Clinical trial NCT03265119
Conditions: Attention Deficit Hyperactivity Disorder
Sponsor: Aevi Genomic Medicine, LLC, a Cerecor company
Start date: 2017-08-28; Completion date: 2018-10-01
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is PART A of a 2-part, 6-week, double-blind, dose-optimization, parallel-group study in children and adolescents (ages 6-17 years) with ADHD with and without CNVs in specific genes implicated in glutamatergic signaling and neuronal activity. Parts A will include subjects determined to have a specific gene mutations implicated in glutamatergic signaling and neuronal connectivity.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: AEVI-001 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral doses of 100 mg, 200 mg or 400 mg of AEVI-001 will be administered twice daily during the treatment period. intervention 2: Oral doses of 100 mg, 200 mg or 400 mg of Placebo will be administered twice daily during the treatment period.

Protocol documents:
Prot_001.pdf: 



























































































































































SAP_000.pdf: 
Aevi Genomic Medicine, Inc.
AEVI-001-ADHD-202 (Part A)
Statistical Analysis Plan
CONFIDENTIAL
Final Version 2.0
24 September 2018
AEVI GENOMIC MEDICINE
PROTOCOL NUMBER: AEVI-001-ADHD-202 (Part A)
A Multicenter, 2-Part, 6-Week, Double-blind, Randomized,
Placebo-controlled, Parallel-design Study to Assess the Efﬁcacy
and Safety of AEVI-001 in Children and Adolescents (Ages 6-17
Years) with Attention Deﬁcit Hyperactivity Disorder and with or
without Copy Number Variants in Speciﬁc Genes Implicated in
Glutamatergic Signaling and Neuronal Connectivity
STATISTICAL ANALYSIS PLAN
Final Version 2.0
24 September 2018
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Aevi Genomic Medicine, Inc.
AEVI-001-ADHD-202 (Part A)
Statistical Analysis Plan
CONFIDENTIAL
Final Version 2.0
24 September 2018
TABLE OF CONTENTS
1
OVERVIEW
7
2
STUDY DETAILS
7
2.1
Study objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2.1.1
Primary objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2.1.2
Secondary objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2.1.3
Exploratory objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.2
Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.3
Determination of sample size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
3
ANALYSIS SETS
8
3.1
Intent-to-treat analysis set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
3.2
Safety analysis set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
3.3
Full analysis set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
3.4
Per-protocol analysis set
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
4
DEFINITION OF STUDY VARIABLES
10
4.1
Subject disposition
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
4.2
Protocol deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
4.3
Demographics and other baseline characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.1
Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.2
Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.3
Ethnicity
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.4
Race . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.5
Height . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.6
Weight
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.7
Body mass index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4.3.8
Copy number variant type
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
4.3.9
Kaufman Brief Intelligence Test, Second Edition . . . . . . . . . . . . . . . . . . . . . . . .
12
4.3.10 Child Behavior Checklist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
4.4
Baseline disease characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
4.4.1
Mini International Neuropsychiatric Interview for Children and Adolescents . . . . . . . . . .
13
4.4.2
Age at ADHD diagnosis/Time since ADHD diagnosis
. . . . . . . . . . . . . . . . . . . . .
13
4.4.3
Age at ADHD Onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
4.5
Prior and concomitant medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
4.6
Study drug exposure variables
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
4.7
Efﬁcacy variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
4.7.1
Attention Deﬁcit Hyperactivity Disorder Rating Scale Version 5 . . . . . . . . . . . . . . . .
16
4.7.2
Clinical Global Impression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
4.7.3
Combined ADHD-RS-5/CGI-I response and remission . . . . . . . . . . . . . . . . . . . . .
17
4.7.4
Conners 3rd Edition – Parent Short Form . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
4.8
Safety variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
4.8.1
Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
4.8.2
Laboratory test results
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
4.8.3
Vital sign results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.8.4
Electrocardiogram results
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.8.5
Physical exam ﬁndings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.8.6
Columbia–Suicide Severity Rating Scale
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
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AEVI-001-ADHD-202 (Part A)
Statistical Analysis Plan
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5
ANALYSIS METHODS
23
5.1
Summary of subject disposition, demographics, and baseline characteristics . . . . . . . . . . . . . .
23
5.1.1
Subject disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
5.1.2
Demographics and other baseline characteristics
. . . . . . . . . . . . . . . . . . . . . . . .
23
5.1.3
Baseline disease characteristics
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
5.1.4
Medical history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
5.1.5
Prior medications and behavioral therapies
. . . . . . . . . . . . . . . . . . . . . . . . . . .
24
5.2
Protocol deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
5.3
Primary efﬁcacy analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
5.4
Secondary efﬁcacy analyses
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
5.5
Safety analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
5.5.1
Concomitant medications and study drug exposure . . . . . . . . . . . . . . . . . . . . . . .
25
5.5.2
AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
5.5.3
Laboratory test results
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
5.5.4
Vital sign results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
5.5.5
ECG results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
5.5.6
Physical exam ﬁndings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
5.5.7
C-SSRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
5.6
Interim analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
6
CHANGES TO PLANNED ANALYSES
27
6.1
Changes to analyses speciﬁed in protocol
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
6.2
Changes to approved prior versions of the SAP
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
7
REFERENCES
28
APPENDIX A Schedule of Events (Parts A and B)
30
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Statistical Analysis Plan
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LIST OF ABBREVIATIONS
ADHD
Attention deﬁcit hyperactivity disorder
ADHD-RS-5
Attention Deﬁcit Hyperactivity Disorder Rating Scale Version 5
AE
Adverse event
ATC
Anatomical Therapeutic Chemical
BMI
Body mass index
C-SSRS
Columbia Suicide Severity Rating Scale
CBCL
Child Behavior Checklist
CGI
Clinical Global Impressions
CGI-I
Clinical Global Impression – Improvement
CGI-S
Clinical Global Impression – Severity
CI
Conﬁdence interval
CNV
Copy number variation
Conners-3-P(S)
Conners 3rd Edition – Parent Short Form
CRO
Contract research organization
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
Electrocardiogram
eCRF
Electronic case report form
ET
Early termination
FDA
Food and Drug Administration
ICH
International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use
IP
Investigation product
IQ
Intelligence quotient
IRT
Interactive response technology
ITT
Intent-to-treat
KBIT-2
Kaufman Brief Intelligence Test, Second Edition
LOCF
Last observation carried forward
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Affairs
MINI-KID
Mini International Neuropsychiatric Interview for Children and Adolescents
MMRM
Mixed model repeated measures
n
Number of subjects
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Aevi Genomic Medicine, Inc.
AEVI-001-ADHD-202 (Part A)
Statistical Analysis Plan
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PP
Per protocol
PR Interval
Interval between the P and R waves on an electrocardiogram tracing
QRS Duration
Width of the QRS complex from beginning to end on an electrocardiogram tracing
QT Interval
Interval between the Q and T waves on an electrocardiogram tracing
QTcB Interval
QT interval corrected for heart rate using the Bazett formula
QTcF Interval
QT interval corrected for heart rate using the Fridericia formula
RR Interval
Interval from the beginning of a QRS complex to the beginning of the next QRS complex
SAP
Statistical analysis plan
SD
Standard deviation
SI
International System of Units
SOC
System organ class
TEAE
Treatment emergent adverse event
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Aevi Genomic Medicine, Inc.
AEVI-001-ADHD-202 (Part A)
Statistical Analysis Plan
CONFIDENTIAL
Final Version 2.0
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1
OVERVIEW
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Aevi Genomics Medicine Proto-
col AEVI-001-ADHD-202 (A Multicenter, 2-Part, 6-Week, Double-blind, Randomized, Placebo-controlled, Parallel-
design Study to Assess the Efﬁcacy and Safety of AEVI-001 in Children and Adolescents [Ages 6-17 Years] with
Attention Deﬁcit Hyperactivity Disorder and with or without Copy Number Variants in Speciﬁc Genes Implicated in
Glutamatergic Signaling and Neuronal Connectivity), Final Version 7.0 dated 25 July 2018. This SAP is for Part A of
the study only; a separate SAP will be prepared for Part B.
The statistical analyses and summaries described in this SAP will follow the International Conference on Harmoniza-
tion of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline for Statistical
Principles for Clinical Trials (ICH E9 Expert Working Group, 1999) and will form the basis of the results sections of
the clinical study report (CSR) in accordance with the ICH guideline for Structure and Content of Clinical Study Re-
ports (ICH Harmonised Tripartite Guideline E3, 1995). This SAP will be ﬁnalized and signed-off before database lock
and unblinding of treatment codes. Any changes to the analyses that are not included in this SAP will be documented
in the CSR.
2
STUDY DETAILS
2.1
Study objectives
2.1.1
Primary objectives
The primary objective of each part of this study is:
• To evaluate the efﬁcacy of AEVI-001 compared with placebo in children and adolescents (6-17 years of age
inclusive) with Attention Deﬁcit Hyperactivity Disorder (ADHD) and with or without copy number variants
(CNVs) in speciﬁc genes implicated in glutamatergic signaling and neuronal connectivity as measured by the
change in ADHD Rating Scale Version 5 (ADHD-RS-5) total score.
2.1.2
Secondary objectives
The key secondary objective of each part of this study will be:
• To evaluate the efﬁcacy of AEVI-001 compared with placebo using a global clinical measure of improvement,
the Clinical Global Impression – Improvement (CGI-I) at Visit 8/Early Termination (ET) (Week 6/ET).
Additional secondary objectives of each part of the study include:
• To evaluate AEVI-001 compared with placebo on response at Visit 8/ET (Week 6/ET), based on the following
parameters:
– A ≥30% reduction from baseline in ADHD-RS-5 total score.
– Improved on the CGI-I which includes the categories of 1 (very much improved) and 2 (much improved).
– Both a ≥30% reduction in ADHD-RS-5 total score and improved (1 [very much improved] and 2 [much
improved]) on the CGI-I.
• To evaluate AEVI-001 compared with placebo on remission at Visit 8/ET (Week 6/ET), based on the following
parameters:
– An ADHD-RS-5 total score ≤18.
– A CGI-I of 1 (very much improved).
– Both an ADHD-RS-5 total score ≤18 and a CGI-I of 1 (very much improved).
• To evaluate the efﬁcacy of AEVI-001 compared with placebo using a global clinical measure of severity, the
Clinical Global Impression – Severity (CGI-S) at Visit 8 (Week 6).
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AEVI-001-ADHD-202 (Part A)
Statistical Analysis Plan
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• To evaluate the safety and tolerability of AEVI-001 compared with placebo based on occurrence of treatment-
emergent adverse events (TEAEs), vital signs, clinical laboratory results, electrocardiogram (ECG) results, and
the Columbia-Suicide Severity Rating Scale (C-SSRS).
2.1.3
Exploratory objectives
Exploratory objectives of each part of the study include:
• To evaluate the efﬁcacy of AEVI-001 compared with placebo on behavior as measured by the change from
baseline at Visit 8 (Week 6) on the Conners 3rd Edition–Parent Short Form (Conners 3–P(S)).
2.2
Study design
This is a 2-part, 6-week, double-blind, dose-optimization, parallel-group study in children and adolescents (ages 6-
17 years) with ADHD with and without CNVs in speciﬁc genes implicated in glutamatergic signaling and neuronal
connectivity (see Figure 1 for the study design of both parts). Only subjects who had genetic testing performed during
another Aevi study (i.e., MDGN-NFC1-ADHD-001, MDGN-NFC1-ADHD-101, or AEVI-001-ADHD-002) and who
consented to future research were considered for participation in this study. Part A will include subjects determined to
have one of 8 speciﬁc gene mutation(s) implicated in glutamatergic signaling and neuronal connectivity. Part B will
be conducted and will assess subjects who do not have CNVs in any of the 272 speciﬁc gene mutation(s) implicated
in glutamatergic signaling and neuronal connectivity. The list of excluded mutations includes the 8 gene mutations
studied in Part A and an additional 264 mutations identiﬁed in an antecedent study. Once subjects are conﬁrmed as
eligible for each part of the study, they will be randomized to one of two treatment groups (AEVI-001 or placebo) in a
1:1 ratio. The randomization will be stratiﬁed by age (6 to 12, 13 to 17 years old) and part (A, B) with each part of the
study analyzed separately.
During both parts of the study, randomized subjects will receive investigational product (IP) at the Baseline Visit
(Visit 2; Day 0) and will begin taking IP at a dose of 100 mg twice daily on Day 1, once in the morning upon
awakening (between 7:00 AM to 9:00 AM) and once in the mid-afternoon (between 3:00 PM to 5:00 PM). Dosing will
be optimized weekly (±2 days) to 100 mg, 200 mg, or 400 mg twice daily, as appropriate, over the ﬁrst 4 weeks of
treatment (Dose-optimization Period), based on clinical response and tolerability. If the subject tolerates a dose well,
the dose will be maintained for an additional 2 weeks (Dose Maintenance Period). Visits during the Dose-optimization
and Dose Maintenance Periods are to be conducted every 7 days (±2 days). Visits conducted after randomization
should be scheduled relative to the Baseline Visit (Visit 2). The primary assessments of safety and efﬁcacy will be
performed weekly during the 6-week treatment period. A follow-up telephone call will be performed 7 days (+2 days)
after the last dose of IP. The complete Schedule of Events is included in Appendix A.
2.3
Determination of sample size
For Part A of the study, 42 unique subjects are planned to be randomized to yield approximately 34 subjects who
provide post-baseline efﬁcacy data on the primary endpoint. Assuming an effect size of 1.0, this number will yield
approximately 80% power to detect a signiﬁcant difference in mean change from baseline for the ADHD-RS-5 total
score at Visit 8 (Week 6) between the treatment groups, based on a 2-tailed test with α = 0.05 and 1:1 randomization.
In Part A of the study, an interim analysis will be performed when approximately 75% of randomized subjects have
completed the study. The sample size could be increased to 64 randomized subjects.
3
ANALYSIS SETS
An analysis data set will be created for each efﬁcacy and safety assessment. In addition to reported data values, each
analysis data set will include derived variables as speciﬁed in Section 4 (e.g., baseline, total, and change from baseline
values). All analysis data sets will also include key study- and subject-level information (including but not limited to:
study identiﬁer, study site identiﬁer, subject identiﬁer, age, sex, race, randomization number, analysis set eligibility
ﬂags, randomized treatment, actual treatment received, study treatment start and stop dates, reason for discontinuation
[if applicable], and age strata).
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Aevi Genomic Medicine, Inc.
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Statistical Analysis Plan
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Figure 1: Study design (Parts A and B)
All data analyses will be performed using at least one of the following analysis sets. Subject eligibility for each analysis
set will be ﬁnalized before unblinding of the data, where applicable.
3.1
Intent-to-treat analysis set
The intent-to-treat (ITT) analysis set includes all subjects who are randomized and dispensed study drug at the Baseline
Visit (Visit 2). Subjects will be categorized according to randomized treatment. This analysis set will be used for all
demographics, baseline characteristics, and prior medication analyses.
3.2
Safety analysis set
The safety analysis set will include all subjects who are randomized and take at least one dose of randomized study
drug during this trial. Subjects will be categorized according to actual treatment received. This analysis set will be
used for all concomitant medication, study drug exposure, and safety analyses.
3.3
Full analysis set
The full analysis set will include all randomized subjects who took at least one dose of randomized study drug and
have a valid baseline ADHD-RS-5 assessment and at least 1 valid post baseline ADHD-RS-5 assessment. Subjects will
be categorized according to randomized treatment. This analysis set will be used for all efﬁcacy analyses.
3.4
Per-protocol analysis set
The per-protocol (PP) analysis set is a subset of the full analysis set which will include data from subjects who do
not have any signiﬁcant protocol deviations. Subjects will be categorized according to actual treatment received. This
analysis set will be used for sensitivity analyses to examine the robustness of the ITT results for the primary efﬁcacy
variable and key secondary efﬁcacy variables.
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4
DEFINITION OF STUDY VARIABLES
4.1
Subject disposition
The subject number, previous subject number from the Aevi study where genetic testing was performed, informed con-
sent date, screening date, randomization number, and randomization date will be recorded in the Interactive Response
Technology (IRT) system and transferred to the electronic case report form (eCRF).
In addition, screen failure date, reason for screen failure, study completion status, the date of study completion or
ET, date of last dose, reason for discontinuation, follow-up completion status, date of follow-up telephone call, and
date of last contact will be recorded in the eCRF. The reason for screen failure will be recorded as “Does not meet
inclusion/exclusion criteria”; “Withdrawal of consent”; “Lost to follow up”; or “Other”. Study/follow-up completion
status will be recorded as “Yes” or “No”. The reason for discontinuation will be recorded as “Adverse Event”; “Lack
of efﬁcacy”; “Major protocol deviation”; “Withdrawal by subject”; “Lost to follow up”; “Other”; or “Identity not
conﬁrmed”.
4.2
Protocol deviations
The failure to meet any inclusion/exclusion criteria and the speciﬁc criteria not met will be recorded in the eCRF.
All subject data will be reviewed for the occurrence of protocol deviations; identiﬁed protocol deviations will be
captured by the contract research organization (CRO) and categorized as follows:
• Informed consent/assent form
• Inclusion/exclusion criteria
• Concomitant medication
• Study assessments/procedures
• Investigational product
• Compliance
• Overdose, misuse, and abuse
• Medication error
• Visit window
• Identity conﬁrmation
• Other
In addition to the above categories, all deviations will also be classiﬁed as “Major” or “Minor”. Major deviations
include any deviation from the protocol that could potentially affect the scientiﬁc soundness of the research plan or
the rights, safety, or welfare of human subjects. The following deviations will be considered “Major”, but are not
considered all-inclusive as others may be added during the study.
• Failure to obtain written informed consent and assent (if required) from the parent or legally authorized repre-
sentative and subject, respectively.
• Randomization of a subject who did not meet inclusion criteria.
• Randomization of a subject who met exclusion criteria.
• Use of a prohibited medication on ≥3 consecutive days during the double-blind treatment period (Visit 2 through
Visit 8/ET).
• Protocol deﬁned screening/baseline evaluations needed to assess eligibility were not performed or required re-
sults were not obtained prior to randomization.
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• Failure to conﬁrm the subject’s identity prior to randomization.
• Medication error related to IP dispensation (e.g., incorrect dose, incorrect blister card, etc.).
• Overall noncompliance with IP dosing deﬁned as <80% or >120%.
• Subject overdoses, abuses, and/or misuses the study drug.
• Site failure to follow steps/guidelines/procedures established in the safety monitoring plan such that the safety
of the subject or other subjects in the study is potentially endangered.
The Sponsor project team will review all protocol deviations and their major/minor classiﬁcations prior to database
lock. Subjects with conﬁrmed “Major” protocol deviations will be excluded from the PP analysis set (see Section 3.4).
4.3
Demographics and other baseline characteristics
4.3.1
Age
The date of consent and date of birth will be recorded in the IRT system. In addition, age at informed consent in years
and age stratum will be derived within the IRT system. Age stratum will be derived at randomization based on the
subject’s age at informed consent. Table 1 shows the stratum codes and descriptions assigned to subjects in Part A.
Prior to analysis, all age-related data recorded or derived in the IRT system will be transferred into the eCRF.
Table 1: Age stratum codes and descriptions for Part A
Stratum code
Stratum description
1
Age at informed consent 6 to 12 years old, Part A
2
Age at informed consent 13 to 17 years old, Part A
4.3.2
Sex
Sex will be recorded in the IRT system and transferred into the eCRF as “Male” or “Female”.
4.3.3
Ethnicity
Ethnicity will be recorded in the eCRF as “Hispanic or Latino”; “Not Hispanic or Latino”; “Not Reported”; or “Un-
known”.
4.3.4
Race
Race will be recorded in the eCRF as “American Indian or Alaska Native”; “Asian”; “Black or African American”;
“Native Hawaiian or Other Paciﬁc Islander”; “White”; or “Other”.
4.3.5
Height
Height (in) will be recorded in the eCRF.
4.3.6
Weight
Weight (lb) will be recorded in the eCRF.
4.3.7
Body mass index
Body mass index (BMI; kg/m2) will be calculated as weight (lb) divided by height squared (in2) and multiplied by 703.
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4.3.8
Copy number variant type
Saliva samples will have been processed for identiﬁcation of genetic mutations; these samples could have been col-
lected during participation in this study or another AEVI-001 study (i.e., the MDGN-NFC1-ADHD-001, MDGN-
NFC1-ADHD-101, AEVI-001-ADHD-002 studies). Only those subjects determined to have a copy number variant
(CNV) in one of the 8 genes implicated in glutamatergic signaling and neuronal connectivity will be eligible for Part
A of this study. The presence of individual CNVs of interest will be determined using a microarray based technology
from Illumnia (Illumnia, San Diego) and will be recorded in a separate CNV identiﬁcation dataset.
An indicator for the CNTN4 CNV will be calculated as:
• IF the subject has at least one CNV type of “CNTN4”, THEN set the CNTN4 CNV indicator equal to 1.
• OTHERWISE set the CNTN4 CNV indicator equal to 0.
4.3.9
Kaufman Brief Intelligence Test, Second Edition
The Kaufman Brief Intelligence Test, Second Edition (KBIT-2; Kaufman & Kaufman, 2004) is designed to measure
both the verbal and nonverbal intelligence in children and adults (ages 4 years, 0 months through 90 years, 11 months)
using a brief, individual format. The KBIT-2 includes 3 subtests; 2 classiﬁed as verbal and 1 as nonverbal. Adminis-
tration of the KBIT-2 yields a Verbal score, Nonverbal score, and intelligence quotient (IQ) Composite score.
The KBIT-2 Verbal, Nonverbal, and IQ Composite standard scores will be recorded in the eCRF.
4.3.10
Child Behavior Checklist
The Child Behavior Checklist (CBCL; Achenbach & Rescorla, 1996) was designed to address the problem of deﬁning
child behavior problems. The checklist assesses the behavioral problems and social competencies of children as re-
ported by parents using a standardized format. The CBCL can be self-administered or administered by an interviewer
and consists of items related to behavior problems. There are social competency items used to obtain parent reports of
the amount and quality of their child’s participation in speciﬁc tasks and activities. In addition, there are 120 syndrome
scale items. Only 118 of these syndrome scale items will be assessed in this study; items 56H and 113 will not be
assessed. Each syndrome scale item is scored on a 3-point scale ranging from 0 = “not true (as far as I know)” to 2 =
“very true or often true”.
Each CBCL competence scale response and syndrome scale item score will be recorded in the eCRF. Various CBCL
syndrome scale and problem scores will be calculated as described in Achenbach & Rescorla (1996). For each calcu-
lated syndrome scale and problem score, standard scores will also be derived according to the subject’s age (6 to 10
years, 11 to 18 years) and sex using normative samples of CBCL scores. All CBCL standard scores are scaled so that
a score of 50 is average (with a standard deviation of 10 points) for the subject’s respective age and sex categories.
Standard scores will be calculated using the Group 2 scoring spreadsheet (i.e., CBCGroup2-ProbScales.xls). Higher
scores indicate greater problems.
4.3.10.1
CBCL syndrome scale scores
Eight empirically-based CBCL syndrome scale scores will be calculated as follows:
• Anxious/Depressed syndrome score = sum of items 14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, and 112
• Withdrawn/Depressed syndrome score = sum of items 5, 42, 65, 69, 75, 102, 103, and 111
• Somatic Complaints syndrome score = sum of items 47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, and 56g
• Social Problems syndrome score = sum of items 11, 12, 25, 27, 34, 36, 38, 48, 62, 64, and 79
• Thought Problems syndrome score = sum of items 9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, and 100
• Attention Problems syndrome score = sum of items 1, 4, 8, 10, 13, 17, 41, 61, 78, and 80
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• Rule-Breaking Behavior syndrome score = sum of items 2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 101,
105, and 106
• Aggressive Behavior syndrome score = sum of items 3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 94, 95,
97, and 104
Standard scores will be derived for each syndrome scale (as described in Section 4.3.10). In addition, CBCL syndrome
scale clinical range categories will be calculated for each syndrome scale as:
• IF the syndrome scale standard score is <65, THEN set the clinical range category equal to “Normal”.
• IF the syndrome scale standard score is ≥65 and ≤69, THEN set the clinical range category equal to “Border-
line”.
• IF the syndrome scale standard score is ≥70, THEN set the clinical range category equal to “Clinical”.
According to the CBCL scoring manual (see Achenbach & Rescorla, 1996, p. 90), these clinical range categories
correspond to the following cutoff criteria: scores below the 93rd percentile are considered “Normal”, scores between
the 93rd to 97th percentile are “Borderline” clinical, and any scores above the 97th percentile are in the “Clinical”
range.
4.3.10.2
CBCL problem scores
In addition to syndrome scores, CBCL problem scores will be derived. The Internalizing Problems score will be
calculated as the sum of the Anxious/Depressed, Withdrawn/Depressed, and Somatic Complaints syndrome scores; the
Externalizing Problems score will be calculated as the sum of the Rule-Breaking and Aggressive Behavior syndrome
scores; the Total Problems score will be derived as the sum of all syndrome scale item scores.
Standard scores will be derived for each problem score (as described in Section 4.3.10). In addition, CBCL problem
score clinical range categories will be calculated for each problem score as:
• IF the problem standard score is <60, THEN set the clinical range category equal to “Normal”.
• IF the problem standard score is ≥60 and ≤63, THEN set the clinical range category equal to “Borderline”.
• IF the problem standard score is ≥64, THEN set the clinical range category equal to “Clinical”.
According to the CBCL scoring manual (see Achenbach & Rescorla, 1996, p. 96), the “Borderline” clinical range
category is deﬁned as scores between the 84th to 90th percentiles, inclusive.
4.4
Baseline disease characteristics
4.4.1
Mini International Neuropsychiatric Interview for Children and Adolescents
The date of the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) assessment
and those diagnostic criteria met will be recorded in the eCRF. Only the ADHD subtype (past 6 months) and the
medical, organic, drug cause ruled out criteria are required; all other MINI-KID criteria will be recorded only if
present. The ADHD (past 6 months) criteria will be recorded as “Combined Presentation”, “Predominantly Inattentive
Presentation”, or “Predominantly Hyperactive Type Presentation”. The medical, organic, drug cause ruled out criteria
will be recorded as “Yes”, “No”, or “Uncertain”.
4.4.2
Age at ADHD diagnosis/Time since ADHD diagnosis
Date of ADHD diagnosis will be recorded in the eCRF. Age at ADHD diagnosis will be calculated in years as the date
of ADHD diagnosis minus the date of birth. Time since ADHD diagnosis will be calculated in years as the date of
consent minus the date of ADHD diagnosis.
4.4.3
Age at ADHD Onset
Age at ADHD Onset in years will be recorded in the eCRF.
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4.5
Prior and concomitant medications
For each prior or concomitant medication, the medication name, indication, dose, frequency, route, start date, ongoing
indicator, and stop date (for those medications not ongoing) will be recorded in the eCRF. Each medication will be
coded using the World Health Organization Drug Dictionary (WHODrug) Enhanced version September 2016.
All medications will be classiﬁed according to the study period in which its use occurred (i.e., Prior, Concomitant, or
Post-treatment). Prior medications are those that started and ended before the initiation of study drug. Concomitant
medications are (i) those that started before initiation of study drug and continued after initiation of study drug or (ii)
those that started after the initiation of study drug; any medications that started on the same day as the initiation of
study drug will be considered concomitant. Post-treatment medications are those that started after completion of study
drug.
If the start date (or end date) of a medication is completely unknown (i.e., the day, month, and year are all missing) or
only the day is known, then the start date (or end date) will not be imputed. Unless the end date is before the start date
of study drug, the medication will be considered concomitant.
For a partial start date of medication, the following conventions will be used for imputing the start date:
• If the year is present and the month and day are missing, then the month and day will be set to January 1.
• If the year and day are present and the month is missing, then the month will be set to January.
• If the year and month are present and the day is missing, then the day will be set to the ﬁrst day of the month.
• If the imputed start date of medication is after the non-imputed end date of medication, then the start date will
be set to the end date of medication.
For a partial end date of medication, the following conventions will be used for imputing the end date:
• If the year is present and the month and day are missing, then the month and day will be set to December 31.
• If the year and day are present and the month is missing, then the month will be set to December.
• If the year and month are present and the day is missing, then the day will be set to the last day of the month.
4.6
Study drug exposure variables
Drug accountability will be performed at each visit during the treatment period. At each visit that study drug is
dispensed to subjects, the dose level, investigator dose assessment, quantity dispensed, intended ﬁrst dose date, and
intended ﬁrst dose AM/PM will be recorded in the IRT system. At each visit that study drug is returned, the quantity
remaining, intended last dose date, intended last dose AM/PM, percent compliance, and an overdose ﬂag will be
recorded in the IRT system. The percent compliance for the prior dosing period will be derived as the number of
capsules taken divided by the expected number of capsules taken. For percent compliance calculations, capsules not
returned will be assumed taken.
• Dose level will be recorded as “Level 1 (100mg or placebo bid)”, “Level 2 (200mg or placebo bid)”, or “Level 3
(400mg or placebo bid)”.
• Intended ﬁrst and last dose AM/PM values will be recorded as “AM Only”, “PM Only”, or “AM and PM”.
• Investigator dose assessment will be recorded as “Increase the dose”, “Maintain the Dose”, or “Decrease the
dose”.
• Overdose ﬂag will be recorded as “Yes” or “No”.
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Prior to analysis, all study drug exposure data recorded or derived in the IRT system will be transferred into the eCRF.
Optimized dose will be calculated as the dose level dispensed at Week 4 (Visit 6). Total study drug exposure (in mg)
will be calculated as the sum of all administered doses not returned. Duration of total exposure (in days) is calculated
as date of last dose −date of ﬁrst dose + 1.
Overall percent compliance for the entire treatment period will also be derived. To calculate overall percent compliance,
a weight for each weekly percent compliance is required; this weight value will be calculated as the number of doses
expected during that week divided by the total number of doses expected during the subject’s participation in the study.
The total number of doses expected will be calculated as:
• IF the latest intended last dose AM/PM value is “AM Only”, THEN the total number of doses expected is equal
to (the latest intended last dose date −the earliest intended ﬁrst dose date + 0.5) × 2
• IF the latest intended last dose AM/PM value is “AM and PM”, THEN the total number of doses expected is
equal to (the latest intended last dose date −the earliest intended ﬁrst dose date + 1) × 2
Overall percent compliance will be calculated as:
6
∑
i=1
(Percent Compliance)i ×(Weight)i, where i is the study week of dosing.
In addition, overall compliance categories will be calculated as:
• <80%
• ≥80% and ≤120%
• >120%
4.7
Efﬁcacy variables
For each efﬁcacy assessment, study day will be calculated as: the date of assessment −the date of ﬁrst dose of study
drug + 1. As deviations are expected in the number of days from the date of ﬁrst dose (i.e., study day 1) to the study
day that planned assessments actually occur, visit windows will be used to derive visit numbers for use in efﬁcacy
analyses. Efﬁcacy variable visit windows and their associated derived visit numbers and labels are deﬁned in Table 2.
Table 2: Visit windows for efﬁcacy variables
Derived visit number
Derived visit label
Visit window (days)
1
Visit 1
≤–1
2
Visit 2 (Week 0)
0
3
Visit 3 (Week 1)
1 to 11
4
Visit 4 (Week 2)
12 to 18
5
Visit 5 (Week 3)
19 to 25
6
Visit 6 (Week 4)
26 to 32
7
Visit 7 (Week 5)
33 to 39
8
Visit 8 (Week 6)
40 to 50
For all efﬁcacy variables, baseline will be deﬁned as the last assessment prior to the ﬁrst dose of IP. Change from
baseline values will be calculated as the assessment value minus the baseline value. For the derivation of any total or
subscale score, if at least 80% of the items needed to calculate a score have valid responses, then that score will be
computed as the sum of all non-missing items divided by the percentage of non-missing items in that scale or subscale.
If fewer than 80% of the items have valid responses, then that score will be considered as missing.
For some efﬁcacy variables, the last observation carried forward (LOCF) method of imputation will be used to calculate
additional LOCF efﬁcacy variables. For LOCF variables, a derived visit number of 99 and a visit label of “LOCF” will
be assigned.
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4.7.1
Attention Deﬁcit Hyperactivity Disorder Rating Scale Version 5
The Attention Deﬁcit Hyperactivity Disorder Rating Scale Version 5 (ADHD-RS-5; DuPaul et al., 2016) is a parent
reported/clinician-rated scale designed to reﬂect the symptomatology of ADHD based on the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The ADHD-RS-5 is comprised of 18 frequency items and
12 impairment items. Each frequency item will be scored on a scale from 0 = “Never or rarely” to 3 = “Very often”.
Each impairment item will be scored on a scale from 0 = “No Problem” to 3 = “Severe Problem”. Each ADHD-RS-5
item score will be recorded in the eCRF.
4.7.1.1
ADHD-RS-5 total score
The ADHD-RS-5 total score will be calculated as the sum of the 18 frequency item scores. The total score ranges from
0 to 54. Higher scores indicate greater symptom severity.
The change from baseline in the ADHD-RS-5 total score is the primary efﬁcacy variable and will be calculated at
each post-baseline timepoint. In addition, the percent reduction in ADHD-RS-5 total score will be calculated at each
post-baseline timepoint as the change from baseline value divided by the baseline value.
4.7.1.2
ADHD-RS-5 response
An indicator of ADHD-RS-5 response will be calculated at each post-baseline timepoint as:
• IF the percent reduction in ADHD-RS-5 total score is ≥30%, THEN set the ADHD-RS-5 response indicator
equal to 1.
• IF the percent reduction in ADHD-RS-5 total score is < 30%, THEN set the ADHD-RS-5 response indicator
equal to 0.
In addition to deriving ADHD-RS-5 response at each timepoint, an LOCF ADHD-RS-5 response indicator will be
calculated.
4.7.1.3
ADHD-RS-5 remission
An indicator of ADHD-RS-5 remission will be calculated at each post-baseline timepoint as:
• IF the ADHD-RS-5 total score is ≤18, THEN set the ADHD-RS-5 remission indicator equal to 1.
• IF the ADHD-RS-5 total score is >18, THEN set the ADHD-RS-5 remission indicator equal to 0.
In addition to deriving ADHD-RS-5 remission at each timepoint, an LOCF ADHD-RS-5 remission indicator will be
calculated.
4.7.1.4
ADHD-RS-5 Inattention subscale score
The ADHD-RS-5 Inattention subscale score will be calculated as the sum of the ﬁrst 9 individual item scores. The
Inattention subscale score ranges from 0 to 27. Higher scores indicate greater symptom severity. The change from
baseline in ADHD-RS-5 Inattention subscale score will be calculated at each post-baseline timepoint.
4.7.1.5
ADHD-RS-5 Hyperactivity–Impulsivity subscale score
The ADHD-RS-5 Hyperactivity–Impulsivity subscale score will be calculated as the sum of the next 9 individual item
scores (i.e., from items 10 to 18). The Hyperactivity–Impulsivity subscale score ranges from 0 to 27. Higher scores
indicate greater symptom severity. The change from baseline in ADHD-RS-5 Hyperactivity–Impulsivity subscale score
will be calculated at each post-baseline timepoint.
4.7.2
Clinical Global Impression
The Clinical Global Impression (CGI; Guy, 1976) scale is a clinician-rated scale consisting of 3 items. Only the CGI
– Severity (CGI-S) and CGI – Improvement (CGI-I) items will be assessed in this study. The CGI-S item is rated on a
7-point scale from 1 = “Normal, not at all ill” to 7 = “Among the most severely ill patients”. The CGI-I item is rated
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on a 7-point scale from 1 = “Very much improved” to 7 = “Very much worse”. Each CGI item score will be recorded
in the eCRF.
A CGI-S or CGI-I score of “0” will be considered as missing as this score denotes “Not assessed”.
4.7.2.1
CGI-I response
An indicator of CGI-I response will be calculated as:
• IF the CGI-I score is ≤2 (i.e., “very much improved” or “much improved”), THEN set the CGI-I response
indicator equal to 1.
• IF the CGI-I score is >2, THEN set the ADHD-RS-5 response indicator equal to 0.
In addition to deriving CGI-I response at each timepoint, an LOCF CGI-I response indicator will be calculated.
4.7.2.2
CGI-I remission
An indicator of CGI-I remission will be calculated as:
• IF the CGI-I score is equal to 1 (i.e., “very much improved”), THEN set the CGI-I response indicator equal to 1.
• IF the CGI-I score is >1, THEN set the CGI-I response indicator equal to 0.
In addition to deriving CGI-I remission at each timepoint, an LOCF CGI-I remission indicator will be calculated.
4.7.2.3
CGI-S score
The change from baseline in CGI-S will be calculated at each post-baseline timepoint.
4.7.3
Combined ADHD-RS-5/CGI-I response and remission
4.7.3.1
Combined ADHD-RS-5/CGI-I response
An indicator of combined ADHD-RS-5/CGI-I response will be calculated as:
• IF the percent reduction in ADHD-RS-5 total score is ≥30% AND the CGI-I score is ≤2 (i.e., “very much
improved” or “much improved”), THEN set the combined ADHD-RS-5/CGI-I response indicator equal to 1.
• OTHERWISE, set the ADHD-RS-5/CGI-I response indicator equal to 0.
In addition to deriving combined response at each timepoint, an LOCF combined ADHD-RS-5/CGI-I response indica-
tor will be calculated.
4.7.3.2
Combined ADHD-RS-5/CGI-I remission
An indicator of combined ADHD-RS-5/CGI-I remission will be calculated as:
• IF the ADHD-RS-5 total score is ≤18 AND the CGI-I score is equal to 1 (i.e., “very much improved”), THEN
set the combined ADHD-RS-5/CGI-I remission indicator equal to 1.
• OTHERWISE, set the combined ADHD-RS-5/CGI-I remission indicator equal to 0.
In addition to deriving combined remission at each timepoint, an LOCF combined ADHD-RS-5/CGI-I remission indi-
cator will be calculated.
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4.7.4
Conners 3rd Edition – Parent Short Form
The Conners 3rd Edition – Parent Short Form [Conners 3-P(S); Conners, 2008] is a parent completed assessment con-
sisting of 45 items to assess the severity of ADHD and other common co-morbid disorders in children and adolescents
aged 6 to 18 years. Only the 43 multiple choice items will be assessed in this study (i.e., the ﬁnal two open ended ques-
tions will not be assessed). The Conners 3-P(S) consists of 6 content subscales: Inattention, Hyperactivity/Impulsivity,
Learning Problems, Executive Functioning, Aggression, and Peer Relations. Each item from these content subscales
will be scored on a scale from 0 = “Not true at all (Never, Seldom)” to 3 = “Very much true (Very often, Very Fre-
quently)”. Additional Positive Impression and Negative Impression items will be scored on a scale from 0 to 1. Each
Conners 3-P(S) item score will be recorded in the eCRF.
4.7.4.1
Conners 3-P(S) Inattention subscale score
The Conners 3-P(S) Inattention subscale score will be calculated as the sum of the item 17, item 27, item 30, item
34, and item 41 scores. The Inattention subscale score ranges from 0 to 15. Higher scores indicate greater symptom
severity. The change from baseline score will be calculated at each applicable post-baseline timepoint.
4.7.4.2
Conners 3-P(S) Hyperactivity/Impulsivity subscale score
The Conners 3-P(S) Hyperactivity/Impulsivity subscale score will be calculated as the sum of the item 3, item 5, item 7,
item 13, item 24, and item 28 scores. The Hyperactivity/Impulsivity subscale score ranges from 0 to 18. Higher scores
indicate greater symptom severity. The change from baseline score will be calculated at each applicable post-baseline
timepoint.
4.7.4.3
Conners 3-P(S) Learning Problems subscale score
The Conners 3-P(S) Learning Problems subscale score will be calculated as the sum of the item 8, item 10, item 25,
item 36, and item 39 scores. The Learning Problems subscale score ranges from 0 to 15. Higher scores indicate greater
symptom severity. The change from baseline score will be calculated at each applicable post-baseline timepoint.
4.7.4.4
Conners 3-P(S) Executive Functioning subscale score
The Conners 3-P(S) Executive Functioning subscale score will be calculated as the sum of the item 1, item 15, item
20, item 32, and item 35 scores. The Executive Functioning subscale score ranges from 0 to 15. Higher scores indicate
greater symptom severity. The change from baseline score will be calculated at each applicable post-baseline timepoint.
4.7.4.5
Conners 3-P(S) Aggression subscale score
The Conners 3-P(S) Aggression subscale score will be calculated as the sum of the item 14, item 19, item 21, item
23, and item 26 scores. The Aggression subscale score ranges from 0 to 15. Higher scores indicate greater symptom
severity. The change from baseline score will be calculated at each applicable post-baseline timepoint.
4.7.4.6
Conners 3-P(S) Peer Relations subscale score
The Conners 3-P(S) Peer Relations subscale score will be calculated as the sum of the item 4, item 6, item 18, item 38,
and item 43 scores. The Peer Relations subscale score ranges from 0 to 15. Higher scores indicate greater symptom
severity. The change from baseline score will be calculated at each applicable post-baseline timepoint.
4.8
Safety variables
For all safety variables, baseline will be deﬁned as the last assessment prior to the ﬁrst dose of IP. Change from baseline
values will be calculated as the assessment value minus the baseline value. For each safety assessment, study day will
be calculated as: the date of assessment −the date of ﬁrst dose + 1.
4.8.1
Adverse events
An adverse event (AE) is deﬁned as any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product that does not necessarily have a causal relationship with the product. An
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AE can therefore be any unfavorable and unintended sign (including a new, clinically important abnormal laboratory
ﬁnding), symptom, or disease, temporally associated with the product, whether related to the product.
AEs are collected from the time of the informed consent is signed until the follow-up call is completed. For each AE,
the following data will be recorded in the eCRF: verbatim text, start date, stop date, outcome, investigator’s assessment
of severity, assessment of seriousness, relationship to IP, action taken with IP, and discontinuation due to AE. The
verbatim text will be coded by using Medical Dictionary for Regulatory Affairs (MedDRA) version 19.
• Outcome will be recorded as “FATAL”; “NOT RECOVERED/NOT RESOLVED”; “RECOVERED/RESOLVED”;
“RECOVERED/RESOLVED WITH SEQUELAE”; “RECOVERING/RESOLVING”; or “UNKNOWN”.
• Investigator’s assessment of severity will be recorded as “MILD”; “MODERATE”; or “SEVERE”.
• Assessment of seriousness will be recorded as “N” or “Y”.
• Relationship to IP will be recorded as “NOT RELATED”; “POSSIBLY RELATED”; or “PROBABLY RE-
LATED”.
• Action taken with IP will be recorded as “DOSE NOT CHANGED”; “DRUG WITHDRAWN”; “NOT APPLI-
CABLE”; “UNKNOWN”; “DOSE INCREASED”; “DOSE REDUCED”; or “DRUG INTERRUPTED”.
• Discontinuation due to AE will be recorded as “N” or “Y”.
A ﬂag for related AEs will be calculated as:
• IF the relationship to IP is “POSSIBLY RELATED” or “PROBABLY RELATED”, THEN set the related AE
ﬂag equal to “Y”.
• OTHERWISE, set the related AE ﬂag equal to “N”.
A ﬂag for AEs leading to study drug withdrawal will be calculated as:
• IF the action taken with IP is “DRUG WITHDRAWN”, THEN set the AE leading to study drug withdrawal ﬂag
equal to “Y”.
• OTHERWISE, set the AE leading to study drug withdrawal ﬂag equal to “N”.
Treatment emergent AEs (TEAEs) are deﬁned as those AEs occurring or worsening after the ﬁrst dose of IP and within
3 days of the last dose of IP. If an AE start date is completely missing (i.e., in which the day, month, and year are all
unknown), then the AE start date will be set to the date of ﬁrst dose of IP. For a partial AE start date, the following
conventions will be used for imputing the AE start date:
• When the year is present and the month and day are missing:
– If the year of AE start = the year of ﬁrst dose of IP, then the month and day will be set to the month and
day of ﬁrst dose of IP.
– If the year of AE start < the year of ﬁrst dose of IP, then the month and day will be set to December 31st.
– If the year of AE start > the year of ﬁrst dose of IP, then month and day will be set to January 1st.
• When the year and day are present and the month is missing:
– If the year of AE start = the year of ﬁrst dose of IP, then the month will be set to the month of ﬁrst dose of
IP.
– If the year of AE start < the year of ﬁrst dose of IP, then the month will be set to December.
– If the year of AE start > the year of ﬁrst dose of IP, then the month will be set to January.
• When the month and year are present and the day is missing:
– If the year of AE start = the year of ﬁrst dose of IP and
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◦the month of AE start = the month of ﬁrst dose of IP, then the day will be set to the day of ﬁrst dose
of IP.
◦the month of AE start < the month of ﬁrst dose of IP, then the day will be set to the last day of the
month.
◦the month of AE start > the month of ﬁrst dose of IP, then the day will be set to the 1st day of the
month.
– If the year of AE start < the year of ﬁrst dose of IP, then the day will be set to the last day of the month.
– If the year of AE start > the year of ﬁrst dose of IP, then the day will be set to the 1st day of the month.
• If the imputed AE start date is after the AE stop date, then the AE start date will be set to the AE stop date.
For each AE, a treatment emergent ﬂag will be calculated using the recorded AE start date (or imputed start date, where
applicable).
• IF the date of ﬁrst dose of IP ≤AE start date ≤date of last dose of IP + 72 hours, THEN set the treatment
emergent ﬂag equal to “Y”.
4.8.2
Laboratory test results
Blood and urine samples will be collected by site staff for clinical laboratory testing. Urine pregnancy tests will be
performed at the site. All other samples will be analyzed at the central laboratory. For all samples collected, the
following data will be recorded in the eCRF: test category (i.e., Hematology, Serum Chemistry, Urinalysis, Serum
Pregnancy Test, Urine Pregnancy Test, or Urine Drug Screen), collection date, and the accession number. For urine
pregnancy tests, the result will also be recorded in the eCRF as “POSITIVE” or “NEGATIVE”.
Collected laboratory samples will then be processed at the central laboratory for the calculation of reported values
for the laboratory tests shown in Table 3. Central laboratory data will include test category, lab test name, reported
result, reported unit, reported reference range (i.e., low and high), International System of Units (SI) result, SI unit,
SI reference range, and reference range indicator. The reference range indicator will be recorded as “NORMAL” or
“ABNORMAL” for character results and as “NORMAL”, “LOW”, or “HIGH” for numeric results. Data from the
central laboratory will be combined with the laboratory eCRF data prior to analysis.
Change from baseline values to each post-baseline assessment will be calculated for all continuous laboratory tests.
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Table 3: Laboratory test categories and tests assessed
Test category
Tests assessed
Hematology
hemoglobin, hematocrit, red blood cell count, red blood cell indices, mean corpuscular
hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume,
platelet count (or estimate), white blood cell count including differential
Serum chemistry
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, alanine
aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, creatine
kinase, glucose, sodium, potassium, chloride, bicarbonate, lactate dehydrogenase,
uric acid, thyroid stimulating hormone1, T41
Urinalysis
pH, speciﬁc gravity, blood, glucose, protein, ketones
Pregnancy test2
serum, urine
Urine drug screen
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine,
cannabinoids, propoxyphene, methadone
1 Screening only
2 Females only
4.8.3
Vital sign results
The following vital sign data will be recorded in the eCRF: assessment date, height, weight, temperature, temperature
measurement method, pulse rate, respiratory rate, systolic blood pressure (BP), and diastolic BP. The temperature
measurement method will be recorded as “Oral” or “Tympanic”.
Change from baseline values to each post-baseline assessment will be calculated for pulse rate, respiratory rate, systolic
BP, and diastolic BP. Potentially clinically important (PCI) ﬂags will be derived for systolic BP, diastolic BP, pulse rate,
respiratory rate, and change in body weight (see Table 4).
Table 4: Potentially clinically important criteria for vital sign results
Vital sign measure
Lower PCI criterion
Upper PCI criterion
Pulse rate
≤50 bpm
≥130 bpm
Systolic BP
<90 mmHg
>130 mmHg
Diastolic BP
<50 mmHg
>85 mmHg
Change in Systolic BP
decrease ≥30 mmHg
increase ≥30 mmHg
Change in Diastolic BP
decrease ≥20 mmHg
increase ≥20 mmHg
Change in body weight
decrease ≥7%
increase ≥7%
BP = blood pressure; PCI = potentially clinically important
4.8.4
Electrocardiogram results
Standard 12-lead ECGs will be performed after the subject has been supine for approximately 5 minutes. All ECGs will
be performed using the equipment supplied by the central ECG vendor. For all ECGs performed, the following data
will be recorded in the eCRF: assessment date and time and the investigator interpretation of the ECG. The investigator
assessment will be recorded as “Normal”, “Abnormal - Not clinically signiﬁcant”, “Abnormal - Clinically signiﬁcant”,
or “Unable to be evaluated”.
Electronic ECG tracings will be analyzed by the central ECG vendor for the calculation of reported values for the
following ECG tests: heart rate, RR interval, PR interval, QRS duration, QT interval, corrected QT interval using the
Bazett formula (QTcB), corrected QT interval using the Fridericia formula (QTcF), and evaluator interpretation. ECG
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vendor data will include ECG test name, reported result/ﬁnding, reported unit, standard result/ﬁnding, standard unit,
and lead location. The evaluator interpretation result will be recorded as “NORMAL”, “ABNORMAL”, or “UNABLE
TO EVALUATE”. Data from the ECG vendor will be combined with the ECG eCRF data prior to analysis.
Change from baseline values to each post-baseline assessment will be calculated for heart rate, RR interval, PR interval,
QRS duration, QT interval, QTcB interval, and QTcF interval. In addition, potentially clinically important ﬂags will be
calculated for heart rate, PR interval, QRS duration, QT interval, QTcB interval, QTcF interval, change from baseline
in heart rate, and change in QT, QTcB, and QTcF intervals (see Table 5).
Table 5: Potentially clinically important criteria for ECG results
ECG measure
Lower PCI criterion
Upper PCI criterion
Heart rate
≤50 bpm
≥130 bpm
PR interval
≥180 msec
QRS duration
≥100 msec
QT interval
≥450 msec
QTcB interval
≥450 msec
QTcF interval
≥450 msec
Change in heart rate
≤50 bpm & decrease ≥5 bpm
Change in QTcB
increase ≥30 msec
Change in QTcF
increase ≥30 msec
ECG = electrocardiogram; PCI = potentially clinically important
4.8.5
Physical exam ﬁndings
The following physical exam data will be recorded in the eCRF: assessment date, body system, result, abnormal
ﬁndings, and clinically signiﬁcant ﬂag.
• Result will be recorded as “NORMAL”, “ABNORMAL”, or “NOT DONE”.
• Clinically signiﬁcant ﬂag will be recorded as “N” or “Y”.
The abnormal ﬁndings and clinically signiﬁcant ﬂag variables are only recorded when the result is “ABNORMAL”.
4.8.6
Columbia–Suicide Severity Rating Scale
The Columbia–Suicide Severity Rating Scale (C-SSRS; available at www.cssrs.columbia.edu) is a semi-structured
interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the
assessment period. The interview includes deﬁnitions and suggested questions to solicit the type of information needed
to determine if a suicide-related thought or behavior has occurred. The C-SSRS has a “Baseline” version that will be
completed at the Screening Visit (Visit 1) and a “Since Last Visit” version that will be completed at Visit 2 through
Visit 8/ET. Both versions contain all 11 categories of suicidal ideation and behavior deﬁned in the Food and Drug
Administration (FDA) guidance document on suicidal behavior and ideation (FDA, 2012). Each category is assessed
using a single question requiring a “Yes” or “No” response with follow-up questions for any “Yes” responses. The
assessment date and each C-SSRS response will be recorded in the eCRF.
In addition, three C-SSRS composite indicator variables will be calculated as follows:
4.8.6.1
C-SSRS suicidal ideation indicator
A composite indicator of C-SSRS suicidal ideation will be calculated as:
• IF the response to any one of the ﬁve suicidal ideation questions is “Yes”, THEN set the suicidal ideation indicator
equal to 1.
• OTHERWISE, set the suicidal ideation indicator equal to 0.
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4.8.6.2
C-SSRS suicidal behavior indicator
A composite indicator of C-SSRS suicidal behavior will be calculated as:
• IF the response to any one of the ﬁve suicidal behavior questions is “Yes”, THEN set the suicidal behavior
indicator equal to 1.
• OTHERWISE, set the suicidal behavior indicator equal to 0.
4.8.6.3
C-SSRS suicidal ideation or behavior indicator
A composite indicator of C-SSRS suicidal ideation or behavior will be calculated as:
• IF the response to any one of the 5 suicidal ideation questions or any of the 5 suicidal behavior questions is
“Yes”, THEN set the suicidal ideation or behavior indicator equal to 1.
• OTHERWISE, set the suicidal ideation or behavior indicator equal to 0.
5
ANALYSIS METHODS
All personnel involved in the conduct and analysis of the study will remain blinded to individual subject treatment
assignments until the study has been completed, the data have been checked for accuracy with any errors corrected,
and all analysis sets have been identiﬁed. Analysis will be carried out using SAS® (version 9.4 or newer, SAS Institute
Inc, Cary, NC). Templates for the summary tables, ﬁgures, and subject data listings will be available separately. Data
listings will include all data recorded for all enrolled subjects; where included in listings, data entered for screen failure
subjects will be ﬂagged.
Descriptive statistics for continuous data will include number of subjects (n), mean, standard deviation (SD), median,
minimum, and maximum. Summaries of change from baseline variables will include only subjects who have both
a baseline value and corresponding value at the timepoint of interest. Descriptive statistics for categorical data will
include frequency and percentage. Calculation of percentages will exclude missing data as a category. Where appro-
priate, descriptive statistics may be presented with 95% conﬁdence intervals (CIs). For analyses by visit (or derived
visit; see Section 4.7), only the latest assessment for each visit will be used.
The minimum and maximum will be reported with the same degree of precision (i.e., the same number of decimal
places) as the recorded data. Measures of location (e.g., mean and median) will be reported to 1 degree of precision
more than the recorded data, and measures of spread (e.g., standard deviation) will be reported to 2 degrees of precision
more than the recorded data.
Any changes to the analyses that are not included in this SAP will be documented in the CSR.
5.1
Summary of subject disposition, demographics, and baseline characteristics
5.1.1
Subject disposition
All subjects who provide informed consent will be included in disposition summaries.
The number of subjects
screened, screen failed, randomized, completed, and discontinued from the study, as well as reason for discontinu-
ation, will be summarized by treatment group and overall. The number of subjects in each analysis set will also be
summarized. All disposition data will listed by subject.
5.1.2
Demographics and other baseline characteristics
Descriptive summaries of the demographic and other baseline characteristics will be provided by treatment group and
overall using the ITT analysis set. These tabulations will include the following variables:
• Demographics (age, age strata, sex, ethnicity, race, height, weight, and BMI)
• CNV type
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• KBIT-2 Verbal, Nonverbal, and IQ Composite standard scores
• CBCL syndrome and problem standard scores and clinical range categories
All demographics and other baseline characteristics data will be listed by subject.
5.1.3
Baseline disease characteristics
Descriptive summaries of baseline disease characteristics will be provided by treatment group and overall using the
ITT analysis set. These tabulations will include the following variables:
• ADHD subtype
• Age at ADHD diagnosis
• Time since ADHD diagnosis
• Age at ADHD onset
• Baseline ADHD-RS-5 total and subscale scores
• Baseline CGI-S score
All baseline disease characteristics data will be listed by subject.
5.1.4
Medical history
All medical history data will be listed by subject.
5.1.5
Prior medications and behavioral therapies
The incidence of prior medication use will be summarized by treatment group and overall and by preferred term using
the ITT analysis set. Each prior medication reported more than one time will only be counted once per subject for each
preferred term. All prior medication use and behavior therapy data will be listed by subject.
5.2
Protocol deviations
Major protocol deviations will be summarized by treatment group and overall using the ITT analysis set. All inclu-
sion/exclusion criteria and protocol deviation data (including all major and minor deviations) will be listed by subject.
5.3
Primary efﬁcacy analysis
The change from baseline in ADHD-RS-5 total score will be analyzed with mixed model repeated measures (MMRM)
methods using the full analysis set. The model will include derived visit (see Section 4.7), age stratum, treatment
group, and treatment-by-visit interaction as ﬁxed factors and baseline ADHD-RS-5 total score as a covariate. Robust
variance estimates for the ﬁxed effects will be used for testing treatment differences. Within subject variability will
be modeled using an unstructured (i.e., TYPE = UN) covariance pattern. In case of convergence problems, a banded
Toeplitz (i.e., TYPE = TOEP(5)) structure for the covariance pattern will be used. The comparison of interest will be
the difference between the AEVI-001 and placebo treatment groups at Visit 8. Model based point estimates (i.e., least
square [LS] means for each treatment group and the treatment difference), 95% conﬁdence interval for the difference,
p-value, and effect size will be reported for each derived visit. Effect size will be calculated as the LS mean difference
divided by an estimate of the pooled standard deviation.
Similar MMRM methods will be used to test for treatment differences in each CNTN4 CNV subgroup (see Sec-
tion 4.3.8 for deﬁnition of CNTN4 CNV indicator). To control the overall type I error rate for these subgroup com-
parisons, a hierarchical testing procedure will be used with comparisons of the primary efﬁcacy variable tested in the
following ﬁxed sequence:
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• Full analysis set
• Full analysis set – CNTN4 CNV subgroup
• Full analysis set – Non-CNTN4 CNV subgroup
Supportive MMRM analyses of the primary endpoint will also be performed using the PP analysis set.
Descriptive statistics for the ADHD-RS-5 total score and change from baseline in ADHD-RS-5 total score will be
presented by treatment group and derived visit. A similar descriptive statistics display will also be presented by CNTN4
CNV indicator and age stratum.
5.4
Secondary efﬁcacy analyses
Logistic regression methods will be used for the analysis of the LOCF ADHD-RS-5 response indicator using the full
analysis set. The logistic regression model will include terms for age stratum, treatment group, and baseline ADHD-
RS-5 total score. The comparison of interest will be the difference between the AEVI-001 and placebo treatment
groups at end-of-treatment. Model based point estimates (i.e., odds ratios), 95% conﬁdence intervals, and p-value will
be reported.
Similar logistic regression models will be used for the LOCF CGI-I remission, LOCF combined ADHD-RS-5/CGI-
I response, and LOCF combined ADHD-RS-5/CGI-I remission indicators using the full analysis set. For the CGI-I
response/remission analyses, baseline CGI-S score will be included in the model. For the combined response/remission
analyses, baseline ADHD-RS-5 total and CGI-S scores will be included in the model.
MMRM methods similar to those described in Section 5.3 will be used for the analysis of the following change from
baseline values: ADHD-RS-5 inattention subscale, ADHD-RS-5 hyperactivity–impulsivity subscale, and CGI-S, Con-
ners 3-P(S) inattention subscale, Conners 3-P(S) hyperactivity–impulsivity subscale, Conners 3-P(S) learning problems
subscale, Conners 3-P(S) executive function subscale, Conners 3-P(S) aggression subscale, and Conners 3-P(S) peer
relations subscale. For each model, the baseline score of the respective subscale used in the model will be used as a
covariate. For the models including Conners 3-P(S) subscale scores, a heterogeneous ﬁrst order autoregressive (i.e.,
TYPE = ARH(1)) covariance structure will be used in cases of convergence problems. As with the primary efﬁcacy
analysis, the comparison of interest for each model will be the difference between the AEVI-001 and placebo treatment
groups at Week 6. Model based point estimates (i.e., LS means for each treatment group and the treatment difference),
95% conﬁdence interval for the difference, p-value, and effect size will be reported for each derived visit.
Subgroup analyses by ADHD subtype (see Section 4.4.1) will be performed for select secondary efﬁcacy variables. No
multiplicity correction to the reported p-values will be made for any secondary efﬁcacy analysis. Supportive analyses
of secondary efﬁcacy endpoints may be performed using the PP analysis set.
Descriptive statistics for all scores, change from baseline scores, and response/remission indicators will be summarized
by treatment group and derived visit. All ADHD-RS-5, CGI, and Conners 3-P(S) data will be listed by subject and
visit.
5.5
Safety analyses
For all safety endpoints, descriptive statistics will be presented by treatment group and visit (where applicable) using the
safety analysis set. In addition, some safety endpoints may be further summarized by optimized dose (see Section 4.6).
In summaries of change from baseline safety variables, only subjects with both baseline and post baseline data will be
included. No formal hypothesis tests will be performed for any safety endpoint.
5.5.1
Concomitant medications and study drug exposure
5.5.1.1
Concomitant medications
The incidence of concomitant medication use will be summarized by treatment group and preferred term (see Sec-
tion 4.5 for deﬁnition of concomitant medications). Each concomitant medication reported more than one time will
only be counted once per subject for each preferred term. All concomitant medication data will be listed by subject.
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5.5.1.2
Study drug exposure
Optimized dose, total study drug exposure, and duration of total exposure will be summarized by treatment group. All
study drug exposure data will be listed by subject.
5.5.1.3
Study drug compliance
Overall percent compliance will be summarized by treatment group. In addition, the frequency and percentage of
subjects in each compliance category (see Section 4.6 for deﬁnition of overall compliance indicator) will be tabulated
by treatment group. All compliance data will be listed by subject.
5.5.2
AEs
The overall incidence of subjects having at least one AE in each of the following categories will be summarized by
treatment group:
• Any TEAE
• Any SAE
• Any AE leading to death
• Any TEAE leading to study drug withdrawal
• Any related TEAE
All AE data will be listed by subject. Separate listings by subject will presented for all SAEs, AEs leading to death,
and TEAEs leading to study drug withdrawal.
5.5.2.1
TEAEs
The incidence of TEAEs will be summarized by treatment group, system organ class (SOC), and preferred term. Each
subject will be counted only once per SOC and preferred term. An additional display may be produced by treatment
group and preferred term.
5.5.2.2
SAEs
The incidence of SAEs will be summarized by treatment group, SOC, and preferred term. Each subject will be counted
only once per SOC and preferred term.
5.5.2.3
TEAEs leading to study drug withdrawal
The incidence of TEAEs leading to study drug withdrawal will be summarized by treatment group, SOC, and preferred
term. Each subject will be counted only once per SOC and preferred term.
5.5.2.4
TEAEs by maximum relationship to study drug
The incidence of TEAEs will be summarized by maximum relationship to study drug, treatment group, SOC, and
preferred term. Each subject is counted only once per preferred term and most related category reported.
5.5.2.5
TEAEs by maximum severity
The incidence of TEAEs will be summarized by maximum severity to study drug, treatment group, SOC, and preferred
term. Each subject is counted only once per preferred term and most severe category reported.
5.5.3
Laboratory test results
Descriptive statistics for all reported values and change from baseline values will be summarized by test category,
treatment group, and visit. Only the original assessment for each visit will contribute to descriptive statistics; repeat
or unscheduled assessments will not be included in the calculation of descriptive statistics by visit. All laboratory test
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results data (including pregnancy test and urine drug screen data and any repeat or unscheduled assessments) will be
listed by subject and visit.
5.5.4
Vital sign results
Descriptive statistics for all reported values and change from baseline values will be summarized by treatment group
and visit. Only the original assessment for each visit will contribute to these summaries; repeat or unscheduled assess-
ments will not be included in the calculation of descriptive statistics by visit. The number and percentage of subjects
with PCI values at any time will be tabulated by treatment group. Summaries of PCI values will include all assessments
regardless of whether an original, repeat, or unscheduled assessment. All vital sign results data will be listed by subject
and visit.
5.5.5
ECG results
Descriptive statistics for all reported values and change from baseline values will be summarized by treatment group,
and visit. Only the original assessment for each visit will contribute to these summaries; repeat or unscheduled assess-
ments will not be included in the calculation of descriptive statistics. The number and percentage of subjects with PCI
values at any time will be tabulated by treatment group; the number and percentage of subjects with abnormal ECG
ﬁndings will be presented similarly. Summaries of PCI values and abnormal ECG ﬁndings will include all assessments
regardless of whether an original, repeat, or unscheduled assessment. All ECG results data will be listed by subject
and visit.
5.5.6
Physical exam ﬁndings
All physical exam ﬁndings data will be listed by subject and visit.
5.5.7
C-SSRS
The incidence of suicidal ideation/behavior at any time will be summarized by treatment group for each C-SSRS
ideation, behavior, and ideation/behavior indicator. All C-SSRS data will be listed by subject and visit.
5.6
Interim analysis
In Part A of the study, an interim analysis will be performed when approximately 75% of randomized subjects have
completed the study. This analysis will focus on the magnitude of placebo response and will determine whether the
enrollment target should be increased to a total of 64 randomized subjects.
The interim analysis will require unblinding of subject-level data and will be conducted by an independent statistician
having no other involvement in the analysis or conduct of this study. The interim analysis will be limited to the
evaluation of ADHD-RS-5 data (i.e., the primary outcome). To maintain the integrity of the experimental blind, the
independent statistician will only share qualitative results with the sponsor (e.g., “increase the sample size” or “do not
increase the sample size”).
Details of the interim analysis will be provided in a separate Interim Analysis Plan.
6
CHANGES TO PLANNED ANALYSES
6.1
Changes to analyses speciﬁed in protocol
Not applicable.
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6.2
Changes to approved prior versions of the SAP
Table 6: Changes to Final Version 1.0 dated 18 April 2018
SAP section
Prior text
Change to text
Rationale
List of Abbreviations
SAP = Statistical analysis
plan
Previously omitted abbrevi-
ation added.
Section 1 – Overview
Final Version 5.0 dated 01
March 2018
Final Version 7.0 dated 25
July 2018
Reference updated to cur-
rent version of the protocol.
Section 2.2 – Study
design
If Part A of the study is
positive (e.g., meets the pri-
mary endpoint), Part B will
be conducted and will assess
subjects who do not have
CNVs in any of the spe-
ciﬁc gene mutation(s) impli-
cated in glutamatergic sig-
naling and neuronal connec-
tivity.
Part B will be conducted and
will assess subjects who do
not have CNVs in any of
the 272 speciﬁc gene muta-
tions(s) implicated in gluta-
matergic signaling. This list
of excluded mutations in-
cludes the 8 gene mutations
studied in Part A and an ad-
ditional 264 mutations iden-
tiﬁed in an antecedent study.
Change made to be consis-
tent with current version of
the protocol. Protocol Ver-
sion 7.0 removed text requir-
ing Part A to be positive
prior to starting Part B and
added text to clarify the mu-
tations to be included in Part
B.
Section 4.6 – Study
drug exposure vari-
ables
(Weight)i ×100
(Weight)i, where i
is the study week of dosing.
Multiplication by 100 re-
moved
from
the
overall
percent compliance formula
as the Percent Compliance
variable is already on a
percent scale; text added to
deﬁne i.
Section 4.7 – Efﬁ-
cacy variables (Table
2)
–28 to –1
≤–1
Visit window for derived
visit number 1 updated to al-
low derivation for visits oc-
curring prior to Day –28.
Section 4.7 – Efﬁ-
cacy variables (Table
2)
≥40
40 to 50
Visit window for derived
visit number 8 updated to re-
strict derivation for visits oc-
curring within a few days of
stopping study drug.
Section 5.4 – Sec-
ondary efﬁcacy anal-
yses
Subgroup
analyses
by
ADHD subtype (see Sec-
tion 4.4.1) will be performed
for select secondary efﬁcacy
variables.
Subgroup
analyses
added
for secondary efﬁcacy vari-
ables by ADHD subtype.
7
REFERENCES
Achenbach, T. M. & Rescorla, L. A. (1996). Manual for the ASEBA School-Age Forms & Proﬁles. Burlington, VT:
University of Vermont, Research Center for Children, Youth, & Families.
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Conners, C. K. (2008). Conners 3rd Edition. North Tonawanda, NY: Multi-Health Systems.
DuPaul, G. J., Power, T. J., Anastopoulos, A. D., & Reid, R. (2016). ADHD Rating Scale-5 for Children and Adoles-
cents Checklists, Norms, and Clinical Interpretation. New York, NY: Guildford Press.
FDA (2012). Guidance for Industry Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical
Trials. https://www.fda.gov/downloads/drugs/guidances/ucm225130.pdf.
Guy, W. (Ed.). (1976). ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Department of
Health, Education, and Welfare.
ICH (1995). ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports E3. Step 4, 30
November 1995. http://www.ich.org/ﬁleadmin/Public Web Site/ICH Products/Guidelines/Efﬁcacy/E3/E3 Guideline.pdf.
ICH E9 Expert Working Group (1999). Statistical Principles for Clinical Trials. Statistics in Medicine, 18, 1905–1942.
Kaufman, A. S. & Kaufman, N. L. (2004). Kaufman Brief Intelligence Test Second Edition. Bloomington, MN:
Pearson, Inc.
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APPENDIX A
Schedule of Events (Parts A and B)
Source: Table 1 from Protocol Version 7.0, 25 July 2018
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