provider at the Children’s Mercy 
Hospital ADHD Clinic.  
 
We reviewed the results from the questionnaires that you and your child’s teachers 
filled out. Based on the answers we received, we believe that there is a high chance that 
your child may have attention deficit/hyperactivity disorder (or ADHD for short). We 
would like to schedule an appointment for you to meet with our physician and clinical 
psychologist for further evaluation. (NB: this italicized section about scheduling may be 
omitted if the caller has no intention to schedule an appointment.) 
 
Because your child has a high likelihood of having ADHD, he/she may be able to 
participate in an ADHD study that is taking place at Children’s Mercy Hospital.  
If you/your child might be are interested in participating in this study, or would like to 
learn more about this study, we would be more than happy to pass your contact 
information to the study coordinator of this study for more detailed information. 
 
Would you be interested in this study, or would you like to learn more about this study? 
1. Yes, please have the study coordinator contact me with more information 
2. No, I am not interested in participating in the study at this time.

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Appendix D – Study Coordinator/Research Assistant Recruitment Script 
 
Hi, my name is ___________, and I work in research at Children’s Mercy Hospital.  My 
team is working on an Attention Deficit and Hyperactivity Disorder, or ADHD, 
medication study for children ages 6-18.  Do you have 5-10 minutes to talk about a 
voluntary study opportunity? 
 
(If yes, continue.  If no, ask to contact at a later date/time.) 
 
Track 1 – I am contacting parents of new patients with upcoming appointments at the 
Children’s Mercy ADHD Clinic on College Blvd to let you know about this study 
opportunity.  I see that your child has an upcoming appt on MM/DD/YYYY.  
 
Track 2 – Your child’s healthcare provider, _______, at PCC on Broadway, contacted me 
about your interest in our ADHD study. 
 
Track 3 – Your child’s healthcare provider, _______, at  _________, contacted me about 
your interest in our ADHD study. 
 
(Track 4 and Track 5 contact us; this would be a return call or incoming call.) 
 
First, I’d like to tell you about what we are studying and why.  Then, if you are interested 
in learning more, I’ll share what would happen during the study.  First, please note that 
all research is voluntary, and your decision to participate or not will not affect the care 
your child receives here at Children’s Mercy in any way.  Feel free to stop me at any 
time if you have questions while I explain the study. 
 
We are studying an ADHD medication, atomoxetine, (the brand is name is Strattera), in 
children ages 6-18 years old.  This study would involve your child taking this medication.  
This medication is approved by the FDA for children with ADHD and has been on the 
market for about 15-20 years.  It isn’t used very often though. This is because it doesn’t 
seem to work very well for some children.  For some children, they behave much better 
in school and pay attention in class while taking this medicine.  However, for other 
children, it doesn’t seem to have much effect.  There are lots of reasons why a medicine 
might not work for someone, and one of those reasons is how fast or slow they break 
down the medicine.  We think that perhaps one reason this medicine doesn’t work as 
well for some children is because the dose is too high or too low for how fast or slow 
they break it down.  What we would like to do is draw a small amount of blood and run 
genetic testing to figure out how fast or slow your child breaks down the medicine.  
Together with other information such as age, weight, height, and ethnicity, we will come 
up with a dose that we think is just right for your child.  We would ask your child to take 
this medicine for several months and see if it helps treat his or her ADHD symptoms.  
There is a chance that this medicine will not work for your child regardless of the dose, 

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and this is because the dose is just one piece of the puzzle.  We want to understand why 
this medicine works for some children and doesn’t for others.  Ultimately by studying 
this drug in your child and other children, we hope to learn how to better use this drug 
for other children with ADHD in the future.  
 
Do you have any questions for me at this point? (yes/no) 
 
Next, I’d like to tell you what we would ask from you and your child during the study if 
you were to enroll. 
  
This study takes place over about 6-8 months.  There are 8 total visits—4 research visits 
and 4 clinic visits.  At research visits, we study how your child is breaking down the 
medicine.  At clinic visits, you and your child visit with a study doctor to see how the 
medicine is working at home and at school and change the dose if needed.  First, we 
would bring you in for a research visit to gather information about your child, including 
his or her ADHD symptoms, health history, and draw blood for genetic testing and to 
make sure your child is health enough for the study.  Then, we would have you and your 
child meet with a study doctor at a clinic visit to see if ATX would be a good fit.  If so, we 
would then calculate a dose for your child and start your child on the medicine. 
We will ask you and your child to come to the research unit (PCRU) at the Adele Hall 
campus to give the first dose of medicine.  After we give the medicine, we will draw 
small blood samples multiple times over the course of several hours to measure the 
amount of drug in your child’s blood.  This visit will generally last about 12-14 hours.  
Depending on the information we learn about your child’s genes, we may ask your child 
to stay overnight to measure more samples. This would be a 24 hour study.  We will 
know how long your child’s visits will last before you ever start the medicine so you can 
decide if this will work for your family. This visit is to help us understand how your child 
breaks down the medicine after just one dose.  
  
Do you have any questions for me at this point? (yes/no) 
 
After this, we will send you and your child home with a prescription of atomoxetine to 
take every day.  Your child will see your study physician every month or 2 to see how the 
medicine is working at home and at school. If needed, the doctor may adjust the dose.  
In addition to these doctor’s visits, we will ask you and your child to come back to 
repeat the blood samples again two times.  One time is anytime between these doctor’s 
visits, and the other time is after all of the doctor’s visits are completed. These help us 
understand how your child breaks down the medicine after your child’s body is used to 
taking the medicine every day.  
 
So altogether, the study will last 6-8 months, include 4 clinic visits, and 4 research visits, 
and your child will take this medicine every day.  This study is voluntary, so if at any 
point you or your child want to stop, you may and it will not affect the care your child 
receives at Children’s Mercy in any way. 

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Do you have any questions for me at this point? (yes/no) 
 
Please note, there are some medications your child cannot take to participate in this 
study. In particular, if your child is currently taking a stimulant medication for ADHD, he 
or she cannot continue this medication during the study. If you and your child choose to 
enroll in the study, we will ask your child to “washout” of his or her ADHD medication. 
This means your child will need to stop the ADHD medication and wait at least 1 week to 
“washout” the effects of the ADHD medication so that your child is back to his or her 
ADHD symptom baseline.  Please note, if you do choose to enroll, we ask that you do 
not stop your child’s ADHD medication until after you and your child have signed the 
study consent form with a study team member in person at your first research visit.  
 
Do you have any questions about this part? (yes/no) 
 
If you are interested in learning more, I would like to email or mail you some further 
information about the study for you to review with your child.  I realize this is a lot of 
information, so please take the necessary time you need before deciding whether you 
and your child want to participate in this study. 
 
Would it be okay to check back in with you? (yes/no) 
 
When would you like me to contact you? (record time or date) 
 
END 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix E – Recruitment Email or Letter 
 
Thank you for your interest in our ADHD study.  I have attached the study consent form,  
and a Frequently Asked Questions (FAQ) sheet for you to review. These include details 
about the study including the purpose of the study, what would happen during the 
study, risks, benefits, alternatives, etc.  The consent form includes sections at the end 
for your signature, but please do not sign this.  This form is simply for your information 
at this time.  If you and your child choose to enroll in our study, a study team member 
will review this with you and your child in person and answer any questions you may 
have before we ask you to sign the form.    
If your child is currently taking stimulant medication for ADHD, he or she cannot 
continue this medication during the study.  Your child will need to stop, or “wash out” of 
his or her medication to start atomoxetine. We ask participants to stop ADHD 
medication for at least a week before starting atomoxetine so that the study team can 
better understand your child’s ADHD symptoms off medicine and how this new 
medicine will work in your child’s body.  We ask that you do NOT stop your child’s ADHD 
medication until after you and your child come in to sign the consent form and meet 
with a study doctor to talk about the washout.  
When your child stops his or her medication, his or her ADHD symptoms will likely 
return.  Your child may have trouble focusing and have more impulsive behavior.  Some 
children may handle this brief time off ADHD medicine just fine while other children 
may have a lot of trouble at school and home.  We know that as the parent, you know 
your child better than anyone else.  Therefore, we want you to think about if washing 
out is okay for your child. These behaviors may impact school performance, after-school 
sports and activities, and how your child interacts with family, teachers, and other 
children. Some children may do better washing out of ADHD medicine over a school 
break when ADHD behaviors are less disruptive.  While you look over the consent form 
and FAQ sheet, please consider if the washout is appropriate for your child.  
If you have any questions or concerns, please feel free to reach out to us via phone or 
email.  
Thank you, 
ADHD Study Team  
(Study Team Email) 
(Study Cell Phone) 
 
 

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Appendix F – Study Coordinator/Research Assistant Scheduling Script 
 
Hi, my name is ________________ and I am a study coordinator/research assistant at 
Children's Mercy Hospital. Thank you for your interest in our study.  I am calling to 
schedule your child’s first research visit.  But first, I’d like to talk to you about a few key 
points in the study.  
First, I want to review how long visits are and how often visits occur. 
1) Research Visit 1 lasts about 4-5 hours; Part 1 is about 1 hour and Part 2 is 3-4 
hours. 
2) Research Visits 2-4 last at least 14 hours. Depending on what we learn about 
your child, some children have 24 – 72 hour visits, and we will ask that your child 
stay overnight at the research center. 
3) The first 2 study physician visits and first 2 research visits happen close together 
over the first 2-3 months of the study. After that, visits happen every month or 2. 
Second, if your child will need to wash out of his or her ADHD medication, please do not 
stop the medication until after you sign the consent form.  
Do you have any questions for me at this time? 
Third, the study medicine, atomoxetine, is only available in capsules (pills), so children 
who enroll in the study will need to be able to swallow pills to start the medicine. If your 
child has trouble swallowing pills or has never tried swallowing pills, we are happy to 
work with your child to help teach him/her how to do this. 
Lastly, I want to talk a little bit about the blood draws that happen in this study.  
In this study, we ask participants to have multiple blood draws, and we know these 
needlesticks can be stressful to some children. We want to help make these needlesticks 
as stress-free as possible for any child who wants to be in the study.  It can be hard to 
predict how a child will react to a needlestick.  However, we have learned some things 
from other children who have enrolled in our study.  Children who have never had a 
needlestick, such as a blood draw at a doctor’s office, vaccinations, or even had an IV, 
tend to be nervous about the blood draw. Also, children who have general fears about 
hospitals, clinics, and healthcare situations and children who “just shut down” in 
unfamiliar situations have more trouble than others.  I want to encourage you to think 
about how your child might do with the needlesticks and let us know what we can do to 
make this a pleasant experience for your child.  When you come in for your first 
research visit, a study team member will talk to you to learn about your child’s comfort 
level with needlesticks before we do any blood draws.   
 
Do you have any questions for me at this time? 
 

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Great! If you are ready, I’d like to schedule your research visit.  
(Schedule Date and Time) 
This visit takes place at the Adele Hall campus, which is the main Children’s Mercy 
campus located downtown. When you arrive, park in the visitor parking garage, check in 
at security, and go to the Pediatric Clinical Research Unit, or PCRU for short. This is 
located on the ground level next to the gift shop.   
Please remember to bring your child’s social security number to the visit. We are 
required to keep a record of this information for payment to any child participating in 
this research study. 
Do you have any final questions for me?   
(END) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix G – U54 Study Booklet Questionnaire (please see PDF attachment for Study Booklet) 
 
1. How much do you agree with each statement? 
This booklet: 
 
Strongly 
Disagree 
 
Disagree 
 
 
Neutral 
 
 
 
Agree 
 
Strongly  
Agree 
Helped me understand why this drug 
works differently in different people. 
 
 
 
 
 
 
Helped understand what a research 
visit is and what clinic visit is. 
 
 
 
 
 
 
Helped me understand what I would 
be doing at each visit. 
 
 
 
 
 
 
Helped me understand that I can 
choose to be, or not be in this study. 
 
 
 
 
 
 
Was useful to me as I was going 
through this study. 
 
 
 
 
 
 
 
2. What would be helpful in future study booklets? 
 

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Appendix H – Example of pupillometry and eye-tracking tasks 
Figure 1 – Valid and invalid examples of the localization task, both with successful responses. 
 
 

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Figure 2 – Valid and invalid examples of the discrimination task, both with successful response. 
 
 

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Appendix I – Example of neurotransmitters in metabolomics panel 
 
1. 3,4-dihydroxyphenylglycol (DHPG) 
2. α-methyltryptophan 
3. α-tocopherol 
4. cysteine 
5. δ-tocopherol 
6. γ-tocopheral 
7. guanine 
8. guanosine 
9. homogentisic acid 
10. homovanillic acid 
11. hypoxanthine 
12. indole-3-acetic acid 
13. indole-3-propionic acid 
14. kynurenine 
15. methionine 
16. salicylic acid 
17. serotonin 
18. tryptophan 
19. tyrosine 
20. uric acid 
21. vanillylmandelic acid 
22. xanthine 
23. xanthosine 
24. 1,3-dimethyl xanthine 
25. 1,7-dimethyl xanthine 
26. 3-methoxy-4-hydroxyphenyl glycol 
27. 4-hydroxybenzoic acid 
28. 4-hydroxyphenylacetic acid 
29. 4-hydroxyphenyllactic acid 
30. 5-hydroxytrptophan 
31. 5-hydroxyindoleacetic acid 
 
 
 

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Appendix J – Study Drug Timeline, a description of drug handling during the ATX PBPK-
PD Clinical Outcomes Study 
 
START of Intervention 
  
 
  
Designated Study Personnel/PI calculates the initial dose with the iGO-PK model 
  
 
  
Study personnel/PI shares the dose calculation with RA/Study coordinator/Designated 
Study Personnel and Study Physician following the participant 
  
 
  
RA/Study coordinator/Designated Study Personnel prepares IDS prescription for 6-8 
weeks for Study Physician to sign. 
  
 
  
Study Physician signs prescription, scans, and emails back to RA/Study 
coordinator/Designated Study Personnel 
  
 
  
RA/Study coordinator/Designated Study Personnel emails the prescription to IDS to fill 
and files the original in the subject binder  
  
 
  
IDS brings the Rx to the PCRU for Research Visit 2/PK1 
  
 
  
At Research Visit 2/PK1 
• 
1 dose from the prescription is administered to the participant, medication label 
from IDS is scanned into MAR at dose administration. RN/Designated personnel 
doses. Topical lidocaine (optional) may also be dispensed. 
• 
PI/Designated Study Personnel teaches family/participant about medication 
(review prescription details, study booklet calendar, when to contact, anticipated 
possible side effects, etc) 
• 
PI/Designated Study Personnel give prescription to the family/participant to take 
home 

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• 
PI/Designated Study Personnel write a note in PowerChart documenting this 
education, the prescription dispensed, and any questions/concerns.  Study 
physician co-signs this note.  
 
 
  
At Research Visit 3/PK2 
• 
A prescription for a single dose (or two doses if Study Design 3) of atomoxetine 
(optional topical lidocaine) will be dispensed at Research Visit 3/PK2. A medication 
label is generated by IDS, so documentation of the dose is recorded in the nurse 
note. RN/Designated personnel doses. 
• 
PI/Designated Study Personnel count the participant’s remaining prescription and 
compare against medication adherence calendar to calculate adherence.  
  
 
  
Prior to 6-Week Visit, RA/Study coordinator/Designated Study Personnel prepares IDS 
prescription for 6-8 weeks for Study Physician to sign 
  
 
  
Study Physician signs prescription, scans, and emails back to RA/Study 
coordinator/Designated Study Personnel  
  
 
  
RA/Study coordinator/Designated Study Personnel emails the prescription to IDS to fill 
and files the original in the subject binder 
  
  
 
  
At 6-Week Visit, 
• 
PI/Designated Study Personnel counts the participant's remaining prescription and 
compares against medication calendar to calculate adherence.  
• 
Dispensing Rx to family occurs by any of the following ways: 
o RA/Study coordinator/Designated Study Personnel obtains prescription from 
IDS and to provide to family/participant. Hand-off of medication may occur in 
clinic or just outside CMH at a pre-determined location (e.g. the front 
entrance).  
o IDS brings the prescription to the outpatient pharmacy for the 
family/participant to pick up 
• 
IDS/ RA/Study coordinator/Designated Study Personnel may use a courier 
service to deliver medication to CMK outpatient pharmacy for the 

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family/participant to pick up. This use of courier service will be determined by 
IDS policies and practices. 
• 
IDS Pharmacy ships the medication to the family in Home Care Pharmacy 
medication coolers via FedEx using OptiFreight. Shipment of medication will be 
follow IDS policies and practices. 
• 
If the dose changes, RA/Study coordinator/Designated Study Personnel takes the 
old prescription and returns to IDS for disposal 
  
 
  
  
Prior to 12-Week Visit, PI/Designated Study Personnel prepares IDS prescription for 6-8 
weeks for Study Physician to sign 
  
  
  
Study Physician signs prescription, scans, and emails to RA/Study 
coordinator/Designated Study Personnel 
  
 
  
  
RA/Study coordinator/Designated Study Personnel emails the prescription to IDS to fill 
and files the original in the subject binder 
  
  
 
  
At 12-Week Visit, 
• 
PI/Designated Study Personnel counts the participant’s remaining prescription and 
compares against medication calendar to calculate adherence.  
• 
Dispensing Rx to family occurs by any of the following ways: 
o IDS brings the prescription to the outpatient pharmacy for the 
family/participant to pick up 
o IDS/RA/Study coordinator/Designated Study Personnel may use a courier 
service to deliver medication to CMK outpatient pharmacy for the 
family/participant to pick up. This use of courier service will be determined 
by IDS policies and practices. 
o IDS Pharmacy ships the medication to the family in Home Care Pharmacy 
medication coolers via FedEx using OptiFreight. Shipment of medication will 
follow IDS policies and practices. 
• 
If the dose changes, RA/Study coordinator/Designated Study Personnel takes the 
old prescription and returns to IDS for disposal 
  

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 
  
  
Prior to 18-Week Visit, PI/Designated Study Personnel prepares IDS prescription for 6-8 
weeks for Study Physician to sign 
  
 
  
  
Study Physician signs prescription, scans, and emails to RA/Study 
coordinator/Designated Study Personnel 
  
 
  
  
RA/Study coordinator/Designated Study Personnel emails the prescription to IDS to fill 
and files the original in the subject binder 
  
 
  
At 18-Week Visit, 
• 
PI/Designated Study Personnel counts the participant’s remaining prescription and 
compares against medication calendar to calculate adherence.  
• 
Dispensing Rx to family occurs by any of the following ways: 
o RA/Study coordinator/Designated Study Personnel obtains prescription from 
IDS and to provide to family/participant. Hand-off of medication may occur in 
clinic or just outside CMH at a pre-determined location (e.g. the front 
entrance).  
o IDS brings the prescription to the outpatient pharmacy for the 
family/participant to pick up 
o IDS/RA/Study coordinator/Designated Study Personnel uses a courier service 
to deliver medication to CMK outpatient pharmacy for the family/participant 
to pick up. This use of courier service will be determined by IDS policies and 
practices. 
o IDS Pharmacy ships the medication to the family in Home Care Pharmacy 
medication coolers via FedEx using OptiFreight. Shipment of medication will 
follow IDS policies and practices. 
• 
If the dose changes, RA/Study coordinator/Designated Study Personnel takes the 
old prescription and returns to IDS for disposal 
  
 
  
 

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At Research Visit 4/PK3 
• 
A prescription for a single dose (or two doses if Study Design 3) of atomoxetine 
(optional topical lidocaine) will be dispensed at Research Visit 3/PK2. A medication 
label is generated by IDS, so documentation of the dose(s) is recorded in the nurse 
note. RN/Designated personnel doses. 
• 
RN/Designated study personnel doses.  
• 
PI/Designated Study Personnel count the participant’s remaining prescription and 
compare against medication adherence calendar to calculate adherence.  
• 
If the participant intends to continue the study medication after study completion, 
the participant/family keep the remaining prescription (in the protocol) 
• 
If the participant does not intend to continue the study medication, RA/Study 
coordinator/Designated Study Personnel take the prescription and return to IDS 
for disposal (Of note, since the new protocol will suggest a taper for those 
discontinuing the drug, this will change).  
 
At any point during this study 
• 
Medication may be dispensed to the participant and their family. Dispensing does 
not need to coincide with Study Physician visits, especially if these occur via 
telehealth in response to the COVID-19 pandemic. Dispensing Rx to family occurs 
by any of the following ways: 
o 
RA/Study coordinator/Designated Study Personnel obtains prescription from 
IDS and to provide to family/participant. Hand-off of medication may occur in 
clinic or just outside CMH at a pre-determined location (e.g. the front 
entrance).  
o IDS brings the prescription to the outpatient pharmacy for the 
family/participant to pick up 
o IDS/RA/Study coordinator/Designated Study Personnel uses a courier service 
to deliver medication to CMK outpatient pharmacy for the family/participant 
to pick up 
o RA/Study coordinator/Designated Study Personnel or IDS Pharmacy ships the 
medication to the family in Home Care Pharmacy medication coolers via 
FedEx using OptiFreight 
• 
NB: For certain scenarios, such as during the COVID-19 pandemic, 
the shipment of medication will be determined by IDS policies. 
o When any member of the study team picks up medication for the participant, 
they are acting as an, “agent of the patient” for the purposes of facilitating 
transfer of drug between IDS Pharmacy and study participant. 
 
  
 
  
END 
  
 
 

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Appendix K – Sample Letter to Release Data and/or Specimens by PI 
 
I, (PI Name), authorize the release of the following data to (Collaborator Name) (list data 
to be shared) for the purposes of achieving the aims of the following research study (Study 
Name, IRB# if applicable): 
• Example 1 (all pharmacokinetic data collected as a part of this) 
• Example 2 (all genetic information for participants that completed this study) 
• Example 3 (demographic information for all children enrolled) 
• Etc. 
PI Signature: 
Date:__________________________ 
 
Collaborator Signature: 
Date:__________________________ 
  
 
 

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Appendix L – Sample letters to Share Genetic Information 
 
To the family of (Participant’s Name) (DOB MM/DD/YYYY): 
 
Your child had genetic testing as a part of this ADHD study.  This was done to help us 
learn how fast or slow your child “metabolizes”—or breaks down and removes 
atomoxetine (Strattera®) from his body.  We want to return the test results to you and 
your child.   
 
What are the results? 
 
In general, atomoxetine is metabolized, or broken down, by CYP2D6 (pronounced “sip-
2-d-6”).  Based on the genetic testing, your child is a(n) ___________ metabolizer for 
CYP2D6. This means when your child takes medicines like atomoxetine, your child’s 
body breaks down the medicine __________ than most people in the population.   
 
There are 4 different types of CYP2D6 metabolizers. They are:  
 
 
 
For most people, CYP2D6 breaks down almost all the atomoxetine a person takes.  For 
some people, CYP2D6 doesn’t work as well.  For these people, another enzyme, 
CYP2C19 (pronounced “sip-2-c-19”), will help break atomoxetine down, too.    
 
 
Types of CYP2D6 Metabolizers 
Ultra-Rapid 
Metabolizer 
  
Break down the medicine much faster than 
most people in the population 
Normal 
Metabolizer 
  
Break down the medicine about the same as 
most people in the population 
Intermediate 
Metabolizer 
  
Break down the medicine a little slower than 
most people in the population 
Poor 
Metabolizer 
  
Break down the medicine much slower than 
most people in the population 

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Your child’s genetic testing also told us your child is a(n) __________ metabolizer for 
CYP2C19. This means when your child takes medicines normally broken down by this 
enzyme, your child’s body breaks down the medicine ___________ than most people in 
the population.   
 
There are 5 different types of CYP2C19 metabolizers. They are:  
 
 
 
What else should I know about the results? 
These enzymes, CYP2D6 and CYP2C19, break down several other medicines.  Your 
child may take these other medications in the future.  However, your child and his/her 
regular doctors cannot use the research study results to help figure out if and how to 
use these other medicines if he/she may need them in the future. These test results can 
only be used for this ADHD medicine in this ADHD study. This means we can’t put the 
results in your child’s medical chart or send the results to his/her regular doctor.  This 
also means your child’s regular doctor cannot use the results to help treat your child for 
any illnesses or diseases outside of this study.  
 
Why can’t these results be used outside the study? 
Types of CYP2C19 Metabolizers 
Ultra-Rapid 
Metabolizer 
  
Break down the medicine much faster than 
most people in the population 
Rapid 
Metabolizer 
 
Break down the medicine a little faster than 
most people in the population 
Normal 
Metabolizer 
  
Break down the medicine about the same as 
most people in the population 
Intermediate 
Metabolizer 
  
Break down the medicine a little slower than 
most people in the population 
Poor 
Metabolizer 
  
Break down the medicine much slower than 
most people in the population 

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By law, we are not able to use these results outside of the study.  This is because our 
tests are run in a “research-grade” lab instead of a “clinical-grade” lab. Clinical grade 
labs have different rules than research grade labs, and the tests they run are often 
different.  When your child goes to his/her regular doctor and has blood drawn for lab 
work, the tests are likely run in a clinical grade lab.  
 
For this study, we wanted to look at your child’s genetics that control how CYP2D6 and 
CYP2C19 works.  If your child’s genetic testing were done in a clinical-grade lab, the test 
would probably look for only a few well-known differences in your child’s genetics that 
might have a big impact on how CYP2D6 and CYP2C19 work. Our research grade tests 
look at these same differences, but we also look for other new and rare differences that 
are not well studied yet.  Our research-grade test works better for our study because we 
want to look for all of these differences, not just the well-known ones.  
   
Please know, even though our study testing is not run in a clinical-grade lab, this does 
not mean they are wrong or unsafe.  We feel very confident that these results are 
accurate enough for the study to help us determine a dose of atomoxetine that works 
and is safe for your child.  However, we are not sure yet what these results mean for 
other medicines that are broken down by these enzymes.  More studies need to be done 
to fully understand what this means for other medicines.  
I want to learn more about my child’s test results. What should I do next? 
If you would like to have your child’s genetic information about CYP2D6 and CYP2C19 
in his medical chart for your child and his/her other doctors to make medical decisions 
outside of the study, you can repeat the test in a clinical grade lab.  Before you decide to 
repeat the test, you and your child should consider what the testing can tell you and how 
it might help your child’s doctors in the future.    
What can the testing tell me and my child’s doctors? 
Learning more information about how fast or slow your child’s CYP2D6 enzyme and 
CYP2C19 enzyme works may help you and your child’s doctors figure out which 
medicines he/she should or should not use and show if he/she may be at risk of side 
effects or a medicine not working at a normal dose. Your child will likely benefit more 
from learning more about these medicines if he/she is a: 
 
• 
CYP2D6 poor metabolizer 
• 
CYP2C19 poor metabolizer 
• 
CYP2D6 intermediate metabolizer 
• 
CYP2C19 intermediate metabolizer 
• 
CYP2D6 ultra-rapid metabolizer 
• 
CYP2C19 ultra-rapid metabolizer 
Learning more may help because regular doses of these medicines may be too high or 
too low for your child or they may not work at all. 
 

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Which medicines should I know about?  
There are several medicines that are affected by CYP2D6 and CYP2C19.  Currently, 
there are guidelines for only a few of these medicines that say the dose should be higher 
or lower than normally prescribed if you break down the medicine faster or slower than 
most people in the population.  Below are some examples of medicines where there are 
guidelines for CYP2D6 and/or CYP2C19 genotype: 
Medicine 
Used for this Disease or Illness 
Atomoxetine (Strattera®) 
Attention Deficit Hyperactivity Disorder 
(ADHD) 
Codeine 
Pain Management 
Ondansetron (Zofran®) 
Nausea/Vomiting 
Selective Serotonin Reuptake Inhibitors 
(SSRIs) 
• 
Paroxetine (Paxil®) 
• 
Fluvoxamine (Luvox®) 
• 
Citalopram (Celexa®) 
• 
Escitalopram (Lexapro®) 
• 
Sertraline (Zoloft®) 
Depression and Anxiety 
Tricyclic Antidepressants 
• 
Amitriptyline (Elavil®) 
• 
Nortriptyline (Pamelor®) 
Depression and Pain Management 
Clopidogrel (Plavix®) 
Stroke or Heart Attack (Blood Thinner) 
 
If your child is prescribed any of these medicines in the future, repeating the genetic 
testing in a clinical-grade laboratory may help your child’s doctors decide if the medicine 
is okay to use and at what dose. Right now, there are only guidelines for these 
medicines.  There may be guidelines for other medicines in the future as more research 
studies are done.  Please talk to your child’s regular doctor to decide if genetic testing for 
metabolizing medicines may be helpful in the future. 
Where can the testing be done and how can I learn more? 
If you would like to learn more about how your child breaks down medicines with 
CYP2D6 and CYP2C19, your child can be seen at a clinic here at Children’s Mercy 
Hospital called GOLDILOKs (Genomic-And-Ontogeny-Linked Dose Individualization and 
Clinical Optimization for Kids) Clinic.  At GOLDILOKs clinic, a physician, or doctor, will 
talk with you and your child and answer your questions.  After this discussion, you and 
your doctor may choose to repeat the genetic test using a clinical-grade lab and discuss 
what the results mean for other medicines.  The study team will not pay for the costs of 
the GOLDILOKs Clinic visit or the testing GOLDILOKs Clinic does.  The costs for these 
services will be billed to your child’s insurer.  You will be responsible for any such costs 
your child’s insurer does not cover.  If your child is uninsured, you will be responsible for 
these costs. 

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If you would like to learn more about GOLDILOKs clinic or make an appointment, please 
visit their website at https://www.childrensmercy.org/departments-and-
clinics/pharmacology-and-toxicology/goldiloks-clinic/ or call the clinic at (816) 234-3059. 
What else should I know about?  
Please note, there is a chance that the results from the clinical grade testing and the 
study genetic testing may be different.  This is because the tests are run differently.  It 
does not necessarily mean the tests from the study were wrong. As mentioned before, 
clinical-grade tests are set up to look for the differences in each person’s genetics that 
might have a big impact on how CYP2D6 and CYP2C19 work. Our research-grade tests 
look at these same differences, but we also look for other new and rare differences that 
are not well studied yet.  Because the tests are not looking for the same differences, the 
results may come out different. 
Who can I talk to if I have questions or concerns? 
We understand that you may have questions about this information.  Please feel free to 
reach out to a member of the study team at either the study cell phone (816) 359-2963 
or the study email ADHDstudyteam@cmh.edu.    
 
Sincerely, 
 
 
 
 
 
 
Sincerely, 
(Principal Investigator Signature) 
 
Principal Investigator Name 
Principal Investigator Contact Information 
 
 
 

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Appendix M – Sample letters to Release ADHD Results or Incidental Findings to 
Participants of this Study 
 
For return of ADHD pertinent results: 
To whom it may concern: 
Attached are parent and teacher completed NICHQ Vanderbilt Assessment Scales (ADHD 
rating scales). These scales were completed during the prescreening process for the 
following research study: An Open-Label, Single- and Multi-Dose Study to Evaluate the 
Relationship between the Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes 
of Atomoxetine in CYP2D6 Extensive, Intermediate, and Poor Metabolizers in Children 
with Attention Deficit/Hyperactivity Disorder. The results have been released back to 
the family at the family’s request. NICHQ Vanderbilt Assessment Scales are interpreted 
in the context of a clinical evaluation for diagnosis and monitoring of ADHD. 
 
Sincerely, 
(Study Physician Signature) 
 
Study Physician Name 
Study Physician Contact 
 
For the return of incidental findings: 
To whom it may concern: 
The following (list study procedures) were completed during the prescreening process 
for the following research study: An Open-Label, Single- and Multi-Dose Study to 
Evaluate the Relationship between the Pharmacokinetics, Pharmacodynamics, and 
Clinical Outcomes of Atomoxetine in CYP2D6 Extensive, Intermediate, and Poor 
Metabolizers in Children with Attention Deficit/Hyperactivity Disorder.  
 
The (list study procedures) may indicate the following (list incidental findings). Further 
evaluation is recommended. 
 
The results are being released back to the family to facilitate care for the participant’s 
primary care provider or specialist of the family’s choosing. 
 
Sincerely, 
(Physician Signature) 
 
Physician Name 
Physician Contact 
 
 
 

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Appendix N – Sample letters for End of Study ADHD Care Transition 
 
To the family of [subject name] (DOB MM/DD/YYYY): 
Thank you for allowing the Division of Developmental and Behavioral Sciences to 
provide care for [subject name]’s Attention Deficit Hyperactivity Disorder (ADHD). I am 
writing this letter to assist you with transferring care to your regular healthcare 
provider.  [Subject] was enrolled in the following research study: An Open-Label, Single- 
and Multi-Dose Study to Evaluate the Relationship between the Pharmacokinetics, 
Pharmacodynamics, and Clinical Outcomes of Atomoxetine in CYP2D6 Extensive, 
Intermediate, and Poor Metabolizers in Children with Attention Deficit/Hyperactivity 
Disorder.  [Subject]’s current dose of atomoxetine is __ mg [frequency]. For future 
comparisons, you may wish to share with his regular provider that his/her most recent 
NICHQ Vanderbilt Assessment Scales ( ADHD rating scales) indicated that # of 9 
symptoms of inattention and # of 9 symptoms of hyperactivity/impulsivity were in the 
significant range.  This demonstrates ________ improvement from the time of 
enrollment when rating scales indicated that # of 9 symptoms of inattention and # of 9 
symptoms of hyperactivity/impulsivity were in the significant range. It is recommended 
not to abruptly stop this medication and to make any future changes under the 
guidance of his physician.  I am happy to provide his physician with additional 
information or guidance if needed.  I can be reached through my clinic nursing staff at 
(816) 855-1927.  
 
Sincerely, 
(Study Physician Signature) 
 
Study Physician Name 
Study Physician Contact 
 
 

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Appendix O – Literature Search and Documentation for Washout and Return to Baseline 
 
When a literature search must be conducted to determine the length of time needed to 
wash out of medications and when to administer baseline questionnaires, the follow 
data should be sought: 
 
• Pharmacokinetics parameters of the drug in question. Ideally, these parameters 
will have been obtained in children, although for many drugs the data do not yet 
exist. When this data is not available in pediatrics, adult data may be used to 
estimate half-life and the expected amount of time needed to for medication to 
be removed from systemic circulation. In some instances, ranges are given for 
half-life. Use the most conservative value for estimating length of time needed 
to wash out of medciation. Additionally, consider estimating if ontogeny plays a 
role in in key processes for drug removal (i.e. CYP2D6, CYP3A4, CYP2C9, CYP2C19 
genotype/activity or renal function). 
• Pharmacodynamics parameters of the drug in question. This information should 
be sought to determine the amount of time needed for the effects of medication 
to wear off. The time needed for this to occur may be longer than the washout 
period for drugs. For many older drugs, this information is not available. Efforts 
should be made to determine if these parameters are reported in children 
and/or adults. Please note that for many neuropsychiatric drugs, there may 
information about the direct action of the drug, however little to no data may 
exist for the downstream modifications caused as of result of taking medication. 
• Behavior of the participant. A proxy of return to baseline behaviors is also 
through evaluation of the participant’s behaviors. This can be done when 
discussing the study with parent and through chart review. 
• Prior trials evaluating the drug in question. Another source of information is 
evaluating how previous clinical trials have washed out of the drug in question. 
Crossover trials with a washout and baseline measure during washout can 
provide some insight to the length of time needed for drug concentrations and 
drug effects to return to baseline.  
• Expert opinion. In addition to the data above, washout duration will be 
discussed at clinical project meetings by study team members. Study team 
members include professionals from various backgrounds including 
developmental and behavioral pediatricians, a pediatric psychologist, and clinical 
pharmacologists.  
• When little to no data exist for a drug. If the study team is unable to make an 
estimation as to how long to wash out of medication, it is advisable that the 
participant not continue further in the study. The participant will have met 
exclusion criteria, “Subject is considered by PI to be unsuitable for participation 
in the study for any reason.” 
 

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A note to file will written to describe the data available and the research team’s 
conclusions about the appropriateness of washout, length of washout, and when to 
administer baseline questionnaires. 

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32.0 List of Supplementary Documents 
Title 
Section Referenced 
Within Protocol 
Clinical Quality Management Plan 
20.5 
Data Safety Monitoring Board Charter 
21.1 
Data Safety Monitoring Board Protocol 
21.1 
Recruitment Flyer 
9.3 
Summer Treatment Program Presentation 
9.3 
U54 Potential Participant Log 
9.3, 9.4 
U54 Master Enrollment Log 
9.4 
U54 Study Booklet 
2.1 
U54 Study Booklet Information Handout 
2.1 
CHADIS Handout 
11.2 
Washout Handout 
11.2 
CMRI Website Information 
9.1, 9.3 
 
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